Olfactory deficits and donepezil treatment in cognitively impaired elderly

认知障碍老年人的嗅觉缺陷和多奈哌齐治疗

• 批准号: 9068726
• 负责人: DAVANGERE P DEVANAND
• 金额: $ 62.29万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9068726
• 关键词: Acetylcholine; Acetylcholinesterase Inhibitors; Acute; Adverse effects; Alzheimer' s Disease; Anti-Cholinergics; Antidepressive Agents; Atropine; Brain; Brain Pathology; Brain region; British; Clinical; Cognition; Cognitive; Data; Dementia; Disease; Elderly; FDA approved; Future; Galantamine; Goals; Health; Health Care Costs; Hippocampus (Brain); Impaired cognition; Interview; Magnetic Resonance Imaging; Measures; Neurobiology; Neurofibrillary Tangles; Nose; Odors; Olfactory tract; Patient Monitoring; Patients; Pennsylvania; Pharmaceutical Preparations; Pilot Projects; Placebos; Process; Public Health; Risk; Sampling; Senile Plaques; Severity of illness; Tacrine; Testing; Time; Universities; abstracting; base; cholinergic; cholinergic neuron; comorbid depression; cost; donepezil; entorhinal cortex; follow-up; impression; improved; indexing; mild cognitive impairment; olfactory bulb; open label; performance tests; personalized medicine; predicting response; response; rivastigmine; sound

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.

描述（由申请人提供）：嗅觉识别缺陷发生在阿尔茨海默病（AD）患者中，与疾病严重程度相关，预测从轻度认知障碍（MCI）向AD的转化，并与健康老年受试者发生MCI相关。气味（嗅觉）识别缺陷可能反映了胆碱能输入的退化， 嗅球和其他嗅脑区域。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适度的作用，但由于需要长期（通常是终身）治疗，可能与不良反应和增加的负担和成本有关。来自四项初步研究（包括我们自己的两项研究）的气味识别测试性能（UPSIT，抓挠和嗅探40项测试）的聚合结果表明，UPSIT对抗胆碱能药物（阿托品鼻喷雾剂）的急性变化，8周内的增量变化，甚至基线UPSIT评分本身，都可以预测MCI和AD患者ACheI治疗后的认知改善。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乙酰胆碱酯酶治疗，这种简单廉价的方法将推进改善个性化治疗的目标，改善乙酰胆碱酯酶治疗患者的选择和监测，减少不必要的乙酰胆碱酯酶暴露的副作用风险，并降低医疗保健费用。 项目目标是评估在ACheI，多奈哌齐开放治疗期间，100例MCI患者（研究1）和100例轻度至中度AD患者（研究2）的气味识别缺陷的变化作为改善的预测因子。在这两项研究中，我们假设，从基线时进行的阿托品鼻喷雾剂激发前到激发后的UPSIT评分降低与多奈哌齐治疗26周和52周时从基线到认知和整体改善相关。其基本原理是，患有AD脑病理的MCI患者在急性阿托品激发时将出现胆碱能缺陷和气味识别恶化，这些患者更有可能在ACheI治疗后改善。在这两项研究中，我们假设UPSIT评分从基线（阿托品前）到多奈哌齐治疗8周的增加将与多奈哌齐治疗0周至26周和52周的认知和整体改善相关。这是第一个系统的努力，以评估气味识别缺陷的短期变化的临床效用，以预测长期的认知和整体改善ACHE I治疗，并包括第一次使用抗胆碱能药物的挑战，有一个健全的神经生物学基础。