Overview Modern subtyping, diagnosis, tracking Burden of caregiving - - PowerPoint PPT Presentation

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bvFTD: The Clinical Syndrome

Bruce L. Miller, MD

A.W. and Mary Margaret Clausen Distinguished Professor in Neurology Director, Memory and Aging Center Co-Director, Global Brain Health Institute

Overview

• Modern subtyping, diagnosis, tracking
• Burden of caregiving
• bvFTD phenotype – empathy and emotion
• Treatment: tauopathies, progranulin, lysosome

Frontotemporal Dementia (FTD)

• Common cause pre-senile dementia
• 1:1 with AD 45–64 years (Ratnavalli, Hodges 2002),

most common dementia <60 (Knopman 2004)

• More common when ALS, PSP & CBD, CTE considered
• Also occurs after 70
• 25% FTD over 65, late onset tau more common (SW Seo 2018)
• TDP-43 & hippocampal sclerosis common in AD-dementia
• ver 80 (Nelson 2007, 2013, Nag 2015)

bvFTD Disorder of Socioemotional Behavior

FRONTOTEMPORAL DEMENTIA Behavioral problems

• Disinhibition
• Apathy
• Emotional blunting
• “Euphoria”
• Obsessions and compulsions
• Mental rigidity
• Depression

Cognitive deficits

• Executive dysfunction/language

ALZHEIMER’S DISEASE Behavioral problems

• Apathy
• Irritability/agitation
• Depression
• Neuroticism

Cognitive deficits

• Memory loss
• Visual-spatial impairment
• Anomia
• Executive loss

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Diagnosis 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

Behavioral Variant Language Variants Semantic Variant Nonfluent Variant

R L

Rarely genetic 83% TDP-C Some genetic 85% Tau, TDP-A Often genetic Tau, TDP, FUS 2/3 TDP

3 Types Frontotemporal Dementia

bvFTD MRI: Frontoinsular Atrophy

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20 mM

Right FI, FTLD-MND, Broe Stage 1

Early FTD: Speckled TDP-43 Inclusions

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

Jonathan Rohrer 2011, Adeline Ng 2015

How Many Familial FTD Do You Follow?

US-South American Initiative for Genetic-Neural- Behavioral Interactions in Neurodegenerative Disease

Polygenetic risk score (T1)

Ibanez, Yokoyama, Possin, Nitrini, Custudio, Lopera, .........

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clinical status brain volume neurofilament inflammation FTLD-CDR questionable asymptomatic symptomatic 0.5 ≥ 1.0 percent maximal

Disease Progression in FTLD Neurofilament Predicts State/Decline

Rojas 2019

Clinical FTD International Research Criteria for Behavioral Variant FTD

1.

Early (2–3 yrs) behavioral disinhibition

2.

Early (2–3 yrs) apathy or inertia

3.

Early (2–3 yrs) loss of emotional reactivity, sympathy & 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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Relationship Turmoil and Empathy in FTD

• Marital dissolution and infidelity significantly greater in the

bvFTD group than nfvPPA, svPPA, CBS, PSP and AD

• Across all patients, empathy loss was associated with

marital dissolution

• bvFTD patients who experienced marital dissolution or

infidelity had significantly lower empathy scores than those who did not

Takeda et al, ADAD accepted

NIH EXAMINER Scales

Executive Composite

Working memory Inhibition Set-Shifting Fluency Planning Social cognition Behavior Insight

Post-Evaluation Behavior Rating

• Agitation
• Stimulus-bound
• Perseverative
• Decreased initiation
• Motor stereotypies
• Distractibility
• Lack of social/emotional

engagement

• Impulsivity
• Socially inappropriate

46 yo with bvFTD

MMSE=26

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Therapies & Mechanisms

Retraining Speech Production Fluency nfvPPA

• Treatment: repeated rehearsal of

scripts via structured treatment with a clinician and practice at home

• Significantly improved production

correct words for trained topics, reduced grammatical errors trained topics, increased intelligibility trained and untrained topics post-treatment

• Follow-up testing, maintenance of

gains for trained scripts up to 1 year post-treatment

Henry et al. 2018

Therapies

bvFTD

• Environment, social, legal
• Consider antidepressant
• Avoid other meds
• Clinical trials beginning

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

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Functional Connectivity Dorsal Midbrain Tegmental Network & Tau PET in PSP

2.5

Gardner et al. Ann Neurol 2013, Rabinovici 2015

Functional Connectivity Tau PET

UPS

Lysosome

MACROAUTOPHAGY

CMA

MICROAUTOPHAGY

Lysosome and Neurodegeneration

Courtesy Ana Maria Cuervo

Lysosome cell’s digestive system degrades:

• Proteins
• Lipids
• Nucleic

Acids

• Bacteria
• Viruses

Disorders of Lysosome: Neuronal Ceroid Lipofuscinosis

Lipid Storage Dx? Homo versus Heterozygosity

Disease Enzyme Peripheral organs Neuropsychiatric Features Heterozygote

Adult neuronal ceroid lipofuscinosis CLN1-8, PPT1 Progranulin (recessive) Granular

• smiophilic deposits

WBC, skin, neurons Manic to dementia, retinopathy, seizures FTD (progranulin) Gaucher’s Glucocerebrosidase Liver spleen, bone marrow Dementia, vertical gaze, parkinsonian PD Niemann-Pick-C NPC-1, NPC-2 (transport protein) Liver spleen Schizophrenia-like, vertical gaze, parkinsonian, cerebellar ataxia PD Adult neuronal ceroid lipofuscinos MFSD8 — Childhood disease,

• retinal. Early death

FTD Nasu-Hakola PLOSL TREM-2 (recessive) DAP-12 Bone cysts FTD-syndrome AD

Coming Next

• Better diagnosis FTD
• New causal and risk genes (Ibanez SAC)
• Big grants (Boxer, Boeve & Rosen ALLFTD, Rohrer GENFI),

Ibanez South American Initiative

• Tau-lowering trials – small molecules, antibodies and

CRISPR

• For TDP-43 subtypes
• Anti-inflammatory compounds for svPPA
• Progranulin-elevating therapies (AAV-delivery)
• Genetic therapies silence gene in C9ORF72 (anti-oligonucleotides)

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2/14/2020 1 Alzheimer’s and other neurodegenerative diseases: The road ahead to a cure

Aimee Kao, MD, PhD

Recent Advances in Neurology February 14th, 2020

Disclosures

Recent Advances in Neurology 2019

• Shareholder in Personalis, Inc.

Why are neurodegenerative diseases important?

• 1 in 9 persons over the

age of 65 has Alzheimer’s Disease

• Aging population
• Long disease course
• In 2019, AD cost the

US ~$290 billion

The Coming Epidemic of Alzheimer’s Disease

Percent change in cause of death (2000-2013)

+71% Breast cancer Prostate cancer Heart disease Stroke HIV Alzheimer’s Disease

• 52%
• 23%
• 14%
• 11%
• 2%

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Future investments are coming…

Alois Alzheimer Frederic Lewy Arnold Pick

Pick Bodies (1892) Lewy Bodies (1912) Plaques/tangles (1906)

Protein aggregates have had an important role in neurodegenerative disease classification and research

Pick Bodies Plaques/tangles

Problem #1: We are in the middle ages of neurodegenerative disease classification

Clinical Diagnosis Neuropathology Genetic Loci Alzheimer’s Disease Frontotemporal dementia Parkinson’s Disease

PSEN1, PSEN2, APP, APOE Pgrn, MAPT, FUS, TARDBP, C9ORF72,VCP… SNCA, Pink, Parkin, DJ1, LRRK2, GBA …

Lewy Bodies

Problem #2: The Amyloid Cascade Hypothesis

Karran Mercken and De Strooper, 2011

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The Tau-ists versus the baptists

Which brings up the important questions, how much do aggregated proteins matter?

Inclusion No inclusion Time (hr) Risk of Death.

www.wiki.brown.edu

Problem #3: A dizzying number of disease mechanisms

Genetics

Gene mutation Gene dosage SNPs Epigenetics Molecules

Proteostasis

Lysosome/Autophagy Proteosome ER stress Chaperones Prion/aggregation PTM

Synapses/activity

Excitotoxicity Selective vulnerability Synaptic dysfunction Excessive pruning Microtubule stability

Aging

Oxidative stress Mitochondrial dysfxn Gene expression Cell quiescence

Injury/Environment

Traumatic Brain Injury Auto-immunity Complement Lipid Homeostasis Metabolism Heavy metals

Trafficking

Nuclear pore Endo/lysosome Axonal Dendritic

RNA

RNA BP miRNA RNA foci Stress granules RNA structure

Neurodegenerative diseases are age-related failures of protein homeostasis

a-synuclein LC/SNpc SNCA, Pink, Parkin, GBA Ab and tau Ent Crtx

APP, PSEN 1/2

TDP-43 tau VENs, Motor N. TARDBP, MAPT, Pgrn C9ORF72,TSC1 Protein inclusion: Cell type of origin: Genes:

Sequestration

Misfolded Properly folded

Age Stress Mutations

Degradation Protein Homeostasis

Alzheimer’s Parkinson’s FTLD/ALS

Proteosome Lysosome

X

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The deeply enigmatic and endlessly alluring lysosome

• Membrane bound organelle (#4)
• More than the “garbage can” of the cell
• Complex regulatory functions
• Cell clearance and recycling
• Nutrient sensing and signaling
• Storage and delivery of metabolites
• Lysosomal exocytosis
• “Acid hydrolases” degrade macromolecules
• Age and disease-related changes
• Mutations associated with lysosomal

storage disorders in youth, neurodegeneration with age

E ndoplasmic reticulum 7 .2 Nucleus 7 .2 C ytosol 7 .2 Lysosome 4.7 Late endosome 5.5 E arly endosome 6.3 R ecycling endosome 6.5 S ecretory granule 5.5 P eroxisomes 7 Mitochondria 8 Cis Medial T rans T rans-golgi network Golgi network 6.7 6

Lysosomes rely on acidic pH to perform its metabolic functions

Extracellular 7.4

Casey, Grinstein & Orlowski Nat Rev Molec Cell Biology, 2010 H+ H+

pHlys

The autophagy-lysosome system is a major player in macromolecular degradation

Kaur & Debnath, Nat Rev Mol Cell Bio 2015

The case for the lysosome as a major player in neurodegenerative disease pathophysiology

Settembre, Nat Rev Mol Biol 2013

Mutation of genes involved in the endolysosomal pathway ATP 13A2 (P D) CA TD (AD) GBA (PD) P SE N1/ 2 (AD) VPS 35 (PD) Ageing Mutation of genes encoding aggregate-prone proteins S NCA (PD) APP (AD) HTT (HD) MAPT (PD/AD) Gain of function Loss of function Lysosomal function and autophagy Enhanced protein aggregation (α-synuclein, HTT , Aβ-peptides and T au) Defective cellular clearance and accumulation of neurotoxic proteins Neurodegeneration P AR KIN (PD) P INK (PD) CHMP 2B (FTD) R AB7 (CMT2B) WDR 45 (S ENDA)

F igure 3 | Defective cellular clearance in neurodegenerative dis eas es . Defective cellular DNAJC5 (PD) MFSD8 (FTD) TSC1 (FTD) Pgrn (FTD)

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Lysosomal composition

L YNUS Glycocalyx Lysosome membrane

Settembre, Nat Rev Mol Biol 2013

Lysosome

The earliest link between neurodegenerative and neurodevelopmental disorders

Glucosylceramide Glucose Ceramide

+

GBA GBA-/- Gaucher Dis GBA+/- Parkinson Dis

*

Gene dosage

GBA+/+

Progranulin: Dose determines disease

PGRN

PGRN

Auto-immune disease

Pgrn Heterozygote

FTLD/neurodegeneration Tumor growth and metastasis

Pgrn Excess Pgrn Null

Neuronal ceroid lipofuscinosis

• --C------C-----CC--------CC------CC----HCCP----C------C-

Granulin consensus motif

Progranulin is a secreted glycoprotein composed

• f “granulin” repeats

7 kDa “granulin” MW= 65-88 kDa

• H. sapiens progranulin

G F B A C D E p

* * * * *

Signal peptide Granulin domain

*

Glycosylation sites

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2/14/2020 6 Progranulin regulates lysosomal protease activity in a complex and nuanced fashion

Intact Progranulin

Age, stress & pH-dependent

Lysosome Function/ Cathepsin D activity

Protein degradation Tx?

Multi-granulin fragments Individual granulins

(+) (++)

TDP-43?

(-) The lysosome: A key player in both neurodevelopmental and neurodegenerative disorders

Future directions…

• What else can neurodevelopmental

disorders teach us about neuro- degeneration?

• Find ways to enhance lysosome

function

• Better disease nosology is required
• Then personalized therapies can be

developed

Thank you!

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