Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK.
Acta Neuropathol. 2014 Apr;127(4):459-75. doi: 10.1007/s00401-014-1261-7. Epub 2014 Feb 20.
Olfactory dysfunction is a common and early symptom of many neurodegenerative diseases, particularly of Parkinson's disease and other synucleinopathies, Alzheimer's disease (AD), and mild cognitive impairment heralding its progression to dementia. The neuropathologic changes of olfactory dysfunction in neurodegenerative diseases may involve the olfactory epithelium, olfactory bulb/tract, primary olfactory cortices, and their secondary targets. Olfactory dysfunction is related to deposition of pathological proteins, α-synuclein, hyperphosphorylated tau protein, and neurofilament protein in these areas, featured by neurofibrillary tangles, Lewy bodies and neurites inducing a complex cascade of molecular processes including oxidative damage, neuroinflammation, and cytosolic disruption of cellular processes leading to cell death. Damage to cholinergic, serotonergic, and noradrenergic systems is likely involved, since such damage is most marked in those diseases with severe anosmia. Recent studies of olfactory dysfunction have focused its potential as an early biomarker for the diagnosis of neurodegenerative disorders and their disease progression. Here, we summarize the current knowledge on neuropathological and pathophysiological changes of the olfactory system in the most frequent neurodegenerative diseases, in particular AD and synucleinopathies. We also present neuropathological findings in the olfactory bulb and tract in a large autopsy cohort (n = 536, 57.8 % female, mean age 81.3 years). The severity of olfactory bulb HPτ, Aβ, and αSyn pathology correlated and increased significantly (P < 0.001) with increasing neuritic Braak stages, Thal Aβ phases, and cerebral Lewy body pathology, respectively. Hence, further studies are warranted to investigate the potential role of olfactory biopsies (possibly restricted to the olfactory epithelium) in the diagnostic process of neurodegenerative diseases in particular in clinical drug trials to identify subjects showing early, preclinical stages of neurodegeneration and to stratify clinically impaired cohorts according to the underlying cerebral neuropathology.
嗅觉功能障碍是许多神经退行性疾病的常见和早期症状，特别是帕金森病和其他突触核蛋白病、阿尔茨海默病 (AD) 和轻度认知障碍，预示着其向痴呆发展。神经退行性疾病嗅觉功能障碍的神经病理学变化可能涉及嗅觉上皮、嗅球/束、初级嗅觉皮质及其二级靶标。嗅觉功能障碍与这些区域病理性蛋白的沉积有关，包括 α-突触核蛋白、过度磷酸化的 tau 蛋白和神经丝蛋白，其特征是神经纤维缠结、路易体和神经原纤维诱导包括氧化损伤、神经炎症和细胞过程的细胞质破坏在内的复杂级联分子过程，导致细胞死亡。胆碱能、5-羟色胺能和去甲肾上腺素能系统的损伤可能涉及，因为在那些有严重嗅觉障碍的疾病中，这种损伤最为明显。最近对嗅觉功能障碍的研究集中在其作为神经退行性疾病诊断和疾病进展的早期生物标志物的潜力上。在这里，我们总结了最常见的神经退行性疾病（特别是 AD 和突触核蛋白病）中嗅觉系统的神经病理学和病理生理学变化的最新知识。我们还介绍了在一个大型尸检队列（n = 536，女性占 57.8%，平均年龄 81.3 岁）中嗅球和嗅束的神经病理学发现。嗅球 HPτ、Aβ 和 αSyn 病理学的严重程度与神经纤维缠结 Braak 分期、Thal Aβ 分期和大脑路易体病理学的增加呈正相关（P < 0.001）。因此，有必要进一步研究嗅觉活检（可能仅限于嗅觉上皮）在神经退行性疾病诊断过程中的潜在作用，特别是在临床药物试验中，以识别显示神经退行性变早期、临床前阶段的受试者，并根据潜在的大脑神经病理学对临床受损队列进行分层。
