Carvalho Diego Z, St Louis Erik K, Przybelski Scott A, Morgenthaler Timothy I, Machulda Mary M, Boeve Bradley F, Petersen Ronald C, Jack Clifford R, Graff-Radford Jonathan, Vemuri Prashanthi, Mielke Michelle M
Department of Neurology, Mayo Clinic, Rochester, MN, United States.
Center for Sleep Medicine, Division of Pulmonary and Critical Care, Department of Medicine, Mayo Clinic, Rochester, MN, United States.
Front Aging Neurosci. 2022 Jul 11;14:930315. doi: 10.3389/fnagi.2022.930315. eCollection 2022.
Sleepiness has been associated with cognitive decline and dementia in the elderly. Older adults with excessive daytime sleepiness appear to be more vulnerable to longitudinal amyloid PET accumulation before the onset of the dementia. However, it remains unclear whether sleepiness is similarly associated with other biomarkers of Alzheimer's disease (AD), axonal integrity, and inflammation, which may also contribute to neurodegeneration and cognitive decline.
In this cross-sectional analysis, we identified 260 cognitively unimpaired adults (>60 years) from the Mayo Clinic Study of Aging, a population-based cohort from Olmsted County (MN), who underwent CSF quantification of AD biomarkers (Aβ42, p-tau, p-tau/Aβ42) in addition to at least one of the following biomarkers [neurofilament light chain (NfL) interleukin-6 (IL-6), IL-10, and tumor necrosis factor-α (TNF-α)]. We fit linear regression models to assess associations between sleepiness, as measured by the Epworth Sleepiness Scale (ESS), and CSF biomarkers, controlling for age, sex, APOε4 status, body mass index, hypertension, dyslipidemia, and prior diagnosis of obstructive sleep apnea.
Higher ESS scores were associated with higher CSF IL-6 and NfL, but not with the other CSF biomarkers. For every ESS score point increase, there was a 0.009 ([95% CI 0.001-0.016], = 0.033) increase in the log of IL-6 and 0.01 ([95% CI 0.002-0.018], = 0.016) increase in the log of NfL. A sensitivity analysis showed an association between ESS scores and log of p-tau/Aβ42 only in participants with an abnormal ratio (>0.023), highly predictive of amyloid positivity. For every ESS score point increase, there was a 0.006 ([95% CI 0.001-0.012], = 0.021) increase in the log of CSF p-tau/Aβ42.
Sleepiness was associated with greater CSF IL-6 and NfL levels, which could contribute to neurodegeneration or alternatively cause sleepiness. Higher NfL levels may result from sleep disruption and/or contribute to sleepiness disturbed connectivity or damage to wake-promoting centers. Associations between sleepiness and p-tau/Aβ42 in participants with abnormal ratio suggest that amyloid positivity contributes to vulnerability to sleep disturbance, which may further amyloid accumulation in a feed-forward loop process. Prospective studies of these markers are needed to determine cause-effect relationships between these associations.
嗜睡与老年人的认知衰退和痴呆症有关。白天过度嗜睡的老年人在痴呆症发作前似乎更容易出现纵向淀粉样蛋白PET积累。然而，目前尚不清楚嗜睡是否同样与阿尔茨海默病（AD）的其他生物标志物、轴突完整性和炎症有关，这些因素也可能导致神经退行性变和认知衰退。
在这项横断面分析中，我们从梅奥诊所衰老研究中确定了260名认知未受损的成年人（>60岁），该研究是明尼苏达州奥尔姆斯特德县的一项基于人群的队列研究，这些参与者除了接受以下生物标志物中的至少一种[神经丝轻链（NfL）、白细胞介素-6（IL-6）、IL-10和肿瘤坏死因子-α（TNF-α）]检测外，还接受了AD生物标志物（Aβ42、p-tau、p-tau/Aβ42）的脑脊液定量检测。我们拟合线性回归模型，以评估由爱泼沃斯嗜睡量表（ESS）测量的嗜睡与脑脊液生物标志物之间的关联，并控制年龄、性别、APOε4状态、体重指数、高血压、血脂异常和既往阻塞性睡眠呼吸暂停诊断。
较高的ESS评分与较高的脑脊液IL-6和NfL相关，但与其他脑脊液生物标志物无关。ESS评分每增加1分，IL-6的对数增加0.009（[95%置信区间0.001-0.016]，P=0.033），NfL的对数增加0.01（[95%置信区间0.002-0.018]，P=0.016）。敏感性分析显示，仅在比率异常（>0.023）的参与者中，ESS评分与p-tau/Aβ42的对数之间存在关联，这对淀粉样蛋白阳性具有高度预测性。ESS评分每增加1分，脑脊液p-tau/Aβ42的对数增加0.006（[95%置信区间0.001-0.012]，P=0.021）。
嗜睡与脑脊液中较高的IL-6和NfL水平相关，这可能导致神经退行性变或导致嗜睡。较高的NfL水平可能是由于睡眠中断和/或导致嗜睡，即连接性受损或促醒中枢受损。比率异常的参与者中嗜睡与p-tau/Aβ42之间的关联表明，淀粉样蛋白阳性会导致易受睡眠干扰，这可能在一个前馈循环过程中进一步导致淀粉样蛋白积累。需要对这些标志物进行前瞻性研究，以确定这些关联之间的因果关系。
