Visual tests predict dementia risk inParkinson diseaseLouise-Ann Leyland PhD Fion D Bremner PhD Ribeya Mahmood MSc Sam Hewitt MSc
Marion Durteste MSc Molly RE Cartlidge Michelle M-M Lai FRCOphth Luke E Miller PhD
Ayse P Saygin PhD Pearse A Keane PhD Anette E Schrag PhD and Rimona S Weil PhD
Neurology Clinical Practice Month 2019 vol 00 no 0 1-11 doi101212CPJ0000000000000719
Correspondence
Dr Weil
rweiluclacuk
AbstractObjectiveTo assess the role of visual measures and retinal volume to predictthe risk of Parkinson disease (PD) dementia
MethodsIn this cohort study we collected visual cognitive and motor datain people with PD Participants underwent ophthalmic examina-tion retinal imaging using optical coherence tomography andvisual assessment including acuity and contrast sensitivity and high-level visuoperception measures of skew tolerance and biologicalmotion We assessed the risk of PD dementia using a recently de-scribed algorithm that combines age at onset sex depressionmotor scores and baseline cognition
ResultsOne hundred forty-six people were included in the study (112 withPD and 34 age-matched controls) The mean disease duration was41 (plusmn2middot5) years None of these participants had dementia Higher risk of dementia wasassociated with poorer performance in visual measures (acuity ρ = 029 p = 00024 contrastsensitivity ρ = minus037 p lt 00001 skew tolerance ρ = minus025 p = 00073 and biological motionρ = minus026 p = 00054) In addition higher risk of PD dementia was associated with thinnerretinal structure in layers containing dopaminergic cells measured as ganglion cell layer (GCL)and inner plexiform layer (IPL) thinning (ρ = minus029 p = 00021 ρ = minus033 p = 000044) Theserelationships were not seen for the retinal nerve fiber layer that does not contain dopaminergiccells and were not seen in unaffected controls
ConclusionVisual measures and retinal structure in dopaminergic layers were related to risk of PD de-mentia Our findings suggest that visual measures and retinal GCL and IPL volumes may beuseful to predict the risk of dementia in PD
Dementia Research Centre (L-AL RM RSW) Institute of Neurology University College London United Kingdom Neuro-ophthalmology (FDB MM-ML) National Hospital for Neurology andNeurosurgery University College London Hospitals London United Kingdom Institute of Neurology (SH MD MREC) University College London UCL United Kingdom School ofBiomedical Sciences (MREC) Biological Sciences Leeds University United Kingdom ImpAct (LEM) Lyon Neuroscience Research Center France Department of Cognitive Science (APS)University of California San Diego Kavli Institute for Brain and Mind (APS) University of California San Diego Institute of Ophthalmology (PAK) UCL United Kingdom Moorfields EyeHospital (PAK) London United Kingdom Department of Clinical Neuroscience (AES) Institute of Neurology UCL Hampstead Campus London United Kingdom Movement DisordersConsortium (AES RSW) UCL United Kingdom and The Wellcome Centre for Human Neuroimaging (RSW) Institute of Neurology University College London United Kingdom
Funding information and disclosures are provided at the end of the article Full disclosure form information provided by the authors is available with the full text of this article atNeurologyorgcp
The Article Processing Charge was funded by Wellcome Trust
This is an open access article distributed under the terms of the Creative Commons Attribution License 40 (CC BY) which permits unrestricted use distribution and reproduction in anymedium provided the original work is properly cited
Copyright copy 2019 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology 1
Dementia is a debilitating aspect of Parkinson disease (PD)affecting 50 of patients within 10 years of diagnosis withvariability in timing and severity Patients with PD who showvisual deficits including color and higher-order visualchanges may have higher rates of converting to PD dementiaor develop dementia earlier in their disease course1ndash3
However this has not yet been examined systematically andwhether earlier stages of visual processing and retinalstructure are linked to the risk of PD dementia is not yetknown
Retinal structure can be imaged noninvasively using opticalcoherence tomography (OCT)4 and shows thinning inAlzheimer disease5 and as a population screen fordementia6ndash8 Retinal structural changes are seen in PD butearly studies of retinal nerve fiber layer (RNFL) thinning inPD were not replicated9 The location of dopaminergicamacrine cells in the inner plexiform layer (IPL)10 in non-human studies and postmortem findings of phosphorylatedalpha-synuclein in the IPL suggest that deeper layers aremore likely to be affected in PD11 Recent studies showconsistent thinning in the IPL and ganglion cell layer (GCL)in PD12 but whether IPL or GCL thinning is linked to PDdementia is not known
New algorithms have emerged that combine measures suchas age and motor severity with sensitivity to predict cognitivechange in PD13ndash15 Although these algorithms are usefulthey do not allow tracking of disease progression or relatedirectly to changes in the parkinsonian brain
We therefore examined the association between visualmeasures and retinal structure with the risk of dementia inPD These measures have potential for stratifying high-riskpatients for clinical trials
MethodsParticipantsOne hundred seventeen people with PDwere recruited fromour UK center between October 2017 and November 2018Inclusion criteria were early-stage PD (Queen Square BrainBank criteria) within 10 years of diagnosis aged 49ndash82years Exclusion criteria were confounding neurologic orpsychiatric disorders a diagnosis of dementia or Mini-Mental State Examination (MMSE) less than 2513 andophthalmic disease sufficient to impair visual acuity Twopatients were excluded because of dementia and 3 wereexcluded because of ophthalmic disease (glaucoma)Therefore the data reported here include 112 people withPD Thirty-five age-matched controls unaffected by neuro-logic psychiatric or ophthalmic disease were additionallyrecruited from university databases and unaffected spousesOf these 1 was excluded because of developing mild cog-nitive impairment within 6 months of taking part leaving 34controls in the analysis reported here
Clinical and ophthalmic evaluationAll participants were tested on their usual medications andlevodopa equivalent daily dose calculated Symptom severitywas assessed using the Movement Disorders Society UnifiedPD Rating Scale (UPDRS) Olfaction was assessed using theodor identification subset of the Sniffinrsquo sticks test Partic-ipants completed the Hospital Anxiety and DepressionScale and REM Sleep Behavior Disorder Screening Ques-tionnaire (RBDSQ) A comprehensive ophthalmic assess-ment was performed by a consultant ophthalmologist Thisincluded slit-lamp ophthalmic examination and measure-ment of intraocular pressures using Goldmann applanationtonometry
Assessments of visual functionVisual measures (figure 1) were all performed before my-driasis Visual acuity was measured binocularly using a log-MAR chart (with eyeglasses if worn) (figure 1A) Contrastsensitivity was measured binocularly (with eyeglasses ifworn) using a Pelli-Robson chart (SSV-281-PC) (sussex-visioncouk) (figure 1C) Color vision was assessed usingthe D15 test and error scores log transformed
Visuoperception was measured using 2 tasks probing distinctaspects of higher-order visuoperception the Cats-and-Dogstest measures tolerance to visual skew (figure 1E) and hasbeen associated with PD16 Stimuli were generated as pre-viously described216 Images were presented centrally sub-tending 4deg times 13deg of visual angle and shown for 280 msfollowed by a choice screen (response time 3800 ms) 90repetitions (total time 15 minutes) To calculate discrimi-nation sensitivity missing trials were excluded and perfor-mance at each level of skew calculated A sigmoidpsychometric curve was fitted and threshold for image de-tection was calculated at 75 performance Biological mo-tion measures sensitivity to detect the appearance ofa moving person from moving dots at the position of themajor joints of a person17 It is known to be affected in PD18
Stimuli consisted of point-light walkers (12 white dots ongray background height 7deg) (figure 1G) Control stimuliwere generated using point-light walkers with dot positionand motion scrambled Motion-matched noise dots wereadded to increase difficulty using an adaptive staircase
In this large PD cohort visual
measures across multiple stages of
visual processing and structural
retinal changes are associated with
a higher risk of more rapid
development of PD dementia
2 Neurology Clinical Practice | Volume Number | NeurologyorgCP
Figure 1 Tests of visual function and relationship with risk of Parkinson disease (PD) dementia
(A) LogMAR visual acuity chart Adapted by permission from BMJ Publishing Group Limited35 (B) Relationship between the risk of PD dementia and visualacuity (C) Pelli-Robson chart for assessing contrast sensitivity (D) Relationship between the risk of PD dementia and contrast sensitivity (E) Cats-and-Dogstest of higher-order visuoperception The task is to identify whether the animal shown is a cat or a dog with differing amounts of skew applied to the image todetermine the level of skew tolerated (F) Relationship between the risk of PD dementia and higher-order visuoperception tested by skew tolerance (G)Biological motion Dots are shown at the position of themajor joints of the body The dotsmove to give the strong percept of a person walking Extra dots areadded and the number of dots tolerated where the participant can still detect a person moving is calculated (H) Relationship between the risk of PDdementia and higher-order visuoperception tested with biological motion Poorer performance in each of these measures is linked with a higher risk of PDdementia
NeurologyorgCP Neurology Clinical Practice | Volume Number | 3
procedure17 Stimuli were presented for 800 ms Participantsdetermined whether the animation depicted a moving per-son or scrambled moving dots 225 repetitions total time 15minutes We used the QUEST Bayesian adaptive method tocalculate the maximum number of additional noise dotstolerated for performance to reach 82 accuracy Stimuliwere generated within MATLAB Psychophysics Toolbox 3implemented on a Dell Latitude 3340 in a darkened roomWhether this test relates to the risk of PD dementia is notknown
Retinal structure OCTRetinal imaging was performed on both eyes of each partic-ipant on the same day as other measures were obtained Innerretinal layer structure was measured using high-resolutionspectral domain optical coherence tomography (SD-OCTHeidelberg HRASpectralis manufactured in 2011) ina dimly lit room after pharmacologic mydriasis according toa standard protocol19 Two OCT devices were used at 1 site(National Hospital for Neurology and Neurosurgery) with 4operators (L-AL RM SH and MREC) with viewingmodule v 6950 All participants underwent macular scanprotocols in Infrared-OCT mode laser illumination used forexcitation was 486 nm This allows simultaneous acquisitionof a fundus image with a reflectance wavelength of 816 nmand OCT scan with TruTrack eye-tracking technology to
stabilize the retinal image The volumetric macular protocolof the Spectralis SD-OCT device (NSite application) wasused to measure macular thickness and volume (figure 2A)This uses an internal fixation source and centers on theparticipantrsquos fovea The protocol consists of 25 vertical linescans at a resolution of 1536 (scanning angle 20degtimes20degdensity 240 μm 47 scanss automatic real-time frames49) Quality control of OCT data was performed in com-pliance with international consensus OSCAR 1B OCTquality control standards (OSCAR-IB)20 and OCT datawere collected and reported according to internationalAPOSTEL guidelines21
OCT analysisAutomatic layer segmentation was applied via Heidelbergsoftware v11020 with Nsite module included to computethe thickness of the GCL IPL and RNFL Blinded assessors(SH and MREC) verified layer position and manualsegmentation was undertaken when automatic segmentationdeviated from the visible gradient change for that layer(quality checked by LL) All layers were segmented andexported and total volume and total thickness within each ofthe RNFL GCL and IPL were calculated across all 4 quad-rants and summed for a total layer thickness exported as a 1-3- 6-mm EDTRS grid Retinal data from 9 individuals wereexcluded because of ophthalmic disease or poor-quality scans
Figure 2 Relationship between the retinal volume and risk of Parkinson disease (PD) dementia
(A) Output of optical coherence tomography retinal imaging with cross section at themacula Retinal layers identified by automatic segmentation are shown(B) Relationship between the risk of PD dementia and RNFL volume (C) Relationship between the risk of PD dementia and GCL volume (D) Relationshipbetween the risk of PD dementia and IPL volume Retinal layers that contain dopaminergic cells (GCL and IPL) show greater thinning linked with PD dementiarisk This relationship is not seen in the RNFL that does not contain dopaminergic cells RNFL = retinal nerve fiber layer GCL = ganglion cell layer IPL = innerplexiform layer
4 Neurology Clinical Practice | Volume Number | NeurologyorgCP
(table e-1 linkslwwcomCPJA126) One eye from eachparticipant was selected for analysis In patients with PD thiswas the eye contralateral to the most symptomatic side asidentified during UPDRS-III For controls and patients withsymmetrical motor signs the selected eye was selected ran-domly In 8 patients and in 1 control the selected eye couldnot be used because of ophthalmic disease exclusions and theother eye was included for these participants (table e-1)
Neuropsychological evaluationCognitive assessment was in line with recent MovementDisorder Society guidelines22 with 2 assessments per cog-nitive domain General cognitive function was assessed withthe MMSE and Montreal Cognitive Assessment Memorywas assessed with the Recognition Memory Test for wordsand immediate and delayed versions of the Logical Memorytask (Wechsler Memory Scale IV) Language was assessedwith the Graded Naming Test and letter fluency Visuospa-tial abilities were tested with Benton Judgment of LineOrientation and Hooper Visual Organization Test Executivefunctions were measured with the Stroop task from theDelis-Kaplan Executive Function System and category flu-ency Attention was tested using color naming from theStroop and Digit Span
Defining dementia risk statusWe defined dementia risk using a recently described pro-spectively validated algorithm13 This combines clinical in-formation on sex age at disease onset years of educationUPDRS-III (motor examination) and MMSE to generatea risk score (e-Methods for details linkslwwcomCPJA137) In addition to the continuous scores we categorizedpatients with PD into high vs low risk of dementia usinga median split of these algorithmic scores As this algorithmincludes age at diagnosis it cannot be used to stratify con-trols We repeated our analysis with 2 other recently de-scribed algorithms one using age years of educationUPDRS-III RBDSQ depression and olfaction14 and theother using age UPDRS axial scores and animal fluency15
(e-Methods for further details)
Statistical analysesPerformance was compared between groups using 2-tailedWelch t tests or Mann-Whitney-Wilcoxon tests for non-normally distributed data We used linear regression to ex-amine the effects of visual measures and retinal structure ondementia risk in PD and controls and Spearman rank cor-relation where data were not normally distributed p lt 005Bonferroni corrected for multiple comparisons (8 compar-isons significance lt00063) was accepted as the thresholdfor statistical significance Sample sizes were based on poweranalyses performed before data collection Analyses wereperformed in R (r-projectorg) Data were inspected andoutliers (beyond mean plusmn 3 times SD) removed Participants withmissing data were omitted for that measure (table e-1 linkslwwcomCPJA126)
Standard protocol approvals registrationsand patient consentsAll participants gave written informed consent and the studywas approved by the Queen Square Research Ethics Com-mittee (15LO0476)
Data availabilityAnonymized data can be made available by request fromqualified investigators to the senior author of this publication
ResultsDemographicsOne hundred twelve people with PD and 34 unaffected con-trols took part Age and sex did not differ between PD andcontrols mean age PD 643 plusmn 8 years mean age controls 648plusmn 9 years (t(49) = 03 p = 074) Fifty-six people with PDwereassigned low risk based on a median split of the risk score13
and 56 were high risk The average disease duration was 41 plusmn25 years and did not differ between high- and low-riskpatients There was also no difference in motor sleep olfac-tion or levodopa dose between high- vs low-risk patients(table 1) (age differed between high- and low-risk groups asthis was strongly linked to age at disease onset that definedrisk and sex was included in the risk algorithm)13
Relationship between visual measures and PDdementia riskThere was no difference in visual measures between peoplewith PD and unaffected controls apart from poorer highervisual function (Cats-and-Dogs test) in people with PD thatdid not survive correction for multiple comparisons (table 2)However when patients were split into high vs low risk ofPD dementia using a median split high-risk patients showedworse performance in almost all visual measures (table 2)with similar differences seen when patients were divided intoquartiles for risk (table e-2 linkslwwcomCPJA126)
Poorer visual function across several levels of visual pro-cessing was associated with a higher risk of dementia (table3) although patients did not report deficits in visual func-tion Visual acuity measured using the logMAR and contrastsensitivity measured using the Pelli-Robson and color vi-sion were all associated with a higher risk of dementia
Poorer visual function across several
levels of visual processing was
associated with a higher risk of
dementia although patients did not
report deficits in visual function
NeurologyorgCP Neurology Clinical Practice | Volume Number | 5
(ρ = 029 p = 00024 ρ = minus037 p lt 00001 ρ = 026 p =00054) (table 3 and figure 1AndashD) Higher-order visuo-perception measured using biological motion showed im-paired performance in higher-risk patients (ρ = minus0026 p =00054) with trend to significance for visual skew (ρ = minus025p = 00073) (table 3 and figure 1EndashF)
Relationship between structural retinalmeasures and PD dementia riskPatients at a higher risk of dementia showed more retinalthinning in dopamine-containing layers GCL (ρ = minus029 p =00021) and IPL (ρ = minus033 p = 000044) These differenceswere not seen in the RNFL that does not contain dopami-nergic cells (ρ = 0012 p = 090 (table 3 and figure 2)
Generalizability across other estimates of riskTo ensure that our findings were generalizable across dif-ferent measures of risk we repeated our analysis using 2alternative Parkinson dementia risk algorithms one adaptedfor clinical values14 and found qualitatively the same rela-tionships (table 4)
Relationship between vision anddementia riskin unaffected controlsTo test whether these findings were related to the risk of PDdementia rather than nonspecific effects of aging we exam-ined these relationships in unaffected controlsWe found thatunlike in PD in controls visual measures were not related todementia risk scores or age (table 4)
DiscussionIn this large PD cohort visual measures across multiplestages of visual processing and structural retinal changes areassociated with a higher risk of more rapid development ofPD dementia
Isolated visual measures such as pentagon copying andcolor vision have previously been linked with cognitivechanges in PD13 and involvement of visual processingbrain regions is associated with more rapid PD de-mentia23 Here we show that vision along the entire
Abbreviations GNT = Graded Naming Test HC = healthy control LEDD = levodopa equivalent daily dose MoCA = Montreal Cognitive Assessment PD =Parkinson disease RBDSQ = REM Sleep Behavior Disorder Screening Questionnaire UPRDS = Unified Parkinsonrsquos Disease Rating ScaleHigh and low risk refer to risk of developing PD dementia as calculated using a median split for established algorithms13a Indicates significance after Bonferroni correction (p lt 00063)
6 Neurology Clinical Practice | Volume Number | NeurologyorgCP
visual processing axis is linked with the risk of cognitivechange in PD This spans from higher-order processesinvolving posterior brain regions to contrast sensitivityand visual acuity mediated by ophthalmic structures orprimary visual cortex and dopamine-containing layers ofthe retina
Our finding that retinal thinning is linked with a higher riskof more rapid PD dementia is consistent with a growingliterature showing retinal involvement in PD Dopamine isa key modulatory neurotransmitter in the retina24 Reduceddopamine innervation is seen around the fovea in PD25 andlower retinal dopaminergic concentrations are found atpostmortem in untreated PD26 OCT initially suggestedRNFL thinning in PD9 but this was not replicated by
others27 potentially due to methodological differences in-cluding sample characteristics lack of appropriate statisti-cal correction and segmentation protocols
As OCT technology has improved it has become clearerthat retinal thinning in PD is restricted to the dopamine-containing layers the GCL and IPL rather than theRNFL12 Nuclei of dopaminergic amacrine interneurons lieadjacent to the IPL24 with axons running horizontallyacross the IPL and GCL28 and postmortem studies showthat retinal alpha-synuclein accumulates at the interfacewith the IPL in PD11 Our finding of a link between retinalthinning and dementia risk in these specific layers has im-portant mechanistic implications for progression of PDdementia
Table 2 Visual scores in controls and PD and in low vs high risk for dementia in PD
Visual measure Controls N = 34 PD N = 112 t (or W) p Value
Abbreviations GCL = ganglion cell layer IPL = inner plexiform layer PD = Parkinson disease RNFL = retinal nerve fiber layera Mann-Whitney-Wilcoxon test used for non-normal datab Indicates significance after Bonferroni correction (p lt 00063)c Trend to significance after Bonferroni correction
NeurologyorgCP Neurology Clinical Practice | Volume Number | 7
In the wider population RNFL thinning is linked withhigher rates of cognitive decline7 and another study foundthat GC-IPL thinning (but not RNFL) is linked withprevalent dementia8 Our finding of a link between retinalthinning and risk of dementia may not be wholly specific toParkinson dementia and may also apply to other types ofdementia Ultimately this will need to be tested in pro-spectively followed cohorts developing different forms ofdementia In PD dementia RNFL thinning has previouslybeen shown to correlate with MMSE scores29 but this re-lationship with cognition has not yet been shown in PDwithout dementia but at risk of dementia Recent post-mortem findings of retinal phosphorylated alpha-synucleinstrengthen the link between the retina and brain disease inPD as the amount of phosphorylated alpha-synuclein in theretina correlates with the density of Lewy-type alpha-synuclein in the brain30 This anatomic finding supports theuse of retinal structural measures as a window into brainpathology
The reason for selective vulnerability of dopamine-containing GC and IP layers is not known but may relate
to common properties of dopamine-containing cellsThese show autonomous spiking behavior with low in-trinsic Ca2+ buffering31 This may lead to free-radical ac-cumulation and increased vulnerability toneurodegeneration Whether retinal layers are affectedbefore cortical regions in PD dementia can be examined inlongitudinal evaluation
We did not find impairment of visual dysfunction in theoverall PD group compared with controls apart from skewtolerance (Cats-and-Dogs test) differences were only seenbetween the high- and low-risk individuals Previous studieshave reported visual dysfunction in PD compared withcontrols23233 It is therefore possible that previous studiesreporting visual deficits in PD overall included higher pro-portions of high-risk individuals or patients with cognitiveinvolvement
LimitationsAlthough our study examines risk based on cross-sectionaldata the algorithms we use are validated using prospectivefollow-up Ultimately however whether measures identifiedhere truly predict the development of dementia in PD willneed to be tested in longitudinal analyses
A further question is whether retinal and visual measuresare affected by the same factors that promote Parkinsondementia such as age The relationship between older ageand poorer vision is well established34 and higher age atonset and age in itself is strongly linked with developmentof dementia in PD1415 Whether some factor such as in-creased amyloid deposition in cortical and retinal struc-tures is responsible for both effects or whether there areseparate processes affecting vision more selectively is notyet known Age (or age at onset) is incorporated into allalgorithmic risk scores For this reason we were unable tocorrect for age in our regression analyses However lack ofassociation between visual measures and dementia risk inunaffected controls suggests that this relationship betweenvision and dementia is more specific to the risk of PDdementia and is not purely a result of deteriorating func-tion with age (although we note that the control group issmaller than the group with PD) We will require longi-tudinal assessment of visual and cognitive factors inpatients with PD to determine and validate whether visualmeasures such as those presented here show additionalsensitivity to recently defined algorithms that use moregeneral clinical inputs
Our finding of a link between acuity and PD dementiarisk raises the question of whether higher-order visualchanges are a result of lower acuity or arise independentlydue to cortical changes in at-risk individuals This will needto be tested by examining cortical differences in thesegroups and their timing relative to retinal and acuitydeficits
Table 3 Relationship between visual measures and PDdementia risk
8 Neurology Clinical Practice | Volume Number | NeurologyorgCP
We show that visual measures and retinal thinning are linkedwith a higher risk of more rapid PD dementia This providesuseful insights into the development of PD dementia im-plicating visual brain regions as being involved at early stagesAs Parkinson dementia is becoming better understoodnoninvasive visual measures such as those used in this studymay have potential to be used alone or in combination withother clinical factors as possible biomarkers for PD dementia
and to stratify high-risk patients for disease-modifying trialsThis could enable better-powered trials and ultimately maypave the way toward new treatments for PD dementia
Study fundingRS W is supported by a Wellcome Clinical Research CareerDevelopment Fellowship (201567Z16Z) This work wasfunded by grants from UCLH Biomedical Research Centre
Table 4 Relationship between vision scores and 2 other risk algorithms
NeurologyorgCP Neurology Clinical Practice | Volume Number | 9
Grant (BRC302NSRW101410) andby grants fromNationalInstitute for Health Research (NIHR) and Fight for Sight UK
DisclosureL-A Leyland F D Bremner R Mahmood S HewittM Durteste MRE Cartlidge M M-M Lai LE Miller andA P Saygin report no disclosures P A Keane reports per-sonal fees from Topcon Heidelberg Engineering Deep-Mind Optos Novartis Bayer Allergan and Santen A ESchrag reports personal fees from Medtronic and AstraZe-neca R S Weil has received personal fees from GE Fulldisclosure form information provided by the authors isavailable with the full text of this article at Neurologyorgcp
Publication historyReceived by Neurology Clinical Practice April 9 2019 Accepted in finalform June 7 2019
References1 Anang JB Gagnon JF Bertrand JA et al Predictors of dementia in Parkinson disease
a prospective cohort study Neurology 2014831253ndash12602 Weil RS Pappa K Schade RN et al The Cats-and-Dogs test a tool to identify
visuoperceptual deficits in Parkinsonrsquos disease Mov Disord 2017321789ndash17903 Williams-Gray CH Mason SL Evans JR et al The CamPaIGN study of Parkinsonrsquos
disease 10-year outlook in an incident population-based cohort J Neurol NeurosurgPsychiatry 2013841258ndash1264
4 Bodis-Wollner I Miri S Glazman S Venturing into the no-manrsquos land of the retina inParkinsonrsquos disease Mov Disord 20142915ndash22
5 Cheung CY Ong YT Hilal S et al Retinal ganglion cell analysis using high-definitionoptical coherence tomography in patients with mild cognitive impairment and Alz-heimerrsquos disease J Alzheimers Dis 20154545ndash56
6 Cheung CY Chan VT Mok VC Chen C Wong TY Potential retinal biomarkers fordementia what is new Curr Opin Neurol 20193282ndash91
7 Ko F Muthy ZA Gallacher J et al Association of retinal nerve fiber layer thinningwith current and future cognitive decline a study using optical coherence tomogra-phy JAMA Neurology 2018751198ndash1205
8 Mutlu U Colijn JM Ikram MA et al Association of retinal neurodegeneration onoptical coherence tomography with dementia a population-based study JAMANeurol 2018751256ndash1263
9 Inzelberg R Ramirez JA Nisipeanu P Ophir A Retinal nerve fiber layer thinning inParkinson disease Vision Res 2004442793ndash2797
10 Balasubramanian R Gan L Development of retinal amacrine cells and their dendriticstratification Current Ophthalmol Rep 20142100ndash106
11 Beach TG Carew J Serrano G et al Phosphorylated α-synuclein-immunoreactiveretinal neuronal elements in Parkinsonrsquos disease subjects Neurosci Lett 201457134ndash38
12 Zivkovic M Dayanir V Stamenovic J et al Retinal ganglion cellinner plexiform layerthickness in patients with Parkinsonrsquos disease Folia Neuropathol 201755168ndash173
13 Liu G Locascio JJ Corvol JC et al Prediction of cognition in Parkinsonrsquos disease witha clinical-genetic score a longitudinal analysis of nine cohorts Lancet Neurol 201716620ndash629
14 Schrag A Siddiqui UF Anastasiou Z Weintraub D Schott JM Clinical variables andbiomarkers in prediction of cognitive impairment in patients with newly diagnosedParkinsonrsquos disease a cohort study Lancet Neurol 20171666ndash75
15 Velseboer DC de Bie RM Wieske L et al Development and external validation ofa prognostic model in newly diagnosed Parkinson disease Neurology 201686986ndash993
16 Weil RS Schwarzkopf DS Bahrami B et al Assessing cognitive dysfunction in Par-kinsonrsquos disease an online tool to detect visuo-perceptual deficits Mov Disord 201833544ndash553
17 Saygin AP Superior temporal and premotor brain areas necessary for biologicalmotion perception Brain 20071302452ndash2461
18 Jaywant A Shiffrar M Roy S Cronin-Golomb A Impaired perception of biologicalmotion in Parkinsonrsquos disease Neuropsychology 201630720ndash730
19 Cetin EN Bir LS Sarac G Yaldızkaya F Yaylalı V Optic disc and retinal nerve fibrelayer changes in Parkinsonrsquos disease Neuroophthalmology 20133720ndash23
20 Tewarie P Balk L Costello F et al TheOSCAR-IB consensus criteria for retinal OCTquality assessment PloS one 20127e34823
21 Cruz-Herranz A Balk LJ Oberwahrenbrock T et al The APOSTEL recom-mendations for reporting quantitative optical coherence tomography studies Neu-rology 2016862303ndash2309
22 Litvan I Goldman JG Troster AI et al Diagnostic criteria for mild cognitive im-pairment in Parkinsonrsquos disease movement disorder society task force guidelinesMov Disord 201227349ndash356
23 Toledo JB Gopal P Raible K et al Pathological α-synuclein distribution in subjects withcoincident Alzheimerrsquos and Lewy body pathology Acta Neuropathol 2016131393ndash409
Appendix Authors
Name Location Role Contribution
Louise-AnnLeyland PhD
University CollegeLondon London
Author Designed andconceptualized thestudy collected dataanalyzed data anddrafted themanuscriptfor intellectual content
Fion DBremner PhD
National Hospital forNeurology ampNeurosurgery London
Author Collected andinterpreted data andreviewed themanuscript forintellectual content
RibeyaMahmoodMSc
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
Sam HewittMSc
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
MarionDurteste MSc
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
Molly RECartlidge
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
Michelle M-MLai FRCOphth
National Hospital forNeurology ampNeurosurgery London
Author Collected andinterpreted data andreviewed themanuscript forintellectual content
Luke E MillerPhD
Lyon NeuroscienceResearch CenterFrance
Author Designed aspects ofthe study interpretedthe data and reviewedthe manuscript forintellectual content
Ayse P SayginPhD
University of CaliforniaSan Diego
Author Designed aspects ofthe study interpretedthe data and reviewedthe manuscript forintellectual content
Appendix (continued)
Name Location Role Contribution
Pearse AKeane PhD
University CollegeLondon London
Author Designed aspects ofthe study interpretedthe data and reviewedthe manuscript forintellectual content
Anette ESchrag PhD
University CollegeLondon London
Author Interpreted the dataand reviewed themanuscript forintellectual content
Rimona SWeilPhD
University CollegeLondon London
Author Designed andconceptualized thestudy analyzed thedata interpreted thedata and draftedrevised and edited themanuscript forintellectual content
10 Neurology Clinical Practice | Volume Number | NeurologyorgCP
24 Frederick JM Rayborn ME Laties AM Lam DM Hollyfield JG Dopaminergicneurons in the human retina J Comp Neurol 198221065ndash79
25 Nguyen-Legros J Functional neuroarchitecture of the retina hypothesis on thedysfunction of retinal dopaminergic circuitry in Parkinsonrsquos disease Surg Radiol Anat198810137ndash144
26 Harnois C Di Paolo T Decreased dopamine in the retinas of patients with Parkin-sonrsquos disease Invest Ophthalmol Vis Sci 1990312473ndash2475
27 Tsironi EE Dastiridou A Katsanos A et al Perimetric and retinal nerve fiber layerfindings in patients with Parkinsonrsquos disease BMC Ophthalmol 20121254
28 Archibald NK Clarke MP Mosimann UP Burn DJ Retinal thickness in Parkinsonrsquosdisease Parkinsonism Relat Disord 201117431ndash436
29 Moreno-Ramos T Benito-Leon J Villarejo A Bermejo-Pareja F Retinal nerve fiberlayer thinning in dementia associated with Parkinsonrsquos disease dementia with Lewybodies and Alzheimerrsquos disease J Alzheimerrsquos Dis 201334659ndash664
30 Ortuntildeo-Lizaran I Beach TG Serrano GE Walker DG Adler CH Cuenca N Phos-phorylated α‐synuclein in the retina is a biomarker of Parkinsonrsquos disease pathologyseverity Movement Disorders 2018331315ndash1324
31 Surmeier DJ Obeso JA Halliday GM Selective neuronal vulnerability in Parkinsondisease Nat Rev Neurosci 201718101ndash113
32 Levin BE Llabre MM Reisman S et al Visuospatial impairment in Parkinsonrsquosdisease Neurology 199141365ndash369
33 Regan D Neima D Low-contrast letter charts in early diabetic retinopathy ocularhypertension glaucoma and Parkinsonrsquos disease Br J Ophthalmol 198468885ndash889
34 McKendrick AM Chan YM Nguyen BN Spatial vision in older adults perceptualchanges and neural bases Ophthalmic and Physiol Opt201838(4)363ndash375
35 Laidlaw D Abbott A Rosser DA Development of a clinically feasible logMAR al-ternative to the Snellen chart performance of the ldquocompact reduced logMARrdquo visualacuity chart in amblyopic children Br J Ophthalmol 2003871232ndash1234
NeurologyorgCP Neurology Clinical Practice | Volume Number | 11
DOI 101212CPJ0000000000000719 published online September 18 2019Neurol Clin Pract
Louise-Ann Leyland Fion D Bremner Ribeya Mahmood et al Visual tests predict dementia risk in Parkinson disease
This information is current as of September 18 2019
ServicesUpdated Information amp
19fullhtmlhttpcpneurologyorgcontentearly20190918CPJ00000000000007including high resolution figures can be found at
Citations
19fullhtmlotherarticleshttpcpneurologyorgcontentearly20190918CPJ00000000000007This article has been cited by 2 HighWire-hosted articles
tiahttpcpneurologyorgcgicollectionparkinsons_disease_with_demenParkinsons disease with dementiafollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpcpneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
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reserved Print ISSN 2163-0402 Online ISSN 2163-0933Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightssince 2011 it is now a bimonthly with 6 issues per year Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published continuouslyNeurol Clin Pract
Dementia is a debilitating aspect of Parkinson disease (PD)affecting 50 of patients within 10 years of diagnosis withvariability in timing and severity Patients with PD who showvisual deficits including color and higher-order visualchanges may have higher rates of converting to PD dementiaor develop dementia earlier in their disease course1ndash3
However this has not yet been examined systematically andwhether earlier stages of visual processing and retinalstructure are linked to the risk of PD dementia is not yetknown
Retinal structure can be imaged noninvasively using opticalcoherence tomography (OCT)4 and shows thinning inAlzheimer disease5 and as a population screen fordementia6ndash8 Retinal structural changes are seen in PD butearly studies of retinal nerve fiber layer (RNFL) thinning inPD were not replicated9 The location of dopaminergicamacrine cells in the inner plexiform layer (IPL)10 in non-human studies and postmortem findings of phosphorylatedalpha-synuclein in the IPL suggest that deeper layers aremore likely to be affected in PD11 Recent studies showconsistent thinning in the IPL and ganglion cell layer (GCL)in PD12 but whether IPL or GCL thinning is linked to PDdementia is not known
New algorithms have emerged that combine measures suchas age and motor severity with sensitivity to predict cognitivechange in PD13ndash15 Although these algorithms are usefulthey do not allow tracking of disease progression or relatedirectly to changes in the parkinsonian brain
We therefore examined the association between visualmeasures and retinal structure with the risk of dementia inPD These measures have potential for stratifying high-riskpatients for clinical trials
MethodsParticipantsOne hundred seventeen people with PDwere recruited fromour UK center between October 2017 and November 2018Inclusion criteria were early-stage PD (Queen Square BrainBank criteria) within 10 years of diagnosis aged 49ndash82years Exclusion criteria were confounding neurologic orpsychiatric disorders a diagnosis of dementia or Mini-Mental State Examination (MMSE) less than 2513 andophthalmic disease sufficient to impair visual acuity Twopatients were excluded because of dementia and 3 wereexcluded because of ophthalmic disease (glaucoma)Therefore the data reported here include 112 people withPD Thirty-five age-matched controls unaffected by neuro-logic psychiatric or ophthalmic disease were additionallyrecruited from university databases and unaffected spousesOf these 1 was excluded because of developing mild cog-nitive impairment within 6 months of taking part leaving 34controls in the analysis reported here
Clinical and ophthalmic evaluationAll participants were tested on their usual medications andlevodopa equivalent daily dose calculated Symptom severitywas assessed using the Movement Disorders Society UnifiedPD Rating Scale (UPDRS) Olfaction was assessed using theodor identification subset of the Sniffinrsquo sticks test Partic-ipants completed the Hospital Anxiety and DepressionScale and REM Sleep Behavior Disorder Screening Ques-tionnaire (RBDSQ) A comprehensive ophthalmic assess-ment was performed by a consultant ophthalmologist Thisincluded slit-lamp ophthalmic examination and measure-ment of intraocular pressures using Goldmann applanationtonometry
Assessments of visual functionVisual measures (figure 1) were all performed before my-driasis Visual acuity was measured binocularly using a log-MAR chart (with eyeglasses if worn) (figure 1A) Contrastsensitivity was measured binocularly (with eyeglasses ifworn) using a Pelli-Robson chart (SSV-281-PC) (sussex-visioncouk) (figure 1C) Color vision was assessed usingthe D15 test and error scores log transformed
Visuoperception was measured using 2 tasks probing distinctaspects of higher-order visuoperception the Cats-and-Dogstest measures tolerance to visual skew (figure 1E) and hasbeen associated with PD16 Stimuli were generated as pre-viously described216 Images were presented centrally sub-tending 4deg times 13deg of visual angle and shown for 280 msfollowed by a choice screen (response time 3800 ms) 90repetitions (total time 15 minutes) To calculate discrimi-nation sensitivity missing trials were excluded and perfor-mance at each level of skew calculated A sigmoidpsychometric curve was fitted and threshold for image de-tection was calculated at 75 performance Biological mo-tion measures sensitivity to detect the appearance ofa moving person from moving dots at the position of themajor joints of a person17 It is known to be affected in PD18
Stimuli consisted of point-light walkers (12 white dots ongray background height 7deg) (figure 1G) Control stimuliwere generated using point-light walkers with dot positionand motion scrambled Motion-matched noise dots wereadded to increase difficulty using an adaptive staircase
In this large PD cohort visual
measures across multiple stages of
visual processing and structural
retinal changes are associated with
a higher risk of more rapid
development of PD dementia
2 Neurology Clinical Practice | Volume Number | NeurologyorgCP
Figure 1 Tests of visual function and relationship with risk of Parkinson disease (PD) dementia
(A) LogMAR visual acuity chart Adapted by permission from BMJ Publishing Group Limited35 (B) Relationship between the risk of PD dementia and visualacuity (C) Pelli-Robson chart for assessing contrast sensitivity (D) Relationship between the risk of PD dementia and contrast sensitivity (E) Cats-and-Dogstest of higher-order visuoperception The task is to identify whether the animal shown is a cat or a dog with differing amounts of skew applied to the image todetermine the level of skew tolerated (F) Relationship between the risk of PD dementia and higher-order visuoperception tested by skew tolerance (G)Biological motion Dots are shown at the position of themajor joints of the body The dotsmove to give the strong percept of a person walking Extra dots areadded and the number of dots tolerated where the participant can still detect a person moving is calculated (H) Relationship between the risk of PDdementia and higher-order visuoperception tested with biological motion Poorer performance in each of these measures is linked with a higher risk of PDdementia
NeurologyorgCP Neurology Clinical Practice | Volume Number | 3
procedure17 Stimuli were presented for 800 ms Participantsdetermined whether the animation depicted a moving per-son or scrambled moving dots 225 repetitions total time 15minutes We used the QUEST Bayesian adaptive method tocalculate the maximum number of additional noise dotstolerated for performance to reach 82 accuracy Stimuliwere generated within MATLAB Psychophysics Toolbox 3implemented on a Dell Latitude 3340 in a darkened roomWhether this test relates to the risk of PD dementia is notknown
Retinal structure OCTRetinal imaging was performed on both eyes of each partic-ipant on the same day as other measures were obtained Innerretinal layer structure was measured using high-resolutionspectral domain optical coherence tomography (SD-OCTHeidelberg HRASpectralis manufactured in 2011) ina dimly lit room after pharmacologic mydriasis according toa standard protocol19 Two OCT devices were used at 1 site(National Hospital for Neurology and Neurosurgery) with 4operators (L-AL RM SH and MREC) with viewingmodule v 6950 All participants underwent macular scanprotocols in Infrared-OCT mode laser illumination used forexcitation was 486 nm This allows simultaneous acquisitionof a fundus image with a reflectance wavelength of 816 nmand OCT scan with TruTrack eye-tracking technology to
stabilize the retinal image The volumetric macular protocolof the Spectralis SD-OCT device (NSite application) wasused to measure macular thickness and volume (figure 2A)This uses an internal fixation source and centers on theparticipantrsquos fovea The protocol consists of 25 vertical linescans at a resolution of 1536 (scanning angle 20degtimes20degdensity 240 μm 47 scanss automatic real-time frames49) Quality control of OCT data was performed in com-pliance with international consensus OSCAR 1B OCTquality control standards (OSCAR-IB)20 and OCT datawere collected and reported according to internationalAPOSTEL guidelines21
OCT analysisAutomatic layer segmentation was applied via Heidelbergsoftware v11020 with Nsite module included to computethe thickness of the GCL IPL and RNFL Blinded assessors(SH and MREC) verified layer position and manualsegmentation was undertaken when automatic segmentationdeviated from the visible gradient change for that layer(quality checked by LL) All layers were segmented andexported and total volume and total thickness within each ofthe RNFL GCL and IPL were calculated across all 4 quad-rants and summed for a total layer thickness exported as a 1-3- 6-mm EDTRS grid Retinal data from 9 individuals wereexcluded because of ophthalmic disease or poor-quality scans
Figure 2 Relationship between the retinal volume and risk of Parkinson disease (PD) dementia
(A) Output of optical coherence tomography retinal imaging with cross section at themacula Retinal layers identified by automatic segmentation are shown(B) Relationship between the risk of PD dementia and RNFL volume (C) Relationship between the risk of PD dementia and GCL volume (D) Relationshipbetween the risk of PD dementia and IPL volume Retinal layers that contain dopaminergic cells (GCL and IPL) show greater thinning linked with PD dementiarisk This relationship is not seen in the RNFL that does not contain dopaminergic cells RNFL = retinal nerve fiber layer GCL = ganglion cell layer IPL = innerplexiform layer
4 Neurology Clinical Practice | Volume Number | NeurologyorgCP
(table e-1 linkslwwcomCPJA126) One eye from eachparticipant was selected for analysis In patients with PD thiswas the eye contralateral to the most symptomatic side asidentified during UPDRS-III For controls and patients withsymmetrical motor signs the selected eye was selected ran-domly In 8 patients and in 1 control the selected eye couldnot be used because of ophthalmic disease exclusions and theother eye was included for these participants (table e-1)
Neuropsychological evaluationCognitive assessment was in line with recent MovementDisorder Society guidelines22 with 2 assessments per cog-nitive domain General cognitive function was assessed withthe MMSE and Montreal Cognitive Assessment Memorywas assessed with the Recognition Memory Test for wordsand immediate and delayed versions of the Logical Memorytask (Wechsler Memory Scale IV) Language was assessedwith the Graded Naming Test and letter fluency Visuospa-tial abilities were tested with Benton Judgment of LineOrientation and Hooper Visual Organization Test Executivefunctions were measured with the Stroop task from theDelis-Kaplan Executive Function System and category flu-ency Attention was tested using color naming from theStroop and Digit Span
Defining dementia risk statusWe defined dementia risk using a recently described pro-spectively validated algorithm13 This combines clinical in-formation on sex age at disease onset years of educationUPDRS-III (motor examination) and MMSE to generatea risk score (e-Methods for details linkslwwcomCPJA137) In addition to the continuous scores we categorizedpatients with PD into high vs low risk of dementia usinga median split of these algorithmic scores As this algorithmincludes age at diagnosis it cannot be used to stratify con-trols We repeated our analysis with 2 other recently de-scribed algorithms one using age years of educationUPDRS-III RBDSQ depression and olfaction14 and theother using age UPDRS axial scores and animal fluency15
(e-Methods for further details)
Statistical analysesPerformance was compared between groups using 2-tailedWelch t tests or Mann-Whitney-Wilcoxon tests for non-normally distributed data We used linear regression to ex-amine the effects of visual measures and retinal structure ondementia risk in PD and controls and Spearman rank cor-relation where data were not normally distributed p lt 005Bonferroni corrected for multiple comparisons (8 compar-isons significance lt00063) was accepted as the thresholdfor statistical significance Sample sizes were based on poweranalyses performed before data collection Analyses wereperformed in R (r-projectorg) Data were inspected andoutliers (beyond mean plusmn 3 times SD) removed Participants withmissing data were omitted for that measure (table e-1 linkslwwcomCPJA126)
Standard protocol approvals registrationsand patient consentsAll participants gave written informed consent and the studywas approved by the Queen Square Research Ethics Com-mittee (15LO0476)
Data availabilityAnonymized data can be made available by request fromqualified investigators to the senior author of this publication
ResultsDemographicsOne hundred twelve people with PD and 34 unaffected con-trols took part Age and sex did not differ between PD andcontrols mean age PD 643 plusmn 8 years mean age controls 648plusmn 9 years (t(49) = 03 p = 074) Fifty-six people with PDwereassigned low risk based on a median split of the risk score13
and 56 were high risk The average disease duration was 41 plusmn25 years and did not differ between high- and low-riskpatients There was also no difference in motor sleep olfac-tion or levodopa dose between high- vs low-risk patients(table 1) (age differed between high- and low-risk groups asthis was strongly linked to age at disease onset that definedrisk and sex was included in the risk algorithm)13
Relationship between visual measures and PDdementia riskThere was no difference in visual measures between peoplewith PD and unaffected controls apart from poorer highervisual function (Cats-and-Dogs test) in people with PD thatdid not survive correction for multiple comparisons (table 2)However when patients were split into high vs low risk ofPD dementia using a median split high-risk patients showedworse performance in almost all visual measures (table 2)with similar differences seen when patients were divided intoquartiles for risk (table e-2 linkslwwcomCPJA126)
Poorer visual function across several levels of visual pro-cessing was associated with a higher risk of dementia (table3) although patients did not report deficits in visual func-tion Visual acuity measured using the logMAR and contrastsensitivity measured using the Pelli-Robson and color vi-sion were all associated with a higher risk of dementia
Poorer visual function across several
levels of visual processing was
associated with a higher risk of
dementia although patients did not
report deficits in visual function
NeurologyorgCP Neurology Clinical Practice | Volume Number | 5
(ρ = 029 p = 00024 ρ = minus037 p lt 00001 ρ = 026 p =00054) (table 3 and figure 1AndashD) Higher-order visuo-perception measured using biological motion showed im-paired performance in higher-risk patients (ρ = minus0026 p =00054) with trend to significance for visual skew (ρ = minus025p = 00073) (table 3 and figure 1EndashF)
Relationship between structural retinalmeasures and PD dementia riskPatients at a higher risk of dementia showed more retinalthinning in dopamine-containing layers GCL (ρ = minus029 p =00021) and IPL (ρ = minus033 p = 000044) These differenceswere not seen in the RNFL that does not contain dopami-nergic cells (ρ = 0012 p = 090 (table 3 and figure 2)
Generalizability across other estimates of riskTo ensure that our findings were generalizable across dif-ferent measures of risk we repeated our analysis using 2alternative Parkinson dementia risk algorithms one adaptedfor clinical values14 and found qualitatively the same rela-tionships (table 4)
Relationship between vision anddementia riskin unaffected controlsTo test whether these findings were related to the risk of PDdementia rather than nonspecific effects of aging we exam-ined these relationships in unaffected controlsWe found thatunlike in PD in controls visual measures were not related todementia risk scores or age (table 4)
DiscussionIn this large PD cohort visual measures across multiplestages of visual processing and structural retinal changes areassociated with a higher risk of more rapid development ofPD dementia
Isolated visual measures such as pentagon copying andcolor vision have previously been linked with cognitivechanges in PD13 and involvement of visual processingbrain regions is associated with more rapid PD de-mentia23 Here we show that vision along the entire
Abbreviations GNT = Graded Naming Test HC = healthy control LEDD = levodopa equivalent daily dose MoCA = Montreal Cognitive Assessment PD =Parkinson disease RBDSQ = REM Sleep Behavior Disorder Screening Questionnaire UPRDS = Unified Parkinsonrsquos Disease Rating ScaleHigh and low risk refer to risk of developing PD dementia as calculated using a median split for established algorithms13a Indicates significance after Bonferroni correction (p lt 00063)
6 Neurology Clinical Practice | Volume Number | NeurologyorgCP
visual processing axis is linked with the risk of cognitivechange in PD This spans from higher-order processesinvolving posterior brain regions to contrast sensitivityand visual acuity mediated by ophthalmic structures orprimary visual cortex and dopamine-containing layers ofthe retina
Our finding that retinal thinning is linked with a higher riskof more rapid PD dementia is consistent with a growingliterature showing retinal involvement in PD Dopamine isa key modulatory neurotransmitter in the retina24 Reduceddopamine innervation is seen around the fovea in PD25 andlower retinal dopaminergic concentrations are found atpostmortem in untreated PD26 OCT initially suggestedRNFL thinning in PD9 but this was not replicated by
others27 potentially due to methodological differences in-cluding sample characteristics lack of appropriate statisti-cal correction and segmentation protocols
As OCT technology has improved it has become clearerthat retinal thinning in PD is restricted to the dopamine-containing layers the GCL and IPL rather than theRNFL12 Nuclei of dopaminergic amacrine interneurons lieadjacent to the IPL24 with axons running horizontallyacross the IPL and GCL28 and postmortem studies showthat retinal alpha-synuclein accumulates at the interfacewith the IPL in PD11 Our finding of a link between retinalthinning and dementia risk in these specific layers has im-portant mechanistic implications for progression of PDdementia
Table 2 Visual scores in controls and PD and in low vs high risk for dementia in PD
Visual measure Controls N = 34 PD N = 112 t (or W) p Value
Abbreviations GCL = ganglion cell layer IPL = inner plexiform layer PD = Parkinson disease RNFL = retinal nerve fiber layera Mann-Whitney-Wilcoxon test used for non-normal datab Indicates significance after Bonferroni correction (p lt 00063)c Trend to significance after Bonferroni correction
NeurologyorgCP Neurology Clinical Practice | Volume Number | 7
In the wider population RNFL thinning is linked withhigher rates of cognitive decline7 and another study foundthat GC-IPL thinning (but not RNFL) is linked withprevalent dementia8 Our finding of a link between retinalthinning and risk of dementia may not be wholly specific toParkinson dementia and may also apply to other types ofdementia Ultimately this will need to be tested in pro-spectively followed cohorts developing different forms ofdementia In PD dementia RNFL thinning has previouslybeen shown to correlate with MMSE scores29 but this re-lationship with cognition has not yet been shown in PDwithout dementia but at risk of dementia Recent post-mortem findings of retinal phosphorylated alpha-synucleinstrengthen the link between the retina and brain disease inPD as the amount of phosphorylated alpha-synuclein in theretina correlates with the density of Lewy-type alpha-synuclein in the brain30 This anatomic finding supports theuse of retinal structural measures as a window into brainpathology
The reason for selective vulnerability of dopamine-containing GC and IP layers is not known but may relate
to common properties of dopamine-containing cellsThese show autonomous spiking behavior with low in-trinsic Ca2+ buffering31 This may lead to free-radical ac-cumulation and increased vulnerability toneurodegeneration Whether retinal layers are affectedbefore cortical regions in PD dementia can be examined inlongitudinal evaluation
We did not find impairment of visual dysfunction in theoverall PD group compared with controls apart from skewtolerance (Cats-and-Dogs test) differences were only seenbetween the high- and low-risk individuals Previous studieshave reported visual dysfunction in PD compared withcontrols23233 It is therefore possible that previous studiesreporting visual deficits in PD overall included higher pro-portions of high-risk individuals or patients with cognitiveinvolvement
LimitationsAlthough our study examines risk based on cross-sectionaldata the algorithms we use are validated using prospectivefollow-up Ultimately however whether measures identifiedhere truly predict the development of dementia in PD willneed to be tested in longitudinal analyses
A further question is whether retinal and visual measuresare affected by the same factors that promote Parkinsondementia such as age The relationship between older ageand poorer vision is well established34 and higher age atonset and age in itself is strongly linked with developmentof dementia in PD1415 Whether some factor such as in-creased amyloid deposition in cortical and retinal struc-tures is responsible for both effects or whether there areseparate processes affecting vision more selectively is notyet known Age (or age at onset) is incorporated into allalgorithmic risk scores For this reason we were unable tocorrect for age in our regression analyses However lack ofassociation between visual measures and dementia risk inunaffected controls suggests that this relationship betweenvision and dementia is more specific to the risk of PDdementia and is not purely a result of deteriorating func-tion with age (although we note that the control group issmaller than the group with PD) We will require longi-tudinal assessment of visual and cognitive factors inpatients with PD to determine and validate whether visualmeasures such as those presented here show additionalsensitivity to recently defined algorithms that use moregeneral clinical inputs
Our finding of a link between acuity and PD dementiarisk raises the question of whether higher-order visualchanges are a result of lower acuity or arise independentlydue to cortical changes in at-risk individuals This will needto be tested by examining cortical differences in thesegroups and their timing relative to retinal and acuitydeficits
Table 3 Relationship between visual measures and PDdementia risk
8 Neurology Clinical Practice | Volume Number | NeurologyorgCP
We show that visual measures and retinal thinning are linkedwith a higher risk of more rapid PD dementia This providesuseful insights into the development of PD dementia im-plicating visual brain regions as being involved at early stagesAs Parkinson dementia is becoming better understoodnoninvasive visual measures such as those used in this studymay have potential to be used alone or in combination withother clinical factors as possible biomarkers for PD dementia
and to stratify high-risk patients for disease-modifying trialsThis could enable better-powered trials and ultimately maypave the way toward new treatments for PD dementia
Study fundingRS W is supported by a Wellcome Clinical Research CareerDevelopment Fellowship (201567Z16Z) This work wasfunded by grants from UCLH Biomedical Research Centre
Table 4 Relationship between vision scores and 2 other risk algorithms
NeurologyorgCP Neurology Clinical Practice | Volume Number | 9
Grant (BRC302NSRW101410) andby grants fromNationalInstitute for Health Research (NIHR) and Fight for Sight UK
DisclosureL-A Leyland F D Bremner R Mahmood S HewittM Durteste MRE Cartlidge M M-M Lai LE Miller andA P Saygin report no disclosures P A Keane reports per-sonal fees from Topcon Heidelberg Engineering Deep-Mind Optos Novartis Bayer Allergan and Santen A ESchrag reports personal fees from Medtronic and AstraZe-neca R S Weil has received personal fees from GE Fulldisclosure form information provided by the authors isavailable with the full text of this article at Neurologyorgcp
Publication historyReceived by Neurology Clinical Practice April 9 2019 Accepted in finalform June 7 2019
References1 Anang JB Gagnon JF Bertrand JA et al Predictors of dementia in Parkinson disease
a prospective cohort study Neurology 2014831253ndash12602 Weil RS Pappa K Schade RN et al The Cats-and-Dogs test a tool to identify
visuoperceptual deficits in Parkinsonrsquos disease Mov Disord 2017321789ndash17903 Williams-Gray CH Mason SL Evans JR et al The CamPaIGN study of Parkinsonrsquos
disease 10-year outlook in an incident population-based cohort J Neurol NeurosurgPsychiatry 2013841258ndash1264
4 Bodis-Wollner I Miri S Glazman S Venturing into the no-manrsquos land of the retina inParkinsonrsquos disease Mov Disord 20142915ndash22
5 Cheung CY Ong YT Hilal S et al Retinal ganglion cell analysis using high-definitionoptical coherence tomography in patients with mild cognitive impairment and Alz-heimerrsquos disease J Alzheimers Dis 20154545ndash56
6 Cheung CY Chan VT Mok VC Chen C Wong TY Potential retinal biomarkers fordementia what is new Curr Opin Neurol 20193282ndash91
7 Ko F Muthy ZA Gallacher J et al Association of retinal nerve fiber layer thinningwith current and future cognitive decline a study using optical coherence tomogra-phy JAMA Neurology 2018751198ndash1205
8 Mutlu U Colijn JM Ikram MA et al Association of retinal neurodegeneration onoptical coherence tomography with dementia a population-based study JAMANeurol 2018751256ndash1263
9 Inzelberg R Ramirez JA Nisipeanu P Ophir A Retinal nerve fiber layer thinning inParkinson disease Vision Res 2004442793ndash2797
10 Balasubramanian R Gan L Development of retinal amacrine cells and their dendriticstratification Current Ophthalmol Rep 20142100ndash106
11 Beach TG Carew J Serrano G et al Phosphorylated α-synuclein-immunoreactiveretinal neuronal elements in Parkinsonrsquos disease subjects Neurosci Lett 201457134ndash38
12 Zivkovic M Dayanir V Stamenovic J et al Retinal ganglion cellinner plexiform layerthickness in patients with Parkinsonrsquos disease Folia Neuropathol 201755168ndash173
13 Liu G Locascio JJ Corvol JC et al Prediction of cognition in Parkinsonrsquos disease witha clinical-genetic score a longitudinal analysis of nine cohorts Lancet Neurol 201716620ndash629
14 Schrag A Siddiqui UF Anastasiou Z Weintraub D Schott JM Clinical variables andbiomarkers in prediction of cognitive impairment in patients with newly diagnosedParkinsonrsquos disease a cohort study Lancet Neurol 20171666ndash75
15 Velseboer DC de Bie RM Wieske L et al Development and external validation ofa prognostic model in newly diagnosed Parkinson disease Neurology 201686986ndash993
16 Weil RS Schwarzkopf DS Bahrami B et al Assessing cognitive dysfunction in Par-kinsonrsquos disease an online tool to detect visuo-perceptual deficits Mov Disord 201833544ndash553
17 Saygin AP Superior temporal and premotor brain areas necessary for biologicalmotion perception Brain 20071302452ndash2461
18 Jaywant A Shiffrar M Roy S Cronin-Golomb A Impaired perception of biologicalmotion in Parkinsonrsquos disease Neuropsychology 201630720ndash730
19 Cetin EN Bir LS Sarac G Yaldızkaya F Yaylalı V Optic disc and retinal nerve fibrelayer changes in Parkinsonrsquos disease Neuroophthalmology 20133720ndash23
20 Tewarie P Balk L Costello F et al TheOSCAR-IB consensus criteria for retinal OCTquality assessment PloS one 20127e34823
21 Cruz-Herranz A Balk LJ Oberwahrenbrock T et al The APOSTEL recom-mendations for reporting quantitative optical coherence tomography studies Neu-rology 2016862303ndash2309
22 Litvan I Goldman JG Troster AI et al Diagnostic criteria for mild cognitive im-pairment in Parkinsonrsquos disease movement disorder society task force guidelinesMov Disord 201227349ndash356
23 Toledo JB Gopal P Raible K et al Pathological α-synuclein distribution in subjects withcoincident Alzheimerrsquos and Lewy body pathology Acta Neuropathol 2016131393ndash409
Appendix Authors
Name Location Role Contribution
Louise-AnnLeyland PhD
University CollegeLondon London
Author Designed andconceptualized thestudy collected dataanalyzed data anddrafted themanuscriptfor intellectual content
Fion DBremner PhD
National Hospital forNeurology ampNeurosurgery London
Author Collected andinterpreted data andreviewed themanuscript forintellectual content
RibeyaMahmoodMSc
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
Sam HewittMSc
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
MarionDurteste MSc
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
Molly RECartlidge
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
Michelle M-MLai FRCOphth
National Hospital forNeurology ampNeurosurgery London
Author Collected andinterpreted data andreviewed themanuscript forintellectual content
Luke E MillerPhD
Lyon NeuroscienceResearch CenterFrance
Author Designed aspects ofthe study interpretedthe data and reviewedthe manuscript forintellectual content
Ayse P SayginPhD
University of CaliforniaSan Diego
Author Designed aspects ofthe study interpretedthe data and reviewedthe manuscript forintellectual content
Appendix (continued)
Name Location Role Contribution
Pearse AKeane PhD
University CollegeLondon London
Author Designed aspects ofthe study interpretedthe data and reviewedthe manuscript forintellectual content
Anette ESchrag PhD
University CollegeLondon London
Author Interpreted the dataand reviewed themanuscript forintellectual content
Rimona SWeilPhD
University CollegeLondon London
Author Designed andconceptualized thestudy analyzed thedata interpreted thedata and draftedrevised and edited themanuscript forintellectual content
10 Neurology Clinical Practice | Volume Number | NeurologyorgCP
24 Frederick JM Rayborn ME Laties AM Lam DM Hollyfield JG Dopaminergicneurons in the human retina J Comp Neurol 198221065ndash79
25 Nguyen-Legros J Functional neuroarchitecture of the retina hypothesis on thedysfunction of retinal dopaminergic circuitry in Parkinsonrsquos disease Surg Radiol Anat198810137ndash144
26 Harnois C Di Paolo T Decreased dopamine in the retinas of patients with Parkin-sonrsquos disease Invest Ophthalmol Vis Sci 1990312473ndash2475
27 Tsironi EE Dastiridou A Katsanos A et al Perimetric and retinal nerve fiber layerfindings in patients with Parkinsonrsquos disease BMC Ophthalmol 20121254
28 Archibald NK Clarke MP Mosimann UP Burn DJ Retinal thickness in Parkinsonrsquosdisease Parkinsonism Relat Disord 201117431ndash436
29 Moreno-Ramos T Benito-Leon J Villarejo A Bermejo-Pareja F Retinal nerve fiberlayer thinning in dementia associated with Parkinsonrsquos disease dementia with Lewybodies and Alzheimerrsquos disease J Alzheimerrsquos Dis 201334659ndash664
30 Ortuntildeo-Lizaran I Beach TG Serrano GE Walker DG Adler CH Cuenca N Phos-phorylated α‐synuclein in the retina is a biomarker of Parkinsonrsquos disease pathologyseverity Movement Disorders 2018331315ndash1324
31 Surmeier DJ Obeso JA Halliday GM Selective neuronal vulnerability in Parkinsondisease Nat Rev Neurosci 201718101ndash113
32 Levin BE Llabre MM Reisman S et al Visuospatial impairment in Parkinsonrsquosdisease Neurology 199141365ndash369
33 Regan D Neima D Low-contrast letter charts in early diabetic retinopathy ocularhypertension glaucoma and Parkinsonrsquos disease Br J Ophthalmol 198468885ndash889
34 McKendrick AM Chan YM Nguyen BN Spatial vision in older adults perceptualchanges and neural bases Ophthalmic and Physiol Opt201838(4)363ndash375
35 Laidlaw D Abbott A Rosser DA Development of a clinically feasible logMAR al-ternative to the Snellen chart performance of the ldquocompact reduced logMARrdquo visualacuity chart in amblyopic children Br J Ophthalmol 2003871232ndash1234
NeurologyorgCP Neurology Clinical Practice | Volume Number | 11
DOI 101212CPJ0000000000000719 published online September 18 2019Neurol Clin Pract
Louise-Ann Leyland Fion D Bremner Ribeya Mahmood et al Visual tests predict dementia risk in Parkinson disease
This information is current as of September 18 2019
ServicesUpdated Information amp
19fullhtmlhttpcpneurologyorgcontentearly20190918CPJ00000000000007including high resolution figures can be found at
Citations
19fullhtmlotherarticleshttpcpneurologyorgcontentearly20190918CPJ00000000000007This article has been cited by 2 HighWire-hosted articles
tiahttpcpneurologyorgcgicollectionparkinsons_disease_with_demenParkinsons disease with dementiafollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpcpneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpcpneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
reserved Print ISSN 2163-0402 Online ISSN 2163-0933Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightssince 2011 it is now a bimonthly with 6 issues per year Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published continuouslyNeurol Clin Pract
Figure 1 Tests of visual function and relationship with risk of Parkinson disease (PD) dementia
(A) LogMAR visual acuity chart Adapted by permission from BMJ Publishing Group Limited35 (B) Relationship between the risk of PD dementia and visualacuity (C) Pelli-Robson chart for assessing contrast sensitivity (D) Relationship between the risk of PD dementia and contrast sensitivity (E) Cats-and-Dogstest of higher-order visuoperception The task is to identify whether the animal shown is a cat or a dog with differing amounts of skew applied to the image todetermine the level of skew tolerated (F) Relationship between the risk of PD dementia and higher-order visuoperception tested by skew tolerance (G)Biological motion Dots are shown at the position of themajor joints of the body The dotsmove to give the strong percept of a person walking Extra dots areadded and the number of dots tolerated where the participant can still detect a person moving is calculated (H) Relationship between the risk of PDdementia and higher-order visuoperception tested with biological motion Poorer performance in each of these measures is linked with a higher risk of PDdementia
NeurologyorgCP Neurology Clinical Practice | Volume Number | 3
procedure17 Stimuli were presented for 800 ms Participantsdetermined whether the animation depicted a moving per-son or scrambled moving dots 225 repetitions total time 15minutes We used the QUEST Bayesian adaptive method tocalculate the maximum number of additional noise dotstolerated for performance to reach 82 accuracy Stimuliwere generated within MATLAB Psychophysics Toolbox 3implemented on a Dell Latitude 3340 in a darkened roomWhether this test relates to the risk of PD dementia is notknown
Retinal structure OCTRetinal imaging was performed on both eyes of each partic-ipant on the same day as other measures were obtained Innerretinal layer structure was measured using high-resolutionspectral domain optical coherence tomography (SD-OCTHeidelberg HRASpectralis manufactured in 2011) ina dimly lit room after pharmacologic mydriasis according toa standard protocol19 Two OCT devices were used at 1 site(National Hospital for Neurology and Neurosurgery) with 4operators (L-AL RM SH and MREC) with viewingmodule v 6950 All participants underwent macular scanprotocols in Infrared-OCT mode laser illumination used forexcitation was 486 nm This allows simultaneous acquisitionof a fundus image with a reflectance wavelength of 816 nmand OCT scan with TruTrack eye-tracking technology to
stabilize the retinal image The volumetric macular protocolof the Spectralis SD-OCT device (NSite application) wasused to measure macular thickness and volume (figure 2A)This uses an internal fixation source and centers on theparticipantrsquos fovea The protocol consists of 25 vertical linescans at a resolution of 1536 (scanning angle 20degtimes20degdensity 240 μm 47 scanss automatic real-time frames49) Quality control of OCT data was performed in com-pliance with international consensus OSCAR 1B OCTquality control standards (OSCAR-IB)20 and OCT datawere collected and reported according to internationalAPOSTEL guidelines21
OCT analysisAutomatic layer segmentation was applied via Heidelbergsoftware v11020 with Nsite module included to computethe thickness of the GCL IPL and RNFL Blinded assessors(SH and MREC) verified layer position and manualsegmentation was undertaken when automatic segmentationdeviated from the visible gradient change for that layer(quality checked by LL) All layers were segmented andexported and total volume and total thickness within each ofthe RNFL GCL and IPL were calculated across all 4 quad-rants and summed for a total layer thickness exported as a 1-3- 6-mm EDTRS grid Retinal data from 9 individuals wereexcluded because of ophthalmic disease or poor-quality scans
Figure 2 Relationship between the retinal volume and risk of Parkinson disease (PD) dementia
(A) Output of optical coherence tomography retinal imaging with cross section at themacula Retinal layers identified by automatic segmentation are shown(B) Relationship between the risk of PD dementia and RNFL volume (C) Relationship between the risk of PD dementia and GCL volume (D) Relationshipbetween the risk of PD dementia and IPL volume Retinal layers that contain dopaminergic cells (GCL and IPL) show greater thinning linked with PD dementiarisk This relationship is not seen in the RNFL that does not contain dopaminergic cells RNFL = retinal nerve fiber layer GCL = ganglion cell layer IPL = innerplexiform layer
4 Neurology Clinical Practice | Volume Number | NeurologyorgCP
(table e-1 linkslwwcomCPJA126) One eye from eachparticipant was selected for analysis In patients with PD thiswas the eye contralateral to the most symptomatic side asidentified during UPDRS-III For controls and patients withsymmetrical motor signs the selected eye was selected ran-domly In 8 patients and in 1 control the selected eye couldnot be used because of ophthalmic disease exclusions and theother eye was included for these participants (table e-1)
Neuropsychological evaluationCognitive assessment was in line with recent MovementDisorder Society guidelines22 with 2 assessments per cog-nitive domain General cognitive function was assessed withthe MMSE and Montreal Cognitive Assessment Memorywas assessed with the Recognition Memory Test for wordsand immediate and delayed versions of the Logical Memorytask (Wechsler Memory Scale IV) Language was assessedwith the Graded Naming Test and letter fluency Visuospa-tial abilities were tested with Benton Judgment of LineOrientation and Hooper Visual Organization Test Executivefunctions were measured with the Stroop task from theDelis-Kaplan Executive Function System and category flu-ency Attention was tested using color naming from theStroop and Digit Span
Defining dementia risk statusWe defined dementia risk using a recently described pro-spectively validated algorithm13 This combines clinical in-formation on sex age at disease onset years of educationUPDRS-III (motor examination) and MMSE to generatea risk score (e-Methods for details linkslwwcomCPJA137) In addition to the continuous scores we categorizedpatients with PD into high vs low risk of dementia usinga median split of these algorithmic scores As this algorithmincludes age at diagnosis it cannot be used to stratify con-trols We repeated our analysis with 2 other recently de-scribed algorithms one using age years of educationUPDRS-III RBDSQ depression and olfaction14 and theother using age UPDRS axial scores and animal fluency15
(e-Methods for further details)
Statistical analysesPerformance was compared between groups using 2-tailedWelch t tests or Mann-Whitney-Wilcoxon tests for non-normally distributed data We used linear regression to ex-amine the effects of visual measures and retinal structure ondementia risk in PD and controls and Spearman rank cor-relation where data were not normally distributed p lt 005Bonferroni corrected for multiple comparisons (8 compar-isons significance lt00063) was accepted as the thresholdfor statistical significance Sample sizes were based on poweranalyses performed before data collection Analyses wereperformed in R (r-projectorg) Data were inspected andoutliers (beyond mean plusmn 3 times SD) removed Participants withmissing data were omitted for that measure (table e-1 linkslwwcomCPJA126)
Standard protocol approvals registrationsand patient consentsAll participants gave written informed consent and the studywas approved by the Queen Square Research Ethics Com-mittee (15LO0476)
Data availabilityAnonymized data can be made available by request fromqualified investigators to the senior author of this publication
ResultsDemographicsOne hundred twelve people with PD and 34 unaffected con-trols took part Age and sex did not differ between PD andcontrols mean age PD 643 plusmn 8 years mean age controls 648plusmn 9 years (t(49) = 03 p = 074) Fifty-six people with PDwereassigned low risk based on a median split of the risk score13
and 56 were high risk The average disease duration was 41 plusmn25 years and did not differ between high- and low-riskpatients There was also no difference in motor sleep olfac-tion or levodopa dose between high- vs low-risk patients(table 1) (age differed between high- and low-risk groups asthis was strongly linked to age at disease onset that definedrisk and sex was included in the risk algorithm)13
Relationship between visual measures and PDdementia riskThere was no difference in visual measures between peoplewith PD and unaffected controls apart from poorer highervisual function (Cats-and-Dogs test) in people with PD thatdid not survive correction for multiple comparisons (table 2)However when patients were split into high vs low risk ofPD dementia using a median split high-risk patients showedworse performance in almost all visual measures (table 2)with similar differences seen when patients were divided intoquartiles for risk (table e-2 linkslwwcomCPJA126)
Poorer visual function across several levels of visual pro-cessing was associated with a higher risk of dementia (table3) although patients did not report deficits in visual func-tion Visual acuity measured using the logMAR and contrastsensitivity measured using the Pelli-Robson and color vi-sion were all associated with a higher risk of dementia
Poorer visual function across several
levels of visual processing was
associated with a higher risk of
dementia although patients did not
report deficits in visual function
NeurologyorgCP Neurology Clinical Practice | Volume Number | 5
(ρ = 029 p = 00024 ρ = minus037 p lt 00001 ρ = 026 p =00054) (table 3 and figure 1AndashD) Higher-order visuo-perception measured using biological motion showed im-paired performance in higher-risk patients (ρ = minus0026 p =00054) with trend to significance for visual skew (ρ = minus025p = 00073) (table 3 and figure 1EndashF)
Relationship between structural retinalmeasures and PD dementia riskPatients at a higher risk of dementia showed more retinalthinning in dopamine-containing layers GCL (ρ = minus029 p =00021) and IPL (ρ = minus033 p = 000044) These differenceswere not seen in the RNFL that does not contain dopami-nergic cells (ρ = 0012 p = 090 (table 3 and figure 2)
Generalizability across other estimates of riskTo ensure that our findings were generalizable across dif-ferent measures of risk we repeated our analysis using 2alternative Parkinson dementia risk algorithms one adaptedfor clinical values14 and found qualitatively the same rela-tionships (table 4)
Relationship between vision anddementia riskin unaffected controlsTo test whether these findings were related to the risk of PDdementia rather than nonspecific effects of aging we exam-ined these relationships in unaffected controlsWe found thatunlike in PD in controls visual measures were not related todementia risk scores or age (table 4)
DiscussionIn this large PD cohort visual measures across multiplestages of visual processing and structural retinal changes areassociated with a higher risk of more rapid development ofPD dementia
Isolated visual measures such as pentagon copying andcolor vision have previously been linked with cognitivechanges in PD13 and involvement of visual processingbrain regions is associated with more rapid PD de-mentia23 Here we show that vision along the entire
Abbreviations GNT = Graded Naming Test HC = healthy control LEDD = levodopa equivalent daily dose MoCA = Montreal Cognitive Assessment PD =Parkinson disease RBDSQ = REM Sleep Behavior Disorder Screening Questionnaire UPRDS = Unified Parkinsonrsquos Disease Rating ScaleHigh and low risk refer to risk of developing PD dementia as calculated using a median split for established algorithms13a Indicates significance after Bonferroni correction (p lt 00063)
6 Neurology Clinical Practice | Volume Number | NeurologyorgCP
visual processing axis is linked with the risk of cognitivechange in PD This spans from higher-order processesinvolving posterior brain regions to contrast sensitivityand visual acuity mediated by ophthalmic structures orprimary visual cortex and dopamine-containing layers ofthe retina
Our finding that retinal thinning is linked with a higher riskof more rapid PD dementia is consistent with a growingliterature showing retinal involvement in PD Dopamine isa key modulatory neurotransmitter in the retina24 Reduceddopamine innervation is seen around the fovea in PD25 andlower retinal dopaminergic concentrations are found atpostmortem in untreated PD26 OCT initially suggestedRNFL thinning in PD9 but this was not replicated by
others27 potentially due to methodological differences in-cluding sample characteristics lack of appropriate statisti-cal correction and segmentation protocols
As OCT technology has improved it has become clearerthat retinal thinning in PD is restricted to the dopamine-containing layers the GCL and IPL rather than theRNFL12 Nuclei of dopaminergic amacrine interneurons lieadjacent to the IPL24 with axons running horizontallyacross the IPL and GCL28 and postmortem studies showthat retinal alpha-synuclein accumulates at the interfacewith the IPL in PD11 Our finding of a link between retinalthinning and dementia risk in these specific layers has im-portant mechanistic implications for progression of PDdementia
Table 2 Visual scores in controls and PD and in low vs high risk for dementia in PD
Visual measure Controls N = 34 PD N = 112 t (or W) p Value
Abbreviations GCL = ganglion cell layer IPL = inner plexiform layer PD = Parkinson disease RNFL = retinal nerve fiber layera Mann-Whitney-Wilcoxon test used for non-normal datab Indicates significance after Bonferroni correction (p lt 00063)c Trend to significance after Bonferroni correction
NeurologyorgCP Neurology Clinical Practice | Volume Number | 7
In the wider population RNFL thinning is linked withhigher rates of cognitive decline7 and another study foundthat GC-IPL thinning (but not RNFL) is linked withprevalent dementia8 Our finding of a link between retinalthinning and risk of dementia may not be wholly specific toParkinson dementia and may also apply to other types ofdementia Ultimately this will need to be tested in pro-spectively followed cohorts developing different forms ofdementia In PD dementia RNFL thinning has previouslybeen shown to correlate with MMSE scores29 but this re-lationship with cognition has not yet been shown in PDwithout dementia but at risk of dementia Recent post-mortem findings of retinal phosphorylated alpha-synucleinstrengthen the link between the retina and brain disease inPD as the amount of phosphorylated alpha-synuclein in theretina correlates with the density of Lewy-type alpha-synuclein in the brain30 This anatomic finding supports theuse of retinal structural measures as a window into brainpathology
The reason for selective vulnerability of dopamine-containing GC and IP layers is not known but may relate
to common properties of dopamine-containing cellsThese show autonomous spiking behavior with low in-trinsic Ca2+ buffering31 This may lead to free-radical ac-cumulation and increased vulnerability toneurodegeneration Whether retinal layers are affectedbefore cortical regions in PD dementia can be examined inlongitudinal evaluation
We did not find impairment of visual dysfunction in theoverall PD group compared with controls apart from skewtolerance (Cats-and-Dogs test) differences were only seenbetween the high- and low-risk individuals Previous studieshave reported visual dysfunction in PD compared withcontrols23233 It is therefore possible that previous studiesreporting visual deficits in PD overall included higher pro-portions of high-risk individuals or patients with cognitiveinvolvement
LimitationsAlthough our study examines risk based on cross-sectionaldata the algorithms we use are validated using prospectivefollow-up Ultimately however whether measures identifiedhere truly predict the development of dementia in PD willneed to be tested in longitudinal analyses
A further question is whether retinal and visual measuresare affected by the same factors that promote Parkinsondementia such as age The relationship between older ageand poorer vision is well established34 and higher age atonset and age in itself is strongly linked with developmentof dementia in PD1415 Whether some factor such as in-creased amyloid deposition in cortical and retinal struc-tures is responsible for both effects or whether there areseparate processes affecting vision more selectively is notyet known Age (or age at onset) is incorporated into allalgorithmic risk scores For this reason we were unable tocorrect for age in our regression analyses However lack ofassociation between visual measures and dementia risk inunaffected controls suggests that this relationship betweenvision and dementia is more specific to the risk of PDdementia and is not purely a result of deteriorating func-tion with age (although we note that the control group issmaller than the group with PD) We will require longi-tudinal assessment of visual and cognitive factors inpatients with PD to determine and validate whether visualmeasures such as those presented here show additionalsensitivity to recently defined algorithms that use moregeneral clinical inputs
Our finding of a link between acuity and PD dementiarisk raises the question of whether higher-order visualchanges are a result of lower acuity or arise independentlydue to cortical changes in at-risk individuals This will needto be tested by examining cortical differences in thesegroups and their timing relative to retinal and acuitydeficits
Table 3 Relationship between visual measures and PDdementia risk
8 Neurology Clinical Practice | Volume Number | NeurologyorgCP
We show that visual measures and retinal thinning are linkedwith a higher risk of more rapid PD dementia This providesuseful insights into the development of PD dementia im-plicating visual brain regions as being involved at early stagesAs Parkinson dementia is becoming better understoodnoninvasive visual measures such as those used in this studymay have potential to be used alone or in combination withother clinical factors as possible biomarkers for PD dementia
and to stratify high-risk patients for disease-modifying trialsThis could enable better-powered trials and ultimately maypave the way toward new treatments for PD dementia
Study fundingRS W is supported by a Wellcome Clinical Research CareerDevelopment Fellowship (201567Z16Z) This work wasfunded by grants from UCLH Biomedical Research Centre
Table 4 Relationship between vision scores and 2 other risk algorithms
NeurologyorgCP Neurology Clinical Practice | Volume Number | 9
Grant (BRC302NSRW101410) andby grants fromNationalInstitute for Health Research (NIHR) and Fight for Sight UK
DisclosureL-A Leyland F D Bremner R Mahmood S HewittM Durteste MRE Cartlidge M M-M Lai LE Miller andA P Saygin report no disclosures P A Keane reports per-sonal fees from Topcon Heidelberg Engineering Deep-Mind Optos Novartis Bayer Allergan and Santen A ESchrag reports personal fees from Medtronic and AstraZe-neca R S Weil has received personal fees from GE Fulldisclosure form information provided by the authors isavailable with the full text of this article at Neurologyorgcp
Publication historyReceived by Neurology Clinical Practice April 9 2019 Accepted in finalform June 7 2019
References1 Anang JB Gagnon JF Bertrand JA et al Predictors of dementia in Parkinson disease
a prospective cohort study Neurology 2014831253ndash12602 Weil RS Pappa K Schade RN et al The Cats-and-Dogs test a tool to identify
visuoperceptual deficits in Parkinsonrsquos disease Mov Disord 2017321789ndash17903 Williams-Gray CH Mason SL Evans JR et al The CamPaIGN study of Parkinsonrsquos
disease 10-year outlook in an incident population-based cohort J Neurol NeurosurgPsychiatry 2013841258ndash1264
4 Bodis-Wollner I Miri S Glazman S Venturing into the no-manrsquos land of the retina inParkinsonrsquos disease Mov Disord 20142915ndash22
5 Cheung CY Ong YT Hilal S et al Retinal ganglion cell analysis using high-definitionoptical coherence tomography in patients with mild cognitive impairment and Alz-heimerrsquos disease J Alzheimers Dis 20154545ndash56
6 Cheung CY Chan VT Mok VC Chen C Wong TY Potential retinal biomarkers fordementia what is new Curr Opin Neurol 20193282ndash91
7 Ko F Muthy ZA Gallacher J et al Association of retinal nerve fiber layer thinningwith current and future cognitive decline a study using optical coherence tomogra-phy JAMA Neurology 2018751198ndash1205
8 Mutlu U Colijn JM Ikram MA et al Association of retinal neurodegeneration onoptical coherence tomography with dementia a population-based study JAMANeurol 2018751256ndash1263
9 Inzelberg R Ramirez JA Nisipeanu P Ophir A Retinal nerve fiber layer thinning inParkinson disease Vision Res 2004442793ndash2797
10 Balasubramanian R Gan L Development of retinal amacrine cells and their dendriticstratification Current Ophthalmol Rep 20142100ndash106
11 Beach TG Carew J Serrano G et al Phosphorylated α-synuclein-immunoreactiveretinal neuronal elements in Parkinsonrsquos disease subjects Neurosci Lett 201457134ndash38
12 Zivkovic M Dayanir V Stamenovic J et al Retinal ganglion cellinner plexiform layerthickness in patients with Parkinsonrsquos disease Folia Neuropathol 201755168ndash173
13 Liu G Locascio JJ Corvol JC et al Prediction of cognition in Parkinsonrsquos disease witha clinical-genetic score a longitudinal analysis of nine cohorts Lancet Neurol 201716620ndash629
14 Schrag A Siddiqui UF Anastasiou Z Weintraub D Schott JM Clinical variables andbiomarkers in prediction of cognitive impairment in patients with newly diagnosedParkinsonrsquos disease a cohort study Lancet Neurol 20171666ndash75
15 Velseboer DC de Bie RM Wieske L et al Development and external validation ofa prognostic model in newly diagnosed Parkinson disease Neurology 201686986ndash993
16 Weil RS Schwarzkopf DS Bahrami B et al Assessing cognitive dysfunction in Par-kinsonrsquos disease an online tool to detect visuo-perceptual deficits Mov Disord 201833544ndash553
17 Saygin AP Superior temporal and premotor brain areas necessary for biologicalmotion perception Brain 20071302452ndash2461
18 Jaywant A Shiffrar M Roy S Cronin-Golomb A Impaired perception of biologicalmotion in Parkinsonrsquos disease Neuropsychology 201630720ndash730
19 Cetin EN Bir LS Sarac G Yaldızkaya F Yaylalı V Optic disc and retinal nerve fibrelayer changes in Parkinsonrsquos disease Neuroophthalmology 20133720ndash23
20 Tewarie P Balk L Costello F et al TheOSCAR-IB consensus criteria for retinal OCTquality assessment PloS one 20127e34823
21 Cruz-Herranz A Balk LJ Oberwahrenbrock T et al The APOSTEL recom-mendations for reporting quantitative optical coherence tomography studies Neu-rology 2016862303ndash2309
22 Litvan I Goldman JG Troster AI et al Diagnostic criteria for mild cognitive im-pairment in Parkinsonrsquos disease movement disorder society task force guidelinesMov Disord 201227349ndash356
23 Toledo JB Gopal P Raible K et al Pathological α-synuclein distribution in subjects withcoincident Alzheimerrsquos and Lewy body pathology Acta Neuropathol 2016131393ndash409
Appendix Authors
Name Location Role Contribution
Louise-AnnLeyland PhD
University CollegeLondon London
Author Designed andconceptualized thestudy collected dataanalyzed data anddrafted themanuscriptfor intellectual content
Fion DBremner PhD
National Hospital forNeurology ampNeurosurgery London
Author Collected andinterpreted data andreviewed themanuscript forintellectual content
RibeyaMahmoodMSc
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
Sam HewittMSc
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
MarionDurteste MSc
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
Molly RECartlidge
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
Michelle M-MLai FRCOphth
National Hospital forNeurology ampNeurosurgery London
Author Collected andinterpreted data andreviewed themanuscript forintellectual content
Luke E MillerPhD
Lyon NeuroscienceResearch CenterFrance
Author Designed aspects ofthe study interpretedthe data and reviewedthe manuscript forintellectual content
Ayse P SayginPhD
University of CaliforniaSan Diego
Author Designed aspects ofthe study interpretedthe data and reviewedthe manuscript forintellectual content
Appendix (continued)
Name Location Role Contribution
Pearse AKeane PhD
University CollegeLondon London
Author Designed aspects ofthe study interpretedthe data and reviewedthe manuscript forintellectual content
Anette ESchrag PhD
University CollegeLondon London
Author Interpreted the dataand reviewed themanuscript forintellectual content
Rimona SWeilPhD
University CollegeLondon London
Author Designed andconceptualized thestudy analyzed thedata interpreted thedata and draftedrevised and edited themanuscript forintellectual content
10 Neurology Clinical Practice | Volume Number | NeurologyorgCP
24 Frederick JM Rayborn ME Laties AM Lam DM Hollyfield JG Dopaminergicneurons in the human retina J Comp Neurol 198221065ndash79
25 Nguyen-Legros J Functional neuroarchitecture of the retina hypothesis on thedysfunction of retinal dopaminergic circuitry in Parkinsonrsquos disease Surg Radiol Anat198810137ndash144
26 Harnois C Di Paolo T Decreased dopamine in the retinas of patients with Parkin-sonrsquos disease Invest Ophthalmol Vis Sci 1990312473ndash2475
27 Tsironi EE Dastiridou A Katsanos A et al Perimetric and retinal nerve fiber layerfindings in patients with Parkinsonrsquos disease BMC Ophthalmol 20121254
28 Archibald NK Clarke MP Mosimann UP Burn DJ Retinal thickness in Parkinsonrsquosdisease Parkinsonism Relat Disord 201117431ndash436
29 Moreno-Ramos T Benito-Leon J Villarejo A Bermejo-Pareja F Retinal nerve fiberlayer thinning in dementia associated with Parkinsonrsquos disease dementia with Lewybodies and Alzheimerrsquos disease J Alzheimerrsquos Dis 201334659ndash664
30 Ortuntildeo-Lizaran I Beach TG Serrano GE Walker DG Adler CH Cuenca N Phos-phorylated α‐synuclein in the retina is a biomarker of Parkinsonrsquos disease pathologyseverity Movement Disorders 2018331315ndash1324
31 Surmeier DJ Obeso JA Halliday GM Selective neuronal vulnerability in Parkinsondisease Nat Rev Neurosci 201718101ndash113
32 Levin BE Llabre MM Reisman S et al Visuospatial impairment in Parkinsonrsquosdisease Neurology 199141365ndash369
33 Regan D Neima D Low-contrast letter charts in early diabetic retinopathy ocularhypertension glaucoma and Parkinsonrsquos disease Br J Ophthalmol 198468885ndash889
34 McKendrick AM Chan YM Nguyen BN Spatial vision in older adults perceptualchanges and neural bases Ophthalmic and Physiol Opt201838(4)363ndash375
35 Laidlaw D Abbott A Rosser DA Development of a clinically feasible logMAR al-ternative to the Snellen chart performance of the ldquocompact reduced logMARrdquo visualacuity chart in amblyopic children Br J Ophthalmol 2003871232ndash1234
NeurologyorgCP Neurology Clinical Practice | Volume Number | 11
DOI 101212CPJ0000000000000719 published online September 18 2019Neurol Clin Pract
Louise-Ann Leyland Fion D Bremner Ribeya Mahmood et al Visual tests predict dementia risk in Parkinson disease
This information is current as of September 18 2019
ServicesUpdated Information amp
19fullhtmlhttpcpneurologyorgcontentearly20190918CPJ00000000000007including high resolution figures can be found at
Citations
19fullhtmlotherarticleshttpcpneurologyorgcontentearly20190918CPJ00000000000007This article has been cited by 2 HighWire-hosted articles
tiahttpcpneurologyorgcgicollectionparkinsons_disease_with_demenParkinsons disease with dementiafollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpcpneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpcpneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
reserved Print ISSN 2163-0402 Online ISSN 2163-0933Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightssince 2011 it is now a bimonthly with 6 issues per year Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published continuouslyNeurol Clin Pract
procedure17 Stimuli were presented for 800 ms Participantsdetermined whether the animation depicted a moving per-son or scrambled moving dots 225 repetitions total time 15minutes We used the QUEST Bayesian adaptive method tocalculate the maximum number of additional noise dotstolerated for performance to reach 82 accuracy Stimuliwere generated within MATLAB Psychophysics Toolbox 3implemented on a Dell Latitude 3340 in a darkened roomWhether this test relates to the risk of PD dementia is notknown
Retinal structure OCTRetinal imaging was performed on both eyes of each partic-ipant on the same day as other measures were obtained Innerretinal layer structure was measured using high-resolutionspectral domain optical coherence tomography (SD-OCTHeidelberg HRASpectralis manufactured in 2011) ina dimly lit room after pharmacologic mydriasis according toa standard protocol19 Two OCT devices were used at 1 site(National Hospital for Neurology and Neurosurgery) with 4operators (L-AL RM SH and MREC) with viewingmodule v 6950 All participants underwent macular scanprotocols in Infrared-OCT mode laser illumination used forexcitation was 486 nm This allows simultaneous acquisitionof a fundus image with a reflectance wavelength of 816 nmand OCT scan with TruTrack eye-tracking technology to
stabilize the retinal image The volumetric macular protocolof the Spectralis SD-OCT device (NSite application) wasused to measure macular thickness and volume (figure 2A)This uses an internal fixation source and centers on theparticipantrsquos fovea The protocol consists of 25 vertical linescans at a resolution of 1536 (scanning angle 20degtimes20degdensity 240 μm 47 scanss automatic real-time frames49) Quality control of OCT data was performed in com-pliance with international consensus OSCAR 1B OCTquality control standards (OSCAR-IB)20 and OCT datawere collected and reported according to internationalAPOSTEL guidelines21
OCT analysisAutomatic layer segmentation was applied via Heidelbergsoftware v11020 with Nsite module included to computethe thickness of the GCL IPL and RNFL Blinded assessors(SH and MREC) verified layer position and manualsegmentation was undertaken when automatic segmentationdeviated from the visible gradient change for that layer(quality checked by LL) All layers were segmented andexported and total volume and total thickness within each ofthe RNFL GCL and IPL were calculated across all 4 quad-rants and summed for a total layer thickness exported as a 1-3- 6-mm EDTRS grid Retinal data from 9 individuals wereexcluded because of ophthalmic disease or poor-quality scans
Figure 2 Relationship between the retinal volume and risk of Parkinson disease (PD) dementia
(A) Output of optical coherence tomography retinal imaging with cross section at themacula Retinal layers identified by automatic segmentation are shown(B) Relationship between the risk of PD dementia and RNFL volume (C) Relationship between the risk of PD dementia and GCL volume (D) Relationshipbetween the risk of PD dementia and IPL volume Retinal layers that contain dopaminergic cells (GCL and IPL) show greater thinning linked with PD dementiarisk This relationship is not seen in the RNFL that does not contain dopaminergic cells RNFL = retinal nerve fiber layer GCL = ganglion cell layer IPL = innerplexiform layer
4 Neurology Clinical Practice | Volume Number | NeurologyorgCP
(table e-1 linkslwwcomCPJA126) One eye from eachparticipant was selected for analysis In patients with PD thiswas the eye contralateral to the most symptomatic side asidentified during UPDRS-III For controls and patients withsymmetrical motor signs the selected eye was selected ran-domly In 8 patients and in 1 control the selected eye couldnot be used because of ophthalmic disease exclusions and theother eye was included for these participants (table e-1)
Neuropsychological evaluationCognitive assessment was in line with recent MovementDisorder Society guidelines22 with 2 assessments per cog-nitive domain General cognitive function was assessed withthe MMSE and Montreal Cognitive Assessment Memorywas assessed with the Recognition Memory Test for wordsand immediate and delayed versions of the Logical Memorytask (Wechsler Memory Scale IV) Language was assessedwith the Graded Naming Test and letter fluency Visuospa-tial abilities were tested with Benton Judgment of LineOrientation and Hooper Visual Organization Test Executivefunctions were measured with the Stroop task from theDelis-Kaplan Executive Function System and category flu-ency Attention was tested using color naming from theStroop and Digit Span
Defining dementia risk statusWe defined dementia risk using a recently described pro-spectively validated algorithm13 This combines clinical in-formation on sex age at disease onset years of educationUPDRS-III (motor examination) and MMSE to generatea risk score (e-Methods for details linkslwwcomCPJA137) In addition to the continuous scores we categorizedpatients with PD into high vs low risk of dementia usinga median split of these algorithmic scores As this algorithmincludes age at diagnosis it cannot be used to stratify con-trols We repeated our analysis with 2 other recently de-scribed algorithms one using age years of educationUPDRS-III RBDSQ depression and olfaction14 and theother using age UPDRS axial scores and animal fluency15
(e-Methods for further details)
Statistical analysesPerformance was compared between groups using 2-tailedWelch t tests or Mann-Whitney-Wilcoxon tests for non-normally distributed data We used linear regression to ex-amine the effects of visual measures and retinal structure ondementia risk in PD and controls and Spearman rank cor-relation where data were not normally distributed p lt 005Bonferroni corrected for multiple comparisons (8 compar-isons significance lt00063) was accepted as the thresholdfor statistical significance Sample sizes were based on poweranalyses performed before data collection Analyses wereperformed in R (r-projectorg) Data were inspected andoutliers (beyond mean plusmn 3 times SD) removed Participants withmissing data were omitted for that measure (table e-1 linkslwwcomCPJA126)
Standard protocol approvals registrationsand patient consentsAll participants gave written informed consent and the studywas approved by the Queen Square Research Ethics Com-mittee (15LO0476)
Data availabilityAnonymized data can be made available by request fromqualified investigators to the senior author of this publication
ResultsDemographicsOne hundred twelve people with PD and 34 unaffected con-trols took part Age and sex did not differ between PD andcontrols mean age PD 643 plusmn 8 years mean age controls 648plusmn 9 years (t(49) = 03 p = 074) Fifty-six people with PDwereassigned low risk based on a median split of the risk score13
and 56 were high risk The average disease duration was 41 plusmn25 years and did not differ between high- and low-riskpatients There was also no difference in motor sleep olfac-tion or levodopa dose between high- vs low-risk patients(table 1) (age differed between high- and low-risk groups asthis was strongly linked to age at disease onset that definedrisk and sex was included in the risk algorithm)13
Relationship between visual measures and PDdementia riskThere was no difference in visual measures between peoplewith PD and unaffected controls apart from poorer highervisual function (Cats-and-Dogs test) in people with PD thatdid not survive correction for multiple comparisons (table 2)However when patients were split into high vs low risk ofPD dementia using a median split high-risk patients showedworse performance in almost all visual measures (table 2)with similar differences seen when patients were divided intoquartiles for risk (table e-2 linkslwwcomCPJA126)
Poorer visual function across several levels of visual pro-cessing was associated with a higher risk of dementia (table3) although patients did not report deficits in visual func-tion Visual acuity measured using the logMAR and contrastsensitivity measured using the Pelli-Robson and color vi-sion were all associated with a higher risk of dementia
Poorer visual function across several
levels of visual processing was
associated with a higher risk of
dementia although patients did not
report deficits in visual function
NeurologyorgCP Neurology Clinical Practice | Volume Number | 5
(ρ = 029 p = 00024 ρ = minus037 p lt 00001 ρ = 026 p =00054) (table 3 and figure 1AndashD) Higher-order visuo-perception measured using biological motion showed im-paired performance in higher-risk patients (ρ = minus0026 p =00054) with trend to significance for visual skew (ρ = minus025p = 00073) (table 3 and figure 1EndashF)
Relationship between structural retinalmeasures and PD dementia riskPatients at a higher risk of dementia showed more retinalthinning in dopamine-containing layers GCL (ρ = minus029 p =00021) and IPL (ρ = minus033 p = 000044) These differenceswere not seen in the RNFL that does not contain dopami-nergic cells (ρ = 0012 p = 090 (table 3 and figure 2)
Generalizability across other estimates of riskTo ensure that our findings were generalizable across dif-ferent measures of risk we repeated our analysis using 2alternative Parkinson dementia risk algorithms one adaptedfor clinical values14 and found qualitatively the same rela-tionships (table 4)
Relationship between vision anddementia riskin unaffected controlsTo test whether these findings were related to the risk of PDdementia rather than nonspecific effects of aging we exam-ined these relationships in unaffected controlsWe found thatunlike in PD in controls visual measures were not related todementia risk scores or age (table 4)
DiscussionIn this large PD cohort visual measures across multiplestages of visual processing and structural retinal changes areassociated with a higher risk of more rapid development ofPD dementia
Isolated visual measures such as pentagon copying andcolor vision have previously been linked with cognitivechanges in PD13 and involvement of visual processingbrain regions is associated with more rapid PD de-mentia23 Here we show that vision along the entire
Abbreviations GNT = Graded Naming Test HC = healthy control LEDD = levodopa equivalent daily dose MoCA = Montreal Cognitive Assessment PD =Parkinson disease RBDSQ = REM Sleep Behavior Disorder Screening Questionnaire UPRDS = Unified Parkinsonrsquos Disease Rating ScaleHigh and low risk refer to risk of developing PD dementia as calculated using a median split for established algorithms13a Indicates significance after Bonferroni correction (p lt 00063)
6 Neurology Clinical Practice | Volume Number | NeurologyorgCP
visual processing axis is linked with the risk of cognitivechange in PD This spans from higher-order processesinvolving posterior brain regions to contrast sensitivityand visual acuity mediated by ophthalmic structures orprimary visual cortex and dopamine-containing layers ofthe retina
Our finding that retinal thinning is linked with a higher riskof more rapid PD dementia is consistent with a growingliterature showing retinal involvement in PD Dopamine isa key modulatory neurotransmitter in the retina24 Reduceddopamine innervation is seen around the fovea in PD25 andlower retinal dopaminergic concentrations are found atpostmortem in untreated PD26 OCT initially suggestedRNFL thinning in PD9 but this was not replicated by
others27 potentially due to methodological differences in-cluding sample characteristics lack of appropriate statisti-cal correction and segmentation protocols
As OCT technology has improved it has become clearerthat retinal thinning in PD is restricted to the dopamine-containing layers the GCL and IPL rather than theRNFL12 Nuclei of dopaminergic amacrine interneurons lieadjacent to the IPL24 with axons running horizontallyacross the IPL and GCL28 and postmortem studies showthat retinal alpha-synuclein accumulates at the interfacewith the IPL in PD11 Our finding of a link between retinalthinning and dementia risk in these specific layers has im-portant mechanistic implications for progression of PDdementia
Table 2 Visual scores in controls and PD and in low vs high risk for dementia in PD
Visual measure Controls N = 34 PD N = 112 t (or W) p Value
Abbreviations GCL = ganglion cell layer IPL = inner plexiform layer PD = Parkinson disease RNFL = retinal nerve fiber layera Mann-Whitney-Wilcoxon test used for non-normal datab Indicates significance after Bonferroni correction (p lt 00063)c Trend to significance after Bonferroni correction
NeurologyorgCP Neurology Clinical Practice | Volume Number | 7
In the wider population RNFL thinning is linked withhigher rates of cognitive decline7 and another study foundthat GC-IPL thinning (but not RNFL) is linked withprevalent dementia8 Our finding of a link between retinalthinning and risk of dementia may not be wholly specific toParkinson dementia and may also apply to other types ofdementia Ultimately this will need to be tested in pro-spectively followed cohorts developing different forms ofdementia In PD dementia RNFL thinning has previouslybeen shown to correlate with MMSE scores29 but this re-lationship with cognition has not yet been shown in PDwithout dementia but at risk of dementia Recent post-mortem findings of retinal phosphorylated alpha-synucleinstrengthen the link between the retina and brain disease inPD as the amount of phosphorylated alpha-synuclein in theretina correlates with the density of Lewy-type alpha-synuclein in the brain30 This anatomic finding supports theuse of retinal structural measures as a window into brainpathology
The reason for selective vulnerability of dopamine-containing GC and IP layers is not known but may relate
to common properties of dopamine-containing cellsThese show autonomous spiking behavior with low in-trinsic Ca2+ buffering31 This may lead to free-radical ac-cumulation and increased vulnerability toneurodegeneration Whether retinal layers are affectedbefore cortical regions in PD dementia can be examined inlongitudinal evaluation
We did not find impairment of visual dysfunction in theoverall PD group compared with controls apart from skewtolerance (Cats-and-Dogs test) differences were only seenbetween the high- and low-risk individuals Previous studieshave reported visual dysfunction in PD compared withcontrols23233 It is therefore possible that previous studiesreporting visual deficits in PD overall included higher pro-portions of high-risk individuals or patients with cognitiveinvolvement
LimitationsAlthough our study examines risk based on cross-sectionaldata the algorithms we use are validated using prospectivefollow-up Ultimately however whether measures identifiedhere truly predict the development of dementia in PD willneed to be tested in longitudinal analyses
A further question is whether retinal and visual measuresare affected by the same factors that promote Parkinsondementia such as age The relationship between older ageand poorer vision is well established34 and higher age atonset and age in itself is strongly linked with developmentof dementia in PD1415 Whether some factor such as in-creased amyloid deposition in cortical and retinal struc-tures is responsible for both effects or whether there areseparate processes affecting vision more selectively is notyet known Age (or age at onset) is incorporated into allalgorithmic risk scores For this reason we were unable tocorrect for age in our regression analyses However lack ofassociation between visual measures and dementia risk inunaffected controls suggests that this relationship betweenvision and dementia is more specific to the risk of PDdementia and is not purely a result of deteriorating func-tion with age (although we note that the control group issmaller than the group with PD) We will require longi-tudinal assessment of visual and cognitive factors inpatients with PD to determine and validate whether visualmeasures such as those presented here show additionalsensitivity to recently defined algorithms that use moregeneral clinical inputs
Our finding of a link between acuity and PD dementiarisk raises the question of whether higher-order visualchanges are a result of lower acuity or arise independentlydue to cortical changes in at-risk individuals This will needto be tested by examining cortical differences in thesegroups and their timing relative to retinal and acuitydeficits
Table 3 Relationship between visual measures and PDdementia risk
8 Neurology Clinical Practice | Volume Number | NeurologyorgCP
We show that visual measures and retinal thinning are linkedwith a higher risk of more rapid PD dementia This providesuseful insights into the development of PD dementia im-plicating visual brain regions as being involved at early stagesAs Parkinson dementia is becoming better understoodnoninvasive visual measures such as those used in this studymay have potential to be used alone or in combination withother clinical factors as possible biomarkers for PD dementia
and to stratify high-risk patients for disease-modifying trialsThis could enable better-powered trials and ultimately maypave the way toward new treatments for PD dementia
Study fundingRS W is supported by a Wellcome Clinical Research CareerDevelopment Fellowship (201567Z16Z) This work wasfunded by grants from UCLH Biomedical Research Centre
Table 4 Relationship between vision scores and 2 other risk algorithms
NeurologyorgCP Neurology Clinical Practice | Volume Number | 9
Grant (BRC302NSRW101410) andby grants fromNationalInstitute for Health Research (NIHR) and Fight for Sight UK
DisclosureL-A Leyland F D Bremner R Mahmood S HewittM Durteste MRE Cartlidge M M-M Lai LE Miller andA P Saygin report no disclosures P A Keane reports per-sonal fees from Topcon Heidelberg Engineering Deep-Mind Optos Novartis Bayer Allergan and Santen A ESchrag reports personal fees from Medtronic and AstraZe-neca R S Weil has received personal fees from GE Fulldisclosure form information provided by the authors isavailable with the full text of this article at Neurologyorgcp
Publication historyReceived by Neurology Clinical Practice April 9 2019 Accepted in finalform June 7 2019
References1 Anang JB Gagnon JF Bertrand JA et al Predictors of dementia in Parkinson disease
a prospective cohort study Neurology 2014831253ndash12602 Weil RS Pappa K Schade RN et al The Cats-and-Dogs test a tool to identify
visuoperceptual deficits in Parkinsonrsquos disease Mov Disord 2017321789ndash17903 Williams-Gray CH Mason SL Evans JR et al The CamPaIGN study of Parkinsonrsquos
disease 10-year outlook in an incident population-based cohort J Neurol NeurosurgPsychiatry 2013841258ndash1264
4 Bodis-Wollner I Miri S Glazman S Venturing into the no-manrsquos land of the retina inParkinsonrsquos disease Mov Disord 20142915ndash22
5 Cheung CY Ong YT Hilal S et al Retinal ganglion cell analysis using high-definitionoptical coherence tomography in patients with mild cognitive impairment and Alz-heimerrsquos disease J Alzheimers Dis 20154545ndash56
6 Cheung CY Chan VT Mok VC Chen C Wong TY Potential retinal biomarkers fordementia what is new Curr Opin Neurol 20193282ndash91
7 Ko F Muthy ZA Gallacher J et al Association of retinal nerve fiber layer thinningwith current and future cognitive decline a study using optical coherence tomogra-phy JAMA Neurology 2018751198ndash1205
8 Mutlu U Colijn JM Ikram MA et al Association of retinal neurodegeneration onoptical coherence tomography with dementia a population-based study JAMANeurol 2018751256ndash1263
9 Inzelberg R Ramirez JA Nisipeanu P Ophir A Retinal nerve fiber layer thinning inParkinson disease Vision Res 2004442793ndash2797
10 Balasubramanian R Gan L Development of retinal amacrine cells and their dendriticstratification Current Ophthalmol Rep 20142100ndash106
11 Beach TG Carew J Serrano G et al Phosphorylated α-synuclein-immunoreactiveretinal neuronal elements in Parkinsonrsquos disease subjects Neurosci Lett 201457134ndash38
12 Zivkovic M Dayanir V Stamenovic J et al Retinal ganglion cellinner plexiform layerthickness in patients with Parkinsonrsquos disease Folia Neuropathol 201755168ndash173
13 Liu G Locascio JJ Corvol JC et al Prediction of cognition in Parkinsonrsquos disease witha clinical-genetic score a longitudinal analysis of nine cohorts Lancet Neurol 201716620ndash629
14 Schrag A Siddiqui UF Anastasiou Z Weintraub D Schott JM Clinical variables andbiomarkers in prediction of cognitive impairment in patients with newly diagnosedParkinsonrsquos disease a cohort study Lancet Neurol 20171666ndash75
15 Velseboer DC de Bie RM Wieske L et al Development and external validation ofa prognostic model in newly diagnosed Parkinson disease Neurology 201686986ndash993
16 Weil RS Schwarzkopf DS Bahrami B et al Assessing cognitive dysfunction in Par-kinsonrsquos disease an online tool to detect visuo-perceptual deficits Mov Disord 201833544ndash553
17 Saygin AP Superior temporal and premotor brain areas necessary for biologicalmotion perception Brain 20071302452ndash2461
18 Jaywant A Shiffrar M Roy S Cronin-Golomb A Impaired perception of biologicalmotion in Parkinsonrsquos disease Neuropsychology 201630720ndash730
19 Cetin EN Bir LS Sarac G Yaldızkaya F Yaylalı V Optic disc and retinal nerve fibrelayer changes in Parkinsonrsquos disease Neuroophthalmology 20133720ndash23
20 Tewarie P Balk L Costello F et al TheOSCAR-IB consensus criteria for retinal OCTquality assessment PloS one 20127e34823
21 Cruz-Herranz A Balk LJ Oberwahrenbrock T et al The APOSTEL recom-mendations for reporting quantitative optical coherence tomography studies Neu-rology 2016862303ndash2309
22 Litvan I Goldman JG Troster AI et al Diagnostic criteria for mild cognitive im-pairment in Parkinsonrsquos disease movement disorder society task force guidelinesMov Disord 201227349ndash356
23 Toledo JB Gopal P Raible K et al Pathological α-synuclein distribution in subjects withcoincident Alzheimerrsquos and Lewy body pathology Acta Neuropathol 2016131393ndash409
Appendix Authors
Name Location Role Contribution
Louise-AnnLeyland PhD
University CollegeLondon London
Author Designed andconceptualized thestudy collected dataanalyzed data anddrafted themanuscriptfor intellectual content
Fion DBremner PhD
National Hospital forNeurology ampNeurosurgery London
Author Collected andinterpreted data andreviewed themanuscript forintellectual content
RibeyaMahmoodMSc
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
Sam HewittMSc
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
MarionDurteste MSc
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
Molly RECartlidge
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
Michelle M-MLai FRCOphth
National Hospital forNeurology ampNeurosurgery London
Author Collected andinterpreted data andreviewed themanuscript forintellectual content
Luke E MillerPhD
Lyon NeuroscienceResearch CenterFrance
Author Designed aspects ofthe study interpretedthe data and reviewedthe manuscript forintellectual content
Ayse P SayginPhD
University of CaliforniaSan Diego
Author Designed aspects ofthe study interpretedthe data and reviewedthe manuscript forintellectual content
Appendix (continued)
Name Location Role Contribution
Pearse AKeane PhD
University CollegeLondon London
Author Designed aspects ofthe study interpretedthe data and reviewedthe manuscript forintellectual content
Anette ESchrag PhD
University CollegeLondon London
Author Interpreted the dataand reviewed themanuscript forintellectual content
Rimona SWeilPhD
University CollegeLondon London
Author Designed andconceptualized thestudy analyzed thedata interpreted thedata and draftedrevised and edited themanuscript forintellectual content
10 Neurology Clinical Practice | Volume Number | NeurologyorgCP
24 Frederick JM Rayborn ME Laties AM Lam DM Hollyfield JG Dopaminergicneurons in the human retina J Comp Neurol 198221065ndash79
25 Nguyen-Legros J Functional neuroarchitecture of the retina hypothesis on thedysfunction of retinal dopaminergic circuitry in Parkinsonrsquos disease Surg Radiol Anat198810137ndash144
26 Harnois C Di Paolo T Decreased dopamine in the retinas of patients with Parkin-sonrsquos disease Invest Ophthalmol Vis Sci 1990312473ndash2475
27 Tsironi EE Dastiridou A Katsanos A et al Perimetric and retinal nerve fiber layerfindings in patients with Parkinsonrsquos disease BMC Ophthalmol 20121254
28 Archibald NK Clarke MP Mosimann UP Burn DJ Retinal thickness in Parkinsonrsquosdisease Parkinsonism Relat Disord 201117431ndash436
29 Moreno-Ramos T Benito-Leon J Villarejo A Bermejo-Pareja F Retinal nerve fiberlayer thinning in dementia associated with Parkinsonrsquos disease dementia with Lewybodies and Alzheimerrsquos disease J Alzheimerrsquos Dis 201334659ndash664
30 Ortuntildeo-Lizaran I Beach TG Serrano GE Walker DG Adler CH Cuenca N Phos-phorylated α‐synuclein in the retina is a biomarker of Parkinsonrsquos disease pathologyseverity Movement Disorders 2018331315ndash1324
31 Surmeier DJ Obeso JA Halliday GM Selective neuronal vulnerability in Parkinsondisease Nat Rev Neurosci 201718101ndash113
32 Levin BE Llabre MM Reisman S et al Visuospatial impairment in Parkinsonrsquosdisease Neurology 199141365ndash369
33 Regan D Neima D Low-contrast letter charts in early diabetic retinopathy ocularhypertension glaucoma and Parkinsonrsquos disease Br J Ophthalmol 198468885ndash889
34 McKendrick AM Chan YM Nguyen BN Spatial vision in older adults perceptualchanges and neural bases Ophthalmic and Physiol Opt201838(4)363ndash375
35 Laidlaw D Abbott A Rosser DA Development of a clinically feasible logMAR al-ternative to the Snellen chart performance of the ldquocompact reduced logMARrdquo visualacuity chart in amblyopic children Br J Ophthalmol 2003871232ndash1234
NeurologyorgCP Neurology Clinical Practice | Volume Number | 11
DOI 101212CPJ0000000000000719 published online September 18 2019Neurol Clin Pract
Louise-Ann Leyland Fion D Bremner Ribeya Mahmood et al Visual tests predict dementia risk in Parkinson disease
This information is current as of September 18 2019
ServicesUpdated Information amp
19fullhtmlhttpcpneurologyorgcontentearly20190918CPJ00000000000007including high resolution figures can be found at
Citations
19fullhtmlotherarticleshttpcpneurologyorgcontentearly20190918CPJ00000000000007This article has been cited by 2 HighWire-hosted articles
tiahttpcpneurologyorgcgicollectionparkinsons_disease_with_demenParkinsons disease with dementiafollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpcpneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpcpneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
reserved Print ISSN 2163-0402 Online ISSN 2163-0933Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightssince 2011 it is now a bimonthly with 6 issues per year Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published continuouslyNeurol Clin Pract
(table e-1 linkslwwcomCPJA126) One eye from eachparticipant was selected for analysis In patients with PD thiswas the eye contralateral to the most symptomatic side asidentified during UPDRS-III For controls and patients withsymmetrical motor signs the selected eye was selected ran-domly In 8 patients and in 1 control the selected eye couldnot be used because of ophthalmic disease exclusions and theother eye was included for these participants (table e-1)
Neuropsychological evaluationCognitive assessment was in line with recent MovementDisorder Society guidelines22 with 2 assessments per cog-nitive domain General cognitive function was assessed withthe MMSE and Montreal Cognitive Assessment Memorywas assessed with the Recognition Memory Test for wordsand immediate and delayed versions of the Logical Memorytask (Wechsler Memory Scale IV) Language was assessedwith the Graded Naming Test and letter fluency Visuospa-tial abilities were tested with Benton Judgment of LineOrientation and Hooper Visual Organization Test Executivefunctions were measured with the Stroop task from theDelis-Kaplan Executive Function System and category flu-ency Attention was tested using color naming from theStroop and Digit Span
Defining dementia risk statusWe defined dementia risk using a recently described pro-spectively validated algorithm13 This combines clinical in-formation on sex age at disease onset years of educationUPDRS-III (motor examination) and MMSE to generatea risk score (e-Methods for details linkslwwcomCPJA137) In addition to the continuous scores we categorizedpatients with PD into high vs low risk of dementia usinga median split of these algorithmic scores As this algorithmincludes age at diagnosis it cannot be used to stratify con-trols We repeated our analysis with 2 other recently de-scribed algorithms one using age years of educationUPDRS-III RBDSQ depression and olfaction14 and theother using age UPDRS axial scores and animal fluency15
(e-Methods for further details)
Statistical analysesPerformance was compared between groups using 2-tailedWelch t tests or Mann-Whitney-Wilcoxon tests for non-normally distributed data We used linear regression to ex-amine the effects of visual measures and retinal structure ondementia risk in PD and controls and Spearman rank cor-relation where data were not normally distributed p lt 005Bonferroni corrected for multiple comparisons (8 compar-isons significance lt00063) was accepted as the thresholdfor statistical significance Sample sizes were based on poweranalyses performed before data collection Analyses wereperformed in R (r-projectorg) Data were inspected andoutliers (beyond mean plusmn 3 times SD) removed Participants withmissing data were omitted for that measure (table e-1 linkslwwcomCPJA126)
Standard protocol approvals registrationsand patient consentsAll participants gave written informed consent and the studywas approved by the Queen Square Research Ethics Com-mittee (15LO0476)
Data availabilityAnonymized data can be made available by request fromqualified investigators to the senior author of this publication
ResultsDemographicsOne hundred twelve people with PD and 34 unaffected con-trols took part Age and sex did not differ between PD andcontrols mean age PD 643 plusmn 8 years mean age controls 648plusmn 9 years (t(49) = 03 p = 074) Fifty-six people with PDwereassigned low risk based on a median split of the risk score13
and 56 were high risk The average disease duration was 41 plusmn25 years and did not differ between high- and low-riskpatients There was also no difference in motor sleep olfac-tion or levodopa dose between high- vs low-risk patients(table 1) (age differed between high- and low-risk groups asthis was strongly linked to age at disease onset that definedrisk and sex was included in the risk algorithm)13
Relationship between visual measures and PDdementia riskThere was no difference in visual measures between peoplewith PD and unaffected controls apart from poorer highervisual function (Cats-and-Dogs test) in people with PD thatdid not survive correction for multiple comparisons (table 2)However when patients were split into high vs low risk ofPD dementia using a median split high-risk patients showedworse performance in almost all visual measures (table 2)with similar differences seen when patients were divided intoquartiles for risk (table e-2 linkslwwcomCPJA126)
Poorer visual function across several levels of visual pro-cessing was associated with a higher risk of dementia (table3) although patients did not report deficits in visual func-tion Visual acuity measured using the logMAR and contrastsensitivity measured using the Pelli-Robson and color vi-sion were all associated with a higher risk of dementia
Poorer visual function across several
levels of visual processing was
associated with a higher risk of
dementia although patients did not
report deficits in visual function
NeurologyorgCP Neurology Clinical Practice | Volume Number | 5
(ρ = 029 p = 00024 ρ = minus037 p lt 00001 ρ = 026 p =00054) (table 3 and figure 1AndashD) Higher-order visuo-perception measured using biological motion showed im-paired performance in higher-risk patients (ρ = minus0026 p =00054) with trend to significance for visual skew (ρ = minus025p = 00073) (table 3 and figure 1EndashF)
Relationship between structural retinalmeasures and PD dementia riskPatients at a higher risk of dementia showed more retinalthinning in dopamine-containing layers GCL (ρ = minus029 p =00021) and IPL (ρ = minus033 p = 000044) These differenceswere not seen in the RNFL that does not contain dopami-nergic cells (ρ = 0012 p = 090 (table 3 and figure 2)
Generalizability across other estimates of riskTo ensure that our findings were generalizable across dif-ferent measures of risk we repeated our analysis using 2alternative Parkinson dementia risk algorithms one adaptedfor clinical values14 and found qualitatively the same rela-tionships (table 4)
Relationship between vision anddementia riskin unaffected controlsTo test whether these findings were related to the risk of PDdementia rather than nonspecific effects of aging we exam-ined these relationships in unaffected controlsWe found thatunlike in PD in controls visual measures were not related todementia risk scores or age (table 4)
DiscussionIn this large PD cohort visual measures across multiplestages of visual processing and structural retinal changes areassociated with a higher risk of more rapid development ofPD dementia
Isolated visual measures such as pentagon copying andcolor vision have previously been linked with cognitivechanges in PD13 and involvement of visual processingbrain regions is associated with more rapid PD de-mentia23 Here we show that vision along the entire
Abbreviations GNT = Graded Naming Test HC = healthy control LEDD = levodopa equivalent daily dose MoCA = Montreal Cognitive Assessment PD =Parkinson disease RBDSQ = REM Sleep Behavior Disorder Screening Questionnaire UPRDS = Unified Parkinsonrsquos Disease Rating ScaleHigh and low risk refer to risk of developing PD dementia as calculated using a median split for established algorithms13a Indicates significance after Bonferroni correction (p lt 00063)
6 Neurology Clinical Practice | Volume Number | NeurologyorgCP
visual processing axis is linked with the risk of cognitivechange in PD This spans from higher-order processesinvolving posterior brain regions to contrast sensitivityand visual acuity mediated by ophthalmic structures orprimary visual cortex and dopamine-containing layers ofthe retina
Our finding that retinal thinning is linked with a higher riskof more rapid PD dementia is consistent with a growingliterature showing retinal involvement in PD Dopamine isa key modulatory neurotransmitter in the retina24 Reduceddopamine innervation is seen around the fovea in PD25 andlower retinal dopaminergic concentrations are found atpostmortem in untreated PD26 OCT initially suggestedRNFL thinning in PD9 but this was not replicated by
others27 potentially due to methodological differences in-cluding sample characteristics lack of appropriate statisti-cal correction and segmentation protocols
As OCT technology has improved it has become clearerthat retinal thinning in PD is restricted to the dopamine-containing layers the GCL and IPL rather than theRNFL12 Nuclei of dopaminergic amacrine interneurons lieadjacent to the IPL24 with axons running horizontallyacross the IPL and GCL28 and postmortem studies showthat retinal alpha-synuclein accumulates at the interfacewith the IPL in PD11 Our finding of a link between retinalthinning and dementia risk in these specific layers has im-portant mechanistic implications for progression of PDdementia
Table 2 Visual scores in controls and PD and in low vs high risk for dementia in PD
Visual measure Controls N = 34 PD N = 112 t (or W) p Value
Abbreviations GCL = ganglion cell layer IPL = inner plexiform layer PD = Parkinson disease RNFL = retinal nerve fiber layera Mann-Whitney-Wilcoxon test used for non-normal datab Indicates significance after Bonferroni correction (p lt 00063)c Trend to significance after Bonferroni correction
NeurologyorgCP Neurology Clinical Practice | Volume Number | 7
In the wider population RNFL thinning is linked withhigher rates of cognitive decline7 and another study foundthat GC-IPL thinning (but not RNFL) is linked withprevalent dementia8 Our finding of a link between retinalthinning and risk of dementia may not be wholly specific toParkinson dementia and may also apply to other types ofdementia Ultimately this will need to be tested in pro-spectively followed cohorts developing different forms ofdementia In PD dementia RNFL thinning has previouslybeen shown to correlate with MMSE scores29 but this re-lationship with cognition has not yet been shown in PDwithout dementia but at risk of dementia Recent post-mortem findings of retinal phosphorylated alpha-synucleinstrengthen the link between the retina and brain disease inPD as the amount of phosphorylated alpha-synuclein in theretina correlates with the density of Lewy-type alpha-synuclein in the brain30 This anatomic finding supports theuse of retinal structural measures as a window into brainpathology
The reason for selective vulnerability of dopamine-containing GC and IP layers is not known but may relate
to common properties of dopamine-containing cellsThese show autonomous spiking behavior with low in-trinsic Ca2+ buffering31 This may lead to free-radical ac-cumulation and increased vulnerability toneurodegeneration Whether retinal layers are affectedbefore cortical regions in PD dementia can be examined inlongitudinal evaluation
We did not find impairment of visual dysfunction in theoverall PD group compared with controls apart from skewtolerance (Cats-and-Dogs test) differences were only seenbetween the high- and low-risk individuals Previous studieshave reported visual dysfunction in PD compared withcontrols23233 It is therefore possible that previous studiesreporting visual deficits in PD overall included higher pro-portions of high-risk individuals or patients with cognitiveinvolvement
LimitationsAlthough our study examines risk based on cross-sectionaldata the algorithms we use are validated using prospectivefollow-up Ultimately however whether measures identifiedhere truly predict the development of dementia in PD willneed to be tested in longitudinal analyses
A further question is whether retinal and visual measuresare affected by the same factors that promote Parkinsondementia such as age The relationship between older ageand poorer vision is well established34 and higher age atonset and age in itself is strongly linked with developmentof dementia in PD1415 Whether some factor such as in-creased amyloid deposition in cortical and retinal struc-tures is responsible for both effects or whether there areseparate processes affecting vision more selectively is notyet known Age (or age at onset) is incorporated into allalgorithmic risk scores For this reason we were unable tocorrect for age in our regression analyses However lack ofassociation between visual measures and dementia risk inunaffected controls suggests that this relationship betweenvision and dementia is more specific to the risk of PDdementia and is not purely a result of deteriorating func-tion with age (although we note that the control group issmaller than the group with PD) We will require longi-tudinal assessment of visual and cognitive factors inpatients with PD to determine and validate whether visualmeasures such as those presented here show additionalsensitivity to recently defined algorithms that use moregeneral clinical inputs
Our finding of a link between acuity and PD dementiarisk raises the question of whether higher-order visualchanges are a result of lower acuity or arise independentlydue to cortical changes in at-risk individuals This will needto be tested by examining cortical differences in thesegroups and their timing relative to retinal and acuitydeficits
Table 3 Relationship between visual measures and PDdementia risk
8 Neurology Clinical Practice | Volume Number | NeurologyorgCP
We show that visual measures and retinal thinning are linkedwith a higher risk of more rapid PD dementia This providesuseful insights into the development of PD dementia im-plicating visual brain regions as being involved at early stagesAs Parkinson dementia is becoming better understoodnoninvasive visual measures such as those used in this studymay have potential to be used alone or in combination withother clinical factors as possible biomarkers for PD dementia
and to stratify high-risk patients for disease-modifying trialsThis could enable better-powered trials and ultimately maypave the way toward new treatments for PD dementia
Study fundingRS W is supported by a Wellcome Clinical Research CareerDevelopment Fellowship (201567Z16Z) This work wasfunded by grants from UCLH Biomedical Research Centre
Table 4 Relationship between vision scores and 2 other risk algorithms
NeurologyorgCP Neurology Clinical Practice | Volume Number | 9
Grant (BRC302NSRW101410) andby grants fromNationalInstitute for Health Research (NIHR) and Fight for Sight UK
DisclosureL-A Leyland F D Bremner R Mahmood S HewittM Durteste MRE Cartlidge M M-M Lai LE Miller andA P Saygin report no disclosures P A Keane reports per-sonal fees from Topcon Heidelberg Engineering Deep-Mind Optos Novartis Bayer Allergan and Santen A ESchrag reports personal fees from Medtronic and AstraZe-neca R S Weil has received personal fees from GE Fulldisclosure form information provided by the authors isavailable with the full text of this article at Neurologyorgcp
Publication historyReceived by Neurology Clinical Practice April 9 2019 Accepted in finalform June 7 2019
References1 Anang JB Gagnon JF Bertrand JA et al Predictors of dementia in Parkinson disease
a prospective cohort study Neurology 2014831253ndash12602 Weil RS Pappa K Schade RN et al The Cats-and-Dogs test a tool to identify
visuoperceptual deficits in Parkinsonrsquos disease Mov Disord 2017321789ndash17903 Williams-Gray CH Mason SL Evans JR et al The CamPaIGN study of Parkinsonrsquos
disease 10-year outlook in an incident population-based cohort J Neurol NeurosurgPsychiatry 2013841258ndash1264
4 Bodis-Wollner I Miri S Glazman S Venturing into the no-manrsquos land of the retina inParkinsonrsquos disease Mov Disord 20142915ndash22
5 Cheung CY Ong YT Hilal S et al Retinal ganglion cell analysis using high-definitionoptical coherence tomography in patients with mild cognitive impairment and Alz-heimerrsquos disease J Alzheimers Dis 20154545ndash56
6 Cheung CY Chan VT Mok VC Chen C Wong TY Potential retinal biomarkers fordementia what is new Curr Opin Neurol 20193282ndash91
7 Ko F Muthy ZA Gallacher J et al Association of retinal nerve fiber layer thinningwith current and future cognitive decline a study using optical coherence tomogra-phy JAMA Neurology 2018751198ndash1205
8 Mutlu U Colijn JM Ikram MA et al Association of retinal neurodegeneration onoptical coherence tomography with dementia a population-based study JAMANeurol 2018751256ndash1263
9 Inzelberg R Ramirez JA Nisipeanu P Ophir A Retinal nerve fiber layer thinning inParkinson disease Vision Res 2004442793ndash2797
10 Balasubramanian R Gan L Development of retinal amacrine cells and their dendriticstratification Current Ophthalmol Rep 20142100ndash106
11 Beach TG Carew J Serrano G et al Phosphorylated α-synuclein-immunoreactiveretinal neuronal elements in Parkinsonrsquos disease subjects Neurosci Lett 201457134ndash38
12 Zivkovic M Dayanir V Stamenovic J et al Retinal ganglion cellinner plexiform layerthickness in patients with Parkinsonrsquos disease Folia Neuropathol 201755168ndash173
13 Liu G Locascio JJ Corvol JC et al Prediction of cognition in Parkinsonrsquos disease witha clinical-genetic score a longitudinal analysis of nine cohorts Lancet Neurol 201716620ndash629
14 Schrag A Siddiqui UF Anastasiou Z Weintraub D Schott JM Clinical variables andbiomarkers in prediction of cognitive impairment in patients with newly diagnosedParkinsonrsquos disease a cohort study Lancet Neurol 20171666ndash75
15 Velseboer DC de Bie RM Wieske L et al Development and external validation ofa prognostic model in newly diagnosed Parkinson disease Neurology 201686986ndash993
16 Weil RS Schwarzkopf DS Bahrami B et al Assessing cognitive dysfunction in Par-kinsonrsquos disease an online tool to detect visuo-perceptual deficits Mov Disord 201833544ndash553
17 Saygin AP Superior temporal and premotor brain areas necessary for biologicalmotion perception Brain 20071302452ndash2461
18 Jaywant A Shiffrar M Roy S Cronin-Golomb A Impaired perception of biologicalmotion in Parkinsonrsquos disease Neuropsychology 201630720ndash730
19 Cetin EN Bir LS Sarac G Yaldızkaya F Yaylalı V Optic disc and retinal nerve fibrelayer changes in Parkinsonrsquos disease Neuroophthalmology 20133720ndash23
20 Tewarie P Balk L Costello F et al TheOSCAR-IB consensus criteria for retinal OCTquality assessment PloS one 20127e34823
21 Cruz-Herranz A Balk LJ Oberwahrenbrock T et al The APOSTEL recom-mendations for reporting quantitative optical coherence tomography studies Neu-rology 2016862303ndash2309
22 Litvan I Goldman JG Troster AI et al Diagnostic criteria for mild cognitive im-pairment in Parkinsonrsquos disease movement disorder society task force guidelinesMov Disord 201227349ndash356
23 Toledo JB Gopal P Raible K et al Pathological α-synuclein distribution in subjects withcoincident Alzheimerrsquos and Lewy body pathology Acta Neuropathol 2016131393ndash409
Appendix Authors
Name Location Role Contribution
Louise-AnnLeyland PhD
University CollegeLondon London
Author Designed andconceptualized thestudy collected dataanalyzed data anddrafted themanuscriptfor intellectual content
Fion DBremner PhD
National Hospital forNeurology ampNeurosurgery London
Author Collected andinterpreted data andreviewed themanuscript forintellectual content
RibeyaMahmoodMSc
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
Sam HewittMSc
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
MarionDurteste MSc
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
Molly RECartlidge
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
Michelle M-MLai FRCOphth
National Hospital forNeurology ampNeurosurgery London
Author Collected andinterpreted data andreviewed themanuscript forintellectual content
Luke E MillerPhD
Lyon NeuroscienceResearch CenterFrance
Author Designed aspects ofthe study interpretedthe data and reviewedthe manuscript forintellectual content
Ayse P SayginPhD
University of CaliforniaSan Diego
Author Designed aspects ofthe study interpretedthe data and reviewedthe manuscript forintellectual content
Appendix (continued)
Name Location Role Contribution
Pearse AKeane PhD
University CollegeLondon London
Author Designed aspects ofthe study interpretedthe data and reviewedthe manuscript forintellectual content
Anette ESchrag PhD
University CollegeLondon London
Author Interpreted the dataand reviewed themanuscript forintellectual content
Rimona SWeilPhD
University CollegeLondon London
Author Designed andconceptualized thestudy analyzed thedata interpreted thedata and draftedrevised and edited themanuscript forintellectual content
10 Neurology Clinical Practice | Volume Number | NeurologyorgCP
24 Frederick JM Rayborn ME Laties AM Lam DM Hollyfield JG Dopaminergicneurons in the human retina J Comp Neurol 198221065ndash79
25 Nguyen-Legros J Functional neuroarchitecture of the retina hypothesis on thedysfunction of retinal dopaminergic circuitry in Parkinsonrsquos disease Surg Radiol Anat198810137ndash144
26 Harnois C Di Paolo T Decreased dopamine in the retinas of patients with Parkin-sonrsquos disease Invest Ophthalmol Vis Sci 1990312473ndash2475
27 Tsironi EE Dastiridou A Katsanos A et al Perimetric and retinal nerve fiber layerfindings in patients with Parkinsonrsquos disease BMC Ophthalmol 20121254
28 Archibald NK Clarke MP Mosimann UP Burn DJ Retinal thickness in Parkinsonrsquosdisease Parkinsonism Relat Disord 201117431ndash436
29 Moreno-Ramos T Benito-Leon J Villarejo A Bermejo-Pareja F Retinal nerve fiberlayer thinning in dementia associated with Parkinsonrsquos disease dementia with Lewybodies and Alzheimerrsquos disease J Alzheimerrsquos Dis 201334659ndash664
30 Ortuntildeo-Lizaran I Beach TG Serrano GE Walker DG Adler CH Cuenca N Phos-phorylated α‐synuclein in the retina is a biomarker of Parkinsonrsquos disease pathologyseverity Movement Disorders 2018331315ndash1324
31 Surmeier DJ Obeso JA Halliday GM Selective neuronal vulnerability in Parkinsondisease Nat Rev Neurosci 201718101ndash113
32 Levin BE Llabre MM Reisman S et al Visuospatial impairment in Parkinsonrsquosdisease Neurology 199141365ndash369
33 Regan D Neima D Low-contrast letter charts in early diabetic retinopathy ocularhypertension glaucoma and Parkinsonrsquos disease Br J Ophthalmol 198468885ndash889
34 McKendrick AM Chan YM Nguyen BN Spatial vision in older adults perceptualchanges and neural bases Ophthalmic and Physiol Opt201838(4)363ndash375
35 Laidlaw D Abbott A Rosser DA Development of a clinically feasible logMAR al-ternative to the Snellen chart performance of the ldquocompact reduced logMARrdquo visualacuity chart in amblyopic children Br J Ophthalmol 2003871232ndash1234
NeurologyorgCP Neurology Clinical Practice | Volume Number | 11
DOI 101212CPJ0000000000000719 published online September 18 2019Neurol Clin Pract
Louise-Ann Leyland Fion D Bremner Ribeya Mahmood et al Visual tests predict dementia risk in Parkinson disease
This information is current as of September 18 2019
ServicesUpdated Information amp
19fullhtmlhttpcpneurologyorgcontentearly20190918CPJ00000000000007including high resolution figures can be found at
Citations
19fullhtmlotherarticleshttpcpneurologyorgcontentearly20190918CPJ00000000000007This article has been cited by 2 HighWire-hosted articles
tiahttpcpneurologyorgcgicollectionparkinsons_disease_with_demenParkinsons disease with dementiafollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpcpneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpcpneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
reserved Print ISSN 2163-0402 Online ISSN 2163-0933Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightssince 2011 it is now a bimonthly with 6 issues per year Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published continuouslyNeurol Clin Pract
(ρ = 029 p = 00024 ρ = minus037 p lt 00001 ρ = 026 p =00054) (table 3 and figure 1AndashD) Higher-order visuo-perception measured using biological motion showed im-paired performance in higher-risk patients (ρ = minus0026 p =00054) with trend to significance for visual skew (ρ = minus025p = 00073) (table 3 and figure 1EndashF)
Relationship between structural retinalmeasures and PD dementia riskPatients at a higher risk of dementia showed more retinalthinning in dopamine-containing layers GCL (ρ = minus029 p =00021) and IPL (ρ = minus033 p = 000044) These differenceswere not seen in the RNFL that does not contain dopami-nergic cells (ρ = 0012 p = 090 (table 3 and figure 2)
Generalizability across other estimates of riskTo ensure that our findings were generalizable across dif-ferent measures of risk we repeated our analysis using 2alternative Parkinson dementia risk algorithms one adaptedfor clinical values14 and found qualitatively the same rela-tionships (table 4)
Relationship between vision anddementia riskin unaffected controlsTo test whether these findings were related to the risk of PDdementia rather than nonspecific effects of aging we exam-ined these relationships in unaffected controlsWe found thatunlike in PD in controls visual measures were not related todementia risk scores or age (table 4)
DiscussionIn this large PD cohort visual measures across multiplestages of visual processing and structural retinal changes areassociated with a higher risk of more rapid development ofPD dementia
Isolated visual measures such as pentagon copying andcolor vision have previously been linked with cognitivechanges in PD13 and involvement of visual processingbrain regions is associated with more rapid PD de-mentia23 Here we show that vision along the entire
Abbreviations GNT = Graded Naming Test HC = healthy control LEDD = levodopa equivalent daily dose MoCA = Montreal Cognitive Assessment PD =Parkinson disease RBDSQ = REM Sleep Behavior Disorder Screening Questionnaire UPRDS = Unified Parkinsonrsquos Disease Rating ScaleHigh and low risk refer to risk of developing PD dementia as calculated using a median split for established algorithms13a Indicates significance after Bonferroni correction (p lt 00063)
6 Neurology Clinical Practice | Volume Number | NeurologyorgCP
visual processing axis is linked with the risk of cognitivechange in PD This spans from higher-order processesinvolving posterior brain regions to contrast sensitivityand visual acuity mediated by ophthalmic structures orprimary visual cortex and dopamine-containing layers ofthe retina
Our finding that retinal thinning is linked with a higher riskof more rapid PD dementia is consistent with a growingliterature showing retinal involvement in PD Dopamine isa key modulatory neurotransmitter in the retina24 Reduceddopamine innervation is seen around the fovea in PD25 andlower retinal dopaminergic concentrations are found atpostmortem in untreated PD26 OCT initially suggestedRNFL thinning in PD9 but this was not replicated by
others27 potentially due to methodological differences in-cluding sample characteristics lack of appropriate statisti-cal correction and segmentation protocols
As OCT technology has improved it has become clearerthat retinal thinning in PD is restricted to the dopamine-containing layers the GCL and IPL rather than theRNFL12 Nuclei of dopaminergic amacrine interneurons lieadjacent to the IPL24 with axons running horizontallyacross the IPL and GCL28 and postmortem studies showthat retinal alpha-synuclein accumulates at the interfacewith the IPL in PD11 Our finding of a link between retinalthinning and dementia risk in these specific layers has im-portant mechanistic implications for progression of PDdementia
Table 2 Visual scores in controls and PD and in low vs high risk for dementia in PD
Visual measure Controls N = 34 PD N = 112 t (or W) p Value
Abbreviations GCL = ganglion cell layer IPL = inner plexiform layer PD = Parkinson disease RNFL = retinal nerve fiber layera Mann-Whitney-Wilcoxon test used for non-normal datab Indicates significance after Bonferroni correction (p lt 00063)c Trend to significance after Bonferroni correction
NeurologyorgCP Neurology Clinical Practice | Volume Number | 7
In the wider population RNFL thinning is linked withhigher rates of cognitive decline7 and another study foundthat GC-IPL thinning (but not RNFL) is linked withprevalent dementia8 Our finding of a link between retinalthinning and risk of dementia may not be wholly specific toParkinson dementia and may also apply to other types ofdementia Ultimately this will need to be tested in pro-spectively followed cohorts developing different forms ofdementia In PD dementia RNFL thinning has previouslybeen shown to correlate with MMSE scores29 but this re-lationship with cognition has not yet been shown in PDwithout dementia but at risk of dementia Recent post-mortem findings of retinal phosphorylated alpha-synucleinstrengthen the link between the retina and brain disease inPD as the amount of phosphorylated alpha-synuclein in theretina correlates with the density of Lewy-type alpha-synuclein in the brain30 This anatomic finding supports theuse of retinal structural measures as a window into brainpathology
The reason for selective vulnerability of dopamine-containing GC and IP layers is not known but may relate
to common properties of dopamine-containing cellsThese show autonomous spiking behavior with low in-trinsic Ca2+ buffering31 This may lead to free-radical ac-cumulation and increased vulnerability toneurodegeneration Whether retinal layers are affectedbefore cortical regions in PD dementia can be examined inlongitudinal evaluation
We did not find impairment of visual dysfunction in theoverall PD group compared with controls apart from skewtolerance (Cats-and-Dogs test) differences were only seenbetween the high- and low-risk individuals Previous studieshave reported visual dysfunction in PD compared withcontrols23233 It is therefore possible that previous studiesreporting visual deficits in PD overall included higher pro-portions of high-risk individuals or patients with cognitiveinvolvement
LimitationsAlthough our study examines risk based on cross-sectionaldata the algorithms we use are validated using prospectivefollow-up Ultimately however whether measures identifiedhere truly predict the development of dementia in PD willneed to be tested in longitudinal analyses
A further question is whether retinal and visual measuresare affected by the same factors that promote Parkinsondementia such as age The relationship between older ageand poorer vision is well established34 and higher age atonset and age in itself is strongly linked with developmentof dementia in PD1415 Whether some factor such as in-creased amyloid deposition in cortical and retinal struc-tures is responsible for both effects or whether there areseparate processes affecting vision more selectively is notyet known Age (or age at onset) is incorporated into allalgorithmic risk scores For this reason we were unable tocorrect for age in our regression analyses However lack ofassociation between visual measures and dementia risk inunaffected controls suggests that this relationship betweenvision and dementia is more specific to the risk of PDdementia and is not purely a result of deteriorating func-tion with age (although we note that the control group issmaller than the group with PD) We will require longi-tudinal assessment of visual and cognitive factors inpatients with PD to determine and validate whether visualmeasures such as those presented here show additionalsensitivity to recently defined algorithms that use moregeneral clinical inputs
Our finding of a link between acuity and PD dementiarisk raises the question of whether higher-order visualchanges are a result of lower acuity or arise independentlydue to cortical changes in at-risk individuals This will needto be tested by examining cortical differences in thesegroups and their timing relative to retinal and acuitydeficits
Table 3 Relationship between visual measures and PDdementia risk
8 Neurology Clinical Practice | Volume Number | NeurologyorgCP
We show that visual measures and retinal thinning are linkedwith a higher risk of more rapid PD dementia This providesuseful insights into the development of PD dementia im-plicating visual brain regions as being involved at early stagesAs Parkinson dementia is becoming better understoodnoninvasive visual measures such as those used in this studymay have potential to be used alone or in combination withother clinical factors as possible biomarkers for PD dementia
and to stratify high-risk patients for disease-modifying trialsThis could enable better-powered trials and ultimately maypave the way toward new treatments for PD dementia
Study fundingRS W is supported by a Wellcome Clinical Research CareerDevelopment Fellowship (201567Z16Z) This work wasfunded by grants from UCLH Biomedical Research Centre
Table 4 Relationship between vision scores and 2 other risk algorithms
NeurologyorgCP Neurology Clinical Practice | Volume Number | 9
Grant (BRC302NSRW101410) andby grants fromNationalInstitute for Health Research (NIHR) and Fight for Sight UK
DisclosureL-A Leyland F D Bremner R Mahmood S HewittM Durteste MRE Cartlidge M M-M Lai LE Miller andA P Saygin report no disclosures P A Keane reports per-sonal fees from Topcon Heidelberg Engineering Deep-Mind Optos Novartis Bayer Allergan and Santen A ESchrag reports personal fees from Medtronic and AstraZe-neca R S Weil has received personal fees from GE Fulldisclosure form information provided by the authors isavailable with the full text of this article at Neurologyorgcp
Publication historyReceived by Neurology Clinical Practice April 9 2019 Accepted in finalform June 7 2019
References1 Anang JB Gagnon JF Bertrand JA et al Predictors of dementia in Parkinson disease
a prospective cohort study Neurology 2014831253ndash12602 Weil RS Pappa K Schade RN et al The Cats-and-Dogs test a tool to identify
visuoperceptual deficits in Parkinsonrsquos disease Mov Disord 2017321789ndash17903 Williams-Gray CH Mason SL Evans JR et al The CamPaIGN study of Parkinsonrsquos
disease 10-year outlook in an incident population-based cohort J Neurol NeurosurgPsychiatry 2013841258ndash1264
4 Bodis-Wollner I Miri S Glazman S Venturing into the no-manrsquos land of the retina inParkinsonrsquos disease Mov Disord 20142915ndash22
5 Cheung CY Ong YT Hilal S et al Retinal ganglion cell analysis using high-definitionoptical coherence tomography in patients with mild cognitive impairment and Alz-heimerrsquos disease J Alzheimers Dis 20154545ndash56
6 Cheung CY Chan VT Mok VC Chen C Wong TY Potential retinal biomarkers fordementia what is new Curr Opin Neurol 20193282ndash91
7 Ko F Muthy ZA Gallacher J et al Association of retinal nerve fiber layer thinningwith current and future cognitive decline a study using optical coherence tomogra-phy JAMA Neurology 2018751198ndash1205
8 Mutlu U Colijn JM Ikram MA et al Association of retinal neurodegeneration onoptical coherence tomography with dementia a population-based study JAMANeurol 2018751256ndash1263
9 Inzelberg R Ramirez JA Nisipeanu P Ophir A Retinal nerve fiber layer thinning inParkinson disease Vision Res 2004442793ndash2797
10 Balasubramanian R Gan L Development of retinal amacrine cells and their dendriticstratification Current Ophthalmol Rep 20142100ndash106
11 Beach TG Carew J Serrano G et al Phosphorylated α-synuclein-immunoreactiveretinal neuronal elements in Parkinsonrsquos disease subjects Neurosci Lett 201457134ndash38
12 Zivkovic M Dayanir V Stamenovic J et al Retinal ganglion cellinner plexiform layerthickness in patients with Parkinsonrsquos disease Folia Neuropathol 201755168ndash173
13 Liu G Locascio JJ Corvol JC et al Prediction of cognition in Parkinsonrsquos disease witha clinical-genetic score a longitudinal analysis of nine cohorts Lancet Neurol 201716620ndash629
14 Schrag A Siddiqui UF Anastasiou Z Weintraub D Schott JM Clinical variables andbiomarkers in prediction of cognitive impairment in patients with newly diagnosedParkinsonrsquos disease a cohort study Lancet Neurol 20171666ndash75
15 Velseboer DC de Bie RM Wieske L et al Development and external validation ofa prognostic model in newly diagnosed Parkinson disease Neurology 201686986ndash993
16 Weil RS Schwarzkopf DS Bahrami B et al Assessing cognitive dysfunction in Par-kinsonrsquos disease an online tool to detect visuo-perceptual deficits Mov Disord 201833544ndash553
17 Saygin AP Superior temporal and premotor brain areas necessary for biologicalmotion perception Brain 20071302452ndash2461
18 Jaywant A Shiffrar M Roy S Cronin-Golomb A Impaired perception of biologicalmotion in Parkinsonrsquos disease Neuropsychology 201630720ndash730
19 Cetin EN Bir LS Sarac G Yaldızkaya F Yaylalı V Optic disc and retinal nerve fibrelayer changes in Parkinsonrsquos disease Neuroophthalmology 20133720ndash23
20 Tewarie P Balk L Costello F et al TheOSCAR-IB consensus criteria for retinal OCTquality assessment PloS one 20127e34823
21 Cruz-Herranz A Balk LJ Oberwahrenbrock T et al The APOSTEL recom-mendations for reporting quantitative optical coherence tomography studies Neu-rology 2016862303ndash2309
22 Litvan I Goldman JG Troster AI et al Diagnostic criteria for mild cognitive im-pairment in Parkinsonrsquos disease movement disorder society task force guidelinesMov Disord 201227349ndash356
23 Toledo JB Gopal P Raible K et al Pathological α-synuclein distribution in subjects withcoincident Alzheimerrsquos and Lewy body pathology Acta Neuropathol 2016131393ndash409
Appendix Authors
Name Location Role Contribution
Louise-AnnLeyland PhD
University CollegeLondon London
Author Designed andconceptualized thestudy collected dataanalyzed data anddrafted themanuscriptfor intellectual content
Fion DBremner PhD
National Hospital forNeurology ampNeurosurgery London
Author Collected andinterpreted data andreviewed themanuscript forintellectual content
RibeyaMahmoodMSc
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
Sam HewittMSc
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
MarionDurteste MSc
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
Molly RECartlidge
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
Michelle M-MLai FRCOphth
National Hospital forNeurology ampNeurosurgery London
Author Collected andinterpreted data andreviewed themanuscript forintellectual content
Luke E MillerPhD
Lyon NeuroscienceResearch CenterFrance
Author Designed aspects ofthe study interpretedthe data and reviewedthe manuscript forintellectual content
Ayse P SayginPhD
University of CaliforniaSan Diego
Author Designed aspects ofthe study interpretedthe data and reviewedthe manuscript forintellectual content
Appendix (continued)
Name Location Role Contribution
Pearse AKeane PhD
University CollegeLondon London
Author Designed aspects ofthe study interpretedthe data and reviewedthe manuscript forintellectual content
Anette ESchrag PhD
University CollegeLondon London
Author Interpreted the dataand reviewed themanuscript forintellectual content
Rimona SWeilPhD
University CollegeLondon London
Author Designed andconceptualized thestudy analyzed thedata interpreted thedata and draftedrevised and edited themanuscript forintellectual content
10 Neurology Clinical Practice | Volume Number | NeurologyorgCP
24 Frederick JM Rayborn ME Laties AM Lam DM Hollyfield JG Dopaminergicneurons in the human retina J Comp Neurol 198221065ndash79
25 Nguyen-Legros J Functional neuroarchitecture of the retina hypothesis on thedysfunction of retinal dopaminergic circuitry in Parkinsonrsquos disease Surg Radiol Anat198810137ndash144
26 Harnois C Di Paolo T Decreased dopamine in the retinas of patients with Parkin-sonrsquos disease Invest Ophthalmol Vis Sci 1990312473ndash2475
27 Tsironi EE Dastiridou A Katsanos A et al Perimetric and retinal nerve fiber layerfindings in patients with Parkinsonrsquos disease BMC Ophthalmol 20121254
28 Archibald NK Clarke MP Mosimann UP Burn DJ Retinal thickness in Parkinsonrsquosdisease Parkinsonism Relat Disord 201117431ndash436
29 Moreno-Ramos T Benito-Leon J Villarejo A Bermejo-Pareja F Retinal nerve fiberlayer thinning in dementia associated with Parkinsonrsquos disease dementia with Lewybodies and Alzheimerrsquos disease J Alzheimerrsquos Dis 201334659ndash664
30 Ortuntildeo-Lizaran I Beach TG Serrano GE Walker DG Adler CH Cuenca N Phos-phorylated α‐synuclein in the retina is a biomarker of Parkinsonrsquos disease pathologyseverity Movement Disorders 2018331315ndash1324
31 Surmeier DJ Obeso JA Halliday GM Selective neuronal vulnerability in Parkinsondisease Nat Rev Neurosci 201718101ndash113
32 Levin BE Llabre MM Reisman S et al Visuospatial impairment in Parkinsonrsquosdisease Neurology 199141365ndash369
33 Regan D Neima D Low-contrast letter charts in early diabetic retinopathy ocularhypertension glaucoma and Parkinsonrsquos disease Br J Ophthalmol 198468885ndash889
34 McKendrick AM Chan YM Nguyen BN Spatial vision in older adults perceptualchanges and neural bases Ophthalmic and Physiol Opt201838(4)363ndash375
35 Laidlaw D Abbott A Rosser DA Development of a clinically feasible logMAR al-ternative to the Snellen chart performance of the ldquocompact reduced logMARrdquo visualacuity chart in amblyopic children Br J Ophthalmol 2003871232ndash1234
NeurologyorgCP Neurology Clinical Practice | Volume Number | 11
DOI 101212CPJ0000000000000719 published online September 18 2019Neurol Clin Pract
Louise-Ann Leyland Fion D Bremner Ribeya Mahmood et al Visual tests predict dementia risk in Parkinson disease
This information is current as of September 18 2019
ServicesUpdated Information amp
19fullhtmlhttpcpneurologyorgcontentearly20190918CPJ00000000000007including high resolution figures can be found at
Citations
19fullhtmlotherarticleshttpcpneurologyorgcontentearly20190918CPJ00000000000007This article has been cited by 2 HighWire-hosted articles
tiahttpcpneurologyorgcgicollectionparkinsons_disease_with_demenParkinsons disease with dementiafollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpcpneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpcpneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
reserved Print ISSN 2163-0402 Online ISSN 2163-0933Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightssince 2011 it is now a bimonthly with 6 issues per year Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published continuouslyNeurol Clin Pract
visual processing axis is linked with the risk of cognitivechange in PD This spans from higher-order processesinvolving posterior brain regions to contrast sensitivityand visual acuity mediated by ophthalmic structures orprimary visual cortex and dopamine-containing layers ofthe retina
Our finding that retinal thinning is linked with a higher riskof more rapid PD dementia is consistent with a growingliterature showing retinal involvement in PD Dopamine isa key modulatory neurotransmitter in the retina24 Reduceddopamine innervation is seen around the fovea in PD25 andlower retinal dopaminergic concentrations are found atpostmortem in untreated PD26 OCT initially suggestedRNFL thinning in PD9 but this was not replicated by
others27 potentially due to methodological differences in-cluding sample characteristics lack of appropriate statisti-cal correction and segmentation protocols
As OCT technology has improved it has become clearerthat retinal thinning in PD is restricted to the dopamine-containing layers the GCL and IPL rather than theRNFL12 Nuclei of dopaminergic amacrine interneurons lieadjacent to the IPL24 with axons running horizontallyacross the IPL and GCL28 and postmortem studies showthat retinal alpha-synuclein accumulates at the interfacewith the IPL in PD11 Our finding of a link between retinalthinning and dementia risk in these specific layers has im-portant mechanistic implications for progression of PDdementia
Table 2 Visual scores in controls and PD and in low vs high risk for dementia in PD
Visual measure Controls N = 34 PD N = 112 t (or W) p Value
Abbreviations GCL = ganglion cell layer IPL = inner plexiform layer PD = Parkinson disease RNFL = retinal nerve fiber layera Mann-Whitney-Wilcoxon test used for non-normal datab Indicates significance after Bonferroni correction (p lt 00063)c Trend to significance after Bonferroni correction
NeurologyorgCP Neurology Clinical Practice | Volume Number | 7
In the wider population RNFL thinning is linked withhigher rates of cognitive decline7 and another study foundthat GC-IPL thinning (but not RNFL) is linked withprevalent dementia8 Our finding of a link between retinalthinning and risk of dementia may not be wholly specific toParkinson dementia and may also apply to other types ofdementia Ultimately this will need to be tested in pro-spectively followed cohorts developing different forms ofdementia In PD dementia RNFL thinning has previouslybeen shown to correlate with MMSE scores29 but this re-lationship with cognition has not yet been shown in PDwithout dementia but at risk of dementia Recent post-mortem findings of retinal phosphorylated alpha-synucleinstrengthen the link between the retina and brain disease inPD as the amount of phosphorylated alpha-synuclein in theretina correlates with the density of Lewy-type alpha-synuclein in the brain30 This anatomic finding supports theuse of retinal structural measures as a window into brainpathology
The reason for selective vulnerability of dopamine-containing GC and IP layers is not known but may relate
to common properties of dopamine-containing cellsThese show autonomous spiking behavior with low in-trinsic Ca2+ buffering31 This may lead to free-radical ac-cumulation and increased vulnerability toneurodegeneration Whether retinal layers are affectedbefore cortical regions in PD dementia can be examined inlongitudinal evaluation
We did not find impairment of visual dysfunction in theoverall PD group compared with controls apart from skewtolerance (Cats-and-Dogs test) differences were only seenbetween the high- and low-risk individuals Previous studieshave reported visual dysfunction in PD compared withcontrols23233 It is therefore possible that previous studiesreporting visual deficits in PD overall included higher pro-portions of high-risk individuals or patients with cognitiveinvolvement
LimitationsAlthough our study examines risk based on cross-sectionaldata the algorithms we use are validated using prospectivefollow-up Ultimately however whether measures identifiedhere truly predict the development of dementia in PD willneed to be tested in longitudinal analyses
A further question is whether retinal and visual measuresare affected by the same factors that promote Parkinsondementia such as age The relationship between older ageand poorer vision is well established34 and higher age atonset and age in itself is strongly linked with developmentof dementia in PD1415 Whether some factor such as in-creased amyloid deposition in cortical and retinal struc-tures is responsible for both effects or whether there areseparate processes affecting vision more selectively is notyet known Age (or age at onset) is incorporated into allalgorithmic risk scores For this reason we were unable tocorrect for age in our regression analyses However lack ofassociation between visual measures and dementia risk inunaffected controls suggests that this relationship betweenvision and dementia is more specific to the risk of PDdementia and is not purely a result of deteriorating func-tion with age (although we note that the control group issmaller than the group with PD) We will require longi-tudinal assessment of visual and cognitive factors inpatients with PD to determine and validate whether visualmeasures such as those presented here show additionalsensitivity to recently defined algorithms that use moregeneral clinical inputs
Our finding of a link between acuity and PD dementiarisk raises the question of whether higher-order visualchanges are a result of lower acuity or arise independentlydue to cortical changes in at-risk individuals This will needto be tested by examining cortical differences in thesegroups and their timing relative to retinal and acuitydeficits
Table 3 Relationship between visual measures and PDdementia risk
8 Neurology Clinical Practice | Volume Number | NeurologyorgCP
We show that visual measures and retinal thinning are linkedwith a higher risk of more rapid PD dementia This providesuseful insights into the development of PD dementia im-plicating visual brain regions as being involved at early stagesAs Parkinson dementia is becoming better understoodnoninvasive visual measures such as those used in this studymay have potential to be used alone or in combination withother clinical factors as possible biomarkers for PD dementia
and to stratify high-risk patients for disease-modifying trialsThis could enable better-powered trials and ultimately maypave the way toward new treatments for PD dementia
Study fundingRS W is supported by a Wellcome Clinical Research CareerDevelopment Fellowship (201567Z16Z) This work wasfunded by grants from UCLH Biomedical Research Centre
Table 4 Relationship between vision scores and 2 other risk algorithms
NeurologyorgCP Neurology Clinical Practice | Volume Number | 9
Grant (BRC302NSRW101410) andby grants fromNationalInstitute for Health Research (NIHR) and Fight for Sight UK
DisclosureL-A Leyland F D Bremner R Mahmood S HewittM Durteste MRE Cartlidge M M-M Lai LE Miller andA P Saygin report no disclosures P A Keane reports per-sonal fees from Topcon Heidelberg Engineering Deep-Mind Optos Novartis Bayer Allergan and Santen A ESchrag reports personal fees from Medtronic and AstraZe-neca R S Weil has received personal fees from GE Fulldisclosure form information provided by the authors isavailable with the full text of this article at Neurologyorgcp
Publication historyReceived by Neurology Clinical Practice April 9 2019 Accepted in finalform June 7 2019
References1 Anang JB Gagnon JF Bertrand JA et al Predictors of dementia in Parkinson disease
a prospective cohort study Neurology 2014831253ndash12602 Weil RS Pappa K Schade RN et al The Cats-and-Dogs test a tool to identify
visuoperceptual deficits in Parkinsonrsquos disease Mov Disord 2017321789ndash17903 Williams-Gray CH Mason SL Evans JR et al The CamPaIGN study of Parkinsonrsquos
disease 10-year outlook in an incident population-based cohort J Neurol NeurosurgPsychiatry 2013841258ndash1264
4 Bodis-Wollner I Miri S Glazman S Venturing into the no-manrsquos land of the retina inParkinsonrsquos disease Mov Disord 20142915ndash22
5 Cheung CY Ong YT Hilal S et al Retinal ganglion cell analysis using high-definitionoptical coherence tomography in patients with mild cognitive impairment and Alz-heimerrsquos disease J Alzheimers Dis 20154545ndash56
6 Cheung CY Chan VT Mok VC Chen C Wong TY Potential retinal biomarkers fordementia what is new Curr Opin Neurol 20193282ndash91
7 Ko F Muthy ZA Gallacher J et al Association of retinal nerve fiber layer thinningwith current and future cognitive decline a study using optical coherence tomogra-phy JAMA Neurology 2018751198ndash1205
8 Mutlu U Colijn JM Ikram MA et al Association of retinal neurodegeneration onoptical coherence tomography with dementia a population-based study JAMANeurol 2018751256ndash1263
9 Inzelberg R Ramirez JA Nisipeanu P Ophir A Retinal nerve fiber layer thinning inParkinson disease Vision Res 2004442793ndash2797
10 Balasubramanian R Gan L Development of retinal amacrine cells and their dendriticstratification Current Ophthalmol Rep 20142100ndash106
11 Beach TG Carew J Serrano G et al Phosphorylated α-synuclein-immunoreactiveretinal neuronal elements in Parkinsonrsquos disease subjects Neurosci Lett 201457134ndash38
12 Zivkovic M Dayanir V Stamenovic J et al Retinal ganglion cellinner plexiform layerthickness in patients with Parkinsonrsquos disease Folia Neuropathol 201755168ndash173
13 Liu G Locascio JJ Corvol JC et al Prediction of cognition in Parkinsonrsquos disease witha clinical-genetic score a longitudinal analysis of nine cohorts Lancet Neurol 201716620ndash629
14 Schrag A Siddiqui UF Anastasiou Z Weintraub D Schott JM Clinical variables andbiomarkers in prediction of cognitive impairment in patients with newly diagnosedParkinsonrsquos disease a cohort study Lancet Neurol 20171666ndash75
15 Velseboer DC de Bie RM Wieske L et al Development and external validation ofa prognostic model in newly diagnosed Parkinson disease Neurology 201686986ndash993
16 Weil RS Schwarzkopf DS Bahrami B et al Assessing cognitive dysfunction in Par-kinsonrsquos disease an online tool to detect visuo-perceptual deficits Mov Disord 201833544ndash553
17 Saygin AP Superior temporal and premotor brain areas necessary for biologicalmotion perception Brain 20071302452ndash2461
18 Jaywant A Shiffrar M Roy S Cronin-Golomb A Impaired perception of biologicalmotion in Parkinsonrsquos disease Neuropsychology 201630720ndash730
19 Cetin EN Bir LS Sarac G Yaldızkaya F Yaylalı V Optic disc and retinal nerve fibrelayer changes in Parkinsonrsquos disease Neuroophthalmology 20133720ndash23
20 Tewarie P Balk L Costello F et al TheOSCAR-IB consensus criteria for retinal OCTquality assessment PloS one 20127e34823
21 Cruz-Herranz A Balk LJ Oberwahrenbrock T et al The APOSTEL recom-mendations for reporting quantitative optical coherence tomography studies Neu-rology 2016862303ndash2309
22 Litvan I Goldman JG Troster AI et al Diagnostic criteria for mild cognitive im-pairment in Parkinsonrsquos disease movement disorder society task force guidelinesMov Disord 201227349ndash356
23 Toledo JB Gopal P Raible K et al Pathological α-synuclein distribution in subjects withcoincident Alzheimerrsquos and Lewy body pathology Acta Neuropathol 2016131393ndash409
Appendix Authors
Name Location Role Contribution
Louise-AnnLeyland PhD
University CollegeLondon London
Author Designed andconceptualized thestudy collected dataanalyzed data anddrafted themanuscriptfor intellectual content
Fion DBremner PhD
National Hospital forNeurology ampNeurosurgery London
Author Collected andinterpreted data andreviewed themanuscript forintellectual content
RibeyaMahmoodMSc
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
Sam HewittMSc
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
MarionDurteste MSc
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
Molly RECartlidge
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
Michelle M-MLai FRCOphth
National Hospital forNeurology ampNeurosurgery London
Author Collected andinterpreted data andreviewed themanuscript forintellectual content
Luke E MillerPhD
Lyon NeuroscienceResearch CenterFrance
Author Designed aspects ofthe study interpretedthe data and reviewedthe manuscript forintellectual content
Ayse P SayginPhD
University of CaliforniaSan Diego
Author Designed aspects ofthe study interpretedthe data and reviewedthe manuscript forintellectual content
Appendix (continued)
Name Location Role Contribution
Pearse AKeane PhD
University CollegeLondon London
Author Designed aspects ofthe study interpretedthe data and reviewedthe manuscript forintellectual content
Anette ESchrag PhD
University CollegeLondon London
Author Interpreted the dataand reviewed themanuscript forintellectual content
Rimona SWeilPhD
University CollegeLondon London
Author Designed andconceptualized thestudy analyzed thedata interpreted thedata and draftedrevised and edited themanuscript forintellectual content
10 Neurology Clinical Practice | Volume Number | NeurologyorgCP
24 Frederick JM Rayborn ME Laties AM Lam DM Hollyfield JG Dopaminergicneurons in the human retina J Comp Neurol 198221065ndash79
25 Nguyen-Legros J Functional neuroarchitecture of the retina hypothesis on thedysfunction of retinal dopaminergic circuitry in Parkinsonrsquos disease Surg Radiol Anat198810137ndash144
26 Harnois C Di Paolo T Decreased dopamine in the retinas of patients with Parkin-sonrsquos disease Invest Ophthalmol Vis Sci 1990312473ndash2475
27 Tsironi EE Dastiridou A Katsanos A et al Perimetric and retinal nerve fiber layerfindings in patients with Parkinsonrsquos disease BMC Ophthalmol 20121254
28 Archibald NK Clarke MP Mosimann UP Burn DJ Retinal thickness in Parkinsonrsquosdisease Parkinsonism Relat Disord 201117431ndash436
29 Moreno-Ramos T Benito-Leon J Villarejo A Bermejo-Pareja F Retinal nerve fiberlayer thinning in dementia associated with Parkinsonrsquos disease dementia with Lewybodies and Alzheimerrsquos disease J Alzheimerrsquos Dis 201334659ndash664
30 Ortuntildeo-Lizaran I Beach TG Serrano GE Walker DG Adler CH Cuenca N Phos-phorylated α‐synuclein in the retina is a biomarker of Parkinsonrsquos disease pathologyseverity Movement Disorders 2018331315ndash1324
31 Surmeier DJ Obeso JA Halliday GM Selective neuronal vulnerability in Parkinsondisease Nat Rev Neurosci 201718101ndash113
32 Levin BE Llabre MM Reisman S et al Visuospatial impairment in Parkinsonrsquosdisease Neurology 199141365ndash369
33 Regan D Neima D Low-contrast letter charts in early diabetic retinopathy ocularhypertension glaucoma and Parkinsonrsquos disease Br J Ophthalmol 198468885ndash889
34 McKendrick AM Chan YM Nguyen BN Spatial vision in older adults perceptualchanges and neural bases Ophthalmic and Physiol Opt201838(4)363ndash375
35 Laidlaw D Abbott A Rosser DA Development of a clinically feasible logMAR al-ternative to the Snellen chart performance of the ldquocompact reduced logMARrdquo visualacuity chart in amblyopic children Br J Ophthalmol 2003871232ndash1234
NeurologyorgCP Neurology Clinical Practice | Volume Number | 11
DOI 101212CPJ0000000000000719 published online September 18 2019Neurol Clin Pract
Louise-Ann Leyland Fion D Bremner Ribeya Mahmood et al Visual tests predict dementia risk in Parkinson disease
This information is current as of September 18 2019
ServicesUpdated Information amp
19fullhtmlhttpcpneurologyorgcontentearly20190918CPJ00000000000007including high resolution figures can be found at
Citations
19fullhtmlotherarticleshttpcpneurologyorgcontentearly20190918CPJ00000000000007This article has been cited by 2 HighWire-hosted articles
tiahttpcpneurologyorgcgicollectionparkinsons_disease_with_demenParkinsons disease with dementiafollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpcpneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpcpneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
reserved Print ISSN 2163-0402 Online ISSN 2163-0933Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightssince 2011 it is now a bimonthly with 6 issues per year Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published continuouslyNeurol Clin Pract
In the wider population RNFL thinning is linked withhigher rates of cognitive decline7 and another study foundthat GC-IPL thinning (but not RNFL) is linked withprevalent dementia8 Our finding of a link between retinalthinning and risk of dementia may not be wholly specific toParkinson dementia and may also apply to other types ofdementia Ultimately this will need to be tested in pro-spectively followed cohorts developing different forms ofdementia In PD dementia RNFL thinning has previouslybeen shown to correlate with MMSE scores29 but this re-lationship with cognition has not yet been shown in PDwithout dementia but at risk of dementia Recent post-mortem findings of retinal phosphorylated alpha-synucleinstrengthen the link between the retina and brain disease inPD as the amount of phosphorylated alpha-synuclein in theretina correlates with the density of Lewy-type alpha-synuclein in the brain30 This anatomic finding supports theuse of retinal structural measures as a window into brainpathology
The reason for selective vulnerability of dopamine-containing GC and IP layers is not known but may relate
to common properties of dopamine-containing cellsThese show autonomous spiking behavior with low in-trinsic Ca2+ buffering31 This may lead to free-radical ac-cumulation and increased vulnerability toneurodegeneration Whether retinal layers are affectedbefore cortical regions in PD dementia can be examined inlongitudinal evaluation
We did not find impairment of visual dysfunction in theoverall PD group compared with controls apart from skewtolerance (Cats-and-Dogs test) differences were only seenbetween the high- and low-risk individuals Previous studieshave reported visual dysfunction in PD compared withcontrols23233 It is therefore possible that previous studiesreporting visual deficits in PD overall included higher pro-portions of high-risk individuals or patients with cognitiveinvolvement
LimitationsAlthough our study examines risk based on cross-sectionaldata the algorithms we use are validated using prospectivefollow-up Ultimately however whether measures identifiedhere truly predict the development of dementia in PD willneed to be tested in longitudinal analyses
A further question is whether retinal and visual measuresare affected by the same factors that promote Parkinsondementia such as age The relationship between older ageand poorer vision is well established34 and higher age atonset and age in itself is strongly linked with developmentof dementia in PD1415 Whether some factor such as in-creased amyloid deposition in cortical and retinal struc-tures is responsible for both effects or whether there areseparate processes affecting vision more selectively is notyet known Age (or age at onset) is incorporated into allalgorithmic risk scores For this reason we were unable tocorrect for age in our regression analyses However lack ofassociation between visual measures and dementia risk inunaffected controls suggests that this relationship betweenvision and dementia is more specific to the risk of PDdementia and is not purely a result of deteriorating func-tion with age (although we note that the control group issmaller than the group with PD) We will require longi-tudinal assessment of visual and cognitive factors inpatients with PD to determine and validate whether visualmeasures such as those presented here show additionalsensitivity to recently defined algorithms that use moregeneral clinical inputs
Our finding of a link between acuity and PD dementiarisk raises the question of whether higher-order visualchanges are a result of lower acuity or arise independentlydue to cortical changes in at-risk individuals This will needto be tested by examining cortical differences in thesegroups and their timing relative to retinal and acuitydeficits
Table 3 Relationship between visual measures and PDdementia risk
8 Neurology Clinical Practice | Volume Number | NeurologyorgCP
We show that visual measures and retinal thinning are linkedwith a higher risk of more rapid PD dementia This providesuseful insights into the development of PD dementia im-plicating visual brain regions as being involved at early stagesAs Parkinson dementia is becoming better understoodnoninvasive visual measures such as those used in this studymay have potential to be used alone or in combination withother clinical factors as possible biomarkers for PD dementia
and to stratify high-risk patients for disease-modifying trialsThis could enable better-powered trials and ultimately maypave the way toward new treatments for PD dementia
Study fundingRS W is supported by a Wellcome Clinical Research CareerDevelopment Fellowship (201567Z16Z) This work wasfunded by grants from UCLH Biomedical Research Centre
Table 4 Relationship between vision scores and 2 other risk algorithms
NeurologyorgCP Neurology Clinical Practice | Volume Number | 9
Grant (BRC302NSRW101410) andby grants fromNationalInstitute for Health Research (NIHR) and Fight for Sight UK
DisclosureL-A Leyland F D Bremner R Mahmood S HewittM Durteste MRE Cartlidge M M-M Lai LE Miller andA P Saygin report no disclosures P A Keane reports per-sonal fees from Topcon Heidelberg Engineering Deep-Mind Optos Novartis Bayer Allergan and Santen A ESchrag reports personal fees from Medtronic and AstraZe-neca R S Weil has received personal fees from GE Fulldisclosure form information provided by the authors isavailable with the full text of this article at Neurologyorgcp
Publication historyReceived by Neurology Clinical Practice April 9 2019 Accepted in finalform June 7 2019
References1 Anang JB Gagnon JF Bertrand JA et al Predictors of dementia in Parkinson disease
a prospective cohort study Neurology 2014831253ndash12602 Weil RS Pappa K Schade RN et al The Cats-and-Dogs test a tool to identify
visuoperceptual deficits in Parkinsonrsquos disease Mov Disord 2017321789ndash17903 Williams-Gray CH Mason SL Evans JR et al The CamPaIGN study of Parkinsonrsquos
disease 10-year outlook in an incident population-based cohort J Neurol NeurosurgPsychiatry 2013841258ndash1264
4 Bodis-Wollner I Miri S Glazman S Venturing into the no-manrsquos land of the retina inParkinsonrsquos disease Mov Disord 20142915ndash22
5 Cheung CY Ong YT Hilal S et al Retinal ganglion cell analysis using high-definitionoptical coherence tomography in patients with mild cognitive impairment and Alz-heimerrsquos disease J Alzheimers Dis 20154545ndash56
6 Cheung CY Chan VT Mok VC Chen C Wong TY Potential retinal biomarkers fordementia what is new Curr Opin Neurol 20193282ndash91
7 Ko F Muthy ZA Gallacher J et al Association of retinal nerve fiber layer thinningwith current and future cognitive decline a study using optical coherence tomogra-phy JAMA Neurology 2018751198ndash1205
8 Mutlu U Colijn JM Ikram MA et al Association of retinal neurodegeneration onoptical coherence tomography with dementia a population-based study JAMANeurol 2018751256ndash1263
9 Inzelberg R Ramirez JA Nisipeanu P Ophir A Retinal nerve fiber layer thinning inParkinson disease Vision Res 2004442793ndash2797
10 Balasubramanian R Gan L Development of retinal amacrine cells and their dendriticstratification Current Ophthalmol Rep 20142100ndash106
11 Beach TG Carew J Serrano G et al Phosphorylated α-synuclein-immunoreactiveretinal neuronal elements in Parkinsonrsquos disease subjects Neurosci Lett 201457134ndash38
12 Zivkovic M Dayanir V Stamenovic J et al Retinal ganglion cellinner plexiform layerthickness in patients with Parkinsonrsquos disease Folia Neuropathol 201755168ndash173
13 Liu G Locascio JJ Corvol JC et al Prediction of cognition in Parkinsonrsquos disease witha clinical-genetic score a longitudinal analysis of nine cohorts Lancet Neurol 201716620ndash629
14 Schrag A Siddiqui UF Anastasiou Z Weintraub D Schott JM Clinical variables andbiomarkers in prediction of cognitive impairment in patients with newly diagnosedParkinsonrsquos disease a cohort study Lancet Neurol 20171666ndash75
15 Velseboer DC de Bie RM Wieske L et al Development and external validation ofa prognostic model in newly diagnosed Parkinson disease Neurology 201686986ndash993
16 Weil RS Schwarzkopf DS Bahrami B et al Assessing cognitive dysfunction in Par-kinsonrsquos disease an online tool to detect visuo-perceptual deficits Mov Disord 201833544ndash553
17 Saygin AP Superior temporal and premotor brain areas necessary for biologicalmotion perception Brain 20071302452ndash2461
18 Jaywant A Shiffrar M Roy S Cronin-Golomb A Impaired perception of biologicalmotion in Parkinsonrsquos disease Neuropsychology 201630720ndash730
19 Cetin EN Bir LS Sarac G Yaldızkaya F Yaylalı V Optic disc and retinal nerve fibrelayer changes in Parkinsonrsquos disease Neuroophthalmology 20133720ndash23
20 Tewarie P Balk L Costello F et al TheOSCAR-IB consensus criteria for retinal OCTquality assessment PloS one 20127e34823
21 Cruz-Herranz A Balk LJ Oberwahrenbrock T et al The APOSTEL recom-mendations for reporting quantitative optical coherence tomography studies Neu-rology 2016862303ndash2309
22 Litvan I Goldman JG Troster AI et al Diagnostic criteria for mild cognitive im-pairment in Parkinsonrsquos disease movement disorder society task force guidelinesMov Disord 201227349ndash356
23 Toledo JB Gopal P Raible K et al Pathological α-synuclein distribution in subjects withcoincident Alzheimerrsquos and Lewy body pathology Acta Neuropathol 2016131393ndash409
Appendix Authors
Name Location Role Contribution
Louise-AnnLeyland PhD
University CollegeLondon London
Author Designed andconceptualized thestudy collected dataanalyzed data anddrafted themanuscriptfor intellectual content
Fion DBremner PhD
National Hospital forNeurology ampNeurosurgery London
Author Collected andinterpreted data andreviewed themanuscript forintellectual content
RibeyaMahmoodMSc
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
Sam HewittMSc
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
MarionDurteste MSc
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
Molly RECartlidge
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
Michelle M-MLai FRCOphth
National Hospital forNeurology ampNeurosurgery London
Author Collected andinterpreted data andreviewed themanuscript forintellectual content
Luke E MillerPhD
Lyon NeuroscienceResearch CenterFrance
Author Designed aspects ofthe study interpretedthe data and reviewedthe manuscript forintellectual content
Ayse P SayginPhD
University of CaliforniaSan Diego
Author Designed aspects ofthe study interpretedthe data and reviewedthe manuscript forintellectual content
Appendix (continued)
Name Location Role Contribution
Pearse AKeane PhD
University CollegeLondon London
Author Designed aspects ofthe study interpretedthe data and reviewedthe manuscript forintellectual content
Anette ESchrag PhD
University CollegeLondon London
Author Interpreted the dataand reviewed themanuscript forintellectual content
Rimona SWeilPhD
University CollegeLondon London
Author Designed andconceptualized thestudy analyzed thedata interpreted thedata and draftedrevised and edited themanuscript forintellectual content
10 Neurology Clinical Practice | Volume Number | NeurologyorgCP
24 Frederick JM Rayborn ME Laties AM Lam DM Hollyfield JG Dopaminergicneurons in the human retina J Comp Neurol 198221065ndash79
25 Nguyen-Legros J Functional neuroarchitecture of the retina hypothesis on thedysfunction of retinal dopaminergic circuitry in Parkinsonrsquos disease Surg Radiol Anat198810137ndash144
26 Harnois C Di Paolo T Decreased dopamine in the retinas of patients with Parkin-sonrsquos disease Invest Ophthalmol Vis Sci 1990312473ndash2475
27 Tsironi EE Dastiridou A Katsanos A et al Perimetric and retinal nerve fiber layerfindings in patients with Parkinsonrsquos disease BMC Ophthalmol 20121254
28 Archibald NK Clarke MP Mosimann UP Burn DJ Retinal thickness in Parkinsonrsquosdisease Parkinsonism Relat Disord 201117431ndash436
29 Moreno-Ramos T Benito-Leon J Villarejo A Bermejo-Pareja F Retinal nerve fiberlayer thinning in dementia associated with Parkinsonrsquos disease dementia with Lewybodies and Alzheimerrsquos disease J Alzheimerrsquos Dis 201334659ndash664
30 Ortuntildeo-Lizaran I Beach TG Serrano GE Walker DG Adler CH Cuenca N Phos-phorylated α‐synuclein in the retina is a biomarker of Parkinsonrsquos disease pathologyseverity Movement Disorders 2018331315ndash1324
31 Surmeier DJ Obeso JA Halliday GM Selective neuronal vulnerability in Parkinsondisease Nat Rev Neurosci 201718101ndash113
32 Levin BE Llabre MM Reisman S et al Visuospatial impairment in Parkinsonrsquosdisease Neurology 199141365ndash369
33 Regan D Neima D Low-contrast letter charts in early diabetic retinopathy ocularhypertension glaucoma and Parkinsonrsquos disease Br J Ophthalmol 198468885ndash889
34 McKendrick AM Chan YM Nguyen BN Spatial vision in older adults perceptualchanges and neural bases Ophthalmic and Physiol Opt201838(4)363ndash375
35 Laidlaw D Abbott A Rosser DA Development of a clinically feasible logMAR al-ternative to the Snellen chart performance of the ldquocompact reduced logMARrdquo visualacuity chart in amblyopic children Br J Ophthalmol 2003871232ndash1234
NeurologyorgCP Neurology Clinical Practice | Volume Number | 11
DOI 101212CPJ0000000000000719 published online September 18 2019Neurol Clin Pract
Louise-Ann Leyland Fion D Bremner Ribeya Mahmood et al Visual tests predict dementia risk in Parkinson disease
This information is current as of September 18 2019
ServicesUpdated Information amp
19fullhtmlhttpcpneurologyorgcontentearly20190918CPJ00000000000007including high resolution figures can be found at
Citations
19fullhtmlotherarticleshttpcpneurologyorgcontentearly20190918CPJ00000000000007This article has been cited by 2 HighWire-hosted articles
tiahttpcpneurologyorgcgicollectionparkinsons_disease_with_demenParkinsons disease with dementiafollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpcpneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpcpneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
reserved Print ISSN 2163-0402 Online ISSN 2163-0933Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightssince 2011 it is now a bimonthly with 6 issues per year Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published continuouslyNeurol Clin Pract
We show that visual measures and retinal thinning are linkedwith a higher risk of more rapid PD dementia This providesuseful insights into the development of PD dementia im-plicating visual brain regions as being involved at early stagesAs Parkinson dementia is becoming better understoodnoninvasive visual measures such as those used in this studymay have potential to be used alone or in combination withother clinical factors as possible biomarkers for PD dementia
and to stratify high-risk patients for disease-modifying trialsThis could enable better-powered trials and ultimately maypave the way toward new treatments for PD dementia
Study fundingRS W is supported by a Wellcome Clinical Research CareerDevelopment Fellowship (201567Z16Z) This work wasfunded by grants from UCLH Biomedical Research Centre
Table 4 Relationship between vision scores and 2 other risk algorithms
NeurologyorgCP Neurology Clinical Practice | Volume Number | 9
Grant (BRC302NSRW101410) andby grants fromNationalInstitute for Health Research (NIHR) and Fight for Sight UK
DisclosureL-A Leyland F D Bremner R Mahmood S HewittM Durteste MRE Cartlidge M M-M Lai LE Miller andA P Saygin report no disclosures P A Keane reports per-sonal fees from Topcon Heidelberg Engineering Deep-Mind Optos Novartis Bayer Allergan and Santen A ESchrag reports personal fees from Medtronic and AstraZe-neca R S Weil has received personal fees from GE Fulldisclosure form information provided by the authors isavailable with the full text of this article at Neurologyorgcp
Publication historyReceived by Neurology Clinical Practice April 9 2019 Accepted in finalform June 7 2019
References1 Anang JB Gagnon JF Bertrand JA et al Predictors of dementia in Parkinson disease
a prospective cohort study Neurology 2014831253ndash12602 Weil RS Pappa K Schade RN et al The Cats-and-Dogs test a tool to identify
visuoperceptual deficits in Parkinsonrsquos disease Mov Disord 2017321789ndash17903 Williams-Gray CH Mason SL Evans JR et al The CamPaIGN study of Parkinsonrsquos
disease 10-year outlook in an incident population-based cohort J Neurol NeurosurgPsychiatry 2013841258ndash1264
4 Bodis-Wollner I Miri S Glazman S Venturing into the no-manrsquos land of the retina inParkinsonrsquos disease Mov Disord 20142915ndash22
5 Cheung CY Ong YT Hilal S et al Retinal ganglion cell analysis using high-definitionoptical coherence tomography in patients with mild cognitive impairment and Alz-heimerrsquos disease J Alzheimers Dis 20154545ndash56
6 Cheung CY Chan VT Mok VC Chen C Wong TY Potential retinal biomarkers fordementia what is new Curr Opin Neurol 20193282ndash91
7 Ko F Muthy ZA Gallacher J et al Association of retinal nerve fiber layer thinningwith current and future cognitive decline a study using optical coherence tomogra-phy JAMA Neurology 2018751198ndash1205
8 Mutlu U Colijn JM Ikram MA et al Association of retinal neurodegeneration onoptical coherence tomography with dementia a population-based study JAMANeurol 2018751256ndash1263
9 Inzelberg R Ramirez JA Nisipeanu P Ophir A Retinal nerve fiber layer thinning inParkinson disease Vision Res 2004442793ndash2797
10 Balasubramanian R Gan L Development of retinal amacrine cells and their dendriticstratification Current Ophthalmol Rep 20142100ndash106
11 Beach TG Carew J Serrano G et al Phosphorylated α-synuclein-immunoreactiveretinal neuronal elements in Parkinsonrsquos disease subjects Neurosci Lett 201457134ndash38
12 Zivkovic M Dayanir V Stamenovic J et al Retinal ganglion cellinner plexiform layerthickness in patients with Parkinsonrsquos disease Folia Neuropathol 201755168ndash173
13 Liu G Locascio JJ Corvol JC et al Prediction of cognition in Parkinsonrsquos disease witha clinical-genetic score a longitudinal analysis of nine cohorts Lancet Neurol 201716620ndash629
14 Schrag A Siddiqui UF Anastasiou Z Weintraub D Schott JM Clinical variables andbiomarkers in prediction of cognitive impairment in patients with newly diagnosedParkinsonrsquos disease a cohort study Lancet Neurol 20171666ndash75
15 Velseboer DC de Bie RM Wieske L et al Development and external validation ofa prognostic model in newly diagnosed Parkinson disease Neurology 201686986ndash993
16 Weil RS Schwarzkopf DS Bahrami B et al Assessing cognitive dysfunction in Par-kinsonrsquos disease an online tool to detect visuo-perceptual deficits Mov Disord 201833544ndash553
17 Saygin AP Superior temporal and premotor brain areas necessary for biologicalmotion perception Brain 20071302452ndash2461
18 Jaywant A Shiffrar M Roy S Cronin-Golomb A Impaired perception of biologicalmotion in Parkinsonrsquos disease Neuropsychology 201630720ndash730
19 Cetin EN Bir LS Sarac G Yaldızkaya F Yaylalı V Optic disc and retinal nerve fibrelayer changes in Parkinsonrsquos disease Neuroophthalmology 20133720ndash23
20 Tewarie P Balk L Costello F et al TheOSCAR-IB consensus criteria for retinal OCTquality assessment PloS one 20127e34823
21 Cruz-Herranz A Balk LJ Oberwahrenbrock T et al The APOSTEL recom-mendations for reporting quantitative optical coherence tomography studies Neu-rology 2016862303ndash2309
22 Litvan I Goldman JG Troster AI et al Diagnostic criteria for mild cognitive im-pairment in Parkinsonrsquos disease movement disorder society task force guidelinesMov Disord 201227349ndash356
23 Toledo JB Gopal P Raible K et al Pathological α-synuclein distribution in subjects withcoincident Alzheimerrsquos and Lewy body pathology Acta Neuropathol 2016131393ndash409
Appendix Authors
Name Location Role Contribution
Louise-AnnLeyland PhD
University CollegeLondon London
Author Designed andconceptualized thestudy collected dataanalyzed data anddrafted themanuscriptfor intellectual content
Fion DBremner PhD
National Hospital forNeurology ampNeurosurgery London
Author Collected andinterpreted data andreviewed themanuscript forintellectual content
RibeyaMahmoodMSc
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
Sam HewittMSc
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
MarionDurteste MSc
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
Molly RECartlidge
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
Michelle M-MLai FRCOphth
National Hospital forNeurology ampNeurosurgery London
Author Collected andinterpreted data andreviewed themanuscript forintellectual content
Luke E MillerPhD
Lyon NeuroscienceResearch CenterFrance
Author Designed aspects ofthe study interpretedthe data and reviewedthe manuscript forintellectual content
Ayse P SayginPhD
University of CaliforniaSan Diego
Author Designed aspects ofthe study interpretedthe data and reviewedthe manuscript forintellectual content
Appendix (continued)
Name Location Role Contribution
Pearse AKeane PhD
University CollegeLondon London
Author Designed aspects ofthe study interpretedthe data and reviewedthe manuscript forintellectual content
Anette ESchrag PhD
University CollegeLondon London
Author Interpreted the dataand reviewed themanuscript forintellectual content
Rimona SWeilPhD
University CollegeLondon London
Author Designed andconceptualized thestudy analyzed thedata interpreted thedata and draftedrevised and edited themanuscript forintellectual content
10 Neurology Clinical Practice | Volume Number | NeurologyorgCP
24 Frederick JM Rayborn ME Laties AM Lam DM Hollyfield JG Dopaminergicneurons in the human retina J Comp Neurol 198221065ndash79
25 Nguyen-Legros J Functional neuroarchitecture of the retina hypothesis on thedysfunction of retinal dopaminergic circuitry in Parkinsonrsquos disease Surg Radiol Anat198810137ndash144
26 Harnois C Di Paolo T Decreased dopamine in the retinas of patients with Parkin-sonrsquos disease Invest Ophthalmol Vis Sci 1990312473ndash2475
27 Tsironi EE Dastiridou A Katsanos A et al Perimetric and retinal nerve fiber layerfindings in patients with Parkinsonrsquos disease BMC Ophthalmol 20121254
28 Archibald NK Clarke MP Mosimann UP Burn DJ Retinal thickness in Parkinsonrsquosdisease Parkinsonism Relat Disord 201117431ndash436
29 Moreno-Ramos T Benito-Leon J Villarejo A Bermejo-Pareja F Retinal nerve fiberlayer thinning in dementia associated with Parkinsonrsquos disease dementia with Lewybodies and Alzheimerrsquos disease J Alzheimerrsquos Dis 201334659ndash664
30 Ortuntildeo-Lizaran I Beach TG Serrano GE Walker DG Adler CH Cuenca N Phos-phorylated α‐synuclein in the retina is a biomarker of Parkinsonrsquos disease pathologyseverity Movement Disorders 2018331315ndash1324
31 Surmeier DJ Obeso JA Halliday GM Selective neuronal vulnerability in Parkinsondisease Nat Rev Neurosci 201718101ndash113
32 Levin BE Llabre MM Reisman S et al Visuospatial impairment in Parkinsonrsquosdisease Neurology 199141365ndash369
33 Regan D Neima D Low-contrast letter charts in early diabetic retinopathy ocularhypertension glaucoma and Parkinsonrsquos disease Br J Ophthalmol 198468885ndash889
34 McKendrick AM Chan YM Nguyen BN Spatial vision in older adults perceptualchanges and neural bases Ophthalmic and Physiol Opt201838(4)363ndash375
35 Laidlaw D Abbott A Rosser DA Development of a clinically feasible logMAR al-ternative to the Snellen chart performance of the ldquocompact reduced logMARrdquo visualacuity chart in amblyopic children Br J Ophthalmol 2003871232ndash1234
NeurologyorgCP Neurology Clinical Practice | Volume Number | 11
DOI 101212CPJ0000000000000719 published online September 18 2019Neurol Clin Pract
Louise-Ann Leyland Fion D Bremner Ribeya Mahmood et al Visual tests predict dementia risk in Parkinson disease
This information is current as of September 18 2019
ServicesUpdated Information amp
19fullhtmlhttpcpneurologyorgcontentearly20190918CPJ00000000000007including high resolution figures can be found at
Citations
19fullhtmlotherarticleshttpcpneurologyorgcontentearly20190918CPJ00000000000007This article has been cited by 2 HighWire-hosted articles
tiahttpcpneurologyorgcgicollectionparkinsons_disease_with_demenParkinsons disease with dementiafollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpcpneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpcpneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
reserved Print ISSN 2163-0402 Online ISSN 2163-0933Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightssince 2011 it is now a bimonthly with 6 issues per year Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published continuouslyNeurol Clin Pract
Grant (BRC302NSRW101410) andby grants fromNationalInstitute for Health Research (NIHR) and Fight for Sight UK
DisclosureL-A Leyland F D Bremner R Mahmood S HewittM Durteste MRE Cartlidge M M-M Lai LE Miller andA P Saygin report no disclosures P A Keane reports per-sonal fees from Topcon Heidelberg Engineering Deep-Mind Optos Novartis Bayer Allergan and Santen A ESchrag reports personal fees from Medtronic and AstraZe-neca R S Weil has received personal fees from GE Fulldisclosure form information provided by the authors isavailable with the full text of this article at Neurologyorgcp
Publication historyReceived by Neurology Clinical Practice April 9 2019 Accepted in finalform June 7 2019
References1 Anang JB Gagnon JF Bertrand JA et al Predictors of dementia in Parkinson disease
a prospective cohort study Neurology 2014831253ndash12602 Weil RS Pappa K Schade RN et al The Cats-and-Dogs test a tool to identify
visuoperceptual deficits in Parkinsonrsquos disease Mov Disord 2017321789ndash17903 Williams-Gray CH Mason SL Evans JR et al The CamPaIGN study of Parkinsonrsquos
disease 10-year outlook in an incident population-based cohort J Neurol NeurosurgPsychiatry 2013841258ndash1264
4 Bodis-Wollner I Miri S Glazman S Venturing into the no-manrsquos land of the retina inParkinsonrsquos disease Mov Disord 20142915ndash22
5 Cheung CY Ong YT Hilal S et al Retinal ganglion cell analysis using high-definitionoptical coherence tomography in patients with mild cognitive impairment and Alz-heimerrsquos disease J Alzheimers Dis 20154545ndash56
6 Cheung CY Chan VT Mok VC Chen C Wong TY Potential retinal biomarkers fordementia what is new Curr Opin Neurol 20193282ndash91
7 Ko F Muthy ZA Gallacher J et al Association of retinal nerve fiber layer thinningwith current and future cognitive decline a study using optical coherence tomogra-phy JAMA Neurology 2018751198ndash1205
8 Mutlu U Colijn JM Ikram MA et al Association of retinal neurodegeneration onoptical coherence tomography with dementia a population-based study JAMANeurol 2018751256ndash1263
9 Inzelberg R Ramirez JA Nisipeanu P Ophir A Retinal nerve fiber layer thinning inParkinson disease Vision Res 2004442793ndash2797
10 Balasubramanian R Gan L Development of retinal amacrine cells and their dendriticstratification Current Ophthalmol Rep 20142100ndash106
11 Beach TG Carew J Serrano G et al Phosphorylated α-synuclein-immunoreactiveretinal neuronal elements in Parkinsonrsquos disease subjects Neurosci Lett 201457134ndash38
12 Zivkovic M Dayanir V Stamenovic J et al Retinal ganglion cellinner plexiform layerthickness in patients with Parkinsonrsquos disease Folia Neuropathol 201755168ndash173
13 Liu G Locascio JJ Corvol JC et al Prediction of cognition in Parkinsonrsquos disease witha clinical-genetic score a longitudinal analysis of nine cohorts Lancet Neurol 201716620ndash629
14 Schrag A Siddiqui UF Anastasiou Z Weintraub D Schott JM Clinical variables andbiomarkers in prediction of cognitive impairment in patients with newly diagnosedParkinsonrsquos disease a cohort study Lancet Neurol 20171666ndash75
15 Velseboer DC de Bie RM Wieske L et al Development and external validation ofa prognostic model in newly diagnosed Parkinson disease Neurology 201686986ndash993
16 Weil RS Schwarzkopf DS Bahrami B et al Assessing cognitive dysfunction in Par-kinsonrsquos disease an online tool to detect visuo-perceptual deficits Mov Disord 201833544ndash553
17 Saygin AP Superior temporal and premotor brain areas necessary for biologicalmotion perception Brain 20071302452ndash2461
18 Jaywant A Shiffrar M Roy S Cronin-Golomb A Impaired perception of biologicalmotion in Parkinsonrsquos disease Neuropsychology 201630720ndash730
19 Cetin EN Bir LS Sarac G Yaldızkaya F Yaylalı V Optic disc and retinal nerve fibrelayer changes in Parkinsonrsquos disease Neuroophthalmology 20133720ndash23
20 Tewarie P Balk L Costello F et al TheOSCAR-IB consensus criteria for retinal OCTquality assessment PloS one 20127e34823
21 Cruz-Herranz A Balk LJ Oberwahrenbrock T et al The APOSTEL recom-mendations for reporting quantitative optical coherence tomography studies Neu-rology 2016862303ndash2309
22 Litvan I Goldman JG Troster AI et al Diagnostic criteria for mild cognitive im-pairment in Parkinsonrsquos disease movement disorder society task force guidelinesMov Disord 201227349ndash356
23 Toledo JB Gopal P Raible K et al Pathological α-synuclein distribution in subjects withcoincident Alzheimerrsquos and Lewy body pathology Acta Neuropathol 2016131393ndash409
Appendix Authors
Name Location Role Contribution
Louise-AnnLeyland PhD
University CollegeLondon London
Author Designed andconceptualized thestudy collected dataanalyzed data anddrafted themanuscriptfor intellectual content
Fion DBremner PhD
National Hospital forNeurology ampNeurosurgery London
Author Collected andinterpreted data andreviewed themanuscript forintellectual content
RibeyaMahmoodMSc
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
Sam HewittMSc
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
MarionDurteste MSc
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
Molly RECartlidge
University CollegeLondon London
Author Collected and analyzeddata and reviewed themanuscript forintellectual content
Michelle M-MLai FRCOphth
National Hospital forNeurology ampNeurosurgery London
Author Collected andinterpreted data andreviewed themanuscript forintellectual content
Luke E MillerPhD
Lyon NeuroscienceResearch CenterFrance
Author Designed aspects ofthe study interpretedthe data and reviewedthe manuscript forintellectual content
Ayse P SayginPhD
University of CaliforniaSan Diego
Author Designed aspects ofthe study interpretedthe data and reviewedthe manuscript forintellectual content
Appendix (continued)
Name Location Role Contribution
Pearse AKeane PhD
University CollegeLondon London
Author Designed aspects ofthe study interpretedthe data and reviewedthe manuscript forintellectual content
Anette ESchrag PhD
University CollegeLondon London
Author Interpreted the dataand reviewed themanuscript forintellectual content
Rimona SWeilPhD
University CollegeLondon London
Author Designed andconceptualized thestudy analyzed thedata interpreted thedata and draftedrevised and edited themanuscript forintellectual content
10 Neurology Clinical Practice | Volume Number | NeurologyorgCP
24 Frederick JM Rayborn ME Laties AM Lam DM Hollyfield JG Dopaminergicneurons in the human retina J Comp Neurol 198221065ndash79
25 Nguyen-Legros J Functional neuroarchitecture of the retina hypothesis on thedysfunction of retinal dopaminergic circuitry in Parkinsonrsquos disease Surg Radiol Anat198810137ndash144
26 Harnois C Di Paolo T Decreased dopamine in the retinas of patients with Parkin-sonrsquos disease Invest Ophthalmol Vis Sci 1990312473ndash2475
27 Tsironi EE Dastiridou A Katsanos A et al Perimetric and retinal nerve fiber layerfindings in patients with Parkinsonrsquos disease BMC Ophthalmol 20121254
28 Archibald NK Clarke MP Mosimann UP Burn DJ Retinal thickness in Parkinsonrsquosdisease Parkinsonism Relat Disord 201117431ndash436
29 Moreno-Ramos T Benito-Leon J Villarejo A Bermejo-Pareja F Retinal nerve fiberlayer thinning in dementia associated with Parkinsonrsquos disease dementia with Lewybodies and Alzheimerrsquos disease J Alzheimerrsquos Dis 201334659ndash664
30 Ortuntildeo-Lizaran I Beach TG Serrano GE Walker DG Adler CH Cuenca N Phos-phorylated α‐synuclein in the retina is a biomarker of Parkinsonrsquos disease pathologyseverity Movement Disorders 2018331315ndash1324
31 Surmeier DJ Obeso JA Halliday GM Selective neuronal vulnerability in Parkinsondisease Nat Rev Neurosci 201718101ndash113
32 Levin BE Llabre MM Reisman S et al Visuospatial impairment in Parkinsonrsquosdisease Neurology 199141365ndash369
33 Regan D Neima D Low-contrast letter charts in early diabetic retinopathy ocularhypertension glaucoma and Parkinsonrsquos disease Br J Ophthalmol 198468885ndash889
34 McKendrick AM Chan YM Nguyen BN Spatial vision in older adults perceptualchanges and neural bases Ophthalmic and Physiol Opt201838(4)363ndash375
35 Laidlaw D Abbott A Rosser DA Development of a clinically feasible logMAR al-ternative to the Snellen chart performance of the ldquocompact reduced logMARrdquo visualacuity chart in amblyopic children Br J Ophthalmol 2003871232ndash1234
NeurologyorgCP Neurology Clinical Practice | Volume Number | 11
DOI 101212CPJ0000000000000719 published online September 18 2019Neurol Clin Pract
Louise-Ann Leyland Fion D Bremner Ribeya Mahmood et al Visual tests predict dementia risk in Parkinson disease
This information is current as of September 18 2019
ServicesUpdated Information amp
19fullhtmlhttpcpneurologyorgcontentearly20190918CPJ00000000000007including high resolution figures can be found at
Citations
19fullhtmlotherarticleshttpcpneurologyorgcontentearly20190918CPJ00000000000007This article has been cited by 2 HighWire-hosted articles
tiahttpcpneurologyorgcgicollectionparkinsons_disease_with_demenParkinsons disease with dementiafollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpcpneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpcpneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
reserved Print ISSN 2163-0402 Online ISSN 2163-0933Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightssince 2011 it is now a bimonthly with 6 issues per year Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published continuouslyNeurol Clin Pract
24 Frederick JM Rayborn ME Laties AM Lam DM Hollyfield JG Dopaminergicneurons in the human retina J Comp Neurol 198221065ndash79
25 Nguyen-Legros J Functional neuroarchitecture of the retina hypothesis on thedysfunction of retinal dopaminergic circuitry in Parkinsonrsquos disease Surg Radiol Anat198810137ndash144
26 Harnois C Di Paolo T Decreased dopamine in the retinas of patients with Parkin-sonrsquos disease Invest Ophthalmol Vis Sci 1990312473ndash2475
27 Tsironi EE Dastiridou A Katsanos A et al Perimetric and retinal nerve fiber layerfindings in patients with Parkinsonrsquos disease BMC Ophthalmol 20121254
28 Archibald NK Clarke MP Mosimann UP Burn DJ Retinal thickness in Parkinsonrsquosdisease Parkinsonism Relat Disord 201117431ndash436
29 Moreno-Ramos T Benito-Leon J Villarejo A Bermejo-Pareja F Retinal nerve fiberlayer thinning in dementia associated with Parkinsonrsquos disease dementia with Lewybodies and Alzheimerrsquos disease J Alzheimerrsquos Dis 201334659ndash664
30 Ortuntildeo-Lizaran I Beach TG Serrano GE Walker DG Adler CH Cuenca N Phos-phorylated α‐synuclein in the retina is a biomarker of Parkinsonrsquos disease pathologyseverity Movement Disorders 2018331315ndash1324
31 Surmeier DJ Obeso JA Halliday GM Selective neuronal vulnerability in Parkinsondisease Nat Rev Neurosci 201718101ndash113
32 Levin BE Llabre MM Reisman S et al Visuospatial impairment in Parkinsonrsquosdisease Neurology 199141365ndash369
33 Regan D Neima D Low-contrast letter charts in early diabetic retinopathy ocularhypertension glaucoma and Parkinsonrsquos disease Br J Ophthalmol 198468885ndash889
34 McKendrick AM Chan YM Nguyen BN Spatial vision in older adults perceptualchanges and neural bases Ophthalmic and Physiol Opt201838(4)363ndash375
35 Laidlaw D Abbott A Rosser DA Development of a clinically feasible logMAR al-ternative to the Snellen chart performance of the ldquocompact reduced logMARrdquo visualacuity chart in amblyopic children Br J Ophthalmol 2003871232ndash1234
NeurologyorgCP Neurology Clinical Practice | Volume Number | 11
DOI 101212CPJ0000000000000719 published online September 18 2019Neurol Clin Pract
Louise-Ann Leyland Fion D Bremner Ribeya Mahmood et al Visual tests predict dementia risk in Parkinson disease
This information is current as of September 18 2019
ServicesUpdated Information amp
19fullhtmlhttpcpneurologyorgcontentearly20190918CPJ00000000000007including high resolution figures can be found at
Citations
19fullhtmlotherarticleshttpcpneurologyorgcontentearly20190918CPJ00000000000007This article has been cited by 2 HighWire-hosted articles
tiahttpcpneurologyorgcgicollectionparkinsons_disease_with_demenParkinsons disease with dementiafollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpcpneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpcpneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
reserved Print ISSN 2163-0402 Online ISSN 2163-0933Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightssince 2011 it is now a bimonthly with 6 issues per year Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published continuouslyNeurol Clin Pract
DOI 101212CPJ0000000000000719 published online September 18 2019Neurol Clin Pract
Louise-Ann Leyland Fion D Bremner Ribeya Mahmood et al Visual tests predict dementia risk in Parkinson disease
This information is current as of September 18 2019
ServicesUpdated Information amp
19fullhtmlhttpcpneurologyorgcontentearly20190918CPJ00000000000007including high resolution figures can be found at
Citations
19fullhtmlotherarticleshttpcpneurologyorgcontentearly20190918CPJ00000000000007This article has been cited by 2 HighWire-hosted articles
tiahttpcpneurologyorgcgicollectionparkinsons_disease_with_demenParkinsons disease with dementiafollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpcpneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpcpneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
reserved Print ISSN 2163-0402 Online ISSN 2163-0933Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightssince 2011 it is now a bimonthly with 6 issues per year Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published continuouslyNeurol Clin Pract
