PFASs in Cerebrospinal Fluids and Blood-CSF Barrier Permeability in Patients with Cognitive Impairment.

Attention has been drawn to the associations between PFASs and human cognitive decline. However, knowledge on the occurrence and permeability of PFASs in the brains of patients with cognitive impairment has not been reported. Here, we determined 30 PFASs in paired sera and cerebrospinal fluids (CSFs) from patients with cognitive impairment (n = 41) and controls without cognitive decline (n = 18). We revealed similar serum PFAS levels but different CSF PFAS levels, with lower CSF PFOA (median: 0.125 vs 0.303 ng/mL, p < 0.05), yet higher CSF PFOS (0.100 vs 0.052 ng/mL, p < 0.05) in patients than in controls. Blood-brain transfer rates also showed lower RCSF/Serum values for PFOA and higher RCSF/Serum values for PFOS in patients, implying potential heterogeneous associations with cognitive function. The RCSF/Serum values for C4-C14 perfluoroalkyl carboxylates exhibited a U-shape trend with increasing chain length. Logistic regression analyses demonstrated that CSF PFOS levels were linked to the heightened risk of cognitive impairment [odds ratio: 3.22 (1.18-11.8)] but not for serum PFOS. Toxicity inference results based on the Comparative Toxicogenomics Database suggested that PFOS in CSF may have a greater potential to impair human cognition than other PFASs. Our results contribute to a better understanding of brain PFAS exposure and its potential impact on cognitive function.

High burdens of phosphorylated tau protein and distinct precuneus atrophy in sporadic early-onset Alzheimer's disease.

Early-onset Alzheimer's disease (EOAD) is a rare devastating subclassification of Alzheimer's disease (AD). EOAD affects individuals <65 years old, and accounts for 5%-10% of all AD cases. Previous studies on EOAD primarily focused on familial forms, whereas research on sporadic EOAD (sEOAD), which represents 85%-90% of EOAD cases, is limited. In this prospective cohort study, participants were recruited between 2018 and 2023 and included patients with sEOAD (n = 110), late-onset AD (LOAD, n = 89), young controls (YC, n = 50), and older controls (OC, n = 25). All AD patients fulfilled the diagnostic criteria based on biomarker evidence. Familial EOAD patients or non-AD dementia patients were excluded. Single molecule array technology was used to measure fluid biomarkers, including cerebrospinal fluid (CSF) and plasma amyloid beta (Aß) 40, Aß42, phosphorylated tau (P-tau) 181, total tau (T-tau), serum neurofilament light chain and glial fibrillary acidic protein (GFAP). Patients with sEOAD exhibited more severe executive function impairment and bilateral precuneus atrophy (P < 0.05, family-wise error corrected) than patients with LOAD. Patients with sEOAD showed elevated CSF and plasma P-tau181 levels (154.0 ± 81.2 pg/mL, P = 0.002; and 6.1 ± 2.3 pg/mL, P = 0.046). Moreover, precuneus atrophy was significantly correlated with serum GFAP levels in sEOAD (P < 0.001). Serum GFAP levels (area under the curve (AUC) = 96.0%, cutoff value = 154.3 pg/mL) displayed excellent diagnostic value in distinguishing sEOAD patients from the control group. These preliminary findings highlight the crucial role of tau protein phosphorylation in the pathogenesis and progression of sEOAD.

Blood-based biomarkers for Alzheimer's disease: a multicenter-based cross-sectional and longitudinal study in China.

Discrepancies in diagnostic biomarkers for Alzheimer's Disease (AD) may arise from racial disparities, risk factors, or lifestyle differences. Moreover, there has been a lack of systematic and multicenter studies to evaluate baselines of the AD biomarkers in Chinese populations. Thus, there is an urgent need for research to investigate the effectiveness of blood biomarkers for AD, specifically in the Chinese Han population, using a multicenter approach. In the present multicenter-based cross-sectional and longitudinal study, we evaluated 817 blood samples from 6 different clinical centers. We measured plasma amyloid beta (Aß)-40, Aß42, phosphorylated tau 181 (pTau), total tau (tTau), serum neurofilament light (NFL), and glial fibrillary acidic protein (GFAP). Additionally, 18F-florbetapir positron electron tomography and magnetic resonance imaging were also performed. A combination of the APOE genotype with plasma pTau and serum GFAP demonstrated exceptional performance in distinguishing Aß status. Furthermore, baseline GFAP levels exhibited a strong association with cognitive decline over time and brain atrophy, with higher GFAP levels predicting a faster rate of neurodegeneration. In summary, these results validate the practicality of blood biomarkers in the Chinese Han population, encompassing various regions within China. Additionally, they emphasize the potential of pTau and GFAP as non-invasive methods for detecting and screening AD at an early stage.

Molecules of senescent glial cells differentiate Alzheimer's disease from ageing.

BACKGROUND: Ageing is a major risk factor for Alzheimer's disease (AD), which is accompanied by cellular senescence and thousands of transcriptional changes in the brain. OBJECTIVES: To identify the biomarkers in the cerebrospinal fluid (CSF) that could help differentiate healthy ageing from neurodegenerative processes. METHODS: Cellular senescence and ageing-related biomarkers were assessed in primary astrocytes and postmortem brains by immunoblotting and immunohistochemistry. The biomarkers were measured in CSF samples from the China Ageing and Neurodegenerative Disorder Initiative cohort using Elisa and the multiplex Luminex platform. RESULTS: The cyclin-dependent kinase inhibitors p16/p21-positive senescent cells in human postmortem brains were predominantly astrocytes and oligodendrocyte lineage cells, which accumulated in AD brains. CCL2, YKL-40, HGF, MIF, S100B, TSP2, LCN2 and serpinA3 are biomarkers closely related to human glial senescence. Moreover, we discovered that most of these molecules, which were upregulated in senescent glial cells, were significantly elevated in the AD brain. Notably, CSF YKL-40 (ß=0.5412, p<0.0001) levels were markedly elevated with age in healthy older individuals, whereas HGF (ß=0.2732, p=0.0001), MIF (ß=0.33714, p=0.0017) and TSP2 (ß=0.1996, p=0.0297) levels were more susceptible to age in older individuals with AD pathology. We revealed that YKL-40, TSP2 and serpinA3 were useful biomarkers for discriminating patients with AD from CN individuals and non-AD patients. DISCUSSION: Our findings demonstrated the different patterns of CSF biomarkers related to senescent glial cells between normal ageing and AD, implicating these biomarkers could identify the road node in healthy path off to neurodegeneration and improve the accuracy of clinical AD diagnosis, which would help promote healthy ageing.

Correlation of blood-brain barrier leakage with cerebral small vessel disease including cerebral microbleeds in Alzheimer's disease.

Background: Blood-brain barrier (BBB) damage is considered an important part of Alzheimer's disease (AD) progression, and cerebral small-vessel disease (CSVD) is commonly associated with AD. However, the relationship between BBB damage, small cerebrovascular lesions, especially cerebral microbleeds (CMBs), and amyloid and tau biomarkers remains controversial. Therefore, our study aimed to further investigate their association in our cohort of patients with AD. Methods: A total of 139 individuals were divided into probable AD (18F-florbetapir PET positive, n = 101) and control group (cognitively normal, n = 38). The levels of cerebrospinal fluid (CSF) and plasma t-tau, p-tau181, Aß40, Aß42, and albumin were measured using corresponding commercial assay kits, and the CSF/plasma albumin ratio (Qalb), an indicator of BBB dysfunction, was calculated. CSVD burden and the number of CMBs were defined using magnetic resonance imaging. Results: Patients with AD had higher Qalb (p = 0.0024), higher numbers of CMBs (p = 0.03), and greater CSVD burden (p < 0.0001). In the AD group, CMBs and CSVD correlated with a higher Qalb (p = 0.03), and the numbers of CMBs negatively correlated with CSF Aß42 (p = 0.02). Conclusion: Blood-brain barrier damage was accompanied by a more severe burden of CSVD, including CMB, in patients with AD.

Changes in CSF sPDGFRß level and their association with blood-brain barrier breakdown in Alzheimer's disease with or without small cerebrovascular lesions.

BACKGROUND: CSF-soluble platelet-derived growth factor receptor beta (sPDGFRß) is closely associated with pericyte damage. However, the changes in CSF sPDGFRß levels and their role in blood-brain barrier (BBB) leakage at different stages of Alzheimer's disease (AD), with or without cerebral small vessel disease (CSVD) burden, remain unclear. METHODS: A total of 158 individuals from the China Aging and Neurodegenerative Disorder Initiative cohort were selected, including 27, 48, and 83 individuals with a clinical dementia rating (CDR) score of 0, 0.5, and 1-2, respectively. CSF total tau, phosphorylated tau181 (p-tau181), Aß40, and Aß42 were measured using the Simoa assay. Albumin and CSF sPDGFRß were measured by commercial assay kits. CSVD burden was assessed by magnetic resonance imaging. RESULTS: CSF sPDGFRß was the highest level in the CDR 0.5 group. CSF sPDGFRß was significantly correlated with the CSF/serum albumin ratio (Q-alb) in the CDR 0-0.5 group (ß = 0.314, p = 0.008) but not in the CDR 1-2 group (ß = - 0.117, p = 0.317). In the CDR 0-0.5 group, CSF sPDGFRß exhibited a significant mediating effect between Aß42/Aß40 levels and Q-alb (p = 0.038). Q-alb, rather than CSF sPDGFRß, showed a significant difference between individuals with or without CSVD burden. Furthermore, in the CDR 0.5 group, CSF sPDGFRß was higher in subjects with progressive mild cognitive impairment than in those with stable mild cognitive impairment subjects (p < 0.001). Meanwhile, CSF sPDGFRß was significantly associated with yearly changes in MMSE scores in the CDR 0.5 group (ß = - 0.400, p = 0.020) and CDR 0.5 (A+) subgroup (ß = - 0.542, p = 0.019). CONCLUSIONS: We provide evidence that increased CSF sPDGFRß is associated with BBB leakage in the early cognitive impairment stage of AD, which may contribute to cognitive impairment in AD progression.

General anesthesia vs. non-general anesthesia for vertebrobasilar stroke endovascular therapy.

Background: The optimal type of anesthesia for acute vertebrobasilar artery occlusion (VBAO) remains controversial. We aimed to assess the influence of anesthetic management on the outcomes in VBAO patients received endovascular treatment (EVT). Methods: Patients underwent EVT for acute VBAO at 21 stroke centers in China were retrospectively enrolled and compared between the general anesthesia (GA) group and non-GA group. The primary outcome was the favorable outcome, defined as a modified Rankin Scale (mRS) score 0-3 at 90 days. Secondary outcomes included functional independence (90-day mRS score 0-2), and the rate of successful reperfusion. The safety outcomes included all-cause mortality at 90 days, the occurrence of any procedural complication, and the rate of symptomatic intracranial hemorrhage (sICH). In addition, we performed analyses of the outcomes in subgroups that were defined by Glasgow Coma Scale (GCS) score (≤8 or >8). Results: In the propensity score matched cohort, there were no difference in the primary outcome, secondary outcomes and safety outcomes between the two groups. Among patients with a GCS score of 8 or less, the proportion of successful reperfusion was significantly higher in the GA group than the non-GA group (aOR, 3.57, 95% CI 1.06-12.50, p = 0.04). In the inverse probability of treatment weighting-propensity score-adjusted cohort, similar results were found. Conclusions: Patients placed under GA during EVT for VBAO appear to be as effective and safe as non-GA. Furthermore, GA might yield better successful reperfusion for worse presenting GCS score (≤8). Registration: URL: http://www.chictr.org.cn/; Unique identifier: ChiCTR2000033211.

Identification of hub proteins in cerebrospinal fluid as potential biomarkers of Alzheimer's disease by integrated bioinformatics.

BACKGROUND: Alzheimer's disease (AD) is a heterogeneous neurodegenerative disease with complex pathophysiology. Therefore, the identification of novel effective fluid biomarkers is essential for Alzheimer's disease diagnosis and drug development. This study aimed to identify potential candidate hub proteins in cerebrospinal fluid for precise Alzheimer's disease diagnosis using bioinformatics methods. METHODS: A total of 29 co-significant differentially expressed proteins were identified by differential protein expression analysis in four different cohorts. Functional enrichment analysis revealed that most of these proteins were enriched in pathways related to glycometabolism. Using the Least Absolute Shrinkage and Selection Operator (LASSO) and random forest feature selection methods, six hub proteins [14-3-3 protein zeta/delta (YWHAZ), SPARC-related modular calcium-binding protein 1 (SMOC1), aldolase A (ALDOA), pyruvate kinase isoenzyme type M2 (PKM), chitinase-3-like protein 1 (CHI3L1), and secreted phosphoprotein 1 (SPP1)] were identified. RESULTS: These six hub proteins were upregulated in the cerebrospinal fluid of patients with Alzheimer's disease compared with cognitively unimpaired control individuals. Meanwhile, SMOC1, ALDOA, and PKM were specifically upregulated in the cerebrospinal fluid of patients with Alzheimer's disease but not in other neurodegenerative diseases. Build AD diagnostic models showed that a single hub protein or six hub proteins combination had an excellent ability to discriminate Alzheimer's disease. CONCLUSIONS: In conclusion, our study suggests that these identified hub proteins, which are related to glycometabolism, may be potential biomarkers for further basic and clinical research in Alzheimer's disease.

Features of Cerebral Small Vessel Disease Contributes to the Differential Diagnosis of Alzheimer's Disease.

BACKGROUND: Cerebral small vessel disease (CSVD), which comprises the typical features of white matter hyperintensity (WMH) and Vichor-Robin spaces (VRSs) in the brain, is one of the leading causes of aging-related cognitive decline and, ultimately, contributes to the occurrence of dementia, including Alzheimer's disease (AD). OBJECTIVE: To investigate whether CSVD imaging markers modify the pathological processes of AD and whether these markers improve AD diagnosis. METHODS: 208 participants were enrolled in the China Aging and Neurodegenerative Initiative (CANDI). Fluid AD biomarkers were detected using a single-molecule array, and cerebral small vessel dysfunction was determined using magnetic resonance imaging. RESULTS: WMH contributed to AD pathology only within the NC and MCI groups (CDR ≤0.5), whereas VRSs had no effect on AD pathology. The associations between AD biomarkers and cognitive mental status were consistent with the presence of CSVD pathology. That is, within individuals without CSVD pathology, the MMSE scores were correlated with AD fluid biomarkers, except for plasma Aß42 and Aß40. Increased plasma p-Tau levels were associated with worse cognitive performance in individuals with WMH (ß= -0.465, p = 0.0016) or VRSs (ß= -0.352, p = 0.0257) pathology. Plasma AD biomarkers combined with CSVD markers showed high accuracy in diagnosing dementia. CONCLUSION: Findings from this cross-sectional cohort study support the notion that CSVD is a risk factor for dementia and highlights that vascular pathology can promote AD biomarker levels, especially in the early course of the disease. Moreover, our results suggest that adding a vascular category to the ATN framework improves the diagnostic accuracy of AD.

A combination model of AD biomarkers revealed by machine learning precisely predicts Alzheimer's dementia: China Aging and Neurodegenerative Initiative (CANDI) study.

INTRODUCTION: To test the utility of the "A/T/N" system in the Chinese population, we study core Alzheimer's disease (AD) biomarkers in a newly established Chinese cohort. METHODS: A total of 411 participants were selected, including 96 cognitively normal individuals, 94 patients with mild cognitive impairment (MCI) patients, 173 patients with AD, and 48 patients with non-AD dementia. Fluid biomarkers were measured with single molecule array. Amyloid beta (Aß) deposition was determined by 18 F-Flobetapir positron emission tomography (PET), and brain atrophy was quantified using magnetic resonance imaging (MRI). RESULTS: Aß42/Aß40 was decreased, whereas levels of phosphorylated tau (p-tau) were increased in cerebrospinal fluid (CSF) and plasma from patients with AD. CSF Aß42/Aß40, CSF p-tau, and plasma p-tau showed a high concordance in discriminating between AD and non-AD dementia or elderly controls. A combination of plasma p-tau, apolipoprotein E (APOE) genotype, and MRI measures accurately predicted amyloid PET status. DISCUSSION: These results revealed a universal applicability of the "A/T/N" framework in a Chinese population and established an optimal diagnostic model consisting of cost-effective and non-invasive approaches for diagnosing AD.