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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