disclosures, bruce l. miller, md

[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

8/31/20171

Frontotemporal Dementia:The Behavioral Phenotype

8/31/2017

Bruce L. Miller, MDA.W. and Mary Margaret Clausen Distinguished Professor in NeurologyDirector, Memory and Aging CenterCo-Director, Global Brain Health InstituteJoint Appointment in PsychiatryUCSF School of Medicine

Disclosures, Bruce L. Miller, MDBruce L. Miller, MD, has financial interests to disclose. Potential conflicts of interest have been resolved.

• Research Support/Grants– NIH/NIA grants: P50AG023501, P01AG019724, P50 AG1657303, T32 AG023481– CMS grant 1C1CMS331346-01-00– UCSF/Quest Diagnostics Dementia Pathway Collaboration Research Grant

• Consulting/Employment– The 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 the Biomedical Research Unit in Dementia (UK)– American Brain Foundation – Board Member– University of Washington ADRC – External Advisor– Stanford University ADRC – External Advisor– Arizona Alzheimer’s Disease Center – External Advisor– International Society of FTD – President

• Speakers Bureau/Honoraria– Cambridge University Press– Guilford Publications, Inc.– Oxford University Press– Neurocase– Elsevier, Inc.

UCSF Memory and Aging Center 2016

UCSF Mission Bay Campus, Sculpture Mark di Suvero


8/31/20172

Overview

• Introduction of FTD (it’s important)

• Brief neuropathology/genetics

• Clinical bvFTD

– Crime

– Emotion

• Tau imaging

• Progranulin therapeutics

• Tau therapeutics

Frontotemporal Dementia (FTD)

• 1892, Arnold Pick describes a focal neurodegenerative condition

• Pick’s disease preferentially affects the frontal and temporal lobes

• Pick body (Alzheimer 2011)

VBM of FTD & AD vs Controls

Concept from Delay, Brion Escourolle 1950s, Thibodeau MP, Miller BL. Neurocase. 2013


8/31/20173

Frontotemporal Dementia (FTD)

• Common cause pre-senile dementia

– 1:1 with AD 45–64 years (Hodges 2002), most common dementia <60

– 40% familial, 10% dominant (Chow, 1999)

• Rare after 70?

– Strong links with ALS, PSP, CBD

– TDP-43 & hippocampal sclerosis common dementia over 80 (Nelson 2007, 2013, Nag 2015)

Chronic Traumatic Encephalopathy/Tau

McKee AC et al. J Neuropathol Exp Neurol. 2009

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


8/31/20174

Network-based Neurodegeneration

Time (sec)

Single subject

Seeley et al Neuron 2009

C9ORF72 Small Medial PulvinarSalience Network Disruption

Lee SE et al. Brain 2014

Pick 3R PSP 4R CBD 4R

TDP-A TDP-B TDP-C

FTLD-TDP

FTLD-tau

Dipeptides(C9ORF72)

FTLD-FUS


8/31/20175

LeftPick’s

CBD

PSP*

TDP-A

TDP-B

TDP-C

TDP-U

aFTLD-U

VBM, pFWE < 0.05

FTLD-tau FTLD-TDP FTLD-FUS

frontotemporal lobar degeneration (FTLD)

bvFTD

Three Main Genetic Mutations

• MAPT: 52 years, MRI symmetrical, bvFTD with parkinsonian syndromes, 1998

• GRN: 62 years, MRI asymmetric, bvFTD, progressive aphasia, PD, AD, 2006

• C9ORF72: 56 years, MRI symmetric, cerebellar involvement (subtler frontal involvement), bvFTD and ALS, 2011

*Adeline Ng Neurology 2015

How Many Familial FTLD Do You Follow?


8/31/20176

Rare Variants with FTD-ALS Syndromes 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

Giovanni Coppola personal communication

Behavioral Variant Frontotemporal Dementia (bvFTD): A SocioemotionalDisease

• Behavioral disinhibition• Apathy or inertia• Loss of sympathy or

empathy• Perseverative, stereotyped,

or compulsive behavior• Hyperorality and dietary

changes• Executive dysfunction

International Consortium Brain 2011

Medial Versus Lateral Orbital Cortex

+ monitoring reward value

+ punishers leading to change in behavior

(Kringelbach & Rolls 2004 meta-analysis)


8/31/20177

Crime with Dementia

Dx Number Percentage

AD 545 7.7%

bvFTD 171 37.4%

svPPA 89 27%

HD 30 20%

MCI 243 3.3%

Liljegren & Naasan et al JAMA Neurol 2015

Crime: bvFTD, svPPA & ADbvFTD svPPA AD

Frequency 37.40% 27% 7.70%

OnsetEarly Early Late

Types

Sexual advance, theft, public urination, violence

Theft, traffic violation Traffic violation, trespass/wander

Cause

Disinhibition, impulsivity, reward/punish

Compulsive attracted to visual stimuli

Cognitive dysfunction

Anatomy

Anterior insular, orbitofrontal, ventral striatum

Ant. temporal orbitofrontal, ventral striatum

Hippocampus, parietal lobe

Liljegren & Naasan et al JAMA Neurol 2015

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 changes

6. FTD neuropsychological profile

7. Frontal or anterior temporal atrophy on MRI

8. Presence of known mutation

International Consortium, Brain, 2011


8/31/20178

n=148

Abnormal Behavior Driven by Right Hemisphere Dysfunction

3 T-score 5

Aberrant Motor BehaviorApathyDisinhibition

3 T-score 5

3 T-score 5

VMFC

Medial SFG

Left Right

Axial, z=72Sagittal, x=4

Right

Rosen et al. Brain, 2005

Dorsal ACC

Precentral sulcus

Rankin et al. Brain 2006

R temporal pole R medial OFC R caudate R medial frontal

Only right hemisphere mediates these empathy changes

Loss of Empathy

Leaders of the Neuroscience of Emotion

Guillaume-Benjamin-AmandDuchenne de Boulogne Paul Ekman Robert Levenson


8/31/20179

Disgust: Levenson Lab Methods

BehaviorPhysiological reactivitySelf-report

baseline

1 min.

film

~1 min.

Eckart et al., 2012

X

Eliciting Disgust in the Laboratory

• Autonomic Reactivity: change from baseline

• Facial Expression: disgust behavior

• Subjective Experience: self-report

Eckart, Sturm, Miller & Levenson, 2012

baseline

1 min.

disgusting film clip

~1 min.

XQ & A

~1 min.

Impaired Disgust Reactivity in bvFTD

* p < .05

Self-Reported Experience: bvFTD< controls when controlling for total emotion

Eckart, Sturm, Miller & Levenson, 2012

Mean Disgust Beh

avior

ANS Reactivity (z‐score)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

bvFTD

Controls‐0.15

‐0.1

‐0.05

0

0.05

0.1

0.15* *


8/31/201710

Loss of Disgust in FTD

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Disgust Behavior

FTD

Control

Self-Reported Experience: FTD < controls

-0.2

-0.15

-0.1

-0.05

0

0.05

0.1

0.15FTD

Control

ANS Reactivity

Eckart et al., 2012

*

Me

an

Em

oti

on

al B

eh

av

ior

* p < .05

*

Disgust Behaviors

Disgust Recognition

Overlap

Woolley et al.,Biol Psych 2015

Frontoinsula Atrophy Relates to Diminished Disgust

• Lower disgust reactivity (ANSand self-reported experience) related to smaller bilateral insula volume

• Frontoinsula atrophy related to real-world disgust behavior and disgust recognition deficits

Kurth et al., 2010; Verstaen et al., 2015; Woolley et al., 2015

Disgusting behavior

Disgust recognition deficit

Overlap

disgust reactivity

impairment

disgust recognition

deficits

lack of disgust

avoidance

bvFTD


8/31/201711

Overlapping Anatomy of Reward Processing and bvFTD

Haber and Knutson, Neuropsychopharmacology, 2010

Seeley et al, Archives of Neurology, 2008

Reward Seeking in bvFTD

Perry, Brain, 2014

Overeating

Drug use4

33

10

2046

Hypersexuality

Olfactory Reward TasksLess aversion to unpleasant smells in bvFTD

Perry et al, unpublished


8/31/201712

Reward Changes in FTD Relate to Atrophy in Reward Processing Structures

3.6

4.4

5.2R7 R63

3.5

4.5

5.5R-1

Greater atrophy with smaller gaps between ratings of pleasant and unpleasant

Greater atrophy with more positive rating of unpleasant smells

Displayed at p<.001 within regions known to be involved in reward

Psychiatric Misdiagnosis

0

10

20

30

40

50

60

70

bvFTD(n=69)

AD (n=65) svPPA(n=41)

nfvPPA(n=17)

CBD(n=25)

PSP(n=15)

ALS(n=20)

Men

Women

Total

Rates of Psychiatric Diagnosis within each Neurodegenerative Disease

Woolley et al. J Clin Psychiatry 2011

Per

cent

of S

ampl

e *

†

Treatable Disorders Missed

Sagging Brain K channel ab

Klassen & Ahlskog 2011 M Hong et al. 2002 M Geschwind et al. 2008

NPH


8/31/201713

Therapies

• bvFTD

– Environment, social, legal

– Consider antidepressant

– Avoid other meds

– Clinical trials beginning

AD vs FTD Amyloid PET > FDG-PET

47 autopsy-proven cases

Amyloid (PIB) PET visual reads

100% sensitivity

90% specificity

FDG-PET visual reads

87% sensitivity

79% specificity

Rabinovici et al. Neurology 2011

Tau PET: The New Frontier

Amyloid, tau &brain metabolism 57 year-old AD

Brain dysfunction correlates with tau but not amyloid

Ossenkoppele R et al. Brain 2016


8/31/201714

Ossenkoppele et al., Brain 2016

Tau PET Patterns Correlate with AD Phenotype

bvFTD V337M MAPT Mutation

Salvo Spina et al, Neurology, 2017

Consortium for Frontotemporal Dementia Research (progranulin)

• Progranulin knockout mouse (B Farese, Harvard)

• Behavior(E Roberson, UAB; L Gan, UCSF)

• Progranulin & granulin pathways (L Gan, UCSF)

• High throughput screen (J Herz, Y Gang, UT)

• Clinical/pathology/gene carrier (B Seeley, S Lee, B Miller, UCSF)– Early detection: clinical, fMRI

• Skin/iPS/neuron (B Farese M Ward NIH) • PGRN genetics (R Rademakers, Mayo)• Lysosome (S Ferguson, Yale; B Farese)• Treatments (Adam Boxer, UCSF)


8/31/201715

Restoring Progranulin LevelsTHERAPEUTIC GOAL: Increase GRN transcription from the remaining WT alleleSCREEN: FDA-approved compound library using luciferase-tagged PGRN reporterSAHA greatly altered progranulin levels

Joachim Herz & Gang Yu labs, UTSW

Michael E. Ward et al., Sci Transl Med 2017;9:eaah5642

Lysosomal Storage Features

Michael E. Ward et al., Sci Transl Med 2017

• Homozygote GRN lysosomal storage disease neuronal ceroid lipofuscinosis (NCL) (Smith K 2012, Almeida M 2016)

• Heterozygous GRNmutation show autofluorescent NCL-like storage material in the CNS

Chronic Neuroinflammation Contributes to Neurodegeneration

Pgr

n+

/+P

grn

-/-

Ahmed et al, Am J Pathol 2010

Iba1+ microglia

Kao et al, Nat Rev Neurosci 2017

Loss PGRN activates innate immune cells


8/31/201716

Critical Role of Microglia and TNFSignaling in Progranulin Deficient FTD

Aaccumulation

PGRN-deficientmicroglia

TNF-

Neuronal deficits & OCD-like behaviors

Minami et al., Nat. Med., 2014

Krabbe et al., PNAS., 2017

PGRN Deficient FTD Patients Exhibit OCD-like Behavior

David Perry, Bruce Miller, UCSF Krabbe et al., PNAS, 2017

I = 250 pA

Reducing TNFα Restored the Firing Frequency in PGRN Deficient Striatal Neurons to WT Levels

Krabbe et al., PNAS, 2017

N = 107, 99, 61, 47cells from 16, 14, 8, 7 mice


8/31/201717

In Vivo Imaging of Microglial Motility

Yang et al., Nature Protocols, 2010

Progranulin Deficiency Impairs Microglial Baseline Motility in Vivo


n=6, 4-5 mice, Student’s t-test, p=0.04

Grn+/+Grn–/–

Microglia’s Response to Injury is Attenuated PGRN Deficient Mice


n=7, 4-5 mice

n=4 independent experiments, Student’s t-test, p<0.05

Grn+/+

Grn–/–


8/31/201718

PGRN Loss Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation

Lui H, Huang EJ et al., Cell 2016;165:921–935

Removing C1qa in Grn−/−;C1qa−/− Mice Protects Synaptic Pruning, Restores Thalamic Microcircuit Function, Mitigates OCD-like Behaviors, and Improves Survival

E Huang Lab in Cell

Tau Consortium

Stem cells(Crary, Goate, Haggarty, Ichida, Kampmann, Kao, Karch, Temple)

Genomics(Coppola, Geschwind, Goate, Lee, Yokoyama)

Biomarkers(Boxer, Geschwind, Grinberg, Jagust, Kramer, Mathis, B Miller, Neylan, Rabinovici, Rankin, Seeley, Steen, Vasdev, Walsh)

Treatments(Arkin, Boxer, Cuervo, Diamond, Disney, Gan, Gestwicki, Haggarty, Kosik, Krichevsky, T Miller, Prusiner, Rubinsztein)

Synthesis (Bateman, Disney, Gan, Holtzman, Kao, T Miller)

Propagation(Diamond, Duff, Goate, Han, Prusiner)

Clearance(Cuervo, Gestwicki, Haggarty, Rubinsztein)

Models(Mucke, Rubinsztein)


8/31/201719

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• Postencephalitic

Parkinson’s• Niemann-Pick

disease

Tau Spreads Like a Prion

Courtesy of Marc Diamond

Functional Connectivity Dorsal Midbrain Tegmental Network & Tau PET in PSP

0 2.5

Gardner et al. Ann Neurol 2013, Rabinovici 2015

Functional Connectivity Tau PET


8/31/201720

UPS

Lysosome

MACROAUTOPHAGY

CMA

MICROAUTOPHAGY

Tau Clearance – Ana Maria Cuervo

Courtesy Ana Maria Cuervo

2017

• Better diagnosis of tau-related FTD

• New causal and risk genes

• U grants (Boxer Orphan Disease, Boeve, Rosen FTD Genetics), GENFI (Jonathan Rohrer)

• Tau-lowering trials with antibodies

• For TDP-43 subtypes

– Anti-inflammatory compounds for svPPA

– Progranulin-elevating therapies

– Genetic therapies silence gene in C9orf72 forms of FTD-ALS

disclosures, bruce l. miller, md

Documents