Incidence estimates of mild cognitive impairment (MCI) range widely. We obtained contemporary age-specific MCI incidence rates and examined sources of heterogeneity.
We conducted a systematic review ...of population-based studies from the Americas, Europe, and Australia using restrictive inclusion criteria to limit heterogeneity. Incidence was examined using 5-year age categories for MCI and amnestic/nonamnestic subtypes. Data were synthesized using quantitative and qualitative descriptive analyses and quantitative meta-analyses.
Meta-analysis estimates (95% CI) of MCI incidence per 1000 person-years were 22.5 (5.1–51.4) for ages 75–79y, 40.9 (7.7–97.5) for ages 80–84y, and 60.1 (6.7–159.0) for ages 85+y. Despite restrictive inclusion criteria, considerable heterogeneity (measured by I2) remained. Meta-analysis findings and simple descriptive statistics were consistent and supported by qualitative review.
Heterogeneity in MCI incidence estimates persisted across age-specific estimates from population samples, likely reflecting differences in populations and methods. Incidence rate ranges are important to consider with summary point estimates.
•Summary estimates for MCI incidence are not available, largely due to heterogeneity.•This study generated summary estimates using a multipronged approach.•Heterogeneity in our synthesized data remained, reflecting real-world challenges.•Incidence rate ranges may be more useful guides than single summary point estimates.
Intelligence is associated with important economic and health-related life outcomes. Despite intelligence having substantial heritability (0.54) and a confirmed polygenic nature, initial genetic ...studies were mostly underpowered. Here we report a meta-analysis for intelligence of 78,308 individuals. We identify 336 associated SNPs (METAL P < 5 × 10
) in 18 genomic loci, of which 15 are new. Around half of the SNPs are located inside a gene, implicating 22 genes, of which 11 are new findings. Gene-based analyses identified an additional 30 genes (MAGMA P < 2.73 × 10
), of which all but one had not been implicated previously. We show that the identified genes are predominantly expressed in brain tissue, and pathway analysis indicates the involvement of genes regulating cell development (MAGMA competitive P = 3.5 × 10
). Despite the well-known difference in twin-based heritability for intelligence in childhood (0.45) and adulthood (0.80), we show substantial genetic correlation (r
= 0.89, LD score regression P = 5.4 × 10
). These findings provide new insight into the genetic architecture of intelligence.
Apolipoprotein E is a glycoprotein best known as a mediator and regulator of lipid transport and uptake. The APOE-ε4 allele has long been associated with increased risks of Alzheimer's disease and ...mortality, but the effect of the less prevalent APOE-ε2 allele on diseases in the elderly and survival remains elusive.
We aggregated data of 38,537 individuals of European ancestry (mean age 65.5 years; 55.6% women) from six population-based cohort studies (Rotterdam Study, AGES-Reykjavik Study, Cardiovascular Health Study, Health-ABC Study, and the family-based Framingham Heart Study and Long Life Family Study) to determine the association of APOE, and in particular APOE-ε2, with survival in the population.
During a mean follow-up of 11.7 years, 17,021 individuals died. Compared with homozygous APOE-ε3 carriers, APOE-ε2 carriers were at lower risk of death (hazard ratio,95% confidence interval: 0.94,0.90-0.99; P = 1.1*10-2), whereas APOE-ε4 carriers were at increased risk of death (HR 1.17,1.12-1.21; P = 2.8*10-16). APOE was associated with mortality risk in a dose-dependent manner, with risk estimates lowest for homozygous APOE-ε2 (HR 0.89,0.74-1.08), and highest for homozygous APOE-ε4 (HR 1.52,1.37-1.70). After censoring for dementia, effect estimates remained similar for APOE-ε2 (HR 0.95,0.90-1.01), but attenuated for APOE-ε4 (HR 1.07,1.01-1.12). Results were broadly similar across cohorts, and did not differ by age or sex. APOE genotype was associated with baseline lipid fractions (e.g. mean difference(95%CI) in LDL(mg/dL) for ε2 versus ε33: -17.1(-18.1-16.0), and ε4 versus ε33: +5.7(4.8;6.5)), but the association between APOE and mortality was unaltered after adjustment for baseline LDL or cardiovascular disease. Given the European ancestry of the study population, results may not apply to other ethnicities.
Compared with APOE-ε3, APOE-ε2 is associated with prolonged survival, whereas mortality risk is increased for APOE-ε4 carriers. Further collaborative efforts are needed to unravel the role of APOE and in particular APOE-ε2 in health and disease.
Inflammatory markers are often elevated in patients with dementia, including Alzheimer's disease (AD). However, it remains unclear whether inflammatory markers are associated with the risk of ...developing dementia.
We searched PubMed, Embase, and Cochrane library for prospective population-based studies reporting associations between inflammatory markers and all-cause dementia or AD. We used random effects meta-analyses to obtain pooled hazard ratios (HRs) and 95% confidence intervals of inflammatory markers (highest vs. lowest quantile) for all-cause dementia and AD.
Fifteen articles from 13 studies in six countries reported data that could be meta-analyzed. C-reactive protein (HR = 1.37 1.05; 1.78), interleukin-6 (HR = 1.40 1.13; 1.73), α1-antichymotrypsin (HR = 1.54 1.14; 2.80), lipoprotein-associated phospholipase A2 activity (HR = 1.40 1.03; 1.90), and fibrinogen were each associated with all-cause dementia, but neither was significantly associated with AD.
Several inflammatory markers are associated with an increased risk of all-cause dementia; however, these markers are not specific for AD. Whether inflammatory markers closely involved in AD pathology are associated with the risk of AD remains to be elucidated.
Cardiovascular disease (CVD) is one of the major causes of death worldwide. For improved accuracy of CVD prediction, risk classification was performed using national time-series health examination ...data. The data offers an opportunity to access deep learning (RNN-LSTM), which is widely known as an outstanding algorithm for analyzing time-series datasets. The objective of this study was to show the improved accuracy of deep learning by comparing the performance of a Cox hazard regression and RNN-LSTM based on survival analysis.
We selected 361,239 subjects (age 40 to 79 years) with more than two health examination records from 2002-2006 using the National Health Insurance System-National Health Screening Cohort (NHIS-HEALS). The average number of health screenings (from 2002-2013) used in the analysis was 2.9 ± 1.0. Two CVD prediction models were developed from the NHIS-HEALS data: a Cox hazard regression model and a deep learning model. In an internal validation of the NHIS-HEALS dataset, the Cox regression model showed a highest time-dependent area under the curve (AUC) of 0.79 (95% CI 0.70 to 0.87) for in females and 0.75 (95% CI 0.70 to 0.80) in males at 2 years. The deep learning model showed a highest time-dependent AUC of 0.94 (95% CI 0.91 to 0.97) for in females and 0.96 (95% CI 0.95 to 0.97) in males at 2 years. Layer-wise Relevance Propagation (LRP) revealed that age was the variable that had the greatest effect on CVD, followed by systolic blood pressure (SBP) and diastolic blood pressure (DBP), in that order.
The performance of the deep learning model for predicting CVD occurrences was better than that of the Cox regression model. In addition, it was confirmed that the known risk factors shown to be important by previous clinical studies were extracted from the study results using LRP.
High blood pressure is considered an important risk factor for cerebral white matter lesions (WMLs) in the aging population. In a longitudinal population-based study of 665 nondemented persons, we ...investigated the longitudinal relationship of systolic blood pressure, diastolic blood pressure, and pulse pressure with annual progression of WMLs. Means of blood pressure were calculated over a 5-year period before longitudinal MRI scanning. WML progression was subsequently measured on 2 scans 3.5 years apart. We performed analyses with linear regression models and evaluated adjustments for age, sex, cardiovascular risk factors, and baseline WML volume. In addition, we evaluated whether treatment of hypertension is related to less WML progression. Both systolic and diastolic blood pressures were significantly associated with annual WML progression (regression coefficient 95% confidence interval, 0.08 0.03; 0.14 mL/y and 0.09 0.03; 0.15 mL/y per SD increase in systolic and diastolic blood pressure, respectively). Pulse pressure was also significantly associated with WML progression, but not independent from hypertension. After adjustment for baseline WML volume, only systolic blood pressure remained significantly associated: 0.05 (0.00; 0.09) mL/y per SD increase. People with uncontrolled untreated hypertension had significantly more WML progression than people with uncontrolled treated hypertension (difference 95% confidence interval, 0.12 0.00; 0.23 mL/y). The present study further establishes high blood pressure to precede WMLs and implies that hypertension treatment could reduce WML progression in the general population.
Cerebral hypoperfusion has previously been associated with mild cognitive impairment and dementia in various cross-sectional studies, but whether hypoperfusion precedes neurodegeneration is unknown. ...We prospectively determined the association of cerebral perfusion with subsequent cognitive decline and development of dementia.
Between 2005 and 2012, we measured cerebral blood flow by 2-dimensional phase-contrast magnetic resonance imaging in participants of the population-based Rotterdam Study without dementia. We determined the association of cerebral perfusion (mL/100mL/min) with risk of dementia (until 2015) using a Cox model, adjusting for age, sex, demographics, cardiovascular risk factors, and apolipoprotein E genotype. We repeated analyses for Alzheimer disease and accounting for stroke. We used linear regression to determine change in cognitive performance during 2 consecutive examination rounds in relation to perfusion. Finally, we investigated whether associations were modified by baseline severity of white matter hyperintensities.
Of 4759 participants (median age 61.3 years, 55.2% women) with a median follow-up of 6.9 years, 123 participants developed dementia (97 Alzheimer disease). Lower cerebral perfusion was associated with higher risk of dementia (adjusted hazard ratio, 1.31; 95% confidence interval per standard deviation decrease, 1.07-1.61), similar for Alzheimer disease only, and unaltered by accounting for stroke. Risk of dementia with hypoperfusion was higher with increasing severity of white matter hyperintensities (with severe white matter hyperintensities; hazard ratio, 1.54; 95% confidence interval, 1.11-2.14). At cognitive reexamination after on average 5.7 years, lower baseline perfusion was associated with accelerated decline in cognition (global cognition: β=-0.029,
=0.003), which was similar after excluding those with incident dementia, and again most profound in individuals with higher volume of white matter hyperintensities (
value for interaction=0.019).
Cerebral hypoperfusion is associated with accelerated cognitive decline and an increased risk of dementia in the general population.
Abstract Along with the aging population, the public health burden of cerebrovascular disease is increasing. Cerebral small vessel disease and accumulation of brain pathology associate with cognitive ...decline and can lead to clinical outcomes, such as stroke and dementia. Chronic Obstructive Pulmonary Disease (COPD) is a common respiratory disease among elderly. The quality of life and prognosis of patients with COPD is greatly determined by the presence of comorbidities including stroke and cognitive impairment. Despite the clinical relevance of cerebral small vessel disease, stroke and (vascular) cognitive impairment in patients with COPD, literature is scarce and underlying mechanisms are unknown. The aim of the present review is therefore to summarize current scientific knowledge, to provide a better understanding of the interplay between COPD and the aging brain and to define remaining knowledge gaps. This narrative review article 1) overviews the epidemiology of cerebral small vessel disease, stroke and cognitive impairment in patients with COPD; 2) discusses potential underlying mechanisms including aging, smoking, systemic inflammation, vasculopathy, hypoxia and genetic susceptibility; and 3) highlights areas requiring further research.
Imaging plays an essential role in research on neurological diseases in the elderly. The Rotterdam Scan Study was initiated as part of the ongoing Rotterdam Study with the aim to elucidate the causes ...of neurological disease by performing imaging of the brain in a prospective population-based setting. Initially, in 1995 and 1999, random subsamples of participants from the Rotterdam Study underwent neuroimaging, whereas from 2005 onwards MRI has been implemented into the core protocol of the Rotterdam Study. In this paper, we discuss the background and rationale of the Rotterdam Scan Study. Moreover, we describe the imaging protocol, image post-processing techniques, and the main findings to date. Finally, we provide recommendations for future research, which will also be topics of investigation in the Rotterdam Scan Study.
To determine whether classes of diabetes medications are associated with cognitive health and dementia risk, above and beyond their glycemic control properties.
Findings were pooled from 5 ...population-based cohorts: the Framingham Heart Study, the Rotterdam Study, the Atherosclerosis Risk in Communities (ARIC) Study, the Aging Gene-Environment Susceptibility-Reykjavik Study (AGES) and the Sacramento Area Latino Study on Aging (SALSA). Differences between users and non-users of insulin, metformin and sulfonylurea were assessed in each cohort for cognitive and brain MRI measures using linear regression models, and cognitive decline and dementia/AD risk using mixed effect models and Cox regression analyses, respectively. Findings were then pooled using meta-analytic techniques, including 3,590 individuals with diabetes for the prospective analysis.
After adjusting for potential confounders including indices of glycemic control, insulin use was associated with increased risk of new-onset dementia (pooled HR (95% CI) = 1.58 (1.18, 2.12);p = 0.002) and with a greater decline in global cognitive function (β = -0.014±0.007;p = 0.045). The associations with incident dementia remained similar after further adjustment for renal function and excluding persons with diabetes whose treatment was life-style change only. Insulin use was not related to cognitive function nor to brain MRI measures. No significant associations were found between metformin or sulfonylurea use and outcomes of brain function and structure. There was no evidence of significant between-study heterogeneity.
Despite its advantages in controlling glycemic dysregulation and preventing complications, insulin treatment may be associated with increased adverse cognitive outcomes possibly due to a greater risk of hypoglycemia.
PDF
