病理学、影像学和遗传学特征支持在非额颞叶痴呆大脑中存在不同的 TDP-43 类型。
Pathological, imaging and genetic characteristics support the existence of distinct TDP-43 types in non-FTLD brains.
机构信息
Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA.
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
出版信息
Acta Neuropathol. 2019 Feb;137(2):227-238. doi: 10.1007/s00401-018-1951-7. Epub 2019 Jan 2.
TDP-43 is present in a high proportion of aged brains that do not meet criteria for frontotemporal lobar degeneration (FTLD). We determined whether there are distinct TDP-43 types in non-FTLD brains. From a cohort of 553 brains (Braak neurofibrillary tangle (NFT) stage 0-VI), excluding cases meeting criteria for FTLD, we identified those that had screened positive for TDP-43. We reviewed 14 different brain regions in these TDP-43 positive cases and classified them into those with "typical" TDP-43 immunoreactive inclusions (TDP type-α), and those in which TDP-43 immunoreactivity was adjacent to/associated with NFTs in the same neuron (TDP type-β). We compared pathological, genetic (APOE4, TMEM106B and GRN variants), neuroimaging and clinical data between types, as well as compared neuroimaging between types and a group of TDP-43 negative cases (n = 309). Two-hundred forty-one cases were classified as TDP type-α (n = 131, 54%) or TDP type-β (n = 110, 46%). Type-α cases were older than type-β at death (median 89 years vs. 87 years; p = 0.02). Hippocampal sclerosis was present in 78 (60%) type-α cases and 16 (15%) type-β cases (p < 0.001). Type-α cases showed a pattern of widespread TDP-43 deposition commonly extending into temporal, frontal and brainstem regions (84% TDP-43 stage 4-6) while in type-β cases deposition was predominantly limbic, located in amygdala, entorhinal cortex and subiculum of the hippocampus (84% TDP-43 stages 1-3) (p < 0.001). There was a difference in the frequency of TMEM106B protective (GG) and risk (CC) haplotypes (SNP rs3173615 encoding p.T185S) in type-α cases compared to type-β cases (GG/CG/CC: 8%/42%/50% vs. 24%/49%/27%; p = 0.01). Type-α cases had smaller amygdala (- 10.6% [- 17.6%, - 3.5%]; p = 0.003) and hippocampal (- 14.4% [- 21.6%, - 7.3%]; p < 0.001) volumes on MRI at death compared to type-β cases, although both types had smaller amygdala and hippocampal volumes compared to TDP-43 negative cases (- 7.77%, - 21.6%; p < 0.001). These findings demonstrate that there is distinct heterogeneity of TDP-43 deposition in non-FTLD brains.
TDP-43 存在于很大一部分不符合额颞叶变性（FTLD）标准的老年大脑中。我们确定了在非 FTLD 大脑中是否存在不同类型的 TDP-43。在排除符合 FTLD 标准的病例的 553 例脑队列（Braak 神经原纤维缠结（NFT）阶段 0-VI）中，我们确定了那些对 TDP-43 呈阳性筛查的病例。我们在这些 TDP-43 阳性病例中检查了 14 个不同的大脑区域，并将它们分为具有“典型”TDP-43 免疫反应性内含物（TDP 型-α）的那些，以及 TDP-43 免疫反应性与同一神经元中的 NFT 相邻/相关的那些（TDP 型-β）。我们比较了两种类型之间的病理、遗传（APOE4、TMEM106B 和 GRN 变体）、神经影像学和临床数据，以及两种类型之间的神经影像学与 TDP-43 阴性病例组（n=309）的比较。241 例被分类为 TDP 型-α（n=131，54%）或 TDP 型-β（n=110，46%）。TDP 型-α病例的死亡年龄大于 TDP 型-β（中位数 89 岁与 87 岁；p=0.02）。78 例（60%）TDP 型-α病例和 16 例（15%）TDP 型-β病例存在海马硬化（p<0.001）。TDP 型-α病例表现出广泛的 TDP-43 沉积模式，通常延伸到颞叶、额叶和脑干区域（84% TDP-43 分期 4-6），而 TDP 型-β病例的沉积主要位于边缘系统，位于杏仁核、内嗅皮层和海马回（84% TDP-43 分期 1-3）（p<0.001）。与 TDP 型-β病例相比，TDP 型-α病例中 TMEM106B 保护性（GG）和风险（CC）单倍型（编码 p.T185S 的 SNP rs3173615）的频率存在差异（GG/CG/CC：8%/42%/50%与 24%/49%/27%；p=0.01）。与 TDP 型-β病例相比，TDP 型-α病例在死亡时的杏仁核（-10.6%[-17.6%，-3.5%]；p=0.003）和海马（-14.4%[-21.6%，-7.3%]；p<0.001）体积较小，尽管这两种类型的杏仁核和海马体积都比 TDP-43 阴性病例小（-7.77%，-21.6%；p<0.001）。这些发现表明，在非 FTLD 大脑中，TDP-43 沉积存在明显的异质性。
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