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2/9/20171
The Use of Biomarkers to Classify Dementia
2/9/2017
Bruce L. Miller, MDA.W. and Mary Margaret Clausen Distinguished Professor in NeurologyDirector, Memory and Aging CenterJoint Appointment in PsychiatryUCSF School of Medicine
DisclosuresAdvisor / DirectorThe Tau Consortium, Scientific Advisor
The John Douglas French Foundation, Medical Advisor
The Larry L. Hillblom Foundation, Medical Advisory Board
National Institute for Health Research, Director
Cambridge Biomedical Research Centre and its subunit, the Biomedical Research Unit in Dementia (UK)
American Brain Foundation, Board Member
University of Washington ADRC, External Advisor
Stanford University ADRC, External Advisor
Arizona ADC, External Advisor
International Society of FTD, USA-President, Executive Committee
GrantsNational Institute of Health/National Institute of Aging grants: P50 AG023501, P01 AG019724, P50 AG1657303, and T32 AG023481
Centers for Medicare & Medicaid Services Dementia Care Ecosystem 1C1CMS331346-01-00
UCSF / Quest Diagnostics Dementia Pathway Collaboration Research Grant
RoyaltiesCambridge University Press
Guilford Publications, Inc.
Oxford University Press
Neurocase
Elsevier, Inc.
UCSF Memory and Aging Center 2016
UCSF Mission Bay Campus, Sculpture by Mark di Suvero
“A public health approach to dementia could prevent up to 30 percent of the dementia cases projected around the world in the next two decades.Norton, Matthews, Barnes, et al. 2014
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2/9/20172
Neurodegenerative Causes
Alzheimer’s diseasefrontotemporal dementia
Lewy body diseaseand more
Dementiacognitive decline that interferes
with everyday functioningmemory, executive, behavioral,
and/or motor symptoms
Overview• Neurodegeneration caused by protein
aggregation in specific circuits
• Research criteria for AD and FTD
• FTD genes – towards precision medicine
• Molecular markers in AD• Molecular markers in FTD
• Drug development
Models of Degenerative DementiaAll degenerative dementias have:
– Genetic and sporadic form– Cell culture and animal model
– Preclinical, early symptomatic and symptomatic phase
– Abnormal protein aggregation– Proteins spread from cell to cell
Neuropathology & Chemistry of Inclusions • CJD: prions (1982)• AD: plaque (Aβ-42, 1984),
tangle (tau, 1986)• PD/DLB: Lewy body (α-synuclein, 1998) • FTLD: Pick body (tau, 1990), ubiquitin positive
tau negative inclusions (TDP43, 2006), (FUS, 2009), dipeptides from C9 mutations (2013)
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2/9/20173
Molecular Changes Underlying AD Pick 3R PSP 4R CBD 4R
TDP-A TDP-B TDP-C
FTLD-TDP
FTLD-tau
Dipeptides(C9ORF72)
FTLD-FUS
NFL Player: Amygdala/Tau
McKee AC et al. J Neuropathol Exp Neurol. 2009
Lewy body
Idiopathic Parkinson’s DiseaseParkinson (1817): f Lewy (1913): concentric hyaline inclusions. Trétiakoff (1919): Substantia nigra degeneration
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2/9/20174
Differing Anatomy Defines Dementias Disease Imaging Anatomy 1st Symptom Spared
AD Hippocampus posterior temporal-parietal
Memory, naming, visuospatial
Social behavior
Movement
FTD Frontal (emotional > cognitive neocortex)
Apathy, behaviorNavigation, memory
DLB Amygdala temporal-occipital
Movement, hallucinations visuospatial
sleep
Behavior, memory
Research Criteria for Alzheimer’s Disease• At least two of the following:
• Impairment in ability to remember new information• Impaired reasoning ability to manage complex
tasks• Impaired visuospatial abilities• Impaired language functions (speaking, reading,
writing)• Changes in behavior, personality or comportment
• Insidious onset of decline and progressive worsening of symptoms and function
• Evidence of a causative genetic mutation• Biomarkers for amyloid deposition
Preclinical AD – Staging• Stage I: Asymptomatic
– Elevated amyloid PET/low CSF Aβ42
• Stage II: Early synaptic dysfunction– Positive amyloid biomarker– Abnormal CSF tau or MRI or FDG-PET
• Stage III: Symptomatic– Positive amyloid biomarker– Abnormal CSF tau or MRI or FDG-PET– Abnormal cognitive testing
International Research Criteria for Behavioral Variant FTD1. Early (2–3 yrs) behavioral disinhibition
2. Early (2–3 yrs) apathy or inertia
3. Early (2–3 yrs) loss of emotional reactivity/sympathy and empathy
4. Perseverative, stereotyped or compulsive/ritualistic behavior
5. Hyperorality and dietary changes6. FTD neuropsychological profile
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2/9/20175
VBM of FTD & AD vs Controls
Concept from Delay, Brion Escourolle 1950s, Thibodeau MP, Miller BL. Neurocase. 2013
Behavioral Variant Language Variants
SemanticVariant
NonfluentVariant
R L
Rarely genetic83% TDP-C
Some genetic85% Tau, TDP-A
Often geneticTau, TDP, FUS2/3 TDP
3 Types Frontotemporal Dementia
R Ossenkoppele et al. Brain. 2015
Voxel-wise Comparisons of Grey Matter Volumes How Classify C9ORF72 Carriers?
n=41
bvFTD
nfvPPA
svPPA
ALS
PSP
CBS
Other
Parkinsonism
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2/9/20176
How Classify GRN Carriers?n=41
ALS
bvFTD
nfvPPA
svPPA
CBS
PSP Other
Parkinsonism
How Classify MAPT Carriers?n=41
bvFTD nfvPPA
svPPA
ALS
CBS
PSP Other
Parkinsonism
Rare Variants with FTD-ALS Gene Variant Phenotype Publication
TARDBP P112H FTD Moreno et al 2015
FUS Q140H tauopathy Ferrer et al 2015
LRRK2 C2154F tauopathy Chen-Plotkin et al 2008
TBK-1 Nonsense variant FTD-ALS Le Ber et al 2015
PRNP Q160X dementia Fong et al 2016
OPTNdeletion, nonsense & missense mutation
ALS Maruyama et al 2010
UBQLN2 PXX ALS Deng et al 2011
Pick’s, 8 CBD, 3
PSP, 2FTDP-17, 2
Tau unclassifiable,
3TDP-A, 6
TDP-A, MND, 1
TDP-B, 5
TDP-B, MND, 15
TDP-C, 3
TDP-U, 1
TDP-U, MND, 7
ALS-TDP, 1
aFTLD-U (FUS), 7 AD,
4
bvFTD, high confidence, n = 68
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2/9/20177
Role of Biomarker • Capture early disease (sensitive)
• Separate healthy aging from neurodegeneration (specific)
• Determine molecular determinants of neurodegeneration (AD vs. FTD due to tau, TDP, FUS, and PDD or DLB (specific)
• Help with staging of disease
Tablet-based Cognitive Assessments
FTD vs. AD: Executive Control• AD & bvFTD are similar:
– Working memory: Spatial 1-Back, Dot count– Category fluency: Animal generation– Attention: Set shift, Flanker
• bvFTD worse than AD– Letter fluency– Antisaccade accuracy – Social decision making: Social norms– Social behavior: Behavior checklist
• Discriminant function classify 73% bvFTD vs AD Possin et al. Neurology 2014
Executive Control in bvFTD & ADPerformance on executive tasks, emotion recognition increasing disease severityAD (n= 678) vsbvFTD (n=206)
Ranasinghe & Rankin Neurol 2016
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2/9/20178
PSP Disease Severity Circadian Activity
Walsh et al, Sleep Medicine, 2016
Rest-activity Rhythm Disruption PSP
Walsh et al, Sleep Medicine, 2016
Automated Classification Analysis of sMRI Scans• Averaging across patient maps can be very insensitive• Machine-learning algorithms (e.g., using support vector
machines) more effectively discriminate when atrophy patterns heterogeneous within same clinical class patient
Network-based Neurodegeneration
Time (sec)
Single subject
Seeley et al Neuron 2009
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2/9/20179
Plasma Neurofilament PSP vs. Controls
Rojas et al., Ann Clin Transl Neurol. 2016
Neurofilament Level Cognitive Decline
Rojas et al, Ann Clin Transl Neurol. 2016
Amyloid Deposition in Autosomal Dominant AD
Bateman et al., NEJM 2012
Carriers
Non-carriers
Years from symptom onset
NHCH3NO
OO
18F
18F-florbetapir (Amyvid TM)FDA approved April 2012
18F-flutemetamol (Vizamyl TM)FDA approved October 2013
18F-florbetaben (Neuraceq TM)FDA approved March 2014
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2/9/201710
AD
FTLD
CONT
DVR
0
2.5
Amyloid vs. FDG-PET in Differential Diagnosis of AD vs. FTD
AD (N=62, age 65, MMSE 22)FTD (N=45, age 65, MMSE 22)Amyloid (PIB) PET visual reads
90% sensitivity, 83% specificityInter-rater agreement κ=0.96
FDG-PET visual reads78% sensitivity*, 84% specificityInter-rater agreement κ=0.72*
70 autopsy-proven casesPIB: Sensitivity 96%, Specificity 88%FDG: Sensitivity 88%, Specificity 89%
Rabinovici et al. Neurology 2011
* - p<0.05 vs. PIB
Amyloid PET vs. CSF Aβ
Landau et al, Ann Neurol 2013
Florbetapir cortical retention ratio
κ = 0.72
Both positive
Both negative Normal κ = 0.76
EMCI κ = 0.65LMCI κ = 0.71AD κ = 0.70
�ab
norm
alCS
F Aβ 1-
42no
rmal
� • National, open-label study on clinical utility of amyloid PET in ~18,500 Medicare beneficiaries with MCI or dementia of uncertain cause
• Eligible patients referred for PET by dementia experts
• Scans covered by CMS, performed and interpreted locally
• Aim 1: Impact of scan on management plan at 3 months
• Aim 2: Impact on major medical outcomes at 12 months
The primary hypothesis is that, in diagnostically uncertain cases, amyloid PET will lead to significant changes in patient management, and this will translate into improved medical outcomes
IDEAS-Study@acr.orgIDEAS-Study.org
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2/9/201711
462 active dementia practices772 dementia experts
302 active PET facilities
6,924 patients registered6,300 scans completedMedian age 76 (range: 65-99)61.8% MCI, 38.2% dementiaAβ-PET positive:
MCI 54.65%, dementia 69.9%
96.3% consent to use images86.8% consent to be contacted about other research
D
D
Dialkylamino-naphyelthyilidenederivatives
Quinolinederivatives
Benzoimidazopyrimidine and pyridoindolederivatives
Benzimidazolederivatives
Phenyl/pyridinyl-butadienyl-benzothiazoles/benzothiazoliums derivatives
18F-FDDNP18F-THK-523
18F-THK-5105
18F-THK-5317
18F-THK-5351
18F-AV1451 (a.k.a. T807)
18F-T808
18F-RO69558948
11C-PBB3
11C-N-Methyl Lansoprazole
18F-N-Methyl Lansoprazole
18F-GT1
18F-MK-6240
Azaindole derivatives
Slide courtesy of Victor Villemagne
Tau Imaging Radiotracers
Pure Tauopathies vs. Mixed Tauopathy• Mutations – bvFTD,
nfvPPA, PSP, CBD
• Pick – bvFTD, nfvPPA
• CBD – bvFTD, nfvPPA, executive/motor
• PSP – falls, gaze, axial PD, dementia
• AD*
• CTE*
• Guam-PD-Dementia
• PostencephaliticParkinson’s
• Niemann-Pick disease
T807 Tau PET in AD
Healthy Very Mild AD Mild AD Severe AD
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2/9/201712
Tau PET: The New Frontier
Amyloid, tau &brain metabolism 57 year-old AD
Brain dysfunction correlates with tau but not amyloid
Amyloid (PIB-PET)
Atrophy (MRI)
Tau (AV1451-PET)
Ossenkoppele et al., Brain 2016
Tau PET Patterns Correlate with AD Phenotype
Tau PET Correlates of Cognition in AD (N=40, Mean MMSE 22.2)
Bejanin et al., in prep
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2/9/201713
68 yo Retired NFL Player With Neurobehavioral Decline, PIB-neg
0.0 2.3AV1451 SUVR
CTE Stage III
McKee et al. Brain 2013
bvFTD V337M MAPTMutation
Spina et al Neurology 2017
Functional Connectivity Dorsal Midbrain Tegmental Network & Tau PET in PSP
Gardner et al. Ann Neurol 2013, Rabinovici 2015
0 2.5
Functional Connectivity Tau PET
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2/9/201714
Roles of Tau PET Drug Development• Accurate patient selection for clinical trials
of tau-based therapies
• PSP (>90% have tau), CBS (~60%)
• Provide early evidence of drug effect
• Does drug lower tau levels, prevent spread?
• Early detection ➙ early intervention and disease prevention
Trail of Tears (AD Trials)• Misdiagnosis (36% bapineuzumab, solenezumab
apoE3 carriers amyloid negative)• Oversimplification – 60-95 years all dementia is
AD– TDP43– Vascular disease– α-synuclein
• Too late• Wrong molecule?
MAC Clinical Trials
• Crenezumab• Levetiracetam• Solanezumab• Aducanumab• TPI-287
Alzheimer• FRM-0334• Tau
• TPI-287• Oral
salsalate• Plasma
transfusion• BMS-986168• C2N-8E12
FTD PSP/CBD
GBHI LeadershipIan Robertson, PhD Chair Psychology at Trinity College Dublin, Founding Director of the Trinity College Institute of Neuroscience Research. Studies the brain’s attention systems. Has developed new therapeutic methods that improve cognitive function and may delay dementia.
Bruce Miller, MD A.W. and Mary Margaret Clausen Distinguished Professor in Neurology at UCSF. Directs Memory and Aging Center with 30 full-time faculty. Research into frontal lobes and FTD. Explores brain regions involved in altruism and prosocial behavior. Leads research consortia for dementia therapies.
Brian Lawlor, MD Conolly Norman Professor of Old Age Psychiatry at Trinity College Dublin and consultant psychiatrist at St. James’s Hospital. He directs the Memory Disorders Clinic at Mercer’s Institute for Research on Aging. His research programs range from clinical trials, biomarkers, and early detection to caregiver burden.
Victor Valcour, MD, PhD Geriatrician trained behavioral neurology. Professor Neurology & Geriatrics at UCSF. Research brain protection and early intervention for HIV. Co-Directs SEARCH-Thailand research group and the International NeuroHIV Cure Consortium. His programs stretch from San Francisco to Africa and Southeast Asia. Studies HIV and aging.
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2/9/201715
ApproachFellows(8/year)
Scholars(32/year)
Comprehensive Learning Environment
UCSF/TCD Core Strength in Basic and Clinical Neuroscience
GBHI Curriculum• Core 1: Neuroscience
- Brain-Behavior Relationships- Cognitive Assessment- Alzheimer’s Disease, MCI, & Other Dementias- Pathology of Aging- Alcohol and Mental Health- Risk Factors for Neurodegenerative Disease
• Core 2: Public Health & Epidemiology- Introduction to Clinical Trials- Understanding Validity and Reliability- Type of Bias, Confounding, Interaction- Use of Epidemiology in Public Health- Introduction to Survey Data- Intro to Cost Analysis in Health Care
• Core 3: Health Policy & Economics- Intro to Behavioral Economics- Intro to Health Policy- Intro to Implementation Science- Intro to Health Law
• Core 4: Leadership & Communications- Principles of Global Health leadership - Strategy Formulation and Implementation - Teambuilding, Funding & Stakeholder
Engagement - Bioethics
• Core 5: Social Science- Features of Dementia- Pharmaceuticals for the Elderly- Ethical Issues in Brain Health- Legal Issues in Brain Health- End of Life Care and Decision-making
• Core 6: Supplementary- Caregiver Burden in Dementia- Building a Career in Brain Health- Health Behaviors and Brain Health- Social Factors and Dementia- Mental Health Disorders and Brain Health
Over 75 modules to be available for asynchronous lea rning
ILLUSTRATIVE
2016 Atlantic FellowsJalayne Arias, JD, MAUSA, UCSFneuroethics, bioethics, health policy, law
Mircea Balasa, MD, PhDBarcelona, Spain, TCDneurology, dementia, AD, FTD, biomarkers, medical education
Alissa Bernstein, PhD, MPHUSA, UCSFmedical anthropology, public health policy, social determinants, ethnography diversity
Dominic CampbellIreland, TCDelder activism, creativity, positive aging, ageism, social enterprise
Heidi Clare, MMAUSA, UCSFmusic, creativity, song writing podcast on music and aging
Jorge Llibre Guerra, MD, MSHavana, Cuba, UCSFneurology, dementia, cognition, behavior, cerebrovascular disease
Geeske Peeters, PhDNetherlands, TCDpublic health, preventive medicine, musculoskeletal health, fall prevention
Elisa França Resende, MDBelo Horizonte, Brazil, UCSFneurology, memory impairment, control of risk factors, prevention strategies
Adrià Rofes, MSc, PhDBarcelona, Spain, TCDneuroscience clinical linguistics, brain mapping, language processing
Lina Velilla, MSMedellin, Colombia, UCSFpsychology, epidemiology, training, public health
Atlantic Institute• Hosted by Rhodes House
in Oxford, England• Career-long global network
of Atlantic Fellows• Atlantic Fellows programs:
1. Global Brain Health Institute2. Heath Equity
in South Africa at Tekano3. Health Equity in Southeast Asia4. The Narrative Initiative
with the Ford Foundation5. Racial Equity
at Columbia University6. Social & Economic Equity
at International Inequalities Institute7. Social Equity University Melbourne
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2/9/201716
Sustained Connected Community Committed to Social Change
Shared identity
Lateral connectivity
Learning from each
other
Collective strength
International Inequalities
Institute
Health Equity South Africa
Racial Equity
Global Brain Health Institute
The Equity Initiative /
Health Equity SE Asia
Social Equity
The Atlantic Philanthropies
Narrative Initiative
Atlantic Institute
Learning & Evaluation Partners
The Narrative Initiative
Summary1. Clinical symptoms are associated with specific atrophy in the
underlying functional brain networks affected by disease
2. Circadian activity rhythms are disrupted in individuals with PSP
3. Neurodegenerative disease leads to long term changes in CSF biochemical markers, brain amyloid deposition, and brain metabolism – in addition to progressive cognitive impairment
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2/9/201717
Selected Bibliography1. Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ, Xie X, Blazey TM, Holtzman
DM, Santacruz A, Buckles V, Oliver A, Moulder K, Aisen PS, Ghetti B, Klunk WE, McDade E, Martins RN, Masters CL, Mayeux R, Ringman JM, Rossor MN, Schofield PR, Sperling RA, Salloway S, Morris JC; Dominantly Inherited Alzheimer Network. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med. 2012 Aug 30;367(9):795-804. Erratum in: N Engl J Med. 2012 Aug 23;367(8):780.
2. Gardner RC, Boxer AL, Trujillo A, Mirsky JB, Guo CC, Gennatas ED, Heuer HW, Fine E, Zhou J, Kramer JH, Miller BL, Seeley WW. Intrinsic connectivity network disruption in progressive supranuclear palsy. Ann Neurol. 2013 May;73(5):603-16.
3. Landau SM, Lu M, Joshi AD, Pontecorvo M, Mintun MA, Trojanowski JQ, Shaw LM, Jagust WJ; Alzheimer's Disease Neuroimaging Initiative. Comparing positron emission tomography imaging and cerebrospinal fluid measurements of β-amyloid. Ann Neurol. 2013 Dec;74(6):826-36.
4. McKee AC, Cantu RC, Nowinski CJ, Hedley-Whyte ET, Gavett BE, Budson AE, Santini VE, Lee HS, Kubilus CA, Stern RA. Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol. 2009 Jul;68(7):709-35.
5. McKee AC, Stern RA, Nowinski CJ, Stein TD, Alvarez VE, Daneshvar DH, Lee HS, Wojtowicz SM, Hall G, Baugh CM, Riley DO, Kubilus CA, Cormier KA, Jacobs MA, Martin BR, Abraham CR, Ikezu T, Reichard RR, Wolozin BL, Budson AE, Goldstein LE, Kowall NW, Cantu RC. The spectrum of disease in chronic traumatic encephalopathy. Brain. 2013 Jan;136(Pt 1):43-64.
6. Ossenkoppele R, Pijnenburg YA, Perry DC, Cohn-Sheehy BI, Scheltens NM, Vogel JW, Kramer JH, van der Vlies AE, La Joie R, Rosen HJ, van der Flier WM, Grinberg LT, Rozemuller AJ, Huang EJ, van Berckel BN, Miller BL, Barkhof F, Jagust WJ, Scheltens P, Seeley WW, Rabinovici GD. The behavioural/dysexecutive variant of Alzheimer's disease: clinical, neuroimaging and pathological features. Brain. 2015 Sep;138(Pt 9):2732-49.
7. Ossenkoppele R, Schonhaut DR, Schöll M, Lockhart SN, Ayakta N, Baker SL, O'Neil JP, Janabi M, Lazaris A, Cantwell A, Vogel J, Santos M, Miller ZA, Bettcher BM, Vossel KA, Kramer JH, Gorno-Tempini ML, Miller BL, Jagust WJ, Rabinovici GD. Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer's disease. Brain. 2016;139:1551–67.
8. Possin KL, Feigenbaum D, Rankin KP, Smith GE, Boxer AL, Wood K, Hanna SM, Miller BL, Kramer JH. Dissociable executive functions in behavioral variant frontotemporal and Alzheimer dementias. Neurology. 2013 Jun 11;80(24):2180-5.
Selected Bibliography, cont.9. Rabinovici GD, Rosen HJ, Alkalay A, Kornak J, Furst AJ, Agarwal N, Mormino EC, O'Neil JP, Janabi M, Karydas
A, Growdon ME, Jang JY, Huang EJ, Dearmond SJ, Trojanowski JQ, Grinberg LT, Gorno-Tempini ML, Seeley WW, Miller BL, Jagust WJ. Amyloid vs FDG-PET in the differential diagnosis of AD and FTLD. Neurology. 2011 Dec 6;77(23):2034-42.
10. Ossenkoppele R, Cohn-Sheehy BI, La Joie R, Vogel JW, Möller C, Lehmann M, van Berckel BN, Seeley WW, Pijnenburg YA, Gorno-Tempini ML, Kramer JH, Barkhof F, Rosen HJ, van der Flier WM, Jagust WJ, Miller BL, Scheltens P, Rabinovici GD. Atrophy patterns in early clinical stages across distinct phenotypes of Alzheimer's disease. Hum Brain Mapp. 2015 Nov;36(11):4421-37.
11. Racine AM, Koscik RL, Nicholas CR, Clark LR, Okonkwo OC, Oh JM, Hillmer AT, Murali D, Barnhart TE, Betthauser TJ, Gallagher CL, Rowley HA, Dowling NM, Asthana S, Bendlin BB, Blennow K, Zetterberg H, Carlsson CM, Christian BT, Johnson SC. Cerebrospinal fluid ratios with Aβ42 predict preclinical brain β-amyloid accumulation. Alzheimers Dement (Amst). 2016;2:27-38.
12. Ranasinghe KG, Rankin KP, Pressman PS, Perry DC, Lobach IV, Seeley WW, Coppola G, Karydas AM, Grinberg LT, Shany-Ur T, Lee SE, Rabinovici GD, Rosen HJ, Gorno-Tempini ML, Boxer AL, Miller ZA, Chiong W, DeMay M, Kramer JH, Possin KL, Sturm VE, Bettcher BM, Neylan M, Zackey DD, Nguyen LA, Ketelle R, Block N, Wu TQ, Dallich A, Russek N, Caplan A, Geschwind DH, Vossel KA, Miller BL. Distinct Subtypes of Behavioral Variant Frontotemporal Dementia Based on Patterns of Network Degeneration. JAMA Neurol. 2016 Sep 1;73(9):1078-88.
13. Rojas JC, Karydas A, Bang J, Tsai RM, Blennow K, Liman V, Kramer JH, Rosen H, Miller BL, Zetterberg H, Boxer AL. Plasma neurofilament light chain predicts progression in progressive supranuclear palsy. Ann Clin Transl Neurol. 2016 Feb 1;3(3):216-25.
14. Seeley WW, Crawford RK, Zhou J, Miller BL, Greicius MD. Neurodegenerative diseases target large-scale human brain networks. Neuron. 2009 Apr 16;62(1):42-52.
15. Spina S, Schonhaut DR, Boeve BF, Seeley WW, Ossenkoppele R, O'Neil JP, Lazaris A, Rosen HJ, Boxer AL, Perry DC, Miller BL, Dickson DW, Parisi JE, Jagust WJ, Murray ME, Rabinovici GD. Frontotemporal dementia with the V337M MAPT mutation: Tau-PET and pathology correlations. Neurology. 2017 Jan 27.
16. Walsh CM, Ruoff L, Varbel J, Walker K, Grinberg LT, Boxer AL, Kramer JH, Miller BL, Neylan TC. Rest-activity rhythm disruption in progressive supranuclear palsy. Sleep Med. 2016 Jun;22:50-6.
CSF Measures & Baseline PiBBurden
Racine AM et al. AlzheimersDement (Amst). 2016