Department of Pathology, Stanford University School of Medicine, Edwards Building, Room R-241, 300 Pasteur Drive, Stanford, CA, 94305, USA.
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Acta Neuropathol Commun. 2015 Jul 10;3:43. doi: 10.1186/s40478-015-0216-0.
Transthyretin/TTR gene mutations usually cause systemic amyloidotic diseases. Few TTR variants preferentially affect the central nervous system, manifesting as oculoleptomeningeal amyloidosis. Patients with TTR meningovascular amyloidosis often show dementia, however the neuropathologic features of dementia in these cases have not been elucidated. We report the neuropathologic findings from a brain autopsy of a 72-year-old man with the rare Tyr69His (Y69H) TTR gene variant, dementia and ataxia. Severe amyloid deposits were observed in the leptomeninges and in a subpial and subependymal distribution. Mass spectrometry analysis demonstrated that the amyloid deposits were comprised of over 80 % of the variant TTR. TTR was undetectable by mass spectrometry in the neocortex subjacent to the subpial amyloid deposits. Subpial TTR amyloid deposits were associated with brisk superficial reactive gliosis and siderosis in the neocortex and cerebellar cortex. Subependymal TTR amyloid deposits were associated with subjacent myelin pallor in the hippocampal outflow tract structures including the alveus, fimbria and fornix. Phospho-tau immunostains demonstrated transentorhinal-stage neurofibrillary degeneration (Braak stage II) which, in the absence of neocortical amyloid-beta and neuritic plaques, was indicative of primary age-related tauopathy (PART). However, distinctive phospho-tau aggregates were observed subjacent to the subpial TTR amyloid deposits in all regions of the neocortex, including the primary motor and striate cortices, suggesting a potential link between TTR amyloid and neocortical tauopathy. Our report reveals novel insights into the potential neuropathologic substrates of dementia in variant TTR amyloidosis that need to be investigated in larger autopsy series.
转甲状腺素蛋白/TTR 基因突变通常会导致全身性淀粉样变性疾病。少数 TTR 变体优先影响中枢神经系统，表现为眼神经病性脑脊髓炎。患有 TTR 脑膜血管淀粉样变性的患者常表现为痴呆，但这些病例中痴呆的神经病理学特征尚未阐明。我们报告了一例罕见的 Tyr69His（Y69H）TTR 基因突变、痴呆和共济失调患者的脑尸检神经病理学发现。在软脑膜和皮质下及室管膜下分布中观察到严重的淀粉样沉积物。质谱分析表明，淀粉样沉积物由超过 80%的变异 TTR 组成。TTR 在紧邻皮质下淀粉样沉积物的大脑新皮层中无法通过质谱检测到。皮质下 TTR 淀粉样沉积物与大脑皮质和小脑皮质的浅层反应性神经胶质增生和含铁血黄素沉着有关。室管膜下 TTR 淀粉样沉积物与海马传出束结构（包括齿状回、穹窿和穹窿柱）的髓鞘苍白有关。磷酸化 tau 免疫染色显示跨颞叶阶段神经纤维缠结变性（Braak Ⅱ期），在没有皮质层淀粉样-β和神经突斑的情况下，提示原发性年龄相关性 tau 病（PART）。然而，在所有大脑皮质区域（包括初级运动和纹状体皮质）的皮质下 TTR 淀粉样沉积物下观察到独特的磷酸化 tau 聚集，表明 TTR 淀粉样蛋白和皮质 tau 病之间可能存在联系。我们的报告揭示了变异 TTR 淀粉样变性中痴呆的潜在神经病理学基础的新见解，需要在更大的尸检系列中进行研究。
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