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This is the published version of a paper published in Journal of Neurology, Neurosurgery andPsychiatry.
Citation for the original published paper (version of record):
Menke, R A., Proudfoot, M., Wuu, J., Andersen, P M., Talbot, K. et al. (2016)Increased functional connectivity common to symptomatic amyotrophic lateral sclerosis andthose at genetic risk.Journal of Neurology, Neurosurgery and Psychiatry, 87(6): 580-588http://dx.doi.org/10.1136/jnnp-2015-311945
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RESEARCH PAPER
Increased functional connectivity common tosymptomatic amyotrophic lateral sclerosis and thoseat genetic riskRicarda A L Menke,1,2 Malcolm Proudfoot,1 Joanne Wuu,3 Peter M Andersen,4
Kevin Talbot,1 Michael Benatar,3 Martin R Turner1,2
1Nuffield Department ofClinical Neurosciences,University of Oxford, Oxford,UK2FMRIB Centre, John RadcliffeHospital, University of Oxford,Oxford, UK3Miller School of Medicine,University of Miami, Miami,Florida, USA4Department of Pharmacologyand Clinical Neuroscience,Ume University, Ume,Sweden
Correspondence toProfessor Martin Turner,Clinical Neurosciences, WestWing Level 6, John RadcliffeHospital, Oxford OX3 9DU,UK; [email protected] Michael Benatar,Department of Neurology,Miller School of Medicine,University of Miami, Miami, FL,USA; [email protected]
Received 5 August 2015Revised 20 October 2015Accepted 18 November 2015Published Online First5 January 2016
To cite: Menke RAL,Proudfoot M, Wuu J, et al. JNeurol Neurosurg Psychiatry2016;87:580588.
ABSTRACTObjective To discern presymptomatic changes in brainstructure or function using advanced MRI in carriers ofmutations predisposing to amyotrophic lateral sclerosis(ALS).Methods T1-weighted, diffusion weighted and restingstate functional MRI data were acquired at 3 T for 12asymptomatic mutation carriers (psALS), 12 age-matched controls and affected patients with ALS.Cortical thickness analysis, voxel-based morphometry,volumetric and shape analyses of subcortical structures,tract-based spatial statistics of metrics derived from thediffusion tensor, and resting state functional connectivity(FC) analyses were performed.Results Grey matter cortical thickness and shapeanalysis revealed significant atrophy in patients with ALS(but not psALS) compared with controls in the rightprimary motor cortex and right caudate. Comparison ofdiffusion tensor metrics showed widespread fractionalanisotropy and radial diffusivity differences in patientswith ALS compared to controls and the psALS group,encompassing parts of the corpus callosum, corticospinaltracts and superior longitudinal fasciculus. While FC inthe resting-state sensorimotor network was similar inpsALS and controls, FC between the cerebellum and anetwork comprising the precuneus, cingulate & middlefrontal lobe was significantly higher in psALS andaffected ALS compared to controls.Conclusions Rather than structural brain changes,increased FC may be among the earliest detectable brainabnormalities in asymptomatic carriers of ALS-causinggene mutations. With replication and significantrefinement, this technique has potential in the futureassessment of neuroprotective strategies.
INTRODUCTIONMounting evidence from the fields of Alzheimersdisease, Parkinsons disease and Huntingtonsdisease (HD) supports the conclusion that neurode-generative diseases are characterised by a presymp-tomatic phase during which pathological processesat the molecular, cellular and perhaps networklevels accumulate prior to the appearance of clinic-ally manifest disease. The same is believed to betrue of amyotrophic lateral sclerosis (ALS),1 butevidence to this effect has been slow to accumulateand controversy persists as to the duration of sucha phase. In part, this is a consequence of the diffi-culties inherent to studying ALS prior to theappearance of clinically apparent disease, most
notably the challenge of identifying people at riskfor ALS and the paucity of biomarkers that are suf-ficiently sensitive to permit quantification of diseasein the presymptomatic state.Over recent years, an approach has been devel-
oped and refined for studying presymptomatic ALSthrough the longitudinal and systematic evaluationof asymptomatic carriers of pathogenic mutationslinked to the development of ALS.1 Importantly,the utility of biomarkers identified to be sensitiveto pathology during the presymptomatic stateextends beyond simply providing profound insightinto the biology of this complex and devastatingdisorder. In addition, they present an opportunityto use the quantification of presymptomatic diseaseprogression as a pharmacodynamic biomarker oftreatment effect in disease prevention trials.2
Similar approaches have been successful in HD, forexample, where striatal atrophy is apparent andprogressive during the premanifest stage of disease,and has now been used as a surrogate end point ina small phase II disease prevention trial.3
With the growing evidence that advanced neuroi-maging techniques are sensitive to the brain andspinal cord pathology of ALS,4 a range of structuralanalyses on T1-weighted MRI and DiffusionTensor Imaging (DTI) data, as well as rs-fMRI ana-lysis, was applied to a group of asymptomatic car-riers of ALS gene mutations. We compared them,in parallel with a group of affected patients, tohealthy controls in order to explore the potentialof advanced MRI as a source of presymptomaticbiomarkers in ALS.
METHODSParticipantsAsymptomatic gene carriers, with the exception ofone local participant from the Oxford Study forBiomarkers in MND (BioMOx), were all partici-pants in the Pre-Symptomatic Familial ALS(Pre-fALS) study (MB, JW) at the University ofMiami, who travelled to Oxford University for thisadd-on MRI study. All were genotyped (PMA) ascarriers of dominant SOD1 mutations (A4V (n=8),I113T (n=1), N139K (n=1)); or C9ORF72 repeatexpansions (n=2). Their presymptomatic state wasevidenced by the absence of symptoms, a normalneuromuscular examination, a normal electromyo-graphic study that included evaluation of armand leg muscles bilaterally, thoracic paraspinalmuscles and bulbar musculature, and no
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evidence of cognitive or behavioural dysfunction on neuro-psychological testing (MB and MRT). Established cases of ALSwere selected from the BioMOx study, diagnosed with ALS in atertiary referral clinic according to standard criteria (MRT andKT). All affected patients with ALS in the present study wereapparently sporadic (ie, reported no family history of ALS orfrontotemporal dementia). Healthy controls were a mixture ofspouses and friends of affected patients, with no significantmedical conditions. In order to achieve the best possible agematching, the ALS group included a higher proportion of maleparticipants than the other two groups. Demographic and clin-ical characteristics of all participants who were included in thestudy are summarised in table 1.
Ethics committee approval for the study was granted by theSouth Central Oxford Ethics Committee (08/H0605/85), withwritten informed consent obtained from all participants.Pre-fALS participants were originally recruited under the author-ity of the Institutional Review Board of the University ofMiami, USA (20101021).
MRI data acquisitionAll study participants were scanned at the Oxford Centre forClinical Magnetic Resonance Research using a 3 T Siemens Trioscanner (Siemens AG, Erlangen, Germany) with a 12-channelhead coil. High-resolution three-dimensional whole-brainT1-weighted MRI scans were acquired using a magnetisation-prepared rapid gradient echo (MPRAGE) sequence (TR/TE=2040 ms/4.7 ms, flip angle=8, 1 mm isotropic resolution,6 min acquisition time). Whole-brain diffusion-weighted imageswere acquired using an echoplanar sequence (60 isotropic direc-tions; b value=1000 s/mm2; echo time/repetition time=94 ms/10 000 ms; 222 mm3 voxel size; 65 slices). In addition, fourimages without diffusion weighting were acquired. Whole-brainfunctional imaging at rest was performed using a gradient echoEcho Planar Imaging (EPI) sequence (TR/TE=3000/28 ms, flipangle=89, 3 mm isotropic resolution, 6 min acquisition time).For consistency, participants were instructed to close their eyesthroughout, but to remain awake. Furthermore, a field map wasacquired using a gradient echo imaging sequence (222 mm3
voxel size; 65 slices; echo time 1/echo time 2/repetitiontime=5.19 ms/7.65 ms/655 ms) to account for distortionspresent in the DTI and functional MRI data caused by fieldinhomogeneities.
MRI data analysisVolumetric analysis of cortical grey matter (VBM)T1-weighted MPRAGE data were analysed with FSL-VBM, avoxel-based morphometry style analysis. A standard optimisedFSL-VBM protocol was run for the structural images of all parti-cipants. First, structural images were brain-extracted.5 Next,tissue-type segmentation was carried out using FAST4.6 Theresulting grey matter partial volume images were then aligned toMNI152 standard space using the affine registration toolFLIRT,7 followed by non-linear registration using FMRIB Non-linear Integration and Registration Tool (FNIRT).8 The resultingimages were averaged to create a symmetric, study-specific tem-plate, to w
