Department of Psychiatry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Department of Psychiatry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, USA.
Alzheimers Dement. 2019 Apr;15(4):553-560. doi: 10.1016/j.jalz.2018.10.009. Epub 2019 Jan 25.
Primary progressive aphasia (PPA) is a neurological syndrome, associated with both frontotemporal dementia and Alzheimer's disease, in which progressive language impairment emerges as the most salient clinical feature during the initial stages of disease.
We screened the main genes associated with Alzheimer's disease and frontotemporal dementia for pathogenic and risk variants in a cohort of 403 PPA cases.
In this case series study, 14 (3.5%) cases carried (likely) pathogenic variants: four C9orf72 expansions, nine GRN, and one TARDBP mutation. Rare risk variants, TREM2 R47H and MAPT A152T, were associated with a three- to seven-fold increase in risk for PPA.
Our results show that while pathogenic variants within the most common dementia genes were rarely associated with PPA, these were found almost exclusively in GRN and C9orf72, suggesting that PPA is more TDP43- than tau-related in our series. This is consistent with the finding that PPA frequency in dominantly inherited dementias is the highest in kindreds with GRN variants.
原发性进行性失语症（PPA）是一种与额颞叶痴呆和阿尔茨海默病相关的神经综合征，在疾病的初始阶段，进行性语言障碍是最突出的临床特征。
我们在一个 403 例 PPA 病例的队列中筛查了与阿尔茨海默病和额颞叶痴呆相关的主要基因的致病和风险变异。
在这项病例系列研究中，14 例（3.5%）携带（可能）致病变异：四个 C9orf72 扩展，九个 GRN 和一个 TARDBP 突变。罕见的风险变异 TREM2 R47H 和 MAPT A152T 与 PPA 的风险增加三到七倍相关。
我们的结果表明，虽然最常见的痴呆基因中的致病变异很少与 PPA 相关，但这些变异几乎只存在于 GRN 和 C9orf72 中，这表明在我们的系列中，PPA 与 TDP43 相关，而非与 tau 相关。这与在具有 GRN 变异的家族中，显性遗传性痴呆症中 PPA 的频率最高的发现一致。
