Sleep Disordered Breathing in normal elderly and risk for Alzheimers Disease

描述(申请人提供)：睡眠呼吸障碍(SDB)是一种常见的疾病，估计在老年人中的患病率从30%到80%不等。这种高频率在晚年生活中的相关性正在显现，因为最近的证据表明，SDB可能与轻度认知障碍和痴呆症的发展有关。阿尔茨海默病(AD)是最常见的痴呆症，影响着近45%的85岁以上人口。海马区萎缩和葡萄糖代谢不足，以及脑脊液中淀粉样β-42(A-�42)、磷酸化-tau(P-tau)和总tau(T-tau)水平的变化，已被证明有助于预测认知正常老年人未来的衰退，这表明在高危受试者认知损害之前就可以发现AD的病理。在这种“症状前阶段”，组织损伤最小，其检测先于临床症状，是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%脱饱和度的呼吸事件[AHI4%]来衡量)与脑脊液P-Tau和T-Tau增加、内侧颞叶葡萄糖摄取减少(FDG-PET测量)、海马体积减少和纵向记忆下降有关。这些发现提出了一个问题，即AD组织损伤是否会导致老年人的SDB，或者SDB是否会成为神经退化的风险因素。该项目的父母资助项目(R01AG022374)由纽约大学脑健康中心(CBH)进行，是一项由美国国立卫生研究院资助的为期5年的纵向研究，对象为180名正常老年人(50-95岁)，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：使用新的纽约大学动脉自旋标记(ASL)协议以避免易感性伪影的结构和脑血流(CBF)，以及二氧化碳呼吸后局部脑血管反应性(VR-CO2)评估；以及血浆和脑脊液生物标记物。目前与纽约大学睡眠障碍中心合作进行的这项辅助提案将调查：1)SDB作为记忆变化、P-tau和T-tau水平、海马体萎缩和钝化的VR-CO2反应的纵向预测因子(在我们的试点工作中横断面观察到了SDB的所有这些影响)；以及2)在正常老年人中，这些与SDB相关的现象是否容易受到中到重度SDB受试者鼻腔持续正压(CPAP)干预的影响。这项研究有可能确定：1)SDB促进认知功能下降的高度流行的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通过AD相关途径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.