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

Overview  Modern subtyping, diagnosis, tracking  Burden of caregiving bvFTD:  bvFTD phenotype – empathy and emotion The Clinical Syndrome  Treatment: tauopathies, progranulin, lysosome 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 1 2 Frontotemporal Dementia (FTD) bvFTD Disorder of Socioemotional Behavior FRONTOTEMPORAL DEMENTIA ALZHEIMER’S DISEASE  Common cause pre-senile dementia Behavioral problems Behavioral problems - 1:1 with AD 45–64 years (Ratnavalli, Hodges 2002) , Disinhibition Apathy   most common dementia <60 (Knopman 2004) Apathy Irritability/agitation   Emotional blunting Depression   - More common when ALS, PSP & CBD, CTE considered “Euphoria” Neuroticism    Also occurs after 70 Obsessions and compulsions  Cognitive deficits Mental rigidity  - 25% FTD over 65, late onset tau more common (SW Seo 2018) Memory loss Depression   - TDP-43 & hippocampal sclerosis common in AD-dementia Visual-spatial impairment  Anomia Cognitive deficits  over 80 (Nelson 2007, 2013, Nag 2015) Executive dysfunction/language Executive loss   3 4 1

AD vs FTD Amyloid PET > FDG-PET 47 autopsy-proven cases Amyloid (PIB) PET visual reads 100% sensitivity Diagnosis 90% specificity FDG-PET visual reads 87% sensitivity 79% specificity Rabinovici et al. Neurology 2011 5 6 bvFTD MRI: Frontoinsular Atrophy 3 Types Frontotemporal Dementia Behavioral Variant Language Variants Semantic Nonfluent Variant Variant R L Often genetic Tau, TDP, FUS Rarely genetic Some genetic 2/3 TDP 83% TDP-C 85% Tau, TDP-A 7 8 2

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 20 m M Jonathan Rohrer 2011, Adeline Ng 2015 Right FI, FTLD-MND, Broe Stage 1 9 10 US-South American Initiative for Genetic-Neural- How Many Familial FTD Do You Follow? Behavioral Interactions in Neurodegenerative Disease Polygenetic risk score (T1) Ibanez, Yokoyama, Possin, Nitrini, Custudio, Lopera, ......... 11 12 3

Disease Progression in FTLD Neurofilament Predicts State/Decline clinical status brain volume percent maximal inflammation neurofilament asymptomatic questionable symptomatic FTLD-CDR 0 0.5 ≥ 1.0 Rojas 2019 13 14 International Research Criteria for Behavioral Variant FTD Early (2–3 yrs) behavioral disinhibition 1. Early (2–3 yrs) apathy or inertia 2. Early (2–3 yrs) loss of emotional reactivity, sympathy & empathy 3. Clinical FTD Perseverative, stereotyped or compulsive/ritualistic behavior 4. Hyperorality and dietary changes 5. FTD neuropsychological profile 6. Frontal or anterior temporal atrophy on MRI 7. Presence of known mutation 8. International Consortium, Brain, 2011 15 16 4

Relationship Turmoil and Empathy in FTD NIH EXAMINER Scales  Marital dissolution and infidelity significantly greater in the Working memory bvFTD group than nfvPPA, svPPA, CBS, PSP and AD Inhibition Set-Shifting  Across all patients, empathy loss was associated with Executive Composite Fluency marital dissolution Planning Social cognition  bvFTD patients who experienced marital dissolution or Behavior infidelity had significantly lower empathy scores than Insight those who did not Takeda et al, ADAD accepted 17 18 Post-Evaluation Behavior Rating 46 yo with bvFTD MMSE=26  Agitation  Distractibility  Stimulus-bound  Lack of social/emotional engagement  Perseverative  Impulsivity  Decreased initiation  Socially inappropriate  Motor stereotypies 19 20 5

Retraining Speech Production Fluency nfvPPA Treatment: repeated rehearsal of  scripts via structured treatment with a clinician and practice at home Significantly improved production  Therapies & Mechanisms 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 21 22 Therapies Pure Tauopathies vs. Mixed Tauopathy bvFTD  Mutations – bvFTD,  AD* nfvPPA, PSP, CBD  CTE*  Environment, social, legal  Pick – bvFTD, nfvPPA  Guam-PD-Dementia  Consider antidepressant  CBD – bvFTD, nfvPPA,  Postencephalitic  Avoid other meds executive/motor Parkinson’s  Clinical trials beginning  PSP – falls, gaze,  Niemann-Pick disease axial PD, dementia 23 24 6

Functional Connectivity Dorsal Midbrain Lysosome and Neurodegeneration Tegmental Network & Tau PET in PSP Lysosome cell’s Functional Connectivity Tau PET digestive system degrades: • Proteins CMA • Lipids UPS • Nucleic MICROAUTOPHAGY Acids • Bacteria • Viruses Disorders of Lysosome: Lysosome Neuronal Ceroid MACROAUTOPHAGY 0 2.5 Lipofuscinosis Gardner et al. Ann Neurol 2013, Rabinovici 2015 Courtesy Ana Maria Cuervo 25 26 Coming Next Lipid Storage Dx? Homo versus Heterozygosity Neuropsychiatric Disease Enzyme Peripheral organs Features Heterozygote  Better diagnosis FTD Adult neuronal CLN1-8, PPT1 Granular Manic to dementia, FTD (progranulin)  New causal and risk genes (Ibanez SAC) ceroid Progranulin (recessive) osmiophilic deposits retinopathy, seizures lipofuscinosis WBC, skin, neurons  Big grants (Boxer, Boeve & Rosen ALLFTD, Rohrer GENFI), Gaucher’s Glucocerebrosidase Liver spleen, bone Dementia, vertical PD marrow gaze, parkinsonian Ibanez South American Initiative Niemann-Pick-C NPC-1, NPC-2 Liver spleen Schizophrenia-like, PD  Tau-lowering trials – small molecules, antibodies and (transport protein) vertical gaze, parkinsonian, CRISPR cerebellar ataxia  For TDP-43 subtypes Adult neuronal MFSD8 — Childhood disease, FTD ceroid retinal. Early death Anti-inflammatory compounds for svPPA - lipofuscinos Progranulin-elevating therapies (AAV-delivery) - AD Nasu-Hakola TREM-2 (recessive) Bone cysts FTD-syndrome Genetic therapies silence gene in C9ORF72 (anti-oligonucleotides) PLOSL DAP-12 - 27 28 7

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2/14/2020 Disclosures • Shareholder in Personalis, Inc. Alzheimer’s and other neurodegenerative diseases: The road ahead to a cure Aimee Kao, MD, PhD Recent Advances in Neurology February 14 th , 2020 Recent Advances in Neurology 2019 1 2 The Coming Epidemic of Alzheimer’s Disease Why are neurodegenerative diseases Percent change in cause of death (2000-2013) important? +71% • 1 in 9 persons over the age of 65 has Alzheimer’s Disease • Aging population -2% -11% -14% -23% -52% • Long disease course • In 2019, AD cost the US ~$290 billion Breast Prostate Heart Stroke HIV Alzheimer’s cancer cancer disease Disease 3 4 1

2/14/2020 Protein aggregates have had an important role in Future investments are coming… neurodegenerative disease classification and research Arnold Pick Alois Alzheimer Frederic Lewy Pick Bodies (1892) Plaques/tangles (1906) Lewy Bodies (1912) 5 6 Problem #1: We are in the middle ages of Problem #2: The Amyloid Cascade Hypothesis neurodegenerative disease classification Neuropathology Genetic Loci Clinical Diagnosis PSEN1, PSEN2, Alzheimer’s Disease APP, APOE Plaques/tangles Pgrn, MAPT, FUS, Frontotemporal dementia TARDBP, C9ORF72,VCP… Pick Bodies SNCA, Pink, Parkin, Parkinson’s Disease DJ1, LRRK2, GBA … Lewy Bodies Karran Mercken and De Strooper, 2011 7 9 2

2/14/2020 The Tau-ists versus the b aptists Which brings up the important questions, how much do aggregated proteins matter? Risk of Death. No inclusion Inclusion Time (hr) 10 11 Problem #3 : A dizzying number of disease mechanisms Neurodegenerative diseases are age-related failures of protein homeostasis Proteostasis Genetics Lysosome/Autophagy Gene mutation Protein Homeostasis Proteosome Gene dosage RNA Age ER stress SNPs Stress Chaperones Proteosome RNA BP Mutations Epigenetics Prion/aggregation miRNA Molecules Degradation PTM RNA foci Aging X Stress granules Oxidative stress Properly folded Misfolded RNA structure Lysosome Mitochondrial dysfxn Sequestration Gene expression Synapses/activity Cell quiescence Alzheimer’s Parkinson’s FTLD/ALS Excitotoxicity Selective vulnerability Injury/Environment Synaptic dysfunction Traumatic Brain Injury Excessive pruning Trafficking Auto-immunity Microtubule stability Nuclear pore Complement A b and tau a -synuclein Protein inclusion: TDP-43 tau Endo/lysosome Lipid Homeostasis Cell type of origin: Ent Crtx LC/SNpc VENs, Motor N. Axonal Metabolism Genes: APP, PSEN 1/2 SNCA, Pink, TARDBP, MAPT, Pgrn Dendritic Heavy metals www.wiki.brown.edu Parkin, GBA C9ORF72,TSC1 12 13 3