Sleep Disordered Breathing in normal elderly and risk for Alzheimers Disease

描述（由申请人提供）：睡眠呼吸障碍（SDB）是一种常见的疾病，估计在老年人中患病率为30-80%。随着最近的证据表明SDB可能与轻度认知障碍和痴呆的发展有关，这种高频率在晚年的相关性正在显现。阿尔茨海默病（AD）是最常见的痴呆症，影响了近45%的85岁以上人口。海马萎缩和葡萄糖低代谢，以及脑脊液（CSF）中淀粉样蛋白β -42 （a42）、磷酸化Tau （P-Tau）和总Tau （T- Tau）水平的变化，已被证明可用于预测认知正常老年人未来的衰退，这表明阿尔茨海默病病理可在高危受试者的认知障碍之前检测到。在这个“症状前阶段”，组织损伤最小，在临床症状出现之前就能发现，是进行风险因素分析和干预试验的理想阶段。我们的初步数据首次显示，在认知正常的老年人中，SDB的严重程度（通过4%去饱和呼吸事件[AHI4%]测量）与脑脊液P-Tau和T-Tau的增加、内侧颞叶葡萄糖摄取的减少（通过FDG-PET测量）、海马体积的减少和纵向记忆的下降有关。这些发现提出了一个问题，即阿尔茨海默病组织损伤是否导致老年人SDB，或者SDB是否作为神经退行性变的危险因素。本项目的拟议父母资助（R01AG022374）由纽约大学脑健康中心（CBH）进行，是一项由NIH资助的对180名正常老年人（50-95岁）进行的为期5年的纵向研究，他们将接受完整的基线和24个月的随访评估。检查包括磁共振成像：结构和脑血流量（CBF），使用新的纽约大学动脉自旋标记（ASL）方案，以避免敏感性伪影，以及二氧化碳呼吸后的区域脑血管反应性估计（VR-CO2）；以及血浆和脑脊液生物标志物。目前，与纽约大学睡眠障碍中心合作的辅助方案将研究：1)SDB作为记忆变化、P-tau和T-Tau水平、海马萎缩和VR-CO2反应减弱的纵向预测因子（SDB的所有这些影响在我们的试点工作中都是在横断面上观察到的）；2)正常老年人SDB相关现象是否易受中重度SDB患者鼻持续气道正压通气（CPAP）干预。本研究有可能确定：1)SDB导致认知能力下降的高度普遍的ad相关机制；2)替代假说，AD生物标志物特征的存在是SDB的危险因素；3) CPAP治疗SDB可通过AD相关通路改善老年人的认知能力。

DESCRIPTION (provided by applicant): Sleep disordered breathing (SDB) is a common disorder with an estimated prevalence in the elderly ranging from 30-80%. The relevance of this high frequency in late life is emerging, as recent evidence suggests that SDB may be associated with the development of mild cognitive impairment and dementia. Alzheimer's disease (AD) is the most common form of dementia and affects nearly 45% of the population older than 85. Hippocampal atrophy and glucose hypometabolism, as well as changes in cerebrospinal fluid (CSF) levels of amyloid beta-42 (A�42), phosphorylated-tau (P-Tau) and total-tau (T- Tau), have been shown to be useful in predicting future decline in cognitively normal older adults, which suggests that AD pathology is detectable prior to cognitive impairment in at-risk subjects. This "presymptomatic phase", in which tissue damage is minimal and whose detection precedes clinical symptoms, is an ideal stage for risk factor analysis and intervention trials. Our preliminary data show, for the first time in cognitively-normal elderly, tat the severity of SDB (as measured by respiratory events with 4% desaturation [AHI4%]) is associated with the increase of CSF P-Tau and T-Tau, a decrease in glucose uptake (measured by FDG-PET) in the medial temporal lobe, reduced hippocampal volume, and longitudinal memory decline. These findings raise the question as to whether AD tissue damage causes SDB in the elderly, or alternatively, if SDB acts as a risk factor for neurodegeneration. The proposed parent grant for this project (R01AG022374), conducted at the NYU Center for Brain Health (CBH), is a 5-year NIH- funded longitudinal study of 180 normal elderly (50-95 years), who will undergo complete baseline and 24 month follow-up evaluations. The exams include MR imaging: both structural and cerebral blood flow (CBF) using a novel NYU arterial spin labeling (ASL) protocol to avoid susceptibility artifacts, and regional brain vasoreactivity estimates after CO2 breathing (VR-CO2); as well as both plasma and CSF biomarkers. The present ancillary proposal, performed in collaboration with NYU's Sleep Disorders Center, will investigate: 1) SDB as a longitudinal predictor of changes in memory, levels of P-tau and T-Tau, hippocampal atrophy, and the blunted VR-CO2 response (all these effects of SDB were observed in cross- section in our pilot work); and 2) if these SDB related phenomena in normal elderly are susceptible to intervention with nasal continuous positive airway pressure (CPAP) in moderate-to-severe SDB subjects. This study has the potential to identify: 1) a highly prevalent AD-related mechanism by which SDB contributes to cognitive decline; 2) the alternative hypothesis, the presence of biomarker features of AD as risks factors for SDB; and 3) that the treatment of SDB with CPAP improves cognition through an AD- related pathway in the elderly.