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a-突触核蛋白病理的早期沉积。然而，PD患者低氧症的病理生理机制仍然知之甚少。嗅觉系统中更多中枢或边缘皮层成分的神经变性可能导致PD低血症。PD的嗅觉功能缺陷描述在气味识别，气味辨别，阈值检测和气味识别记忆。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。我们之前报道过，在（非常）早期PD中，气味识别受损与海马的关系比纹状体多巴胺能去神经更密切。这些发现提示海马多巴胺能失神经支配和/或功能障碍可能导致PD低血症。然而，嗅觉损伤不受多巴胺能药物的影响，也与PD疾病分期或PD运动特征持续时间无关。这表明多巴胺能去神经支配对低体温的影响存在早期“底”现象。低氧症也发生在阿尔茨海默病（AD）中，并随着痴呆的严重程度而增加。高密度的内嗅皮层和海马神经原纤维缠结与更大的气味识别缺陷相关，提示海马形成功能障碍在AD低血症中的作用。阿尔茨海默病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，这是阿尔茨海默病的早期现象。至少在一部分患者中，胆碱能系统变性也是帕金森病的早期特征，并随着痴呆的出现而恶化。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，帕金森病进展期低血症的恶化可能与胆碱能神经元变性和相关的认知功能障碍有关。我们的初步数据表明PD低血症的严重程度与海马胆碱能神经支配的下降有关。因此，在有早期认知功能障碍证据的PD受试者中，预测PD低血症最为显著；我们的初步数据证实了这一预测。本前瞻性队列研究的目的是检验两个假设。第一，重度低血症与晚期PD患者认知能力下降的风险增加有关。第二，低氧症的恶化与海马胆碱能去神经并行。如果这些假设得到证实，嗅觉功能评估可能为有效的临床筛查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患者。

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.