Associations of liver dysfunction with incident dementia, cognition, and brain structure: A prospective cohort study of 431 699 adults.

The relationship between liver dysfunction and dementia has been researched extensively but remains poorly understood. In this study, we investigate the longitudinal and cross-sectional associations between liver function and liver diseases and risk of incident dementia, impaired cognition, and brain structure abnormalities using Cox proportion hazard model and linear regression model. 431 699 participants with a mean of 8.65 (standard deviation [SD] 2.61) years of follow-up were included from the UK Biobank; 5542 all-cause dementia (ACD), 2427 Alzheimer's disease (AD), and 1282 vascular dementia (VaD) cases were documented. We observed that per SD decreases in alanine transaminase (ALT; hazard ratio [HR], 0.917; PFDR <0.001) and per SD increases in aspartate aminotransferase (AST; HR, 1.048; PFDR = 0.010), AST to ALT ratio (HR, 1.195; PFDR <0.001), gamma-glutamyl transpeptidase (GGT; HR, 1.066; PFDR <0.001), alcoholic liver disease (ALD; HR, 2.872; PFDR <0.001), and fibrosis and cirrhosis of liver (HR, 2.285; PFDR = 0.002), being significantly associated with a higher risk of incident ACD. Restricted cubic spline models identified a strong U-shaped association between Alb and AST and incident ACD (Pnonlinear <0.05). Worse cognition was positively correlated with AST, AST to ALT ratio, direct bilirubin (DBil), and GGT; negatively correlated with ALT, Alb, and total bilirubin (TBil); and ALD and fibrosis and cirrhosis of liver (PFDR <0.05). Moreover, changes in ALT, GGT, AST to ALT ratio, and ALD were significantly associated with altered cortical and subcortical regions, including hippocampus, amygdala, thalamus, pallidum, and fusiform (PFDR <0.05). In sensitivity analysis, metabolic dysfunction-associated steatotic liver disease (MASLD) was associated with the risk of ACD and brain subcortical changes. Our findings provide substantial evidence that liver dysfunction may be an important factor for incident dementia. Early intervention in the unhealthy liver may help prevent cognitive impairment and dementia incidence.

Associations between liver function and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in non-demented adults: The CABLE study.

Liver function has been suggested as a possible factor in the progression of Alzheimer's disease (AD) development. However, the association between liver function and cerebrospinal fluid (CSF) levels of AD biomarkers remains unclear. In this study, we analyzed the data from 1687 adults without dementia from the Chinese Alzheimer's Biomarker and LifestylE study to investigate differences in liver function between pathological and clinical AD groups, as defined by the 2018 National Institute on Aging-Alzheimer's Association Research Framework. We also examined the linear relationship between liver function, CSF AD biomarkers, and cognition using linear regression models. Furthermore, mediation analyses were applied to explore the potential mediation effects of AD pathological biomarkers on cognition. Our findings indicated that, with AD pathological and clinical progression, the concentrations of total protein (TP), globulin (GLO), and aspartate aminotransferase/alanine transaminase (ALT) increased, while albumin/globulin (A/G), adenosine deaminase, alpha-L-fucosidase, albumin, prealbumin, ALT, and glutamate dehydrogenase (GLDH) concentrations decreased. Furthermore, we also identified significant relationships between TP (ß = -0.115, pFDR < 0.001), GLO (ß = -0.184, pFDR < 0.001), and A/G (ß = 0.182, pFDR < 0.001) and CSF ß-amyloid1-42 (Aß1-42 ) (and its related CSF AD biomarkers). Moreover, after 10 000 bootstrapped iterations, we identified a potential mechanism by which TP and GLDH may affect cognition by mediating CSF AD biomarkers, with mediation effect sizes ranging from 3.91% to 16.44%. Overall, our results suggested that abnormal liver function might be involved in the clinical and pathological progression of AD. Amyloid and tau pathologies also might partially mediate the relationship between liver function and cognition. Future research is needed to fully understand the underlying mechanisms and causality to develop an approach to AD prevention and treatment approach.

Genome-wide meta-analysis identifies ancestry-specific loci for Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is a devastating neurological disease with complex genetic etiology. Yet most known loci have only identified from the late-onset type AD in populations of European ancestry. METHODS: We performed a two-stage genome-wide association study (GWAS) of AD totaling 6878 Chinese and 63,926 European individuals. RESULTS: In addition to the apolipoprotein E (APOE) locus, our GWAS of two independent Chinese samples uncovered three novel AD susceptibility loci (KIAA2013, SLC52A3, and TCN2) and a novel ancestry-specific variant within EGFR (rs1815157). More replicated variants were observed in the Chinese (31%) than in the European samples (15%). In combining genome-wide associations and functional annotations, EGFR and TCN2 were prioritized as two of the most biologically significant genes. Phenome-wide Mendelian randomization suggests that high mean corpuscular hemoglobin concentration might protect against AD. DISCUSSION: The current study reveals novel AD susceptibility loci, emphasizes the importance of diverse populations in AD genetic research, and advances our understanding of disease etiology. HIGHLIGHTS: Loci KIAA2013, SLC52A3, and TCN2 were associated with Alzheimer's disease (AD) in Chinese populations. rs1815157 within the EGFR locus was associated with AD in Chinese populations. The genetic architecture of AD varied between Chinese and European populations. EGFR and TCN2 were prioritized as two of the most biologically significant genes. High mean corpuscular hemoglobin concentrations might have protective effects against AD.

Plasma Glial Fibrillary Acidic Protein in the Alzheimer Disease Continuum: Relationship to Other Biomarkers, Differential Diagnosis, and Prediction of Clinical Progression.

BACKGROUND: Plasma glial fibrillary acidic protein (GFAP) has emerged as a promising biomarker in neurological disorders, but further evidence is required in relation to its usefulness for diagnosis and prediction of Alzheimer disease (AD). METHODS: Plasma GFAP was measured in participants with AD, non-AD neurodegenerative disorders, and controls. Its diagnostic and predictive value were analyzed alone or combined with other indicators. RESULTS: A total of 818 participants were recruited (210 followed). Plasma GFAP was significantly higher in AD than in non-AD dementia and non-demented individuals. It increased in a stepwise pattern from preclinical AD, through prodromal AD to AD dementia. It effectively distinguished AD from controls [area under the curve (AUC) > 0.97] and non-AD dementia (AUC > 0.80) and distinguished preclinical (AUC > 0.89) and prodromal AD (AUC > 0.85) from Aß-normal controls. Adjusted or combined with other indicators, higher levels of plasma GFAP displayed predictive value for risk of AD progression (adjusted hazard radio= 4.49, 95%CI, 1.18-16.97, P = 0.027 based on the comparison of those above vs below average at baseline) and cognitive decline (standard-ß=0.34, P = 0.002). Additionally, it strongly correlated with AD-related cerebrospinal fluid (CSF)/neuroimaging markers. CONCLUSIONS: Plasma GFAP effectively distinguished AD dementia from multiple neurodegenerative diseases, gradually increased across the AD continuum, predicted the individual risk of AD progression, and strongly correlated with AD CSF/neuroimaging biomarkers. Plasma GFAP could serve as both a diagnostic and predictive biomarker for AD.

Application of the Amyloid/Tau/Neurodegeneration Framework in Cognitively Intact Adults: The CABLE Study.

OBJECTIVES: The amyloid/tau/neurodegeneration (AT[N]) framework has conceptualized the Alzheimer's disease (AD) continuum as a continuum of disease with evidence of amyloid-related pathologies independent of clinical manifestation. Based on this framework, it is necessary to reveal the distribution and risk factors of AD continuum in the cognitively intact population among different cohorts and races, including the northern Chinese Han population. METHODS: This study classified cognitively intact Chinese Alzheimer's Biomarker and LifestylE (CABLE) participants through the AT(N) scheme. Gaussian mixture models were used to identify the cutoff values of cerebrospinal fluid biomarkers, which distinguished AD continuum ( A + T-N-, A + T + N-, A + T-N + and A + T + N +) from 1,005 participants (mean age 61 years; 40% female). Multivariable logistic regressions and Cochran-Armitage trend tests were used to test neuropsychological performance and risk factors for AD continuum. RESULTS: Approximately one-third of individuals (33.7%) belonged to the AD continuum. Four potential modifiable risk factors, including hypertension, thyroid diseases, social isolation, and minimal depression symptoms, were identified for the AD continuum (OR ranging 1.68-6.90). A trend toward higher prevalence of the AD continuum was associated with a larger number of risk factors (p for trend <0.0001). The risk of AD continuum increased by approximately twofold for each additional modifiable risk factor (OR 1.9, 95% CI 1.65-2.24, p < 0.0001). INTERPRETATION: This study revealed the distribution and potential risk factors of the AD continuum in a cognitively intact Han population in northern China, which filled the gap in the area about the performance of the AT(N) framework in the Asian population. ANN NEUROL 2022;92:439-450.

Lung function and risk of incident dementia: A prospective cohort study of 431,834 individuals.

BACKGROUND: Whether lung function prospectively affects cognitive brain health independent of their overlapping factors remains largely unknown. This study aimed to investigate the longitudinal association between decreased lung function and cognitive brain health and to explore underlying biological and brain structural mechanisms. METHODS: This population-based cohort included 43,1834 non-demented participants with spirometry from the UK Biobank. Cox proportional hazard models were fitted to estimate the risk of incident dementia for individuals with low lung function. Mediation models were regressed to explore the underlying mechanisms driven by inflammatory markers, oxygen-carrying indices, metabolites, and brain structures. FINDINGS: During a follow-up of 3,736,181 person-years (mean follow-up 8.65 years), 5,622 participants (1.30 %) developed all-cause dementia, which consisted of 2,511 Alzheimer's dementia (AD) and 1,308 Vascular Dementia (VD) cases. Per unit decrease in lung function measure was each associated with increased risk for all-cause dementia (forced expiratory volume in 1 s [liter]: hazard ratio [HR, 95 %CI], 1.24 [1.14-1.34], P = 1.10 × 10-07; forced vital capacity [liter]: 1.16 [1.08-1.24], P = 2.04 × 10-05; peak expiratory flow [liter/min]: 1.0013 [1.0010-1.0017], P = 2.73 × 10-13). Low lung function generated similar hazard estimates for AD and VD risks. As underlying biological mechanisms, systematic inflammatory markers, oxygen-carrying indices, and specific metabolites mediated the effects of lung function on dementia risks. Besides, brain grey and white matter patterns mostly affected in dementia were substantially changed with lung function. INTERPRETATION: Life-course risk for incident dementia was modulated by individual lung function. Maintaining optimal lung function is useful for healthy aging and dementia prevention.

Association between Kidney Function and the Burden of Cerebral Small Vessel Disease: An Updated Meta-Analysis and Systematic Review.

INTRODUCTION: Due to anatomical and functional similarities in microvascular beds, the brain and kidney share distinctive susceptibilities to vascular injury and common risk factors of small vessel disease. The aim of this updated meta-analysis is to explore the association between kidney function and the burden of cerebral small vessel disease (CSVD). METHODS: PubMed, EMBASE, and Cochrane Library were systematically searched for observational studies that explored the association between the indicators of kidney function and CSVD neuroimaging markers. The highest-adjusted risk estimates and their 95% confidence intervals (CIs) were aggregated using random-effect models. RESULTS: Twelve longitudinal studies and 51 cross-sectional studies with 57,030 subjects met the inclusion criteria of systematic review, of which 52 were included in quantitative synthesis. According to the pooled results, we found that low estimated glomerular filtration rate (eGFR <60 mL/min/1.73 m2) was associated with cerebral microbleeds (odds ratio (OR) = 1.55, 95% CI = 1.26-1.90), white matter hyperintensities (OR = 1.40, 95% CI = 1.05-1.86), and lacunar infarctions (OR = 1.50, 95% CI = 1.18-1.92), but not with severe perivascular spaces (OR = 1.20, 95% CI = 0.77-1.88). Likewise, patients with proteinuria (OR = 1.75, 95% CI = 1.47-2.09) or elevated serum cystatin C (OR = 1.51, 95% CI = 1.25-1.83) also had an increased risk of CSVD. CONCLUSION: The association between kidney function and CSVD has been comprehensively updated through this study, that kidney insufficiency manifested as low eGFR, proteinuria, and elevated serum cystatin C was independently associated with CSVD burden.

Residential greenness and risk of incident dementia: A prospective study of 375,342 participants.

INTRODUCTION: Incorporation of greenspace may be a novel environmental policy that might result in positive health effects; hence, this study aimed to investigate the association between residential greenness and dementia incidence. The effects of particulate air pollution on mediating dementia were also determined. METHODS: A prospective cohort study involving 375,342 UK biobank participants was conducted, in which Cox regression models were used to determine the association of greenspace exposure with the risks of all-cause dementia (ACD), Alzheimer's disease (AD) and vascular dementia (VD). Sociodemographic variables, lifestyle or dietary characteristics and apolipoprotein E4 status were controlled using two levels of adjusted models. Mediation analyses were performed to determine the mediation effects of PMs. RESULTS: The results indicated that there were 4929 ACD, 2132 AD, and 1184 VD incidents throughout the 8-year study. In the multi-adjusted model, each interquartile increment in greenspace (buffer 300m) conferred the lower risks of ACD (HR = 0.968, 95% confidence intervals [CI]: 0.938-1.000]) and VD (HR = 0.926, 95% CI: 0.867-0.989). The fourth greenspace quartile conferred also reduced risks of ACD (HR = 0.891, 95% CI: 0.804-0.989) and VD (HR = 0.778, 95% CI: 0.630-0.960) in reference to the first quartile. With regard to 1000m catchment, each interquartile increment conferred a 5.0% (95% CI: 1.8-8.1) lower risk of ACD, and the fourth greenspace quartile conferred a 10.9% (95% CI: 0.9-19.8) lower risk of ACD compared to the first quartile. The protective effect of greenness might be mediated based on the reduction of PM2.5 and PM10 (Pindirect effect<0.05). CONCLUSIONS: Increasing greenness reduces the risk of dementia. This study suggests that greenspace is an environmental strategy that helps prevent dementia.

Associations of the A/T/N profiles in PET, CSF, and plasma biomarkers with Alzheimer's disease neuropathology at autopsy.

INTRODUCTION: To examine the extent to which positron emission tomography (PET)-, cerebrospinal fluid (CSF)-, and plasma-related amyloid-ß/tau/neurodegeneration (A/T/N) biomarkers are associated with Alzheimer's disease (AD) neuropathology at autopsy. METHODS: A total of 100 participants who respectively underwent antemortem biomarker measurements and postmortem neuropathology were included in the Alzheimer's Disease Neuroimaging Initiative (ADNI). We examined the associations of PET-, CSF-, and plasma-related A/T/N biomarkers in combinations or alone with AD neuropathological changes (ADNC). RESULTS: PET- and CSF-related A/T/N biomarkers in combination showed high concordance with the ADNC stage and alone showed high accuracy in discriminating autopsy-confirmed AD. However, the plasma-related A/T/N biomarkers alone showed better discriminative performance only when combined with apolipoprotein E (APO)E ε4 genotype. DISCUSSION: This study supports that PET- and CSF-related A/T/N profiles can be used to predict accurately the stages of AD neuropathology. For diagnostic settings, PET-, CSF-, and plasma-related A/T/N biomarkers are all useful diagnostic tools to detect the presence of AD neuropathology. HIGHLIGHTS: PET- and CSF-related A/T/N biomarkers in combination can accurately predict the specific stages of AD neuropathology. PET- and CSF-related A/T/N biomarkers alone may serve as a precise diagnostic tool for detecting AD neuropathology at autopsy. Plasma-related A/T/N biomarkers may need combined risk factors when used as a diagnostic tool. Aß PET and CSF p-tau181/Aß42 were most consistent with Aß pathology, while tau PET and CSF p-tau181/Aß42 were most consistent with tau pathology.

Differences between ante mortem Alzheimer's disease biomarkers in predicting neuropathology at autopsy.

INTRODUCTION: This study aimed to assess whether biomarkers related to amyloid, tau, and neurodegeneration can accurately predict Alzheimer's disease (AD) neuropathology at autopsy in early and late clinical stages. METHODS: We included 100 participants who had ante mortem biomarker measurements and underwent post mortem neuropathological examination. Based on ante mortem clinical diagnosis, participants were divided into non-dementia and dementia, as early or late clinical stages. RESULTS: Amyloid positron emission tomography (PET) and cerebrospinal fluid (CSF) amyloid beta (Aß)42/phosphorylated tau (p-tau)181 showed excellent performance in differentiating autopsy-confirmed AD and predicting the risk of neuropathological changes in early and late clinical stages. However, CSF Aß42 performed better in the early clinical stage, while CSF p-tau181, CSF t-tau, and plasma p-tau181 performed better in the late clinical stage. DISCUSSION: Our findings provide important clinical information that, if using PET, CSF, and plasma biomarkers to detect AD pathology, researchers must consider their differential performances at different clinical stages of AD. HIGHLIGHTS: Amyloid PET and CSF Aß42/p-tau181 were the most promising candidate biomarkers for predicting AD pathology. CSF Aß42 can serve as a candidate predictive biomarker in the early clinical stage of AD. CSF p-tau181, CSF t-tau, and plasma p-tau181 can serve as candidate predictive biomarkers in the late clinical stage of AD. Combining APOE ε4 genotypes can significantly improve the predictive accuracy of AD-related biomarkers for AD pathology.

Time spent in outdoor light is associated with the risk of dementia: a prospective cohort study of 362094 participants.

BACKGROUND: Data on the association between free-living daytime sunlight exposure and incident dementia are scarce. The objective is to evaluate whether the time spent in outdoor light is related to the dementia risk and to investigate whether the optimal duration varies with clinical parameters. METHODS: Data were from a prospective cohort of 362,094 UK Biobank participants. A questionnaire survey was conducted to investigate how many hours the participants spent outdoors on typical summer and winter days. A restricted cubic spline (RCS) was performed to explore the potential nonlinear relationship between sunlight exposure and the risk of dementia. We used multivariate Cox proportional hazard regression models to estimate the hazard ratios (HRs) for the associations between sunlight exposure and dementia outcomes, with the change points as a reference. RESULTS: After a median follow-up of 9.0 years, 4149 (1.15%) individuals were diagnosed with dementia. RCS showed a J-shaped relationship between time spent in outdoor light and the dementia risk, with the lowest risk at three change points (1.5 h/day on average, 2 h/day in summer, and 1 h/day in winter). Cox hazard regression models showed a marked increase in risk at low exposure (HR=1.287, 95%CI 1.094-1.515) but a relatively slow increase at higher exposure (HR=1.070, 95%CI 1.031-1.10). Results are more pronounced among participants over 60 years old, females, and those with exactly 7 h of sleep every night. CONCLUSIONS: Sunlight exposure had a J-shaped association with dementia risk. Giving detailed guidance on sunlight exposure can effectively prevent dementia.

Interleukin-3 is associated with sTREM2 and mediates the correlation between amyloid-ß and tau pathology in Alzheimer's disease.

BACKGROUND: Dysfunction of glial cell communication is involved in Alzheimer's disease (AD) pathogenesis, and the recent study reported that astrocytic secreted interleukin-3 (IL-3) participated in astrocyte-microglia crosstalk and restricted AD pathology in mice, but the effect of IL-3 on the pathological progression of AD in human is still unclear. METHODS: A total of 311 participants with cerebrospinal fluid (CSF) IL-3, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and AD biomarkers were included from the Alzheimer's disease Neuroimaging Initiative (ADNI). We assessed the associations of IL-3 with sTREM2 and AD biomarkers at baseline, and with cognitive change in longitudinal study. The mediation models were used to explore the potential mechanism of how IL-3 affects AD pathology. RESULTS: We found that CSF IL-3 was significantly associated with CSF sTREM2 and CSF AD core biomarkers (Aß42, p-tau, and t-tau) at baseline, and was also markedly related to cognitive decline in longitudinal analysis. Moreover, mediation analysis revealed that CSF IL-3 modulated the level of CSF sTREM2 and contributed to tau pathology (as measured by CSF p-tau/t-tau) and subsequent cognitive decline. In addition, Aß pathology (as measured by CSF Aß42) affected the development of tau pathology partly by modifying the levels of CSF IL-3 and CSF sTREM2. Furthermore, the effect of Aß pathology on cognitive decline was partially mediated by the pathway from CSF IL-3 and CSF sTREM2 to tau pathology. CONCLUSIONS: Our findings provide evidence to suggest that IL-3 is linked to sTREM2 and mediates the correlation between Aß pathology to tau pathology. It indicates that IL-3 may be a major factor in the spreading from Aß pathology to tau pathology to cognitive impairment.

Tau pathologies mediate the association of blood pressure with cognitive impairment in adults without dementia: The CABLE study.

INTRODUCTION: This study delineated the interrelationships among blood pressure (BP), cerebrospinal fluid (CSF) core biomarkers of Alzheimer's disease (AD), and cognition. METHODS: The linear regression analyses were conducted in 1546 non-demented participants (mean age of 61.58 years, range 40 to 89 years; 40% female; average days of BP measurement, 9.10 days). Mediation analyses with 10,000 bootstrapped iterations were used to explore the mediation effects. RESULTS: A clear age-related pattern of BP was delineated. Mid-life hypertension (especially systolic BP), late-life lower diastolic BP, as well as mid- and late-life higher pulse pressure were associated with cognitive impairment and tau-related biomarkers. BP variability was associated only with cognition but not with CSF biomarkers. Overall, the associations between BP and cognition were partially mediated (proportion: 11% to 30%) by tau pathologies, independently of amyloid pathology. DISCUSSION: Tau pathologies might play important roles in the relationship between BP and cognition, with significant age- and BP-type dependences.

Metabolically healthy obesity and lipids may be protective factors for pathological changes of alzheimer's disease in cognitively normal adults.

The associations between obesity and Alzheimer's disease (AD) at different ages have been debated. Recent evidence implied the protective effects of metabolically healthy obesity on AD. We hypothesized that obesity and lipids could mitigate the detrimental impacts of AD pathological changes among metabolically healthy individuals in late life. In this study, a total of 604 metabolically healthy participants with normal cognition were included from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database. Multiple linear regression models were used to test the associations of body mass index (BMI) or lipids with cerebrospinal fluid (CSF) biomarkers after adjustment for age, gender, education, and Apolipoprotein E-ɛ4 (APOE-ɛ4). The results showed the lower CSF levels of total tau protein (t-tau: p = .0048) and phosphorylated tau protein (p-tau: p = .0035) in obese participants than in non-obese participants, even after correcting for covariates. Moreover in late life, higher BMI was associated with decreased CSF t-tau (ß: -0.15, p = .0145) and p-tau (ß: -0.17, p = .0052). As for lipids, higher levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were associated with decreased CSF t-tau (TC: ß: -0.16, p = .0115; LDL-C: ß: -0.16, p = .0082) and p-tau (TC: ß: -0.15, p = .0177; LDL-C: ß: -0.14, p = .0225) in obese participants. Furthermore, these associations were only significant in participants with late-life obesity and APOE-ɛ4 non-carriers. Overall, in a cognitively normal population, we found metabolically healthy obesity and lipids in late life might be protective factors for neurodegenerative changes.

Low-dose chidamide restores immune tolerance in ITP in mice and humans.

Increased macrophage phagocytosis of antibody-coated platelets, as well as decreased numbers and/or impaired function of CD4+CD25+Foxp3+ regulatory T (Treg) cells, has been shown to participate in the pathogenesis of immune thrombocytopenia (ITP). Low-dose histone deacetylase inhibitors (HDACi's) are anti-inflammatory and immunomodulatory agents that can enhance immunosuppression in graft-versus-host disease by increasing the number and function of Foxp3+ Treg cells, but it is unclear whether they have the potential to promote immune tolerance and platelet release in ITP. In this study, we performed in vitro and in vivo experiments and found that a low-dose HDACi (chidamide) alleviated thrombocytopenia in passive and active murine models of ITP. Further, low-dose HDACi's attenuated macrophage phagocytosis of antibody-coated platelets, stimulated the production of natural Foxp3+ Treg cells, promoted the peripheral conversion of T cells into Treg cells, and restored Treg cell suppression in vivo and in vitro. Finally, we confirmed that low-dose HDACi's could regulate CTLA4 expression in peripheral blood mononuclear cells through modulation of histone H3K27 acetylation. Low-dose HDACi treatment in ITP could be offset by blocking the effect of CTLA4. Therefore, we propose that low-dose chidamide administration has potential as a novel treatment for ITP in the clinic.

Associations of the cerebrospinal fluid hepatocyte growth factor with Alzheimer's disease pathology and cognitive function.

BACKGROUND: Hepatocyte growth factor (HGF) plays a role in neuronal survival and development, and has been implicated in neurodegenerative diseases. We sought to examine the associations of the CSF HGF with Alzheimer's disease (AD) pathology and cognitive function. METHODS: A total of 238 participants (including 90 cognitively normal (CN) and 148 mild cognitive impairment (MCI)) who had measurements of CSF HGF were included from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Multiple linear regression models were utilized to explore the cross-sectional associations of CSF HGF with AD biomarkers (including Aß42, pTau, and tTau proteins) in non-demented participants. Moreover, linear mixed-effects regression models were utilized to explore the longitudinal associations of HGF subgroups with cognitive function. Mediation analyses were utilized to explore the mediation effects of AD markers. RESULTS: MCI individuals had significantly increased CSF HGF compared with the CN individuals. Results of multiple linear regressions showed significant correlations of CSF HGF with CSF Aß42, pTau, and tTau in non-demented participants. Higher level of baseline CSF HGF was associated with faster cognitive decline. Influences of the baseline CSF HGF on cognition were partially mediated by Aß42, pTau, and tTau pathologies. CONCLUSIONS: High concentrations of HGF in CSF may be related to faster cognitive decline. The cognitive consequences of higher CSF HGF partly stem from AD pathology, which suggests that the CSF HGF may be an attractive biomarker candidate to track AD progression.

Associations of the neutrophil to lymphocyte ratio with intracranial artery stenosis and ischemic stroke.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) has emerged as an inflammatory marker. However, the associations of NLR with intracranial artery stenosis (ICAS) and ischemic stroke remain unclear. This study aimed to examine the associations of NLR with ICAS and ischemic stroke among a large and high-risk population. METHODS: Participants with records of clinical characteristics were prospectively recruited from the Neurology Department and Health & Physical Examination Center of Qingdao Municipal Hospital. Logistic regression analysis was used to examine the associations of NLR with ICAS and ischemic stroke. Moreover, we also conducted parametric mediation analysis to estimate the effect of NLR on the risk of ischemic stroke mediated through ICAS. RESULTS: A total of 2989 participants were enrolled in this study. After adjusting for covariates, NLR (OR = 1.125, 95%CI 1.070-1.183) and ICAS (OR = 1.638, 95%CI 1.364-1.967) were significantly associated with ischemic stroke. Compared with the first quartile NLR, the second, third and fourth quartiles NLR were independent risk predictors for ischemic stroke (P for trend < 0.001); the third and fourth quartiles were independent predictors for ICAS (P for trend < 0.001). The mediation analysis showed that ICAS partially mediated the association between NLR and ischemic stroke, accounting for 14.4% of the total effect (P < 0.001). CONCLUSIONS: NLR was significantly associated with ICAS and ischemic stroke. Besides, ICAS partially mediated the association between NLR and ischemic stroke.

Association of peripheral neutrophil count with intracranial atherosclerotic stenosis.

BACKGROUND: Inflammation plays an important role in atherosclerosis but the contribution of neutrophils to this process is unclear. We sought to assess whether neutrophil count is associated with intracranial atherosclerotic stenosis (ICAS). METHODS: A total of 2847 individuals were included in our study, including 1363 with acute ischemic stroke and 1484 normal controls without stroke. The presence of ICAS was confirmed by magnetic resonance angiography. The association between neutrophil count and ICAS was evaluated by multivariable logistic regression analysis. RESULTS: Among 2847 individuals included in this study, individuals with ICAS had higher neutrophil counts than those without ICAS in groups with and without stroke (P <  0.0001 for stroke group, P = 0.0097 for group without stroke). The multivariable logistic regression analysis showed that the third and fourth quartiles were independent predictors of ICAS in all the subjects (Q3: OR 1.81, 95% CI 1.39-2.37, Q4: OR 2.29, 95% CI 1.70-3.10) and patients in the fourth quartile had a higher risk for the occurrence of ICAS in stroke group (Q4: OR 2.82, 95% CI 1.79-4.48). However, there was no significant association between neutrophil count and ICAS in the group without stroke. CONCLUSIONS: The levels of circulating neutrophils were associated with the presence of ICAS. Our findings suggest that neutrophils may play a role in the pathogenesis of stroke related to ICAS and emphasize the need to develop proper strategies to control neutrophil response for the treatment of ICAS.

Association of Serum Complement C1q Concentration with Severity of Neurological Impairment and Infarct size in Patients with Acute Ischemic Stroke.

BACKGROUND: Inflammation occurs after acute ischemic stroke (AIS), and complement C1q is involved in inflammation. However, studies about the association of complement C1q with AIS are still rare. The aim of our study is to investigate the relationship between serum C1q concentration and the clinical severity of AIS. METHODS: A total of 1294 patients were enrolled in our study, including 647 patients with AIS and 647 non-stroke controls. The infarction volume of AIS was assessed by the diameter of maximum transverse section (DMTS) based on diffusion-weighted imaging (DWI) of brain magnetic resonance imaging. Neurological impairment was assessed by the National Institute of Health Stroke Scale (NIHSS). The association of serum C1q levels with DMTS or NIHSS was investigated by Pearson's or Spearman's correlation analysis. RESULTS: Serum C1q levels of patients with AIS were significantly higher than those of individuals without AIS. Serum levels of C1q were associated with DMTS (r=0.511, p<0.001) and NIHSS (r=0.433, p<0.001) among patients with AIS. CONCLUSION: Serum C1q concentration was positively associated with DMTS and NIHSS of patients with AIS.

Associations of cerebrospinal fluid complement proteins with Alzheimer's pathology, cognition, and brain structure in non-dementia elderly.

BACKGROUND: Cerebrospinal fluid (CSF) complement activation is a key part of neuroinflammation that occurs in the early stages of Alzheimer's disease (AD). However, the associations of CSF complement proteins with AD pathology, cognition, and structural neuroimaging biomarkers for AD have been rarely investigated. METHODS: A total of 210 participants (125 mild cognitive impairment [MCI] patients and 85 normal controls) were included from Alzheimer's Disease Neuroimaging Initiative (ADNI) database who measured AD pathology, cognition, and neuroimaging at baseline and every 12 months. The mixed-effect linear models were utilized to investigate longitudinal associations of CSF complement proteins with AD pathology, cognition, and neuroimaging in cognitively normal (CN) and mild cognitive impairment (MCI) subjects. Causal mediation analyses were conducted to explore the potential mediators between CSF complement proteins and cognitive changes. RESULTS: We found that the subjects with low CSF complement protein levels at baseline had worse outcomes in AD pathology, indicated by their lowest concentrations observed in A + and A + T + individuals. The reduced CSF complement proteins were associated with faster accumulation of tau among CN subjects and with cognitive decline and greater brain atrophy of specific regions among MCI subjects. Furthermore, mediation analyses showed that the effects of CSF complement proteins on cognitive performance were partially mediated by regional brain structures (mediation proportions range from 19.78 to 94.92%; p < 0.05). CONCLUSIONS: This study demonstrated that CSF complement proteins were involved in the early progression of AD. Our results indicated that regional brain atrophy might be a plausible way to connect CSF complement protein levels and cognition.