From the National Alzheimer's Coordinating Center (K.M.G., M.A.T., C.M., J.E.C., K.C.G.C., W.A.K.), Department of Epidemiology, and Department of Statistics (Y.-C.C.) University of Washington, Seattle; Houston Methodist Hospital (M.D.C.), TX; and Sanders-Brown Center on Aging (Y.K., D.W.F., G.A.J., P.T.N.), Department of Biostatistics (Y.K., D.W.F., A.J.D.), Department of Neurology (G.A.J.), and Department of Pathology (P.T.N.), Division of Neuropathology, University of Kentucky, Lexington.
Neurology. 2022 Apr 5;98(14):e1422-e1433. doi: 10.1212/WNL.0000000000200001. Epub 2022 Feb 4.
Limbic-predominant age-related Tar DNA binding protein 43 (TDP-43) encephalopathy neuropathologic change (LATE-NC) is present in ≈25% of older persons' brains and is strongly associated with cognitive impairment. Hippocampal sclerosis (HS) pathology is often comorbid with LATE-NC, but the clinical and pathologic correlates of HS in LATE-NC are not well understood.
This retrospective autopsy cohort study used data derived from the National Alzheimer's Coordinating Center Neuropathology Data Set, which included neurologic status, medical histories, and neuropathologic results. All autopsies were performed in 2014 or later. Among participants with LATE-NC, those who also had HS pathology were compared with those without HS with regard to candidate risk factors or common underlying diseases. Statistical significance was set at nominal < 0.05 in this exploratory study.
A total of 408 participants were included (n = 221 were LATE-NC+/HS-, n = 145 were LATE-NC+/HS+, and n = 42 were LATE-NC-/HS+). Most of the included LATE-NC+ participants were severely impaired cognitively (83.3% with dementia). Compared to HS- participants, LATE-NC+ participants with HS trended toward having worse cognitive status and scored lower on the Personal Care and Orientation domains (both = 0.03). Among LATE-NC+ participants with Braak neurofibrillary tangle (NFT) stages 0 to IV (n = 88), HS+ participants were more impaired in the Memory and Orientation domains (both = 0.02). There were no differences (HS+ compared with HS-) in the proportion with clinical histories of seizures, stroke, cardiac bypass procedures, diabetes, or hypertension. The HS+ group lacking TDP-43 proteinopathy (n = 42) was relatively likely to have had strokes ( = 0.03). When LATE-NC+ participants with or without HS were compared, there were no differences in Alzheimer disease neuropathologies (Thal β-amyloid phases or Braak NFT stages) or Lewy body pathologies. However, the HS+ group was less likely to have amygdala-restricted TDP-43 proteinopathy (LATE-NC stage 1) and more likely to have neocortical TDP-43 proteinopathy (LATE-NC stage 3) ( < 0.001). LATE-NC+ brains with HS also tended to have more severe circle of Willis atherosclerosis and arteriolosclerosis pathologies.
In this cohort skewed toward participants with severe dementia, LATE-NC+ HS pathology was not associated with seizures or with Alzheimer-type pathologies. Rather, the presence of comorbid HS pathology was associated with more widespread TDP-43 proteinopathy and with more severe non-β-amyloid vessel wall pathologies.
以边缘为主的与年龄相关的 Tar DNA 结合蛋白 43（TDP-43）脑病神经病理改变（LATE-NC）存在于约 25%的老年人的大脑中，与认知障碍密切相关。海马硬化（HS）病理学常与 LATE-NC 合并存在，但 LATE-NC 中 HS 的临床和病理相关性尚不清楚。
本回顾性尸检队列研究使用了来自国家阿尔茨海默病协调中心神经病理学数据集的数据，其中包括神经状态、病史和神经病理学结果。所有尸检均在 2014 年或之后进行。在患有 LATE-NC 的参与者中，比较了伴有 HS 病理学的参与者与不伴有 HS 的参与者的候选风险因素或常见潜在疾病。在这项探索性研究中，设定了名义 < 0.05 的统计学意义。
共纳入 408 名参与者（n = 221 为 LATE-NC+/HS-，n = 145 为 LATE-NC+/HS+，n = 42 为 LATE-NC-/HS+）。大多数纳入的 LATE-NC+参与者认知功能严重受损（83.3%患有痴呆）。与 HS-参与者相比，伴有 HS 的 LATE-NC+参与者的认知状态趋势较差，个人护理和定向领域的得分较低（均为 = 0.03）。在 LATE-NC+伴有 Braak 神经原纤维缠结（NFT）0 至 IV 期（n = 88）的参与者中，HS+参与者在记忆和定向领域的损伤更严重（均为 = 0.02）。在伴有或不伴有 HS 的 LATE-NC+参与者中，无癫痫、中风、心脏旁路手术、糖尿病或高血压病史的比例无差异（HS+与 HS-相比）。缺乏 TDP-43 蛋白病（n = 42）的 HS+组更有可能发生中风（ = 0.03）。当比较伴有或不伴有 HS 的 LATE-NC+参与者时，阿尔茨海默病神经病理学（Thal β-淀粉样蛋白阶段或 Braak NFT 阶段）或路易体病理学无差异。然而，HS+组不太可能出现局限性于杏仁核的 TDP-43 蛋白病（LATE-NC 1 期），而更可能出现皮质 TDP-43 蛋白病（LATE-NC 3 期）（ < 0.001）。伴有 HS 的 LATE-NC+脑还倾向于具有更严重的Willis 环动脉粥样硬化和小动脉硬化病理学。
在本队列中，参与者偏向于严重痴呆，LATE-NC+HS 病理学与癫痫或阿尔茨海默病型病理学无关。相反，合并存在 HS 病理学与更广泛的 TDP-43 蛋白病和更严重的非 β-淀粉样血管壁病理学有关。
