Effection And Mechanism Exploration Of Sleep Fragmentation On Progression And Pathological Changes In Alzheimer’s Disease

PartⅠThe Reciprocal Interaction Between Sleep Fragmentation and Alzheimer’s DiseaseObjectives To definite the reciprocal interaction between sleep fragmentation and Alzheimer’s disease.To investigate the incidence of sleep fragmentation in patients with Alzheimer’s disease(AD)and the effect of sleep fragmentation on the long-term outcome.To reveal whether incidence of sleep fragmentation would be higher in patients with AD compared with healthy aged people or it could harm the long-term outcome.To further reveal the effect of sleep fragmentation on emotional outcomes of spousal caregivers in 5years.Methods In the first study,polysomnography was conducted to monitor sleep status for two full nights in 43 drug-free AD patients and 22 healthy aged people.The daytime sleepiness was assessed by Epworth Sleepiness Scale(ESS).In the second study,a total of 156 low-dose-cholinesterase inhibitor-treated AD patients were recruited,including 93 patients with AD and SD were divided into AD+SD group and 63 patients with AD but without SD were divided into control group(AD-SD).Patients’ status were evaluated by using polysomnography,sleep scale and a series of cognitive scales in 5 years,including MMSE,ADL,NPI and ESS.A total of 14 people died in 5 years.Moreover,all spousal caregivers of all AD+SD patients including medication group and non-medication group were assessed by a series of scales,including PSQI,ESS,HAMA,HAMD and treatment attitude scales.Results The first study shows that 73% AD patients with sleep disorders and 53.5%AD patients with daytime sleepiness.There are significant differences in comparison with sleep time,sleep efficiency,awakenings and wake time between all subjects.There are significant differences in with(ESS score>10)or without(ESS score<10)daytime sleepiness between AD patients and healthy aged people(P<0.01).The significant difference of sleep efficiency was also recognized between these groups(P<0.01).In comparison with awakenings and their wake time,we also report the statistically difference between these groups(P<0.01),however the of AD patients without daytime sleepiness showed significantly decrease in slow wave sleep(SWS)latencies(P<0.05).These results suggest that AD patients may have sleep fragmentation phenomenon.The second study shows that the baseline sleep parameters,including awakenings,ESS scores,PSG indicators(bed time,sleep duration,sleep efficiency,REM latency period,S3 ratio,and REM phase ratio)are significantly worse in AD+SD group compared with AD-SD group(P<0.01).The results verify the inclusion criterion.The MMSE and ADL scores are extremely lower in AD+SD group than AD-SD group(P<0.01).There are more patients in dementia special care unit in AD+SD group compare with AD-SD group,more eating problems and psychotic symptoms in AD+SD group.All of these above evidences indicate sleep fragmentation could progress the deterioration of AD.Furthermore,there are also significant differences between the medication group and non-medication group in AD+SD patients in comparison with the ESS,PSQI,HAMA and HAMD scores of spousal caregivers(P<0.01).The spouses’ expectations for patients’ remaining life time of AD patients and the positive rescue in extremis are obviously reduced in AD+SD group(P<0.01).The results show that sleep fragmentation can significantly affect their caregivers’ care emotions,which has adverse effect on AD patients.Conclusion Patients with AD are more susceptible to sleep fragmentation which could deteriorate the long term outcome of AD.It could benefit the spousal caregivers’ emotional outcome when trying to treat sleep fragmentation for AD patients.However,the mechanism of the reciprocal interaction between AD and SD has not been clarified so far.Part II Effection and mechanism exploration of sleep fragment on cerebral pathological changes in AD ratsObjectives To investigate the possible mechanism of the interaction between AD and sleep fragmentation according to the evidences found by clinic.The AD model rats were employed in this study to examine whether their sleep-wake rhythm changed.Further detect the concentration of amyloid β in the interstitial fluid(ISF A β)and the change of orexin in hypothalamus by executing sleep fragments which were executed sleep interruption to accelerated AD pathological changes in AD rats.We also inquire the effect of orexin and its receptor inhibitor Almorexant on brain β amyloid and wake time in AD rats to investigate whether orexin contributed to the SD progressed deterioration of AD.Methods Sprague-Dawley rats were anesthetized and set EEG recording electrode and microdialysis guide cannula.In the first study,A β 25-35 were injected at bilateral hippocampal of rats to prepare AD model,and injected some volume of saline as sham control.The model was assessed at 21 to 26 day(d21-d26)by using Morris water maze behavioral tests.EEG data were recorded by d30 and d31.In the second part of the first study,the ISF Aβ and orexin baseline data were recorded by d27 after AD modeling,all animals were divided into groups by d28,including SI group which were executed sleep interruption(SI)for 7 days,briefly,rats in this group lived in a modified treadmill cage in which the floor was a horizontal belt to more solwly at a rate of 0.02m/s,the teeadmill ran at this solw speed 30 s,followed by no treadmill activity for 90 s.as an exercise control group,different rats were exposed to treadmill movement producing comparable overall amounts of exercise between the SI and EC groups.The ISF A β and orexin was collected by d38 and d39 from hippocampus and hypothalamus,respectively.In the second study,orexin and vehicle were continuously injected into a group of rats for 6h through the icv by d39.The ISF A β and EEG were recorded by d38 and d39.Almorexant and vehicle were continuously injected into another group of rats for 24 h through lateral ventricles since d39 7:00pm.The ISF A β and EEG were recorded by d38,d39 and d40.The record of sleep EEG was analyzed by Sleep Sign software and corrected manually.ISF A β and orexin were analyzed by ELISA.Results The wake time significantly prolonged in nighttime and daytime in ADgroup compared with sham(P<0.01),the results show that sleep fragmentation appeared in AD rats with disease progression.The concentration of ISF Aβ significantly increased in SI group compare with EC(P<0.01),the results show that sleep fragments progresses the deterioration of AD.The concentration of orexin significantly increased at the same phase in SI group compare with EC(P<0.01),the results show that changes of ISF Aβand orexin at the same phase and the same trend are caused by sleep fragments.The concentration of ISF Aβ(P<0.01)and the wake time(P<0.01)significantly increased after orexin injection compared with baseline.The concentration of ISF Aβ significantly decreased after Almorexant injection compared with baseline(P<0.05),as well as wake time(P<0.01).The icv infusions of the two control vehicle groups did not affect ISF Aβlevels(P>0.05).The results show that the potential mechanism underlying sleep fragmentation regulating ISF Aβ is thought to be the contribution of orexin.Conclusion Sleep fragmentation occurs in AD rats,in contrast,sleep fragments progresses the deterioration of AD.The potential mechanism underlying sleep fragmentation regulating ISF Aβ is thought to be the contribution of orexin.Therefore,there is a reciprocal interaction between AD and sleep fragmentation,orexin plays an important role in the interaction.