Perforant path synaptic loss correlates with cognitive impairment and Alzheimer's disease in the oldest-old
Perforant path synaptic loss correlates with cognitive impairment and Alzheimer's disease in the oldest-old
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DOI：
10.1093/brain/awu190
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发表时间：
2014-09-01
期刊：
影响因子：
14.5
通讯作者：
Trojanowski, John Q.
中科院分区：
文献类型：
--
作者：
Robinson, John L.;Molina-Porcel, Laura;Trojanowski, John Q.
阿尔茨海默氏病的病理学特征是大量淀粉样斑块和神经原纤维缠结，同时伴有突触和神经元损失，是老年人痴呆最常见的根本原因。在90岁及以上的老年人中，除了阿尔茨海默病之外，其他与衰老相关的脑部疾病也很普遍，包括脑血管疾病和海马硬化症。尽管明确的阿尔茨海默氏病病理学可以将痴呆症与正常人区分开来，但认知障碍（尤其是老年人）的认知障碍病理学仍然知之甚少。因此，我们进行了研究，以确定阿尔茨海默病病理学、脑血管疾病、海马硬化以及三种突触蛋白表达的改变对认知状态和整体认知功能的相对贡献。在“90+研究”的前 157 名参加尸检的参与者中，获得了海马齿状回外分子层中的突触素、突触小泡转运蛋白 Sv2（现称为 SV2A）和囊泡谷氨酸转运蛋白 1 的相对免疫组织化学强度测量，其中包括患有痴呆症的参与者（n = 84）、患有认知障碍但无痴呆的参与者（n = 37）和认知正常的人（n = 36）。还分析了Thal期、Braak期、脑血管疾病、海马硬化和病理性43-kDa反式反应序列DNA结合蛋白(TDP-43)。所有测量均在不考虑认知诊断的情况下获得。整体认知通过简易精神状态检查进行测试。逻辑回归分析探讨了病理测量与属于不同认知组的几率之间的关联，而多元回归分析则探讨了病理测量与整体认知得分之间的关联。没有任何措施可以清楚地区分对照组和认知障碍组。比较认知障碍组和痴呆组，突触素和SV2减少，而Braak分期、TDP-43和海马硬化频率增加。 Thal期和VGLUT1没有区分认知障碍和痴呆组。所有测量都区分了痴呆症组和对照组以及与认知测试分数相关的所有标记。当同时分析所有标记物时，发现突触素的减少、高 Braak 阶段以及 TDP-43 和海马硬化的存在与整体认知功能相关。这些发现表明，缠结病理、海马硬化、TDP-43 和穿通通路突触丧失是老年人痴呆的主要原因。尽管斑块病理学的增加和谷氨酸能突触丧失可能是与认知障碍相关的早期事件，但我们得出的结论是，根据本文报告的测量结果，患有认知障碍但无痴呆的受试者与认知正常的受试者没有区别。
Alzheimer's disease, which is defined pathologically by abundant amyloid plaques and neurofibrillary tangles concurrent with synaptic and neuronal loss, is the most common underlying cause of dementia in the elderly. Among the oldest-old, those aged 90 and older, other ageing-related brain pathologies are prevalent in addition to Alzheimer's disease, including cerebrovascular disease and hippocampal sclerosis. Although definite Alzheimer's disease pathology can distinguish dementia from normal individuals, the pathologies underlying cognitive impairment, especially in the oldest-old, remain poorly understood. We therefore conducted studies to determine the relative contributions of Alzheimer's disease pathology, cerebrovascular disease, hippocampal sclerosis and the altered expression of three synaptic proteins to cognitive status and global cognitive function. Relative immunohistochemistry intensity measures were obtained for synaptophysin, Synaptic vesicle transporter Sv2 (now known as SV2A) and Vesicular glutamate transporter 1 in the outer molecular layer of the hippocampal dentate gyrus on the first 157 participants of 'The 90+ Study' who came to autopsy, including participants with dementia (n = 84), those with cognitive impairment but no dementia (n = 37) and those with normal cognition (n = 36). Thal phase, Braak stage, cerebrovascular disease, hippocampal sclerosis and Pathological 43-kDa transactive response sequence DNA-binding protein (TDP-43) were also analysed. All measures were obtained blind to cognitive diagnosis. Global cognition was tested by the Mini-Mental State Examinaton. Logistic regression analysis explored the association between the pathological measures and the odds of being in the different cognitive groups whereas multiple regression analyses explored the association between pathological measures and global cognition scores. No measure clearly distinguished the control and cognitive impairment groups. Comparing the cognitive impairment and dementia groups, synaptophysin and SV2 were reduced, whereas Braak stage, TDP-43 and hippocampal sclerosis frequency increased. Thal phase and VGLUT1 did not distinguish the cognitive impairment and dementia groups. All measures distinguished the dementia and control groups and all markers associated with the cognitive test scores. When all markers were analysed simultaneously, a reduction in synaptophysin, a high Braak stage and the presence of TDP-43 and hippocampal sclerosis associated with global cognitive function. These findings suggest that tangle pathology, hippocampal sclerosis, TDP-43 and perforant pathway synaptic loss are the major contributors to dementia in the oldest-old. Although an increase in plaque pathology and glutamatergic synaptic loss may be early events associated with cognitive impairment, we conclude that those with cognitive impairment, but no dementia, are indistinguishable from cognitively normal subjects based on the measures reported here.