FTD basics!Etienne de Villers-Sidani, MD!

Frontotemporal lobar degeneration (FTLD) comprises 3 clinical syndromes!

•  Frontotemporal dementia (behavioral variant FTD)!

•  Semantic dementia (temporal variant FTD)(original Pick's disease)!

•  Progressive non-fluent aphasia (PNFA)!•  bvFTD, tvFTD and PNFA differ in prevalence,

age of onset, sex distribution, genetic susceptibility and neuropathological features. Frontal involvement, absence of AD-like pathology)!

Distinction from AD!

•  Different pattern of involvement!•  Frontal vs mesial temporal!

•  Different clinical presentation!•  Executive speech dysfunction behavioral change with

mostly intact episodic memory!

•  No aggregation of abeta-42 !

Epidemiology!

•  Patients usually present between 45-65!•  Positive family history in ~40%!•  Prevalence 15/100,000 between (45-65),

which is equal or more prevalent than AD for that age-range. !

FTD epidemiology!

•  56% of FTLD cases!•  Male predominant 2:1!•  Earliest age of onset!•  Progresses most rapidly (3.4 years from

diagnosis to death).!•  Highest genetic susceptibility, strong

association with ALS (20% have clear family history)!

SD epidemiology!

•  Less than 20% of cases!•  Older age of onset !•  Slowest progression (5.2 years from diagnosis

to death)!•  Low percentage of cases with clear pattern of

inheritance!

PNFA epidemiology!

•  25% of FTLD cases.!•  Intermediate rate of progression (4.3 years)

and genetic propensity.!•  High association with corticobasal

degeneration (CBD) and progressive supranuclear palsy (PSP).!

Clinical differences between FTLDs!

•  bvFTD: primarily right frontal involvement!•  disinhibition!•  apathy, emotional blunting!•  Lack of insight!

•  PNFA: selective left fronto-insular degeneration!•  agrammatism, hesitant apraxic speech!

•  SD: either predominant left or right temporal degeneration!

•  left: profound anomia with progressive loss of conceptual knowledge of words.!•  right: deficit in empathy and knowledge about people's emotions!

FTLD often overlaps with other syndromes!

•  CBD!•  Asymmetric parkinsonism with dystonia, rigidity, limb

apraxia, useless/alien limb.!

•  PSP!•  Falls, ophthalmoplegia, axial rigidity and frontal

dementia!

•  Most patients with PNFA show pathological changes consistent with CBD/PSP (neuronal inclusions with tau present in neurons and astrocytes)!

Importance of differentiating from AD!

•  Drug trials!•  AChEI lead to irritability, agitation and

worsening swallowing difficulties in FTD (from increased salivation)!

Clinical presentation : FTD!

•  Behavioral changes:!•  alterations in social decorum (disinhibition, apathy,

overeating, emotional blunting, coldness, repetitive motor behaviors (compulsivity)!

•  Executive dysfunction:!•  planning, organization, shifting pattens, generation of

ideas!

•  Often perceived as "mid-life crisis", delaying visit to neurologist. Tension in family and friends due to change in decorum and coldness!

•  15% develop ALS and extrapyramidal sign are not uncommon!

Clinical presentation : FTD!

•  ventral medial frontal and insular regions are affected early, driving the disinhibition, apathy and eating disorder. Atrophy can be seen at first visit on MRI usually.!

•  MMSE usually normal!•  MoCA more sensitive: trails, word fluency...!

•  Progression towards more apathy, dysphagia, aspiration pneumonia (especially with FTD-MND)!

Clinical presentation : SD!

•  Usually onset on left!•  Speech abnormality:!

•  Fluent speech but word finding difficulty with nouns more than verbs. !

•  Also develop trouble recognizing words.!

•  Behavior:!•  Compulsive interests relating to visually appealing

(shiny/colorful) objects. Compulsive card playing (solitaire)!•  with progessive right sided involvement: trouble recognizing emotions!•  Prosopagnosia (face blindness) and multi-modality agnosia for objects!

Clinical presentation : SD!

•  Lower score on MMSE and MoCA due to speech involvement (will have trouble naming pen watch, will also loose point on word recall and three step command due to impaired word comprehension).!

•  Naming and word recall not helped with category clues or multiple choice.!

•  Also poor word fluency, surface dyslexia.!•  Often preserved or even enhanced drawing skills with

excellent non-verbal memory (remembering detail on the Rey figure for example).!

•  Deficits in recognizing emotions (fear vs sadness). Cannot recognize when family members are upset for example.!

•  MRI: anterior temporal lobe atrophy bilat or L>R!

Clinical presentation : SD!

•  Progression: calls everythting :"thing"!•  MMSE = 1, with figure drawing performed perfectly!•  Swallowing difficulties!•  Autopsy: spogiosis/gliosis and neuronal loss in anterior

frontal lobes, orbitofrontal and mesial frontal cortex.!•  Ubiquitin positive inclusions!

Clinical presentation : PNFA!

•  Speech/language abnormality !•  Patient retains good insight and aware of deficits, often

before others.!•  Decreased word output, short phrases, articulation

difficult (articulatory planning; speech apraxia).!•  Leads to phonemic paraphrasias.!•  Comprehension/naming normal (can have trouble with

complex syntax).!•  Use of nouns good but make mistakes with verbs and

prepositions (agrammatisms).!•  Maintained social decorum. Depression.!•  Motor disorder as in CBD/PSP can appear fairly soon.!•  Most PNF have tau pathology on autopsy.!•  Progression: falls, anarthria, dysphagia!

Pathological findings!•  Gliosis, inclusion bodies, swollen neurons and

microvacuolation.!•  inclusion bodies with tau (PNFA, FTD, CBD, PSP) or

ubiquitin (SD, FTD).!•  Ubiquitin+ cases also have TDP-43 immunoreactivity!

•  Loss of large pyramidal cells in cortical layers III, V. Von Economo neurons are affected early!

•  Neuron swelling (ballooned cell or Pick cell) is found in minority of cases. Pick bodies (tau inclusion in perikaryon) are also rare!

•  In FTD-ALS, inclusions are tau negative but ubiquitin positive. Substantia nigra is pale.!

•  If PSP pathology present, more brainstem atrophy and neurofibrillary tangles (tau positive) are seen.!

Genetic findings!•  Best known is FTFP-17 (FTD with parkinsonism

associated to chromosome 17), which is in fact a tau mutation. !

•  Three mutations to that gene account 50% genetic cases.!•  Same mutation can present as CBC/PSP or FTD in same family.!

•  Progranulin mutation is present in 5-10%!

•  If PSP pathology present, more brainstem atrophy and neurofibrillary tangles (tau positive) are seen.!

Imaging!

•  MRI!•  FDG-PET!•  PIB imaging to differentiate from AD.!

Treatment!

•  ....!

•  AChEI are NOT recommended!

•  SSRI can reduce compulsionss and cravings!

•  Atypical antipsychotics (beware if extrapyramidal signs present) can be given for aggressivity and delusions!

•  Education, family support!

Think about rarer variant of AD!

•  Logopenic aphasia!•  Comparing with PNFA: Hesitant speech and slow due

to profound word finding difficulty. Articulation of words usually intact. Islands of normal speech fluency.!•  Comparing with SD: word recognition normal, they do not progress to generalized semantic loss!