Multipredictor risk models for predicting individual risk of Alzheimer's disease.

BACKGROUND: Early prevention of Alzheimer's disease (AD) is a feasible way to delay AD onset and progression. Information on AD prediction at the individual patient level will be useful in AD prevention. In this study, we aim to develop risk models for predicting AD onset at individual level using optimal set of predictors from multiple features. METHODS: A total of 487 cognitively normal (CN) individuals and 796 mild cognitive impairment (MCI) patients were included from Alzheimer's Disease Neuroimaging Initiative. All the participants were assessed for clinical, cognitive, magnetic resonance imaging and cerebrospinal fluid (CSF) markers and followed for mean periods of 5.6 years for CN individuals and 4.6 years for MCI patients to ascertain progression from CN to incident prodromal stage of AD or from MCI to AD dementia. Least Absolute Shrinkage and Selection Operator Cox regression was applied for predictors selection and model construction. RESULTS: During the follow-up periods, 139 CN participants had progressed to prodromal AD (CDR ≥ 0.5) and 321 MCI patients had progressed to AD dementia. In the prediction of individual risk of incident prodromal stage of AD in CN individuals, the AUC of the final CN model was 0.81 within 5 years. The final MCI model predicted individual risk of AD dementia in MCI patients with an AUC of 0.92 within 5 years. The models were also associated with longitudinal change of Mini-Mental State Examination (p < 0.001 for CN and MCI models). An Alzheimer's continuum model was developed which could predict the Alzheimer's continuum for individuals with normal AD biomarkers within 3 years with high accuracy (AUC = 0.91). CONCLUSIONS: The risk models were able to provide personalized risk for AD onset at each year after evaluation. The models may be useful for better prevention of AD.

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.

Anaemia and cerebrospinal fluid biomarkers of Alzheimer's pathology in cognitively normal elders: the CABLE study.

BACKGROUND: Anaemia has been reported to be associated with cognitive decline and Alzheimer's disease (AD), but the associations between anaemia and cerebrospinal fluid (CSF) AD biomarkers are still unknown. This study aimed to investigate the associations between anaemia and CSF AD biomarkers. METHODS: Participants were included from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study. The associations of anaemia and its severity with CSF AD biomarkers including ß-amyloid 1-42 (Aß42), total tau (t-tau) and phosphorylated tau (p-tau) were analysed by multiple linear regression models. Adjusted for age, gender, educational levels, APOE ε4 alleles, comorbidities (history of coronary heart disease, history of stroke, hypertension, diabetes mellitus, dyslipidaemia) and glomerular filtration rate. RESULTS: A total of 646 cognitively normal older adults, consisting of 117 anaemia patients and 529 non-anaemia individuals, were included in this study. Anaemia patients had lower levels of CSF Aß42 than individuals without anaemia (p = 0.035). Besides, participants with more severe anaemia had lower CSF Aß42 levels (p = 0.045). No significant association of anaemia with CSF t-tau and p-tau levels was found. CONCLUSION: Cross-sectionally, anaemia was associated with lower CSF Aß42 levels. These findings consolidated the causal close relationship between anaemia and AD.

Evidence-based prevention of Alzheimer's disease: systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials.

BACKGROUND: Evidence on preventing Alzheimer's disease (AD) is challenging to interpret due to varying study designs with heterogeneous endpoints and credibility. We completed a systematic review and meta-analysis of current evidence with prospective designs to propose evidence-based suggestions on AD prevention. METHODS: Electronic databases and relevant websites were searched from inception to 1 March 2019. Both observational prospective studies (OPSs) and randomised controlled trials (RCTs) were included. The multivariable-adjusted effect estimates were pooled by random-effects models, with credibility assessment according to its risk of bias, inconsistency and imprecision. Levels of evidence and classes of suggestions were summarised. RESULTS: A total of 44 676 reports were identified, and 243 OPSs and 153 RCTs were eligible for analysis after exclusion based on pre-decided criteria, from which 104 modifiable factors and 11 interventions were included in the meta-analyses. Twenty-one suggestions are proposed based on the consolidated evidence, with Class I suggestions targeting 19 factors: 10 with Level A strong evidence (education, cognitive activity, high body mass index in latelife, hyperhomocysteinaemia, depression, stress, diabetes, head trauma, hypertension in midlife and orthostatic hypotension) and 9 with Level B weaker evidence (obesity in midlife, weight loss in late life, physical exercise, smoking, sleep, cerebrovascular disease, frailty, atrial fibrillation and vitamin C). In contrast, two interventions are not recommended: oestrogen replacement therapy (Level A2) and acetylcholinesterase inhibitors (Level B). INTERPRETATION: Evidence-based suggestions are proposed, offering clinicians and stakeholders current guidance for the prevention of AD.

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.

Models for predicting risk of dementia: a systematic review.

BACKGROUND: Information from well-established dementia risk models can guide targeted intervention to prevent dementia, in addition to the main purpose of quantifying the probability of developing dementia in the future. METHODS: We conducted a systematic review of published studies on existing dementia risk models. The models were assessed by sensitivity, specificity and area under the curve (AUC) from receiver operating characteristic analysis. RESULTS: Of 8462 studies reviewed, 61 articles describing dementia risk models were identified, with the majority of the articles modelling late life risk (n=39), followed by those modelling prediction of mild cognitive impairment to Alzheimer's disease (n=15), mid-life risk (n=4) and patients with diabetes (n=3). Age, sex, education, Mini Mental State Examination, the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological assessment battery, Alzheimer's Disease Assessment Scale-cognitive subscale, body mass index, alcohol intake and genetic variables are the most common predictors included in the models. Most risk models had moderate-to-high predictive ability (AUC>0.70). The highest AUC value (0.932) was produced from a risk model developed for patients with mild cognitive impairment. CONCLUSION: The predictive ability of existing dementia risk models is acceptable. Population-specific dementia risk models are necessary for populations and subpopulations with different characteristics.

The Associations of Cerebrospinal Fluid ApoE and Biomarkers of Alzheimer's Disease: Exploring Interactions With Sex.

BACKGROUND: Sex-related difference in Alzheimer's disease (AD) has been proposed, and apolipoprotein E (ApoE) isoforms have been suggested to be involved in the pathogenesis of AD. OBJECTIVE: We aimed to explore whether cerebrospinal fluid (CSF) ApoE is associated with AD biomarkers and whether the associations are different (between sexes). METHODS: Data of 309 participants [92 with normal cognition, 148 with mild cognitive impairment (MCI), and 69 with AD dementia] from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were cross-sectionally evaluated with the multiple linear regression model and longitudinally with the multivariate linear mixed-effects model for the associations of CSF ApoE with AD biomarkers. Sex-ApoE interaction was used to estimate whether sex moderates the associations of CSF ApoE and AD biomarkers. RESULTS: Significant interactions between CSF ApoE and sex on AD biomarkers were observed [amyloid-ß (Aß): p = 0.0169 and phosphorylated-tau (p-tau): p = 0.0453]. In women, baseline CSF ApoE levels were significantly associated with baseline Aß (p = 0.0135) and total-tau (t-tau) (p < 0.0001) as well as longitudinal changes of the biomarkers (Aß: p = 0.0104; t-tau: p = 0.0110). In men, baseline CSF ApoE levels were only correlated with baseline p-tau (p < 0.0001) and t-tau (p < 0.0001) and did not aggravate AD biomarkers longitudinally. CONCLUSION: The associations between CSF ApoE and AD biomarkers were sex-specific. Elevated CSF ApoE was associated with longitudinal changes of AD biomarkers in women, which indicates that CSF ApoE might be involved in the pathogenesis of AD pathology in a sex-specific way.

Predictors of cognitive impairment in Parkinson's disease: a systematic review and meta-analysis of prospective cohort studies.

INTRODUCTION: Cognitive impairment is a debilitating manifestation in Parkinson's disease (PD). We sought to investigate predictors of PD-CI (PD with cognitive impairment). METHODS: We systematically searched PubMed and Cochrane Library for prospective cohort studies and pooled estimates via random-effects models. Primary analyses for all types of cognitive impairments and subgroup analyses by separate outcomes were conducted. RESULTS: A total of 28,009 studies were identified, of which 57 studies with 31 factors were included in the meta-analysis. In the primary analysis, 13 factors were associated with PD-CI, comprising advanced age [relative risk (RR) = 1.07, 95% confidence interval (CI) = 1.03-1.12], age at onset (RR = 4.43, 95% CI = 1.87-10.54), postural-instability-gait disorder (RR = 3.76, 95% CI = 1.36-10.40), higher Hoehn and Yahr stage (RR = 1.83, 95% CI = 1.35-2.47), higher UPDRS III score (RR = 1.04, 95% CI = 1.01-1.08), rapid eye movement sleep behavior disorder (RR = 3.72, 95% CI = 1.20-11.54), hallucinations (RR = 3.09, 95% CI = 1.61-5.93), orthostatic hypotension (RR = 2.98, 95% CI = 1.41-6.28), anxiety (RR = 2.59, 95% CI = 1.18-5.68), APOE ε2 (RR = 6.47, 95% CI = 1.29-32.53), APOE ε4 (RR = 3.04, 95% CI = 1.88-4.91), electroencephalogram theta power > median (RR = 2.93, 95% CI = 1.61-5.33), and alpha power < median (RR = 1.77, 95% CI = 1.07-2.92). In the subgroup analysis, MAPT H1/H1 genotype increased the risk of dementia in PD. Sixty-four studies were included in the systematic review, of which 12 factors were additionally correlated with PD-CI using single studies. CONCLUSIONS: Advanced age, genetic variation in APOE and MAPT, gait disturbance, motor assessments, non-motor symptoms, and electroencephalogram may be promising predictors for PD-CI.

Associations of healthy lifestyles with cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact older adults: the CABLE study.

OBJECTIVE: We aimed to investigate the associations between healthy lifestyles and Alzheimer's disease (AD) biomarkers in cerebrospinal fluid (CSF). METHODS: A total of 1108 cognitively intact individuals from Chinese Alzheimer's Biomarker and LifestylE (CABLE) study were examined to evaluate the associations of AD biomarkers with healthy lifestyle factors, including no current smoking, no harmful drinking, absence of social isolation, and regular physical activity. The participants were categorized into groups of favorable, intermediate, and unfavorable lifestyles according to the lifestyle factors. The associations between overall lifestyle and CSF biomarkers were also analyzed. RESULTS: Among cognitively intact older adults, those having more social engagement had lower CSF tau (p = 0.009) and p-tau (p < 0.001) than those who had social isolation. Regular physical activity was associated with higher CSF Aß42 (p = 0.013) and lower levels of CSF tau (p = 0.036) and p-tau (p = 0.007). However, no significant associations were found of smoking status or alcohol intake with CSF biomarkers. When the overall lifestyle of the participants was evaluated by all the four lifestyle factors, favorable lifestyle profiles were related to lower levels of CSF tau (p < 0.001) and p-tau (p < 0.001). CONCLUSIONS: These findings suggest that healthy lifestyles had a beneficial effect on AD pathology among cognitively intact elders.

Association between methylation of BIN1 promoter in peripheral blood and preclinical Alzheimer's disease.

The bridging integrator 1 (BIN1) gene is the second most important susceptibility gene for late-onset Alzheimer's disease (LOAD) after apolipoprotein E (APOE) gene. To explore whether the BIN1 methylation in peripheral blood changed in the early stage of LOAD, we included 814 participants (484 cognitively normal participants [CN] and 330 participants with subjective cognitive decline [SCD]) from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database. Then we tested associations of methylation of BIN1 promoter in peripheral blood with the susceptibility for preclinical AD or early changes of cerebrospinal fluid (CSF) AD-related biomarkers. Results showed that SCD participants with significant AD biological characteristics had lower methylation levels of BIN1 promoter, even after correcting for covariates. Hypomethylation of BIN1 promoter were associated with decreased CSF Aß42 (p = 0.0008), as well as increased p-tau/Aß42 (p = 0.0001) and t-tau/Aß42 (p < 0.0001) in total participants. Subgroup analysis showed that the above associations only remained in the SCD subgroup. In addition, hypomethylation of BIN1 promoter was also accompanied by increased CSF p-tau (p = 0.0028) and t-tau (p = 0.0130) in the SCD subgroup, which was independent of CSF Aß42. Finally, above associations were still significant after correcting single nucleotide polymorphic sites (SNPs) and interaction of APOE ɛ4 status. Our study is the first to find a robust association between hypomethylation of BIN1 promoter in peripheral blood and preclinical AD. This provides new evidence for the involvement of BIN1 in AD, and may contribute to the discovery of new therapeutic targets for AD.

Serum Uric Acid May Aggravate Alzheimer's Disease Risk by Affecting Amyloidosis in Cognitively Intact Older Adults: The CABLE Study.

BACKGROUND: Serum uric acid (SUA) affects the reaction of oxidative stress and free radicals in the neurodegenerative processes. However, whether SUA impacts Alzheimer's disease (AD) pathology remains unclear. OBJECTIVE: We aimed to explore whether high SUA levels can aggravate the neurobiological changes of AD in preclinical AD. METHODS: We analyzed cognitively intact participants (n = 839, age 62.16 years) who received SUA and cerebrospinal fluid (CSF) biomarkers (amyloid-ß [Aß], total tau [t-Tau], and phosphorylated tau [p-Tau]) measurements from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database using multivariable-adjusted linear models. RESULTS: Levels of SUA in the preclinical AD elevated compared with the healthy controls (p = 0.007) and subjects with amyloid pathology had higher concentration of SUA than controls (p = 0.017). Roughly, equivalent levels of SUA displayed among cognitively intact individuals with or without tau pathology and neurodegeneration. CSF Aß1 - 42 (p = 0.019) and Aß1 - 42/Aß1 - 40 (p = 0.027) were decreased and CSF p-Tau/Aß1 - 42 (p = 0.009) and t-Tau/Aß1 - 42 (p = 0.043) were increased with the highest (> 75th percentile) SUA when compared to lowest SUA, implying a high burden of cerebral amyloidosis in individuals with high SUA. Sensitivity analyses using the usual threshold to define hyperuricemia and precluding drug effects yielded robust associations. Nevertheless, the quadratic model did not show any U-shaped relationships between them. CONCLUSION: SUA may aggravate brain amyloid deposition in preclinical AD, which corroborated the detrimental role of SUA.

Left Ventricular Ejection Fraction and Cerebrospinal Fluid Biomarkers of Alzheimer's Disease Pathology in Cognitively Normal Older Adults: The CABLE Study.

BACKGROUND: Heart failure has been considered as a potential modifiable risk factor for cognitive impairment and dementia. Left ventricular ejection fraction (LVEF), an indicator of cardiac dysfunction, has also been associated with cognitive aging. However, the effect of LVEF on Alzheimer's disease (AD) pathology is still less known. OBJECTIVE: We aimed to investigate the associations of LVEF with cerebrospinal fluid (CSF) biomarkers for AD in cognitively normal elders. METHODS: A total of 423 cognitively normal individuals without heart failure were included from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study. Participants were divided into low LVEF group (50%≤LVEF < 60%) and high LVEF group (LVEF≥60%). The associations of LVEF with CSF AD biomarkers including CSF amyloid-ß 42 (Aß42), total-tau (t-tau), and phosphorylated tau (p-tau) were analyzed using multivariate linear regression models. RESULTS: Participants with low LVEF had higher levels of CSF t-tau (ß= -0.009, p = 0.006) and t-tau/Aß42 ratios (ß= -0.108, p = 0.026). Subgroup analyses showed that the associations only existed in female and middle-aged groups (< 65 years old). Besides, participants with low LVEF had higher levels of CSF p-tau (ß= -0.002, p = 0.043) in middle-aged group. CONCLUSION: In conclusion, our findings revealed the associations between LVEF and AD pathology, which may provide new insights into AD prevention through maintaining cardiac function.

Social Networks and Cerebrospinal Fluid Biomarkers of Alzheimer's Disease Pathology in Cognitively Intact Older Adults: The CABLE Study.

BACKGROUND: Although social networks are deemed as moderators of incident Alzheimer's disease (AD), few data are available on the mechanism relevant to AD pathology. OBJECTIVE: We aimed to investigate whether social networks affect metabolism of cerebrospinal fluid (CSF) AD biomarkers during early stage and identify modification effects of genetic factor and subjective cognitive decline (SCD). METHODS: We studied participants from the Chinese Alzheimer's disease Biomarker and Lifestyle (CABLE) database who received cognition assessments and CSF amyloid-ß (Aß1-42 and Aß1-40) and tau proteins (total-tau [T-tau] and phosphorylated-tau [P-tau]) measurements. The social networks were measured using self-reported questionnaires about social ties. Linear regression models were used. RESULTS: Data were analyzed from 886 cognitively intact individuals aged 61.91 years (SD = 10.51), including 295 preclinical AD participants and 591 healthy controls. Social networks were mostly associated with CSF indicators of AD multi-pathologies (low P-tau/Aß1-42 and T-tau/Aß1-42 and high Aß1-42/Aß1-40). Significant differences of genetic and cognitive status were observed for CSF indicators, in which associations of social network scores with CSF P-tau and indicators of multi-pathologies appeared stronger in APOE 4 carriers (versus non-carriers) and participants with SCD (versus controls), respectively. Alternatively, more pronounced associations for CSF T-tau (ß= -0.005, p < 0.001), Aß1-42/Aß1-40 (ß= 0.481, p = 0.001), and T-tau/Aß1-42 (ß= -0.047, p < 0.001) were noted in preclinical AD stage than controls. CONCLUSION: These findings consolidated strong links between social networks and AD risks. Social networks as a modifiable lifestyle probably affected metabolisms of multiple AD pathologies, especially among at-risk populations.

Metabolically healthy obesity and risk of stroke: a meta-analysis of prospective cohort studies.

BACKGROUND: Metabolic healthy obesity (MHO) is a unique subgroup of overweight and obese individuals with normal metabolic characteristics. Its association with the risk of stroke remains unclear. We aimed to examine the risk of stroke in MHO individuals and the further associations between stroke and metabolic abnormalities under different bodyweight conditions. METHODS: We systematically searched PubMed, Embase and Cochrane Library from December 1946 to January 2019, and only included prospective cohort studies. Random effects models were used to evaluate the pooled risk ratios (RR) and 95% confidence intervals (95% CI) of incident stroke. RESULTS: A total of eight studies comprising 4,256,888 participants were included in the meta-analysis. MHO individuals had an increased risk of stroke compared with metabolically healthy normal weight (MH-NW) individuals (RR =1.17, 95% CI: 1.11-1.23). However, the stroke risk of metabolically healthy overweight individuals was the same (RR =1.02, 95% CI: 0.84-1.23). All groups with unhealthy metabolism had a similarly elevated risk: normal weight (RR =1.83, 95% CI: 1.57-2.14), overweight (RR =1.93, 95% CI: 1.44-2.58), and obesity (RR =2.00, 95% CI: 1.40-2.87). CONCLUSIONS: The meta-analysis confirms a positive association between MHO phenotype and the risk of stroke. Individuals with metabolic abnormalities under different bodyweight conditions are at elevated risk.

Associations of Vascular Risk with Cognition, Brain Glucose Metabolism, and Clinical Progression in Cognitively Intact Elders.

BACKGROUND: Increasing evidence supports an important role of vascular risk in cognitive decline and dementia. OBJECTIVE: This study aimed to examine whether vascular risk was associated with cognitive decline, cerebral hypometabolism, and clinical progression in cognitively intact elders. METHODS: Vascular risk was assessed by the Framingham Heart Study general Cardiovascular disease (FHS-CVD) risk score. The cross-sectional and longitudinal associations of FHS-CVD risk score with cognition and brain glucose metabolism were explored using multivariate linear regression and linear mixed effects models, respectively. The risk of clinical progression conversion was assessed using Kaplan-Meier survival curves and multivariate Cox proportional hazard models. RESULTS: A total of 491 cognitively intact elders were included from Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Participants with high FHS-CVD risk scores had lower baseline Mini-Mental State Examination (MMSE) (p = 0.009), executive function (EF) (p < 0.001), memory function (MEM) (p < 0.001) scores, and F18-fluorodeoxyglucose positron emission tomography (FDG-PET) uptake (p < 0.001) than those with low FHS-CVD risk scores. In longitudinal analyses, individuals with higher FHS-CVD risk scores had greater longitudinal declines in MMSE (p = 0.043), EF (p = 0.029) scores, and FDG-PET uptake (p = 0.035). Besides, individuals with a higher vascular risk had an increased risk of clinical progression (p = 0.004). CONCLUSION: These findings indicated effects of vascular risk on cognitive decline, cerebral hypometabolism, and clinical progression. Early detection and management of vascular risk factors might be useful in the prevention of dementia.

Serum Calcium Predicts Cognitive Decline and Clinical Progression of Alzheimer's Disease.

Relationship between serum calcium and Alzheimer's disease (AD) remains unclear. The aim of this study is to test whether serum calcium is associated with other AD-associated biomarkers and could predict clinical progression in nondemented elders. This was a longitudinal population-based study. The sample was derived from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, which included 1224 nondemented elders: 413 cognitively normal (CN) and 811 mild cognition impairment (MCI). Associations were investigated between serum calcium and longitudinal changes in Aß/tau pathologic features, brain structure, cognitive function, and disease progression. Serum calcium concentrations increased with disease severity. Serum calcium predicted longitudinal cognitive decline and conversion from nondemented status to AD dementia (adjusted HR = 1.41, 95% CI 1.13-1.76). Furthermore, serum calcium levels were negatively correlated with CSF-Aß42 (ß = - 0.558, P = 0.008), FDG-PET (ß = - 0.292, P < 0.001), whole brain volume (ß = - 0.148, P = 0.001), and middle temporal volume (ß = - 0.216, P = 0.042). Similar results were obtained in CN and MCI groups. Higher serum calcium status (even if not hypercalcemia) may increase the risk of AD in elders. Serum calcium is a useful biomarker in predicting clinical progression in nondemented elders. More researches are needed in the future to explore the underlying mechanism.

Associations of Infectious Agents with Alzheimer's Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: The role of infectious agents in the development of Alzheimer's disease (AD) has long been debated, however, uncertainties still persist. OBJECTIVE: We aimed to illuminate the associations between infectious agents and risk of AD comprehensively. METHODS: Studies examining the associations between AD and infectious agents were identified through a systematic search of PubMed, Embase, and Cochrane library. A random-effects meta-analysis was conducted. Publication bias was explored using funnel plot. RESULTS: Fifty-one studies were included in the systematic review, of which forty-seven studies with 108,723 participants and 4,039 AD cases were eligible for meta-analysis. Evidence based on case control studies demonstrated that Chlamydia pneumoniae [odds ratio (OR): 4.39, 95% CI = 1.81-10.67; I2 = 68%)], Human herpes virus-6 (OR: 3.97, 95% CI = 2.04-7.75; I2 = 0%, Epstein-Barr virus (OR:1.45, 95% CI = 1.00-2.08; I2 = 0%), Herpes simplex virus-1 (OR:1.34, 95% CI = 1.02-1.75; I2 = 0%), and the Herpesviridae family (OR:1.41, 95% CI = 1.15-1.74; I2 = 12%) infection were associated with a higher risk of AD. No significant evidence of publication bias was found. CONCLUSION: These findings strengthened the evidence that infection may play an important role in AD. Additional research is required to determine whether treatment strategies targeting infectious diseases to prevent AD are viable in the future.

Blood Pressure and Risks of Cognitive Impairment and Dementia: A Systematic Review and Meta-Analysis of 209 Prospective Studies.

Controversies persist regarding the association between blood pressure (BP) and the risks of cognitive impairment and dementia due to inconsistent definitions of BP exposure and varying population characteristics. Here, we searched PubMed and performed a meta-analysis of the influence of BP exposure on the risks of cognitive disorders in prospective studies. Dose-response analyses were performed to illustrate the existence of linear/nonlinear relationships. The credibility of each meta-analysis was evaluated according to the risk of bias, inconsistency, and imprecision. Of the 31 628 citations, 209 were included in our systematic review, among which 136 were eligible for the meta-analysis. Overall, stronger associations were found in midlife than late-life. Moderate-quality evidence indicated that midlife hypertension was related to a 1.19- to 1.55-fold excess risk of cognitive disorders. Dose-response analyses of 5 studies indicated that midlife systolic BP >130 mm Hg was associated with an increased risk of cognitive disorders. With regard to BP exposure in late-life, high systolic BP, low diastolic BP, excessive BP variability, and orthostatic hypotension were all associated with an increased dementia risk. Encouragingly, the use of antihypertensive medications exhibited a 21% reduction in dementia risk. The U-shaped dose-response curve indicated that the protective window of diastolic BP level was between 90 and 100 mm Hg for low risk of Alzheimer disease. The relationships between BP variables and cognitive disorders are age- and BP type-dependent. Antihypertensive medications were associated with a reduced risk of dementia. However, the optimal dose, duration, and type for preventing cognitive disorders warrant further investigation.

Association of antinuclear antibodies with the risk of intracranial arterial stenosis.

The prevalence of intracranial arterial stenosis (IAS) as well as antinuclear antibody (ANA) positivity was found to be higher in Asians than that in the Western population. To investigate the relation of ANAs with IAS in patients with acute ischemic cerebrovascular disease, we enrolled 2492 patients with acute ischemic stroke or transient ischemic attack into the study. All the patients were categorized into 3 groups according to the IAS burden. Multinomial logistic regression analyses were used in statistical analysis. The positive rate of ANAs in the IAS ≥ 2 group was higher than that in the single IAS group and the no IAS group (p<0.001). The adjusted odds ratio (OR) for IAS ≥ 2 in ANAs-positive patients was 3.737 (95%CI=2.676-5.220, p<0.001) compared with the ANAs-negative patients. ANAs were associated with multiple IAS rather than single IAS in both male and female subgroups. Besides, ANAs were significantly associated with single and multiple IAS in individuals ≤ 60 years. However, ANAs were only associated with two or more IAS in two age groups (between 61 to 75 years and >75 years old). In summary, ANAs are associated with IAS in patients with acute ischemic cerebrovascular disease.