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Background: The complement system plays crucial roles in cognitive impairment and acute ischemic stroke (AIS). High levels of complement proteins in plasma astrocyte-derived exosomes (ADEs) were proven to be associated with Alzheimer's disease. We aimed to investigate the relationship of complement proteins in serum ADEs with poststroke cognitive impairment in type 2 diabetes mellitus (T2DM) patients., Methods: This study analyzed 197 T2DM patients who suffered AIS. The Beijing version of the Montreal Cognitive Assessment (MoCA) was used to assess cognitive function. Complement proteins in serum ADEs were quantified using ELISA kits., Results: Mediation analyses showed that C5b-9 and C3b in serum ADEs partially mediate the impact of obstructive sleep apnea (OSA), depression, small vessel disease (SVD), and infarct volume on cognitive function at the acute phase of AIS in T2DM patients. After adjusting for age, sex, time, and interaction between time and complement proteins in serum ADEs, the mixed linear regression showed that C3b and complement protein Factor B in serum ADEs were associated with MoCA scores at three-, six-, and twelve-months after AIS in T2DM patients., Conclusions: Our study suggested that the impact of OSA, depression, SVD, and infarct volume on cognitive impairment in the acute stage of AIS may partially mediate through the complement proteins in serum ADEs. Additionally, the complement proteins in serum ADEs at the acute phase of AIS associated with MoCA scores at three-, six-, twelve months after AIS in T2DM patients.REGISTRATION: URL: http://www.chictr.org.cn/,ChiCTR1900021544.

Background: The complement system plays a crucial role in cognitive impairment. The aim of this study is to investigate the correlation between the complement proteins levels in serum astrocyte-derived exosomes (ADEs) and mild cognitive impairment (MCI) in type 1 diabetes mellitus (T1DM) patients., Methods: In this cross-sectional study, the patients with immune-mediated T1DM were enrolled. Healthy subjects matched for age and sex with T1DM patients were selected as controls. The cognitive function was evaluated by a Beijing version of the Montreal Cognitive Assessment (MoCA) questionnaire. The complement proteins including C5b-9, C3b and Factor B in serum ADEs were measured by ELISA kits., Results: This study recruited 55 subjects immune-mediated T1DM patients without dementia, including 31 T1DM patients with MCI, 24 T1DM patients without MCI. 33 healthy subjects were enrolled as controls. The results showed higher complement proteins including C5b-9, C3b and Factor B levels in ADEs from T1DM patients with MCI than those in the controls (P < 0.001, P < 0.001, P = 0.006) and T1DM patients without MCI (P = 0.02, P = 0.02, P = 0.03). The C5b-9 levels in ADEs were independently associated with MCI in T1DM patients(OR: 1.20, 95% CI: 1.00-1.44, P = 0.04). The C5b-9 levels in ADEs were significantly correlated with global cognitive scores (β = -0.360, P＜0.001) and visuo-executive (β = -0.132, P＜0.001), language(β = -0.036, P = 0.026) and delayed recall score (β = -0.090,P = 0.007). There was no correlation between the C5b-9 levels in ADEs and the fasting glucose, HbA1c, fasting c-peptide and GAD65 antibody in T1DM patients. Furthermore, the C5b-9, C3b and Factor B levels in ADEs exhibited a fair combined diagnostic value for MCI, with an area under the curve of 0.76 (95% CI: 0.63-0.88, P = 0.001)., Conclusion: The elevated C5b-9 levels in ADEswere significantly associated with theMCI in T1DM patients. The C5b-9 in ADEs may be used as a marker of MCI in T1DM patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Study Objectives: An association between neuroinflammation and cognitive decline has been established. The complement system regulates neuroinflammation. Dysregulation, impairment, or inadvertent activation of complement components contribute to preclinical Alzheimer's disease. The astrocyte-derived exosome (ADE) complement proteins, including C3b and C5b-9, may be predictive biomarkers of mild cognitive impairment conversion to Alzheimer's disease dementia. We hypothesized that complement proteins might be involved in cognitive impairment during obstructive sleep apnea (OSA). The aim of our study was to explore the correlation between the complement system and mild cognitive impairment (MCI) in patients with OSA., Methods: All participants with subjective snoring complaints from the Sleep Medicine Center underwent polysomnography. OSA was defined as apnea-hypopnea index ≥ 5 events/h. MCI was defined as the Montreal Cognitive Assessment < 26 and met the criteria: (1) a subjective cognitive impairment; (2) an objective impairment in 1 or more cognitive domains; (3) complex instrumental daily abilities can be slightly impaired but independent daily living abilities are maintained; and (4) no dementia. The ADEs were isolated immunochemically for enzyme-linked immunosorbent assay quantification of complement proteins, including C3b, C5b-9, and CD55. The participants who received continuous positive airway pressure were followed up and their complement protein levels were reassessed after 1 year of treatment., Results: A total of 212 participants (66.98% males; mean age of 56.71 ± 10.10 years) were divided into the OSA+MCI group (n = 90), OSA-MCI group (n = 79), and controls (normal cognitive state without OSA) (n = 43). The ADE levels of C3b and C5b-9 in the OSA+MCI group were higher than those in the OSA-MCI and control groups. The C3b and C5b-9 were independently associated with cognitive impairment in patients with OSA. The relationship between apnea-hypopnea index and Montreal Cognitive Assessment scores was mediated by C3b and C5b-9. We found no linear correlation between the complement proteins and the severity of OSA. The complement proteins were negatively correlated with global cognitive performance and cognitive subdomains. The complement protein levels significantly decreased after continuous positive airway pressure treatment., Conclusions: Complement proteins were implicated in cognitive impairment in patients with OSA and may be promising biomarkers for predicting cognitive impairment in patients with OSA., Clinical Trial Registration: Registry: Chinese Clinical Trial Registry; Name: Study on early diagnostic markers in patients with dementia and mild cognitive impairment; URL: https://www.chictr.org.cn/; Identifier: ChiCTR1900021544., Citation: Li M, Sun C, Xue S, et al. Complement proteins levels in serum astrocyte-derived exosomes are associated with cognitive impairment in obstructive sleep apnea. J Clin Sleep Med . 2023;19(4):727-739., (© 2023 American Academy of Sleep Medicine.)

The complement system plays a crucial role in cognitive impairment in obstructive sleep apnea (OSA). The present study aimed to investigate the connections between complement component 8 gamma (C8G) levels in astrocyte-derived exosomes (ADEs) and cognitive impairment in OSA patients without dementia. This cross-sectional cohort study recruited 274 participants without dementia, including 124 OSA patients with mild cognitive impairment (MCI), 100 OSA patients without MCI, and 50 healthy control subjects. Enrolled participants underwent polysomnography (PSG) evaluation, neuropsychological scale assessment, magnetic resonance imaging scanning, and collection of peripheral blood samples for quantification of complement proteins in ADEs. The findings showed higher C8G concentrations in ADEs from OSA patients with MCI than in the controls and OSA without MCI group. Logistic regression analysis suggested that C8G levels in ADEs were independently associated with MCI in OSA patients. Multivariable linear regression analysis demonstrated that C8G levels in ADEs were significantly correlated with global cognitive scores and all cognitive subdomain scores after adjusting for demographic factors (age, sex, education), vascular risk factors (Body mass index, history of hypertension, diabetes, dyslipidemia), depressive symptoms measures, and apnea-hypopnea index (AHI) values. The levels of C8G were linearly positively related to the white matter hyperintensity (WMH) volumes in Pearson's correlation analysis. Our research confirmed that C8G levels are significantly associated with cognitive impairment in OSA patients, which paves the way for novel therapeutic targets for neurocognitive dysfunction progression in OSA patients in the future., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: The purpose of our study was to investigate the correlation between neural-derived plasma exosomal amyloid-β (Aβ)42, total tau (T-tau) and tau phosphorylated at threonine 181 (P-T181-tau) protein levels and cognitive impairment in patients with obstructive sleep apnea (OSA)., Methods: There were 122 subjects without dementia included in the study: 27 patients with OSA and mild cognitive impairment (MCI), 52 OSA patients without MCI, and 43 subjects diagnosed with simple snoring but not MCI as the control group. Neuronal-derived exosomal proteins were measured by ELISA kits for Aβ42, T-tau and P-T181-tau. The cognitive function was evaluated by a Chinese version of the Montreal Cognitive Assessment (MoCA) questionnaire, and a normal cognitive score was ≥26., Results: The exosomal Aβ42, T-tau and P-T181-tau levels in the OSA with MCI group were higher than those in the OSA group. The Aβ42, T-tau, and P-T181-tau levels in the plasma neuronal-derived exosomes were associated with an increased risk of cognitive impairment in OSA patients after additional adjustment for age, gender, education, vascular risk factors, apnea-hypopnea index (AHI) or oxygen reduction index (ODI). Furthermore, there were also significant associations between Aβ42, T-tau, and P-T181-tau in neural-derived plasma exosomes and Epworth Sleepiness Scale, AHI, and ODI in OSA patients. After 1 year of continuous positive airway pressure (CPAP) intervention, the neuronal-derived exosome levels of Aβ42, T-tau, and P-T181-tau were significantly lower than those at baseline (P = 0.001, P = 0.012, and P = 0.034)., Conclusions: These findings indicate that peripheral blood levels of neuronal-derived exosomal Aβ and tau proteins were increased in OSA patients with cognitive impairment. CPAP interventions could possibly improve cognitive function and be associated with decreased levels of exosomal Aβ and tau proteins., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Emerging evidence suggests a role for orthostatic hypotension (OH) in contributing to the progression of Alzheimer's disease (AD). The exosomes in the blood can reflect the pathological changes in the brain., Objective: To investigate whether neural-derived plasma exosomes pathogenic proteins of AD levels are associated with OH in diabetes mellitus (DM) patients., Methods: There were 274 subjects without dementia included in the study: 81 control participants (controls), 101 normotensive patients with DM without OH, and 92 patients with DM and neurogenic OH (DMOH). Neural-derived exosomal proteins were measured by ELISA kits for amyloid-β (Aβ) and tau., Results: The neural-derived exosome levels of Aβ42, total tau (T-tau), and tau phosphorylated at threonine 181 (P-T181-tau) in the DM with OH group were higher than those in the DM and control groups. Multivariable linear regression analysis showed that the presence of OH in patients with DM was associated with elevated exosomal Aβ42 (β= 0.172, p = 0.018), T-tau (β= 0.159, p = 0.030), and P-T181-tau (β= 0.220, p = 0.003) levels after adjustment for age, sex, APOE ɛ4, duration of type 2 diabetes, HbA1c, and cardiovascular risk factors. Furthermore, the levels of Aβ42, T-tau, and P-T181-tau in neural-derived exosomes were correlated with HIF-1α levels and the drop in mean cerebral blood flow velocity from the supine to upright position., Conclusion: The presence of OH in DM patients was independently associated with elevated the Aβ42, T-tau, and P-T181-tau levels in neural-derived plasma exosomes. Cerebral hypoperfusion from DM with OH are likely candidate mechanisms.

Objective: Cognitive decline is a common non-motor symptom of Parkinson disease (PD), and cellular prion protein (PrP C ) has been suggested to play a role in this process. This study aimed to investigate the correlation between plasma exosomal prion protein and cognitive decline in PD patients., Method: A total of 60 participants, which included 23 PD patients without cognitive impairment (the PD-NCI group), 17 PD patients with cognitive impairment (the PD-CI group) and 20 health controls were included in this study. All participants received a complete evaluation of motor symptoms as well as non-motor symptoms, which include devaluations of cognitive function(assessed with the Montreal Cognitive Assessment (MoCA)) and their psychiatric state(assessed with the Hamilton Anxiety Scale(HAM-A) and Hamilton Depression Scale(HAMD-17)). We used an enzyme-linked immunosorbent assay (ELISA) to measure the plasma exosomal prion protein level. The exosomal marker Heat shock protein 70 (HSP 70) was used to normalize the protein level to the exosome content., Result: In PD patients, the plasma exosomal prion protein concentration was negatively correlated with the cognitive level. The plasma exosomal prion protein concentration was significantly higher in the PD-CI group than in the control group (p < 0.05) and the PD-NCI group (p < 0.05).Multivariate regression analysis indicated that plasma exosomal prion protein levels were significantly associated with the cognitive level (t=-3.185, P = 0.001) after adjusting for age, education, disease duration, H&Y stage and MDS-UPDRS-III scores., Conclusion: The plasma exosomal prion protein level is correlated with cognitive decline in PD patients and might be a potential biomarker for PD patients at risk for cognitive impairment., (Copyright © 2020 Elsevier B.V. All rights reserved.)