LANGUAGE AND PATHOLOGY IN FRONTOTEMPORAL DEGENERATION

Transcription

1 LANGUAGE AND PATHOLOGY IN FRONTOTEMPORAL DEGENERATION Murray Grossman University of Pennsylvania Support from NIH (AG17586, AG15116, NS44266, NS35867, AG32953, AG38490), IARPA, ALS Association, and the Wyncote Foundation Consultant for TauRx and Forum Pharmaceuticals No conflict of interest to declare

2 LANGUAGE IN FRONTOTEMPORAL DEGENERATION Language is a uniquely human process Single words are used to construct sentences Sentences are used in conversations Inexpensive screening device with potentially high sensitivity and specificity for FTD spectrum pathology Disease-modifying treatment trials

3 LANGUAGE IN FRONTOTEMPORAL DEGENERATION Plan of talk Disorders of language in aphasic and non-non-aphasic variants of FTD Semantic variant PPA Non-fluent/agrammatic PPA Behavioral variant FTD Impairments in FTD selectively compromise each level of language Markers for specific FTD pathology

4 FRONTOTEMPORAL DEGENERATION Two major phenotypes Primary progressive aphasia Semantic variant PPA (Semantic dementia) Nonfluent/agrammatic PPA (Progressive non-fluent aphasia) Behavioral variant frontotemporal degeneration SD PNFA bvftd

5 SEMANTIC VARIANT PPA Lexical semantic and object knowledge is compromised in

6 VISUAL FEATURE KNOWLEDGE IN SEMANTIC VARIANT PPA Degraded object concepts in svppa Difficulty with naming and comprehension Less impaired abstract concepts % rect Degraded visual features of objects Disease in visual association cortex co r HAND G LOVE SHOE z-score Two-alternative forced-choice ABSTRACT CONCRETE CONTROL svppa Bonner et al, 2009

7 NUMBER CONCEPTS IN svppa Despite profound word comprehension and object knowledge deficits, svppa patients are rapid and accurate at performing written number calculations

8 MUSIC IN svppa Weinstein et al, 2011 Preserved music knowledge in svppa

9 PATHOLOGY IN SEMANTIC VARIANT PPA Autopsy shows anterior temporal atrophy Neuronal dropout in superficial layers TDP-43 neuronal inclusions Found in about 85% of cases

10 SPECTRUM OF CLINICAL DISEASE IN TDP-43 PATHOLOGY TDP-43 pathology in both FTLD and ALS ALS ALS FTLD FTLD FTLD-ALS link confirmed by TARDBP mutation and C9orf72 expansion

11 McCluskey et al, 2014 SPECTRUM OF CLINICAL DISEASE IN TDP-43 PATHOLOGY ALS-classic Pyramidal/neuromuscular disease ALS is a multi-system disorder 10% with ALS-FTD 34% with ALS-MCI 15% with ALS-Plus ALS with cerebellar, extrapyramidal, oculomotor, 40 or autonomic features Significantly poorer prognosis, 20 marker for inherited disease 0 months survival ALS-classic ALS-Plus

12 SEMANTIC VARIANT PPA Semantic variant PPA Degraded representations of single word and object concepts Preserved number and music concepts Related to anterior and ventral temporal disease Clinical marker for TDP-43 pathology Pathology shared with ALS

13 NON-FLUENT/AGRAMMATIC PPA Speech fluency and grammatical comprehension are impaired in progressive

14 NON-FLUENT/AGRAMMATIC PPA Significantly slowed speech Significant grammatical deficit - Expression deficit Significantly simplified grammar in utterances - Comprehension deficit Significantly impaired grammatical comprehension Impaired oral and written langu 100 ect r 90 cor 80 % 70 frontal and superior temporal atrophy Gunawardena Dual white et al, 2010 matter routes % complex structures nap PA nappa svppa bvftd Control words/minute # age Ash et al, 2010 control Grossman et al, cleft 2014 center Grammatical deficit related to left inferior * * * Charles et al, 2014 svppa

15 NON-FLUENT/AGRAMMATIC PPA nappa deficit is selective nappa are good at naming and complex figure construction z-score Boston Naming Rey Figure Copy nappa svppa bvftd CBD Libon et al, 2010

16 NON-FLUENT/AGRAMMATIC PPA Gross pathology in non-fluent/agrammatic PPA

17 NON-FLUENT/AGRAMMATIC PPA Pick bodies balloon cells Courtesy John Q. Trojanowski MD, PhD Microscopic pathology in non-fluent/agrammatic PPA H & E preparation Tau-immunoreactive histopathology Misfolded tau due to hyperphosphorylation Disturbs microtubule structure Tau found in about 75% of cases

18 SPECTRUM OF CLINICAL DISEASE IN TAU PATHOLOGY Ta u pathology in both nappa and PSP/ FTLD% PSP/CBD%

19 SPECTRUM OF CLINICAL DISEASE IN TAU PATHOLOGY Anatomic distribution of tau pathology in PSP and CBD PSP CBD Irwin et al, 2012

20 NON-FLUENT/AGRAMMATIC PPA Non-fluent/agrammatic PPA Specific pattern of impaired language due to limited grammatical processing Associated with left inferior frontal disease Similar pathology in akinetic-rigid disorders such as CBD and PSP Clinical screen for tau pathology

21 BEHAVIORAL VARIANT FRONTOTEMPORAL DEGENERATION Poor self-regulation, impulsive, disinhibited Rigid, obsessive, rituals Apathetic Lack of insight Poor empathy

22 BEHAVIORAL VARIANT FRONTOTEMPORAL DEGENERATION Frontal and anterior temporal gray matter Extensive white matter disease

23 BEHAVIORAL VARIANT FRONTOTEMPORAL DEGENERATION Impaired social judgment in bvftd b vftd impaired Correlation with comp of social judgments cartoon prediction flexibility ToM 2nd order onents empathy Eslinger et al, 2007

24 SEMISTRUCTURED SPEECH SAMPLE Wordless picture story, 30 events, 7 episodes Single word expression Sentence expression Narrative organization

25 BEHAVIORAL VARIANT FRONTOTEMPORAL DEGENERATION Accurate description of content of children s wordless p icture story Poor organization of % global connectedness narrative No sense of the p oint of the story bvftd nappa svppa c ontrol Impaired global connectedness Impaired local connectedness Impaired theme maintenance Ash et al, 2006 Reduced connectedness related to prefrontal atrophy

26 BEHAVIORAL VARIANT FRONTOTEMPORAL DEGENERATION Atrophy in behavioral variant frontotemporal degeneration 50% TDP-43 pathology, 50% tau pathology

27 DIAGNOSIS IN FRONTOTEMPORAL DEGENERATION Multimodal strategy for diagnosis CLINICAL MRI MOLECULAR GENETIC CSF

28 FAMILIAL FRONTOTEMPORAL DEGENERATION FTLD autosomal dominant inheritance in 25.1% Mutation identified in 20.1% of patients Chromosome 17 MAPT Chromosome 17 GRN Chromosome 9 C9orf72 Chromosome 9 VCP Chromosome 3 CHMP2B Chromosome 1 TARDBP Specific pathology associated with each mutation

29 IMAGING BIOMARKERS FOR YOUNG ONSET FTD Eigenanatomy imaging distinguishes FTLD-tau from FTLD-TDP with known pathology tau TDP WM myelin WM inclusions GM neuronal dropout GM inclusions McMillan et al, 2013

30 BIOFLUID BIOMARKERS FOR FTLD CSF phosphorylated tau abnormal in tauopathy Elevated CSF ptau:ttau in tauopathy Lower ptau:ttau in TDP-43 proteinopathy Related to motor and PFC in ALS Grossman et al, 2014 Related to midbrain in PSP

31 McMillan et al, 2014 MOLECULAR BIOMARKERS IN HUMAN TAUOPATHY Myelin oligodendrocyte basic protein Stabilizes myelin rs (MOBP) is associated with reduced white matter fractional anisotropy in midbrain and superior longitudinal fasciculus Locus of white matter pathology in progressive pathology

32 MOLECULAR BIOMARKERS IN HUMAN TAUOPATHY Minor T allele at rs of MOBP associated with reduced survival in clinical FTD and known tauopathy clinical FTD known tau pathology Irwin et al, 2014 Validated by imaging-guided biopsy of SLF showing diseased myelin in risk allele carriers (right) Minor T allele at rs of MOBP associated with reduced FA in white matter of superior longitudinal fasciculus and brain stem

33 LANGUAGE IN FRONTOTEMPORAL DEGENERATION Language is a complex process that can serve as a sensitive and inexpensive screen for FTD Single words and object knowledge compromised in semantic variant PPA Marker of TDP-43 pathology Grammatical expression and comprehension impaired in non-fluent/ agrammatic PPA Marker of tau pathology Narrative conversation difficulty in

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