Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, NE4 5PL Newcastle upon Tyne, UK.
Curr Alzheimer Res. 2013 Jul;10(6):569-77. doi: 10.2174/15672050113109990002.
Age associated neurodegenerative diseases are characterized by intra- and extracellular aggregation and deposition of misfolded proteins. The neuropathological classification of neurodegenerative diseases is based on the semiquantitative assessment of these misfolded proteins, that constitute the neuropathological hallmark lesion for the respective disease: e.g. Alzheimer's disease (AD), amyloid-β (Aβ) hyperphosphorylated tau (tau); Lewy body diseases, α- synuclein (α-syn); frontotemporal lobar degeneration, tau, TDP-43, ubiquitin or FUS. In addition, cerebrovascular lesions are assessed for the diagnosis of vascular dementia. However, in brains of elderly patients suffering from neurodegenerative diseases multiple pathologies are usually present and even in clinically characterized prospective cohorts additional pathologies are frequently found at post mortem examination. On the other hand, various amounts of AD pathology are frequently seen in brains of non-demented elderly and the threshold to cause clinical overt dementia is ill defined as additional co-morbidities (e.g., cerebrovascular lesions) might lower the threshold for clinical dementia in some cases. It becomes increasingly clear that the clinical picture of dementia in most aged patients results from a multimorbid condition in the CNS rather than from one single disease and data from animal studies suggest that Aβ, tau, and α-syn interact in vivo to promote the aggregation and accumulation of each other. We suggest that clinico-pathological correlative studies using a more quantitative approach in the assessment of neuropathological lesions are warranted to elucidate cerebral multimorbidity and to identify suitable targets for targeted therapeutic strategies against age associated neurodegeneration.
与年龄相关的神经退行性疾病的特征是细胞内和细胞外错误折叠蛋白质的聚集和沉积。神经退行性疾病的神经病理学分类是基于对这些错误折叠蛋白质的半定量评估，这些蛋白质构成了各自疾病的神经病理学特征性病变：例如阿尔茨海默病（AD），β淀粉样蛋白（Aβ）过度磷酸化的tau（tau）；路易体疾病，α-突触核蛋白（α-syn）；额颞叶变性，tau、TDP-43、泛素或 FUS。此外，还评估脑血管病变以诊断血管性痴呆。然而，在患有神经退行性疾病的老年患者的大脑中，通常存在多种病理，即使在临床特征明确的前瞻性队列中，在尸检时也经常发现其他病理。另一方面，在没有痴呆的老年人大脑中经常看到各种程度的 AD 病理学，导致临床明显痴呆的阈值定义不明确，因为其他合并症（例如脑血管病变）可能会在某些情况下降低临床痴呆的阈值。越来越清楚的是，大多数老年患者的痴呆临床症状是中枢神经系统多系统疾病的结果，而不是单一疾病，动物研究数据表明，Aβ、tau 和 α-syn 在体内相互作用，促进彼此的聚集和积累。我们建议使用更定量的方法评估神经病理学病变，进行临床病理相关性研究，以阐明大脑的多系统疾病，并确定针对与年龄相关的神经退行性变的靶向治疗策略的合适靶点。
