Hyposmia, Cholinergic Denervation and Incipient Cognitive Decline in PD

描述（由申请人提供）：嗅觉功能障碍在帕金森病（PD）中很常见，并归因于嗅球中α-突触核蛋白病理学的早期沉积。然而，PD患者嗅觉减退的病理生理机制仍知之甚少。嗅觉系统的更多中央或边缘皮质成分内的神经变性可能有助于PD嗅觉减退。PD患者嗅觉功能的缺陷主要表现在气味识别、气味辨别、阈值检测和气味识别记忆等方面。气味识别而不是气味检测的优先下降表明气味记忆受损，可能是由于海马功能障碍。我们以前报道过，受损的气味识别（非常）早期PD更密切相关的海马比纹状体多巴胺能去神经支配。这些结果表明，海马多巴胺能神经支配和/或功能障碍可能有助于PD嗅觉减退。然而，嗅觉障碍不受多巴胺能药物的影响，并且与PD疾病阶段或PD运动特征的持续时间无关。这表明在多巴胺能去神经对嗅觉减退的影响中存在早期“地板”现象。 嗅觉减退也发生在阿尔茨海默病（AD）中，并且随着痴呆的严重程度而增加。内嗅皮层和海马神经元缠结密度较高与更大的气味识别缺陷相关，提示海马结构功能障碍在AD嗅觉减退中的作用。AD海马功能障碍的另一个因素是基底前脑胆碱能神经支配的丧失，这是AD的早期现象。胆碱能系统变性也是PD的早期特征，至少在一部分患者中是如此，并且在PD中出现痴呆。大多数嗅觉和PD的研究本质上是横断面的，不包括认知障碍的受试者。然而，进展性PD中嗅觉减退恶化可能与胆碱能神经元变性和相关的认知功能障碍相关。我们的初步数据表明，PD嗅觉减退的严重程度和海马胆碱能神经支配下降之间的相关性。因此，PD嗅觉减退在有早期认知功能障碍证据的PD受试者中最明显;我们的初步数据证实了这一预测。这项前瞻性队列研究的目的是检验2个假设。第一，在进展性PD受试者中，嗅觉减退的严重程度越高，认知能力下降的风险越高。第二，嗅觉减退恶化与进行性胆碱能海马去神经支配并行。如果这些假设得到证实，嗅觉功能评价可能为有效的临床筛选提供独特的生物标志物，以识别具有认知能力下降高风险的中枢胆碱能缺陷的PD受试者。 公共卫生相关性：非运动功能，如痴呆，是帕金森病残疾和健康相关生活质量降低的主要决定因素。嗅觉测试，也许与其他测试相结合，可用于识别帕金森病受试者的认知能力下降的高风险。该项目的结果可能为独特的生物标志物信息提供基础，以指导临床实践中的年度临床嗅觉测试筛查--这是指导对痴呆风险最高的中枢胆碱能缺陷受试者进行有针对性干预的窗口。

DESCRIPTION (provided by applicant): Olfactory dysfunction is common in Parkinson disease (PD) and has been attributed to early deposition of a-synuclein pathology in the olfactory bulb. The pathophysiology of hyposmia in PD, however, remains poorly understood. Neurodegeneration within more central or limbic cortical components of the olfactory system may contribute to PD hyposmia. Deficits of olfactory function in PD are described in odor identification, odor discrimination, threshold detection, and odor recognition memory. A preferential decline in odor identification rather than odor detection suggests impairment in odor memory, possibly due to hippocampal dysfunction. We reported previously that impaired odor identification in (very) early PD is more closely correlated with hippocampal than striatal dopaminergic denervation. These findings suggest that hippocampal dopaminergic denervation and/or dysfunction may contribute to PD hyposmia. Olfactory impairments, however, are not affected by dopaminergic medications, and do not correlate with PD disease stage or duration of motor features of PD. This suggests an early "floor" phenomenon in the effect of dopaminergic denervation on hyposmia. Hyposmia occurs also in Alzheimer disease (AD) and increases with severity of dementia. Higher density of entorhinal cortex and hippocampal neurofibrillary tangles correlates with greater odor identification deficits, suggesting a role for hippocampal formation dysfunction in AD hyposmia. Another contributor to AD hippocampal dysfunction is loss of basal forebrain cholinergic innervation, an early phenomenon in AD. Cholinergic system degeneration is an early feature of PD also, at least in a subset of patients, and worsens with the appearance of dementia. Most studies of olfaction and PD are cross-sectional in nature and do not include subjects with cognitive impairment. However, worsening hyposmia in advancing PD may be associated with cholinergic neuron degeneration and associated cognitive dysfunction. Our preliminary data indicates correlation between the severity of PD hyposmia and declining hippocampal cholinergic innervation. PD hyposmia is predicted, then, to be most marked in PD subjects with evidence of early cognitive dysfunction; a prediction borne out by our preliminary data. The goals of this prospective cohort study are to test 2 hypotheses. One, greater severity of hyposmia is associated with increased risk of cognitive decline in subjects with advancing PD. Two, worsening hyposmia parallels progressive cholinergic hippocampal denervation. If these hypotheses are confirmed, olfactory function evaluations may provide a unique biomarker for efficient clinical screening to identify PD subjects with a central cholinergic deficit at high risk for cognitive decline. PUBLIC HEALTH RELEVANCE: Non-motor features such as dementia, are major determinants of disability and reduced health- related quality of life in Parkinson disease. Olfactory testing, perhaps combined with other tests, could be used to identify Parkinson disease subjects at high risk for cognitive decline. Results of this project may provide the foundation for unique biomarker information to guide annual clinical smell test screening in clinical practice - a window to guide targeted intervention in subjects with a central cholinergic deficit at highest risk of dementia.