Frontotemporal Dementia (FTD) Frontotemporal dementia: clinical • In 1892, Arnold Pick describes a focal syndromes and pathobiology neurodegenerative condition involving the frontal and anterior temporal lobes William W. Seeley, MD Associate Professor of Neurology and Pathology UCSF • Alois Alzheimer, Pick’s Recent Advances in Neurology student, observes that February 13, 2014 some patients harbor argyophilic “Pick bodies” Bruce Miller, UCSF unlike the neurofibrillary tangles of AD Take home points FTD Prevalence Common cause early age-of-onset dementia • FTD is a common and under-diagnosed form of early age- of-onset dementia strongly linked to ALS • 1:1 with AD 45-64 years ( Ratnavalli et al., Neurology 2002 ) • More common than AD when symptoms begin • FTD refers to a canon of unique clinical syndromes that (1) before age 60 years (Knopman et al., Neurology 2004) reflect focal network-based neurodegeneration and (2) generate a pathological DDX (length varies by syndrome) • Broader FTD spectrum, including CBD/PSP and ALS, even more common • FTLD refers to a spectrum of FTD-associated pathological entities: FTLD-tau, -TDP-43, and -FUS; these misfolded Less common in older patients? proteins may act as prion-like “strains” that seed network- based disease spread • 25% had symptom onset after 65 in one FTLD series (Barborie 2011) • Most FTD is sporadic, but the genetics of familial FTD are helping to shed light on disease pathogenesis • May present with less focal cortical atrophy and a higher rate of hippocampal sclerosis (Barborie 2012) 1
Frontotemporal dementia bvFTD nfvPPA svPPA FTD-MND Behavioral variant PPA variants FTD-MND (bvFTD) Frontotemporal lobar degeneration (FTLD) Semantic variant Nonfluent/agrammatic (svPPA) variant (nfvPPA) FTLD-3 FTLD-tau FTLD-TDP* FTLD-FUS CHMP2b R L Type A Type B Pick’s CBD PSP ( PGRN ) ( C9orf72) aFTLD-U BIBD 3R tau 4R tau 4R tau ( C9orf72 ) ( TARDP? ) FTDP-17 Other Type D ??? Type C NIFID MAPT VCP FUS CTE, AGD, MST R L R L *Mackenzie harmonized scheme, 2011 bvFTD svPPA nfvPPA FTD-MND bvFTD svPPA nfvPPA FTD-MND Frontotemporal lobar degeneration (FTLD) Frontotemporal lobar degeneration (FTLD) FTLD-3 FTLD-3 FTLD-tau FTLD-TDP* FTLD-FUS FTLD-tau FTLD-TDP* FTLD-FUS CHMP2b CHMP2b Type A Type B Type A Type B Pick’s CBD PSP Pick’s CBD PSP ( PGRN ) ( C9orf72) ( PGRN ) ( C9orf72) aFTLD-U BIBD aFTLD-U BIBD 3R tau 4R tau 4R tau 3R tau 4R tau 4R tau ( TARDP? ) ( TARDP? ) ( C9orf72 ) ( C9orf72 ) Other Other FTDP-17 Type D ??? FTDP-17 Type D ??? Type C Type C NIFID NIFID MAPT VCP FUS MAPT VCP FUS CTE, AGD, MST CTE, AGD, MST *Mackenzie harmonized scheme, 2011 *Mackenzie harmonized scheme, 2011 2
bvFTD nfvPPA svPPA FTD-MND bvFTD svPPA nfvPPA FTD-MND CBS PSPS Frontotemporal lobar degeneration (FTLD) Frontotemporal lobar degeneration (FTLD) FTLD-3 FTLD-3 FTLD-tau FTLD-TDP* FTLD-FUS FTLD-tau FTLD-TDP* FTLD-FUS CHMP2b CHMP2b Type A Type B Type A Type B Pick’s CBD PSP Pick’s CBD PSP ( PGRN ) ( C9orf72) ( PGRN ) ( C9orf72) aFTLD-U BIBD aFTLD-U BIBD 3R tau 4R tau 4R tau 3R tau 4R tau 4R tau ( C9orf72 ) ( TARDP? ) ( C9orf72 ) ( TARDP? ) FTDP-17 Other Type D ??? FTDP-17 Other Type D ??? Type C NIFID Type C NIFID MAPT VCP FUS MAPT VCP FUS CTE, AGD, MST CTE, AGD, MST *Mackenzie harmonized scheme, 2011 *Mackenzie harmonized scheme, 2011 bvFTD nfvPPA FTD-MND CBS bvFTD nfvPPA FTD-MND CBS svPPA PSPS svPPA PSPS Alzheimer’s Frontotemporal lobar degeneration (FTLD) Frontotemporal lobar degeneration (FTLD) Disease FTLD-3 FTLD-3 FTLD-tau FTLD-TDP* FTLD-FUS FTLD-tau FTLD-TDP* FTLD-FUS CHMP2b CHMP2b Type A Type B Type A Type B Pick’s CBD PSP Pick’s CBD PSP ( PGRN ) ( C9orf72) ( PGRN ) ( C9orf72) aFTLD-U BIBD aFTLD-U BIBD 3R tau 4R tau 4R tau 3R tau 4R tau 4R tau ( TARDP? ) ( TARDP? ) ( C9orf72 ) ( C9orf72 ) Other Other FTDP-17 Type D Type U ??? FTDP-17 Type D Type U ??? Type C Type C NIFID NIFID MAPT VCP (C9orf72) FUS MAPT VCP (C9orf72) FUS CTE, AGD, MST CTE, AGD, MST *Mackenzie harmonized scheme, 2011 *Mackenzie harmonized scheme, 2011 3
Patient D.C. UCSF Neurodegenerative Disease Brain Bank GGT, 1 Pick's, 1 TDP-U, 1 TDP-A*, 3 PSP, 3 58 y.o. business executive with 2 high school children Pick's, 1 TAU-NOS, 1 TDP-C, CBD, 4 14 Brought in by wife for increasingly uncharacteristic behaviors: bvFTD svPPA nfvPPA • No longer interested in son’s school and sports activities CJD, 1 AD/PSP, 2 Pick's, 1 AD (PS1), 1 • Rises to board aircraft during each boarding call TAU-CBD, 1 Pick's, 1 TDP-A*, 2 • Repeatedly takes out wallet to illustrate the shape of Kansas TDP-U*, 5 AD, 5 ALS-TDP, 5 • New penchant for sweets; overeating in general, gains weight TAU-NOS, 1 CBD, 4 TDP-B, Language, memory, navigation, skilled movements all normal. PSP, 15 14 CBS PSPS bvFTD-MND Patient D.C. Anterior Cingulate Cortex (ACC) and Rostromedial PFC Right Fronto- insula (FI) R L 4
R bvFTD svPPA nfvPPA FTD-MND CBS PSPS Frontotemporal lobar degeneration (FTLD) Frontal Insula (FI) FTLD-3 FTLD-tau FTLD-TDP* FTLD-FUS ( CHMP2b ) Type A Type B Pick’s CBD PSP ( PGRN ) ( C9ORF72) aFTLD-U BIBD 3R tau 4R tau 4R tau ( C9ORF72 ) ( TARDP? ) FTDP-17 Tau NOS Type D ??? Type C NIFID ( MAPT ) ( VCP ) ( FUS ) MST/AGD *Mackenzie harmonized scheme, 2011 bvFTD due to Pick’s Disease (FTLD-tau) H & E GFAP 5
bvFTD due to Pick’s Disease (FTLD-tau) Intrinsic connectivity measured with fcMRI DLPFC R In healthy subjects, baseline low frequency fMRI BOLD signal Frontal pole ACC Lat OFC fluctuations in Right FI Time (sec) Single subject are correlated with… Right Fronto- Left insula (FI) FI FI SLEA VSP Hypothalamus Right FI “Salience Network” seed ROI (Intrinsic connectivity network) Seeley et al J Neurosci 2007 3T fcMRI 19 healthy controls H & E 3R tau Structural covariance measured with Intrinsic connectivity measured with fcMRI “scMRI” THIRST PAIN SPOUSE’S PAIN In healthy subjects, Across healthy subjects, baseline low frequency gray matter volume in fMRI BOLD signal Right FI is correlated fluctuations in Right FI with… S1 S2 S3 S4 S5 S6 S7 are correlated with… DeAruojo 2003 Rainville 1997 Singer 2004 HR DETECTION LOVERS Right FI Right FI “Salience Network” seed seed ROI Bartels and Zeki, 2004 Critchley 2004 ROI (Intrinsic connectivity network) “Salience Network” (Intrinsic connectivity network) 3T fcMRI 1.5T T1 MRI 19 healthy controls 65 healthy controls Seeley et al J Neurosci 2007 6
bvFTD bvFTD bvFTD atrophy pattern VBM, patients vs. controls bvFTD atrophy pattern N = 24 VBM, patients < controls N = 24 Functional connectivity Which regions serve as a gateway to the network? Right FI seed fMRI, healthy controls N = 19 Structural covariance Right FI seed VBM, healthy controls epicenters N = 65 Overlap Seeley et al Neuron 2009 bvFTD pattern N seed-based maps bvFTD bvFTD-vulnerable “salience network” L bvFTD atrophy pattern VBM, patients vs. controls N = 24 Does a node’s connectivity predict its vulnerability? Zhou et al 2012 E bvFTD pattern Healthy correlation matrix Healthy network graph 7
R R bvFTD epicenters bvFTD epicenters Patient C.N. epicenters • 47 y.o. RH former foundation group leader with no complaints other than “mild memory problems” Brought in by wife for 10-15 years slowly progressive behavior change: • Brought home books on death and dying to read to 3 y.o. daughter at bedtime • Took up computer Solitaire, counted white cars • Failed to initiate job search when laid off • Urination ritual: To and from BR x 4 QHS • Mild verbal memory impairment; no executive, language, bvFTD target network or motor deficits 8
Patient C.N. bvFTD svPPA nfvPPA FTD-MND CBS PSPS Frontotemporal lobar degeneration (FTLD) FTLD-3 FTLD-tau FTLD-TDP* FTLD-FUS ( CHMP2b ) Type A Type B Pick’s CBD PSP ( PGRN ) ( C9ORF72) aFTLD-U BIBD 3R tau 4R tau 4R tau ( C9ORF72 ) ( TARDP? ) FTDP-17 Tau NOS Type D ??? Type C NIFID ( MAPT ) ( VCP ) ( FUS ) MST/AGD *Mackenzie harmonized scheme, 2011 bvFTD due to aFTLD-U (FTLD-FUS) Working model: anatomical convergence Different diseases, same onset, same spread bvFTD Tau, TDP-43, or FUS Pick’s mOFC uncus CA1/subic (Tau) E TDP-43 Type B aFTLD-U (FUS) 9
Relationship between bvFTD anatomy and psychiatric disease Early psychiatric mis-diagnoses Imaging (VBM, PET) meta-analyses • Bipolar illness Bora et al, Schroeter et al, Biol Psych 2 1 Neurobiol Aging 2010 • Schizophrenia 2006 bipolar disorder bvFTD • Major Depression • Addiction Disorder (multiple types) • Personality Disorders – Borderline – Passive-aggressive Fornito et al, 3 Schiz Res 2009 – Antisocial schizophrenia – Schizoid – Schizotypal Patient A.T. Patient A.T. Exam: 61 y.o. high school counselor with 5 years of • Surface dyslexia, questions meaning of individual words word-finding and word recognition difficulties. Asks husband to explain words in the • Fluency and repetition spared until late newspaper. • No motor or visuospatial/ • navigation deficits Later: • Approaches strangers for idle conversation • Obsessed with vitamins, takes 15/day • Prefers sweets and chips, gains 10# 10
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