Association Of Sleep Characteristics With Cerebrospinal Fluid STREM2 Level In Cognitively Normal Older Adults

Objective:As an insult to brain,sleep disorders could impair the clearance of metabolic wastes as well as potentially toxic proteins.Sleep disorders could also aggravate the neuronal injury and inflammation in the central nervous system(CNS).Recent studies showed that sleep disorders might enhance the microglial activation.Soluble triggering receptor expressed on myeloid cells 2(sTREM2)in cerebrospinal fluid(CSF)served as a readout for the TREM2-triggered microglial response.CSF sTREM2 play a protective role in the CNS homeostasis in response to neuronal injury.In this study,to study the effects of sleep disorders on microglial activation and neuroinflammation,we investigated the association of sleep characteristics with CSF sTREM2 levels in a large sample of cognitively normal and neurologically healthy older adults.Approximately one-third of cognitively normal adults have Alzheimer’s disease(AD)pathology in their brains.We divided all the participants into amyloid-negative(A-)and amyloid-positive(A+)groups to study whether the influence of sleep was more obvious when there is already evidence of amyloid pathology.Methods:We included 830 cognitively normal participants totally.All the participants were aged between 40-90 years old and neurologically healthy.Linear regression analyses were conducted,with the sleep characteristics in Pittsburgh Sleep Quality Index(PSQI)to be independent variables and CSF sTREM2 levels to be dependent variables.Confounding factors including age,sex,education,the Chinese-Modified Mini-Mental State Examination(CM-MMSE)scores and APOE4 status were adjusted.To examine if there were U-shaped associations between sleep-time measures and CSF sTREM2,the non-linear regression analyses via the quadratic model(y=αx~2+βx+c)were performed after adjusting for covariates.All statistical analyses were performed in amyloid-negative(A-)and amyloid-positive(A+)individuals.Results:Liner relationships between sleep characteristics and CSF sTREM2 levels were found.In all participants,the higher Pittsburgh Sleep Quality Index(PSQI)sleep efficiency score(p=0.037)showed linear relationships with higher level of sTREM2 in CSF.In A+individuals,the higher PSQI ranked score(p=0.011),higher PSQI subjective sleep quality score(p=0.048)and higher PSQI sleep efficiency score(p<0.001)were associated with higher CSF sTREM2 level.Besides,several U-shaped relationships were revealed among sleep-time measures in A+individuals,such as insufficient or excessive nocturnal sleep duration was associated with higher CSF sTREM2 levels(the optimal model:bedtime:22:21 p.m.,time to fall asleep:22:52 p.m.,nocturnal sleep duration:around 7.36 hours).In A-individuals,the above relationships were not found.Conclusions and Significance:Sleep disorders were associated with higher CSF sTREM2 levels in older adults.When there is already evidence of amyloid pathology,the influence of sleep disorders(lower sleep efficiency,poorer subjective sleep quality,insufficient sleep and excessive nocturnal sleep duration)on CSF sTREM2 was more obvious.Sleep played an important role in the regulation of TREM2-triggered microglial activity.This study suggested a novel strategy for alleviating neuroinflammation by sleep management,which may contribute to the treatment of neurological disorders.