Download - Disclosures, Bruce L. Miller, MD
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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
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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
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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
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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
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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?
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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)
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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
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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
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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* *
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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
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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
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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
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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
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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)
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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
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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
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8/31/201717
In Vivo Imaging of Microglial Motility
Yang et al., Nature Protocols, 2010
Progranulin Deficiency Impairs Microglial Baseline Motility in Vivo
Krabbe et al., PNAS, 2017
n=6, 4-5 mice, Student’s t-test, p=0.04
Grn+/+Grn–/–
Microglia’s Response to Injury is Attenuated PGRN Deficient Mice
Krabbe et al., PNAS, 2017
n=7, 4-5 mice
n=4 independent experiments, Student’s t-test, p<0.05
Grn+/+
Grn–/–
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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)
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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
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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