Frontotemporal Dementia

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

Overview

▪ Modern subtyping - molecules, pathology and genes▪ Burden of caregiving ▪ bvFTD phenotype – empathy and emotion▪ Non-medical interventions

Models of Degenerative Dementia

All degenerative dementias have: ▪ Genetic and sporadic form▪ Cell culture and animal models

▪ Preclinical, early symptomatic and symptomatic phase ▪ Abnormal protein aggregation▪ Proteins spread from cell to cell

worm fruit flycells mouse

Neuropathologic Inclusions DISEASE PROTEIN INCLUSION

Alzheimer’s disease (AD) Aβ-42 & tau

Frontotemporal lobar degeneration (FTLD)/amyotrophic lateral sclerosis (ALS)

tau orTDP-43

Progressive supranuclear palsy (PSP), corticobasal degeneration (CBD)

tau

Parkinson’s disease, Lewy body disease, multiple systems atrophy

α-synuclein

Frontotemporal Dementia (FTD)

▪ Common cause pre-senile dementia- 1:1 with Alzheimer’s disease in people 45–64 years

(Ratnavalli, Hodges 2002)

- Most common dementia under age 60 (Knopman 2004)

- More common if ALS, PSP & CBD, CTE considered▪ Also occurs after age 70▪ 60,000 cases listed but likely is an underreported number

Behavioral Variant Language Variants

SemanticVariant

Nonfluent Variant

R L

Rarely genetic Some genetic

Often genetic

3 Types Frontotemporal Dementia

Slide courtesy of Bill Seeley

Chronic Traumatic Encephalopathy/Tau

McKee AC et al. J Neuropathol Exp Neurol. 2009

molecular pathology

clinical status

brain volume

neurofilamentinflammation

FTLD-CDRquestionableasymptomatic symptomatic

0 0.5 ≥ 1.0

perc

ent m

axim

alDisease Progression in FTLD

BiochemicalChanges

Dementia

Mild CognitiveImpairment

Usual time of presentation

Pathophysiology

Symptoms:

Presentation of many patients with memory

complaints

10 years

Transition from “Normal” to “Impaired” in Neurodegenerative Disease

NeurodegenerativeChanges

Psychiatric MisdiagnosisRates of Psychiatric Diagnosis within each Neurodegenerative Disease

Woolley et al. J Clin Psychiatry 2011

Per

cent

of S

ampl

e

*

†

bvFTD – Socioemotional Behavioral SyndromeFRONTOTEMPORAL DEMENTIABehavioral problems▪ Disinhibition▪ Apathy▪ Emotional blunting▪ “Euphoria”▪ Obsessions and compulsions▪ Mental rigidity▪ Depression

Cognitive deficits▪ Executive dysfunction/language

ALZHEIMER’S DISEASEBehavioral problems▪ Apathy▪ Irritability/agitation▪ Depression▪ Neuroticism

Cognitive deficits▪ Memory loss▪ Visual-spatial impairment▪ Anomia (naming)▪ Executive loss

bvFTD Early Changes

▪ Selfishness▪ Passivity▪ Addictive behaviors: alcohol, cigarettes, food▪ Changes in self▪ Disinhibition▪ Criminal behaviors▪ Loss of empathy for others▪ Psychiatric syndromes (particularly in prodrome)

Impulse Control in the Medial Cortex vs Lateral Orbital Cortex

Kringelbach & Rolls 2004 meta-analysis

Blue = reward (medial)Yellow = punishment (lateral)

view

Crime with Dementia

Dx Number Percentage

Behavioral Variant FTD (bvFTD) 171 37.4%

Semantic Variant PPA (svPPA) 89 27%

Huntington’s Disease (HD) 30 20%

Alzheimer’s Disease (AD) 545 7.7%

Mild Cognitive Impairment (MCI) 243 3.3%

Liljegren & Naasan, Englund et al JAMA Neurol 2015 and Liljegren JAMA 2019

Rankin et al. Brain 2006

Loss of Empathy

▪ R temporal pole▪ R medial orbitofrontal cortex▪ R caudate▪ R medial frontal▪ Only right hemisphere

mediates these empathy changes

Relationship Turmoil and Empathy in FTD

▪ Marital dissolution and infidelity significantly greater in the bvFTD group than nfvPPA, svPPA, CBS, PSP, 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 2019

Brain Atrophy Caregiver HealthCaregiver

PsychopathologyPatient Brain

Caregiver Global Health

Covariates:▪ caregiver age and sex▪ patient diagnosis, disease severity, cognitive functioning, head size▪ MRI scanner field strength

Hua, Dementia Geriatric Cognitive Disord, 2019

Neural Correlates of Worse Caregiver Health

Hua, Wells, Haase, Chen, Rosen, Miller, Levenson 2019 Dementia and Geriatric Cognitive Disorders

Lifestyle Moderates Genetic FTD

*Adj. baseline frontotemporal volumes, age, sex, education, FTLD-CDR sum of boxes

Casaletto, et al 2020 Alz Demen

Coming Next

▪ Better diagnosis of frontotemporal dementia (FTD)▪ New causal and risk genes (UCSF PPG, Ibanez SAC)▪ Big grants (Boxer, Boeve & Rosen ALLFTD Genetics,

Rohrer GENFI, Ibanez South American Initiative)▪ Treatment trials – small molecules, antibodies, CRISPR