Neuropathology Unit, Division of Brain Sciences, Department of Medicine, Imperial College London, 4/F, Burlington Danes Building, Du Cane Road, London, W12 0NN, UK.
Laboratory of Neurodegenerative Diseases, School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR.
Acta Neuropathol Commun. 2019 Apr 25;7(1):61. doi: 10.1186/s40478-019-0717-3.
Although the precise neuropathological substrates of cognitive decline in Parkinson's disease (PD) remain elusive, it has long been regarded that pathology in the CA2 hippocampal subfield is characteristic of Lewy body dementias, including dementia in PD (PDD). Early non-human primate tracer studies demonstrated connections from the nucleus of the vertical limb of the diagonal band of Broca (nvlDBB, Ch2) to the hippocampus. However, the relationship between Lewy pathology of the CA2 subfield and cholinergic fibres has not been explored. Therefore, in this study, we investigated the burden of pathology in the CA2 subsector of PD cases with varying degrees of cognitive impairment and correlated this with the extent of septohippocampal cholinergic deficit. Hippocampal sections from 67 PD, 34 PD with mild cognitive impairment and 96 PDD cases were immunostained for tau and alpha-synuclein, and the respective pathology burden was assessed semi-quantitatively. In a subset of cases, the degree of CA2 cholinergic depletion was quantified using confocal microscopy and correlated with cholinergic neuronal loss in Ch2. We found that only cases with dementia have a significantly greater Lewy pathology, whereas cholinergic fibre depletion was evident in cases with mild cognitive impairment and this was significantly correlated with loss of cholinergic neurons in Ch2. In addition, multiple antigen immunofluorescence demonstrated colocalisation between cholinergic fibres and alpha-synuclein but not tau pathology. Such specific Lewy pathology targeting the cholinergic system within the CA2 subfield may contribute to the unique memory retrieval deficit seen in patients with Lewy body disorders, as distinct from the memory storage deficit seen in Alzheimer's disease.
虽然帕金森病 (PD) 认知能力下降的确切神经病理学基础仍不清楚，但长期以来一直认为 CA2 海马亚区的病理学是路易体痴呆症的特征，包括 PD 痴呆 (PDD)。早期的非人类灵长类动物示踪剂研究表明，Broca 垂直肢对角带核 (nvlDBB，Ch2) 与海马之间存在联系。然而，CA2 亚区路易体病理学与胆碱能纤维之间的关系尚未得到探索。因此，在这项研究中，我们研究了具有不同认知障碍程度的 PD 病例中 CA2 亚区的病理学负担，并将其与隔海马胆碱能缺陷的程度相关联。对来自 67 例 PD、34 例轻度认知障碍和 96 例 PDD 病例的海马切片进行 tau 和 alpha-synuclein 的免疫染色，并对各自的病理学负担进行半定量评估。在部分病例中，使用共聚焦显微镜定量评估 CA2 胆碱能耗竭的程度，并与 Ch2 中的胆碱能神经元丢失相关联。我们发现只有痴呆症患者的路易体病理学显著增加，而轻度认知障碍患者的胆碱能纤维耗竭明显，这与 Ch2 中的胆碱能神经元丢失显著相关。此外，多重抗原免疫荧光显示胆碱能纤维与 alpha-synuclein 而不是 tau 病理学之间存在共定位。这种针对 CA2 亚区胆碱能系统的特定路易体病理学可能导致路易体疾病患者出现独特的记忆检索缺陷，与阿尔茨海默病患者的记忆存储缺陷不同。
