Dataset Information

Asymmetric pathology in primary progressive aphasia with progranulin mutations and TDP inclusions.

ABSTRACT:

Objective

To investigate quantitative regional distribution and hemispheric asymmetry of TDP-43 (TAR DNA-binding protein 43) inclusions, neurons, and activated microglia in primary progressive aphasia (PPA) with progranulin (GRN) mutations, and to determine concordance between distribution of pathology, clinical phenotype, and known atrophy patterns.

Methods

Antibodies to phospho-TDP-43, NeuN (neuronal nuclei), and HLA-DR were used to visualize inclusions, neurons, and activated microglia in paraffin-embedded tissue sections from 4 participants with PPA: 2 of the agrammatic and 2 of the logopenic subtype. Unbiased stereological counting techniques were used for quantitation of immunoreactive profiles in language- and memory-related cortical areas bilaterally. Patterns of pathology across cortical areas and hemispheres were compared and their relationships with known patterns of atrophy investigated.

Results

Numerical densities of TDP-43 inclusions, and less so of activated microglia, were greater in language-related areas compared with memory-related areas. In language areas, neuronal density displayed a pattern opposite to inclusions and activated microglia. Densities of inclusions and microglia were greater (p < 0.05), and densities of neurons were lower (p < 0.005), in the left hemisphere compared with the right. In agrammatic PPA, the highest densities of TDP-43 inclusions were observed in left inferior or middle frontal gyri, and in logopenic participants, the highest density of inclusions was seen in left inferior parietal lobule. This distribution is consistent with subtype-specific peak atrophy sites.

Conclusions

Distribution of TDP-43 inclusions and neurons, and to a smaller extent of activated microglia, show a regional and hemispheric pattern consistent with disease phenotype and known patterns of atrophy in PPA with GRN mutations.

SUBMITTER: Kim G

PROVIDER: S-EPMC4762414 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Publications

Asymmetric pathology in primary progressive aphasia with progranulin mutations and TDP inclusions.

Kim Garam G Ahmadian Saman S SS Peterson Melanie M Parton Zach Z Memon Rohail R Weintraub Sandra S Rademaker Alfred A Bigio Eileen E Mesulam M-Marsel MM Geula Changiz C

Neurology 20160120 7

<h4>Objective</h4>To investigate quantitative regional distribution and hemispheric asymmetry of TDP-43 (TAR DNA-binding protein 43) inclusions, neurons, and activated microglia in primary progressive aphasia (PPA) with progranulin (GRN) mutations, and to determine concordance between distribution of pathology, clinical phenotype, and known atrophy patterns.<h4>Methods</h4>Antibodies to phospho-TDP-43, NeuN (neuronal nuclei), and HLA-DR were used to visualize inclusions, neurons, and activated m ...[more]

PMID: 26791154

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Project description:ImportanceWe provide novel evidence of specific clinical and neuroimaging features that may help for the in vivo prediction of underlying pathology in patients with nonfluent/agrammatic primary progressive aphasia (nfvPPA) and progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD) proved by autopsy.ObjectiveTo characterize the neurological, cognitive, and neuroimaging features of patients with nfvPPA-in whom either PSP or CBD was eventually confirmed at autopsy-at initial presentation and at 1-year follow-up.Design, setting, and participantsA prospective longitudinal clinical-pathological study was conducted in a tertiary research clinic that specialized in cognitive disorders. Fourteen patients were evaluated between January 2002 and December 2014. Inclusion criteria for the study were a clinical diagnosis of nfvPPA; the availability of speech, language, and cognitive testing for at least 1 evaluation; magnetic resonance imaging within 6 months of initial evaluation; and a postmortem pathological diagnosis of PSP or CBD. Ten matched healthy control participants were also included.Main outcomes and measuresClinical, cognitive, and neuroimaging longitudinal data were analyzed to characterize the whole nfvPPA-4-repeat-tau group and identify differences between nfvPPA-PSP and nfvPPA-CBD both at presentation and longitudinally.ResultsPatient groups did not differ significantly in age, sex, or handedness (nfvPPA-PSP group: median [interquartile range (IQR)] age, 74 [67-76] years; 1 of 5 male [20%]; 1 of 5 left-handed [20%]; and nfvPPA-CBD group: mean [IQR] age, 65 [54-81] years; 3 of 9 male [33%]; 0 left-handed). Motor speech impairment and left frontal white matter atrophy were the most prominent common features. At presentation, dysarthria (Motor Speech Examination median [IQR] score: nfvPPA-PSP, 4 [2-7]; nfvPPA-CBD, 0 [0-4]; P = .02), depression (Geriatric Depression Scale median [IQR] score: nfvPPA-PSP, 19 [3-28]; nfvPPA-CBD, 4 [0-16]; P = .04), and relatively selective white matter atrophy were typical of the nfvPPA-PSP group, while greater gray matter atrophy and a trend toward greater sentence comprehension deficits (median [IQR] sentence comprehension correct: nfvPPA-PSP, 98% [80-100]; nfvPPA-CBD, 81% [65-98]; P = .08) were found in the nfvPPA-CBD group. At follow-up after 1 year, we observed no significant differences in any speech or language measures. Furthermore, atrophy in patients with PSP progressed within the subcortical/brainstem motor system generating greater oculomotors deficits and swallowing difficulty; atrophy in patients with CBD spread anteriorly in prefrontal regions consistent with their greater working memory impairment and development of behavioral symptoms.Conclusions and relevanceIn patients presenting with nfvPPA, presence of early severe dysarthria, relatively selective white matter atrophy at presentation, and a greater rate of change in the brainstem measured by longitudinal imaging may be useful for differentiating underlying PSP from CBD pathology during life.

Dataset Information

Asymmetric pathology in primary progressive aphasia with progranulin mutations and TDP inclusions.

Objective

Methods

Results

Conclusions

Publications

Asymmetric pathology in primary progressive aphasia with progranulin mutations and TDP inclusions.

Similar Datasets

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