Is in vivo amyloid distribution asymmetric in primary progressive aphasia?
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ABSTRACT:
SUBMITTER: Martersteck A
PROVIDER: S-EPMC4789129 | biostudies-literature | 2016 Mar
REPOSITORIES: biostudies-literature
Publications
Is in vivo amyloid distribution asymmetric in primary progressive aphasia?
Martersteck Adam A Murphy Christopher C Rademaker Alfred A Wieneke Christina C Weintraub Sandra S Chen Kewei K Mesulam M-Marsel MM Rogalski Emily E
Annals of neurology 20160202 3
We aimed to determine whether (18) F-florbetapir amyloid positron emission tomography imaging shows a clinically concordant, left-hemisphere-dominant pattern of deposition in primary progressive aphasia (PPA). Elevated cortical amyloid (Aβ(+) ) was found in 19 of 32 PPA patients. Hemispheric laterality of amyloid burden was compared between Aβ(+) PPA and an Aβ(+) amnestic dementia groups (n = 22). The parietal region showed significantly greater left lateralized amyloid uptake in the PPA group t ...[more]
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Project description:Logopenic primary progressive aphasia (lvPPA) is a progressive language disorder characterized by anomia, difficulty repeating complex sentences, and phonological errors. The majority, although not all, lvPPA patients have underlying Alzheimer's disease. We aimed to determine whether clinical or neuroimaging features differ according to the deposition of A? on Pittsburgh-compound B PET in lvPPA. Clinical features, patterns of atrophy on MRI, hypometabolism on FDG-PET, and white matter tract degeneration were compared between six PiB-negative and 20 PiB-positive lvPPA patients. PiB-negative patients showed more asymmetric left-sided patterns of atrophy, hypometabolism and white matter tract degeneration, with greater left anteromedial temporal and medial prefrontal involvement, than PiB-positive patients. PiB-positive patients showed greater involvement of right temporoparietal and frontal lobes. There was very little evidence for clinical differences between the groups. Strikingly asymmetric neuroimaging findings with relatively preserved right hemisphere may provide clues that AD pathology is absent in lvPPA.
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Project description:Importance:The ability to predict the pathology underlying different neurodegenerative syndromes is of critical importance owing to the advent of molecule-specific therapies. Objective:To determine the rates of positron emission tomography (PET) amyloid positivity in the main clinical variants of primary progressive aphasia (PPA). Design, Setting, and Participants:This prospective clinical-pathologic case series was conducted at a tertiary research clinic specialized in cognitive disorders. Patients were evaluated as part of a prospective, longitudinal research study between January 2002 and December 2015. Inclusion criteria included clinical diagnosis of PPA; availability of complete speech, language, and cognitive testing; magnetic resonance imaging performed within 6 months of the cognitive evaluation; and PET carbon 11-labeled Pittsburgh Compound-B or florbetapir F 18 brain scan results. Of 109 patients referred for evaluation of language symptoms who underwent amyloid brain imaging, 3 were excluded because of incomplete language evaluations, 5 for absence of significant aphasia, and 12 for presenting with significant initial symptoms outside of the language domain, leaving a cohort of 89 patients with PPA. Main Outcomes and Measures:Clinical, cognitive, neuroimaging, and pathology results. Results:Twenty-eight cases were classified as imaging-supported semantic variant PPA (11 women [39.3%]; mean [SD] age, 64 [7] years), 31 nonfluent/agrammatic variant PPA (22 women [71.0%]; mean [SD] age, 68 [7] years), 26 logopenic variant PPA (17 women [65.4%]; mean [SD] age, 63 [8] years), and 4 mixed PPA cases. Twenty-four of 28 patients with semantic variant PPA (86%) and 28 of 31 patients with nonfluent/agrammatic variant PPA (90%) had negative amyloid PET scan results, while 25 of 26 patients with logopenic variant PPA (96%) and 3 of 4 mixed PPA cases (75%) had positive scan results. The amyloid positive semantic variant PPA and nonfluent/agrammatic variant PPA cases with available autopsy data (2 of 4 and 2 of 3, respectively) all had a primary frontotemporal lobar degeneration and secondary Alzheimer disease pathologic diagnoses, whereas autopsy of 2 patients with amyloid PET-positive logopenic variant PPA confirmed Alzheimer disease. One mixed PPA patient with a negative amyloid PET scan had Pick disease at autopsy. Conclusions and Relevance:Primary progressive aphasia variant diagnosis according to the current classification scheme is associated with Alzheimer disease biomarker status, with the logopenic variant being associated with carbon 11-labeled Pittsburgh Compound-B positivity in more than 95% of cases. Furthermore, in the presence of a clinical syndrome highly predictive of frontotemporal lobar degeneration pathology, biomarker positivity for Alzheimer disease may be associated more with mixed pathology rather than primary Alzheimer disease.
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Project description:ObjectiveTo 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.MethodsAntibodies 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.ResultsNumerical 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.ConclusionsDistribution 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.
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Project description:ObjectiveTo estimate the prevalence of amyloid positivity, defined by positron emission tomography (PET)/cerebrospinal fluid (CSF) biomarkers and/or neuropathological examination, in primary progressive aphasia (PPA) variants.MethodsWe conducted a meta-analysis with individual participant data from 1,251 patients diagnosed with PPA (including logopenic [lvPPA, n = 443], nonfluent [nfvPPA, n = 333], semantic [svPPA, n = 401], and mixed/unclassifiable [n = 74] variants of PPA) from 36 centers, with a measure of amyloid-β pathology (CSF [n = 600], PET [n = 366], and/or autopsy [n = 378]) available. The estimated prevalence of amyloid positivity according to PPA variant, age, and apolipoprotein E (ApoE) ε4 status was determined using generalized estimating equation models.ResultsAmyloid-β positivity was more prevalent in lvPPA (86%) than in nfvPPA (20%) or svPPA (16%; p < 0.001). Prevalence of amyloid-β positivity increased with age in nfvPPA (from 10% at age 50 years to 27% at age 80 years, p < 0.01) and svPPA (from 6% at age 50 years to 32% at age 80 years, p < 0.001), but not in lvPPA (p = 0.94). Across PPA variants, ApoE ε4 carriers were more often amyloid-β positive (58.0%) than noncarriers (35.0%, p < 0.001). Autopsy data revealed Alzheimer disease pathology as the most common pathologic diagnosis in lvPPA (76%), frontotemporal lobar degeneration-TDP-43 in svPPA (80%), and frontotemporal lobar degeneration-TDP-43/tau in nfvPPA (64%).InterpretationThis study shows that the current PPA classification system helps to predict underlying pathology across different cohorts and clinical settings, and suggests that age and ApoE genotype should be considered when interpreting amyloid-β biomarkers in PPA patients. Ann Neurol 2018;84:737-748.
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Project description:The aim is to explore the evolution of the logopenic variant of primary progressive aphasia as a distinct clinical entity and to outline recent advances that have clarified its clinical characteristics, neural underpinnings, and potential genetic and pathological bases. This is particularly relevant as researchers attempt to identify clinico-pathological relationships in subtypes of primary progressive aphasia in hopes of utilizing language phenotype as a marker of underlying disease.Recent work has served to refine and expand upon the clinical phenotype of the logopenic variant. Logopenic patients show a unique pattern of spared and impaired language processes that reliably distinguish this syndrome from other variants of progressive aphasia. Specifically, they exhibit deficits in naming and repetition in the context of spared semantic, syntactic, and motor speech abilities. Further, there is a growing body of evidence indicating a possible link between the logopenic phenotype and specific pathological and genetic correlates.Findings indicate that the logopenic variant is a distinct subtype of progressive aphasia that may hold value as a predictor of underlying pathology. Additional research, however, is warranted in order to further clarify the cognitive-linguistic profile and to confirm its relation to certain pathological and genetic processes.
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