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The underacknowledged PPA-ALS: A unique clinicopathologic subtype with strong heritability


OBJECTIVE: To assess the incidence, heritability, and neuropathology of primary progressive aphasia (PPA) with amyotrophic lateral sclerosis (ALS) in a large Australian cohort. METHODS: A total of 130 patients with a primary nonfluent variant of PPA (nfvPPA) or semantic variant of PPA (svPPA) were assessed for concomitant ALS and a strong family history of neurodegenerative diseases (Goldman score </=3). Neuropathologic examination was carried out in 28% (n = 36) of these PPA and PPA-ALS cases that had come to autopsy. RESULTS: ALS was identified in 18% of patients with nfvPPA and 5% of patients with svPPA. PPA-ALS but not PPA was found to have a strong family history. At autopsy, frontotemporal lobar degeneration (FTLD)-TDP was identified in 100% of nfvPPA-ALS cases, 100% of svPPA-ALS cases, 24% of nfvPPA cases, and 78% of svPPA cases. Clinicopathologic assessments revealed a significant association between a strong family history and underlying FTLD-TDP pathology. Pathogenic mutations in known frontotemporal dementia (FTD)/ALS genes were identified in 100% of these familial PPA cases but only 50% of familial PPA-ALS cases, suggesting the involvement of novel genetic variants in this underacknowledged phenotype. CONCLUSION: The present study identified ALS in 12% of a large cohort of patients with nfvPPA and svPPA, which is comparable to the 10%-15% reported in FTD overall, indicating that a third of patients with FTD-ALS will have a predominant language profile. These findings highlight the importance of assessing for ALS in PPA, particularly since this is the only PPA phenotype in which a perfect clinicopathologic association has been reported in to date.

Type Journal
ISBN 1526-632X (Electronic) 0028-3878 (Linking)
Authors Tan, R. H.; Guennewig, B.; Dobson-Stone, C.; Kwok, J. B. J.; Kril, J. J.; Kiernan, M. C.; Hodges, J. R.; Piguet, O.; Halliday, G. M.
Responsible Garvan Author (missing name)
Publisher Name NEUROLOGY
Published Date 2019-03-19
Published Volume 92
Published Issue 12
Published Pages e1354-e1366
Status Always Electronic
DOI 10.1212/WNL.0000000000007146
URL link to publisher's version