From the Brain and Mind Centre and Central Clinical School (R.H.T., B.G., C.D.-S., J.B.J.K., M.C.K., J.R.H., G.M.H.) and School of Medical Sciences (J.J.K.), Faculty of Medicine and Health, and Brain and Mind Centre and School of Psychology (O.P.), The University of Sydney; School of Medical Sciences (R.H.T., C.D.-S., G.M.H.), University of New South Wales & Neuroscience Research Australia; Department of Neurology (M.C.K.), Royal Prince Alfred Hospital; ARC Centre of Excellence in Cognition and its Disorders (J.R.H., O.P.); and Division of Neuroscience (B.G.), Garvan Institute of Medical Research and St Vincent's Clinical School, UNSW Sydney, New South Wales, Australia.
Neurology. 2019 Mar 19;92(12):e1354-e1366. doi: 10.1212/WNL.0000000000007146. Epub 2019 Feb 15.
To assess the incidence, heritability, and neuropathology of primary progressive aphasia (PPA) with amyotrophic lateral sclerosis (ALS) in a large Australian cohort.
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.
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.
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.
在一个大型澳大利亚队列中评估伴有肌萎缩侧索硬化症（ALS）的原发性进行性失语症（PPA）的发病率、遗传性和神经病理学。
共评估了 130 名原发性非流利型 PPA（nfvPPA）或语义性 PPA（svPPA）患者是否伴有 ALS 和神经退行性疾病的强烈家族史（Goldman 评分≤3）。对其中 28%（n=36）有尸检的 PPA 和 PPA-ALS 病例进行了神经病理学检查。
在 nfvPPA 患者中发现了 18%，在 svPPA 患者中发现了 5%患有 ALS。发现 PPA-ALS 但不是 PPA 具有强烈的家族史。尸检时，nfvPPA-ALS 病例中 100%、svPPA-ALS 病例中 100%、nfvPPA 病例中 24%和 svPPA 病例中 78%发现了额颞叶变性（FTLD）-TDP。临床病理评估显示，强烈的家族史与潜在的 FTLD-TDP 病理之间存在显著关联。在这些家族性 PPA 病例中，鉴定出已知的额颞痴呆（FTD）/ALS 基因的致病性突变 100%，而在家族性 PPA-ALS 病例中仅 50%，这表明在这种未被充分认识的表型中涉及新的遗传变异。
本研究在一个大型 nfvPPA 和 svPPA 患者队列中发现了 12%的 ALS，与总体 FTD 报告的 10%-15%相当，这表明三分之一的 FTD-ALS 患者将具有主要的语言特征。这些发现强调了在 PPA 中评估 ALS 的重要性，特别是因为迄今为止这是唯一报告具有完美临床病理关联的 PPA 表型。
