Olfactory deficits and donepezil treatment in cognitively impaired elderly

描述(申请人提供)：嗅觉识别缺陷发生在阿尔茨海默病(AD)患者中，与疾病的严重程度相关，预测从轻度认知障碍(MCI)转变为AD，并与健康的老年受试者发展MCI有关。气味(嗅觉)识别缺陷可能反映了胆碱能输入到 嗅球和其他嗅觉脑区。乙酰胆碱酯酶抑制剂(ACheI)，如多奈哌齐，在改善认知方面显示出温和的效果，但可能与不良反应和增加的负担和成本有关，因为需要长期的，通常是终生的治疗。四项先导性研究(包括我们自己的两项)对气味识别测试性能(UPSIT、Scratch和Sniff 40项测试)的一致研究结果表明，UPSIT在抗胆碱能挑战(阿托品鼻喷剂)反应中的急性变化，8周内的增量变化，甚至基线UPSIT评分本身，可能预测ACheI治疗对MCI和AD的认知改善。如果气味识别缺陷的改变可以帮助确定哪些患者应该接受AChei治疗，这种简单、廉价的方法将推进改善个性化治疗的目标，改善对AChei治疗患者的选择和监测，减少不必要的AChei暴露和副作用风险，并降低医疗保健成本。项目目标是评估100名MCI患者(研究1)和100名轻中度AD患者(研究2)在开放使用ACheI多奈哌齐治疗期间气味识别缺陷的变化，作为改善的预测因素。在这两项研究中，我们假设，在基线条件下，UPSIT评分从阿托品鼻腔喷雾治疗前到治疗后的下降将与从基线到多奈哌齐治疗26周和52周的认知和整体改善有关。其基本原理是，那些有AD脑病理的MCI患者将在急性阿托品挑战下出现胆碱能缺陷和气味识别恶化，而这些患者更有可能通过AChei治疗而改善。在这两项研究中，我们假设UPSIT评分从基线(阿托品前)增加到多奈哌齐治疗8周将与认知和整体改善有关，从0周到26周和52周治疗。这是第一次系统地评估气味识别缺陷的短期变化的临床效用，以预测ACheI治疗的长期认知和全球改善，并包括首次使用具有良好神经生物学基础的抗胆碱能挑战。

DESCRIPTION (provided by applicant): Olfactory identification deficits occur in patients with Alzheimer's disease (AD), are associated with disease severity, predict conversion from mild cognitive impairment (MCI) to AD and are associated with healthy elderly subjects developing MCI. Odor (olfactory) identification deficits may reflect degeneration of cholinergic inputs to the olfactory bulb and other olfactory brain regions. Acetylcholinesterase inhibitors (ACheI) like donepezil show modest effects in improving cognition but can be associated with adverse effects and increased burden and costs because of the need for prolonged, often lifelong, treatment. Converging findings on odor identification test performance (UPSIT, scratch and sniff 40-item test) from four pilot studies, including two of our own, suggest that acute change in the UPSIT in response to an anticholinergic challenge (atropine nasal spray), incremental change over 8 weeks, and even the baseline UPSIT score by itself, may predict cognitive improvement with ACheI treatment in MCI and AD. If change in odor identification deficits can help to identify which patients should receive ACheI treatment, this simple inexpensive approach will advance the goal of improving personalized treatment, improve selection and monitoring of patients for ACheI treatment, reduce needless ACheI exposure with risk of side effects, and decrease health care costs. Project goals are to evaluate change in odor identification deficits as predictors of improvement in 100 patients with MCI (Study 1) and in 100 patients with mild to moderate AD (Study 2) during open treatment with the ACheI, donepezil. In both studies, we hypothesize that the decrease in UPSIT scores from pre- to post-atropine nasal spray challenge conducted at baseline will be associated with cognitive and global improvement from baseline to both 26 weeks and 52 weeks of donepezil treatment. The rationale is that those MCI patients who have AD brain pathology will have a cholinergic deficit and worsening of odor identification with the acute atropine challenge, and these patients will be more likely to improve with ACheI treatment. In both studies, we hypothesize that the increase in UPSIT scores from baseline (pre-atropine) to 8 weeks of donepezil treatment will be associated with cognitive and global improvement from 0 weeks to both 26 weeks and 52 weeks of donepezil treatment. This is the first systematic effort to evaluate the clinical utility of short-term changes in odor identificatin deficits to predict long-term cognitive and global improvement on ACheI treatment, and includes the first use of an anticholinergic challenge that has a sound neurobiological basis.