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Molecular Psychiatry Feb 2022Aging is associated with chronic systemic inflammation, which contributes to the development of many age-related diseases, including vascular disease. The world's... (Review)
Review
Aging is associated with chronic systemic inflammation, which contributes to the development of many age-related diseases, including vascular disease. The world's population is aging, leading to an increasing prevalence of both stroke and vascular dementia. The inflammatory response to ischemic stroke is critical to both stroke pathophysiology and recovery. Age is a predictor of poor outcomes after stroke. The immune response to stroke is altered in aged individuals, which contributes to the disparate outcomes between young and aged patients. In this review, we describe the current knowledge of the effects of aging on the immune system and the cerebral vasculature and how these changes alter the immune response to stroke and vascular dementia in animal and human studies. Potential implications of these age-related immune alterations on chronic inflammation in vascular disease outcome are highlighted.
Topics: Aged; Aging; Animals; Dementia, Vascular; Humans; Inflammation; Stroke
PubMed: 34711943
DOI: 10.1038/s41380-021-01361-1 -
Stroke Apr 2022High blood pressure (BP) is detrimental to brain health. High BP contributes to cognitive impairment and dementia through pathways independent of clinical stroke.... (Review)
Review
High blood pressure (BP) is detrimental to brain health. High BP contributes to cognitive impairment and dementia through pathways independent of clinical stroke. Emerging evidence shows that the deleterious effect of high BP on cognition occurs across the life span, increasing the risk for early-onset and late-life dementia. The term vascular cognitive impairment includes cognitive disorders associated with cerebrovascular disease, regardless of the pathogenesis. This focused report is a narrative review that aims to summarize the epidemiology of BP and vascular cognitive impairment, including differences by sex, race, and ethnicity, as well as the management and reversibility of BP and vascular cognitive impairment. It also discusses knowledge gaps and future directions.
Topics: Blood Pressure; Cognition Disorders; Cognitive Dysfunction; Dementia; Dementia, Vascular; Humans; Hypertension; Risk Factors
PubMed: 35264009
DOI: 10.1161/STROKEAHA.121.036140 -
BMC Medicine Mar 2023Emerging data suggests the neuroprotective and anti-neuroinflammatory effects of glucosamine. We aimed to examine the association between regular glucosamine use and...
BACKGROUND
Emerging data suggests the neuroprotective and anti-neuroinflammatory effects of glucosamine. We aimed to examine the association between regular glucosamine use and risk of incident dementia, including dementia subtypes.
METHODS
We conducted large-scale observational and two-sample Mendelian randomization (MR) analyses. Participants in UK Biobank having accessible data for dementia incidence and who did not have dementia at baseline were included in the prospective cohort. Through the Cox proportional hazard model, we examined the risks of incident all-cause dementia, Alzheimer's disease (AD), and vascular dementia among glucosamine users and non-users. To further test the causal association between glucosamine use and dementia, we conducted a 2-sample MR utilizing summary statistics from genome-wide association studies (GWAS). The GWAS data were obtained from observational cohort participants of mostly European ancestry.
RESULTS
During a median follow-up of 8.9 years, there were 2458 cases of all-cause dementia, 924 cases of AD, and 491 cases of vascular dementia. In multivariable analysis, the hazard ratios (HR) of glucosamine users for all-cause dementia, AD, and vascular dementia were 0.84 (95% CI 0.75-0.93), 0.83 (95% CI 0.71-0.98), and 0.74 (95% CI 0.58-0.95), respectively. The inverse associations between glucosamine use and AD appeared to be stronger among participants aged below 60 years than those aged above 60 years (p = 0.04 for interaction). The APOE genotype did not modify this association (p > 0.05 for interaction). Single-variable MR suggested a causal relationship between glucosamine use and lower dementia risk. Multivariable MR showed that taking glucosamine continued to protect against dementia after controlling for vitamin, chondroitin supplement use and osteoarthritis (all-cause dementia HR 0.88, 95% CI 0.81-0.95; AD HR 0.78, 95% CI 0.72-0.85; vascular dementia HR 0.73, 95% CI 0.57-0.94). Single and multivariable inverse variance weighted (MV-IVW) and MR-Egger sensitivity analyses produced similar results for these estimations.
CONCLUSIONS
The findings of this large-scale cohort and MR analysis provide evidence for potential causal associations between the glucosamine use and lower risk for dementia. These findings require further validation through randomized controlled trials.
Topics: Humans; Aged; Glucosamine; Dementia, Vascular; Genome-Wide Association Study; Mendelian Randomization Analysis; Prospective Studies; Alzheimer Disease; Polymorphism, Single Nucleotide
PubMed: 36978077
DOI: 10.1186/s12916-023-02816-8 -
The Lancet. Healthy Longevity Aug 2021People with dementia die prematurely. Identifying differences in mortality rates between different types of dementia might aid in the development of preventive... (Meta-Analysis)
Meta-Analysis
BACKGROUND
People with dementia die prematurely. Identifying differences in mortality rates between different types of dementia might aid in the development of preventive interventions for the most vulnerable populations. The aim of this study was to compare the difference in mortality rates between individuals without dementia and individuals with various types of dementia.
METHODS
For this systematic review and meta-analysis, we did a systematic search of MEDLINE, PubMed, Embase, and Cochrane Library from inception to July 11, 2020, for cross-sectional or cohort studies that assessed mortality and survival-related outcomes among people with different types of dementia compared with people without dementia. Single-arm studies without comparison groups and autopsy studies or family studies that used a selected sample were excluded. The Newcastle-Ottawa Scale was used by two authors (D-JL and C-SC) independently to measure the methodological quality of included studies, and two authors (F-CY and P-TT) independently extracted data. We assessed differences in all-cause mortality rate and survival time from dementia diagnosis between individuals without dementia, individuals with Alzheimer's disease, and individuals with non-Alzheimer's disease dementias. The secondary outcomes were age at death and survival time from disease onset. Random-effects meta-analyses were done. Effect sizes included hazard ratios (HRs) and mean differences (MDs) with 95% CIs. Potential moderators, including age-associated moderators, were identified through meta-regression and subgroup analyses. This study is registered with PROSPERO, CRD42020198786.
FINDINGS
Our database search identified 11 973 records, and we included 78 eligible studies in our analyses, encompassing 63 125 individuals with dementia and 152 353 controls. Individuals with any type of dementia had a higher mortality rate than individuals without dementia (HR 5·90, 95% CI 3·53 to 9·86), and the HR for all-cause mortality was highest for Lewy body dementia (17·88, 5·87 to 54·46). After diagnosis, the mean survival time for people with Alzheimer's disease was 5·8 years (SD 2·0). Compared with people with Alzheimer's disease, a diagnosis of any non-Alzheimer's disease dementia was associated with a higher risk of all-cause mortality (HR 1·33, 1·21 to 1·46), a shorter survival time from diagnosis (MD -1·12 years, 95% CI -1·52 to -0·72), and a younger age at death (-1·76 years, -2·66 to -0·85). Survival time from disease onset was also shorter in people with non-Alzheimer's dementia, across types, compared with people with Alzheimer's disease, but the subgroup analysis revealed that this difference was only significant for vascular dementia (MD -1·27 years, -1·90 to -0·65) and dementia with Lewy bodies (MD -1·06 years, -1·68 to -0·44). The interactions between age and several survival-related outcomes were significant. 39 (50%) of the 78 included studies were rated as good quality, and large heterogeneity (I>75%) was observed for most of the study outcomes.
INTERPRETATION
Alzheimer's disease is the most common type of dementia and one of the major causes of mortality worldwide. However, the findings from the current study suggest that non-Alzheimer's disease dementias were associated with higher morality rates and shorter life expectancy than Alzheimer's disease. Developing tailored treatment and rehabilitation programmes for different types of dementia is important for mental health providers, patients, and their families.
FUNDING
None.
Topics: Alzheimer Disease; Cross-Sectional Studies; Dementia; Dementia, Vascular; Humans; Lewy Body Disease
PubMed: 36097997
DOI: 10.1016/S2666-7568(21)00140-9 -
The Cochrane Database of Systematic... Feb 2021Vascular cognitive impairment (VCI) describes a broad spectrum of cognitive impairments caused by cerebrovascular disease, ranging from mild cognitive impairment to... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Vascular cognitive impairment (VCI) describes a broad spectrum of cognitive impairments caused by cerebrovascular disease, ranging from mild cognitive impairment to dementia. There are currently no pharmacological treatments recommended for improving either cognition or function in people with VCI. Three cholinesterase inhibitors (donepezil, galantamine, and rivastigmine) are licenced for the treatment of dementia due to Alzheimer's disease. They are thought to work by compensating for reduced cholinergic neurotransmission, which is also a feature of VCI. Through pairwise comparisons with placebo and a network meta-analysis, we sought to determine whether these medications are effective in VCI and whether there are differences between them with regard to efficacy or adverse events.
OBJECTIVES
(1) To assess the efficacy and safety of cholinesterase inhibitors in the treatment of adults with vascular dementia and other VCI. (2) To compare the effects of different cholinesterase inhibitors on cognition and adverse events, using network meta-analysis.
SEARCH METHODS
We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's register, MEDLINE (OvidSP), Embase (OvidSP), PsycINFO (OvidSP), CINAHL (EBSCOhost), Web of Science Core Collection (ISI Web of Science), LILACS (BIREME), ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform on 19 August 2020.
SELECTION CRITERIA
We included randomised controlled trials in which donepezil, galantamine, or rivastigmine was compared with placebo or in which the drugs were compared with each other in adults with vascular dementia or other VCI (excluding cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)). We included all drug doses and routes of administration.
DATA COLLECTION AND ANALYSIS
Two review authors independently identified eligible trials, extracted data, assessed risk of bias, and applied the GRADE approach to assess the certainty of the evidence. The primary outcomes were cognition, clinical global impression, function (performance of activities of daily living), and adverse events. Secondary outcomes were serious adverse events, incidence of development of new dementia, behavioural disturbance, carer burden, institutionalisation, quality of life and death. For the pairwise analyses, we pooled outcome data at similar time points using random-effects methods. We also performed a network meta-analysis using Bayesian methods.
MAIN RESULTS
We included eight trials (4373 participants) in the review. Three trials studied donepezil 5 mg or 10 mg daily (n= 2193); three trials studied rivastigmine at a maximum daily dose of 3 to 12 mg (n= 800); and two trials studied galantamine at a maximum daily dose of 16 to 24 mg (n= 1380). The trials included participants with possible or probable vascular dementia or cognitive impairment following stroke. Mean ages were between 72.2 and 73.9 years. All of the trials were at low or unclear risk of bias in all domains, and the evidence ranged from very low to high level of certainty. For cognition, the results showed that donepezil 5 mg improves cognition slightly, although the size of the effect is unlikely to be clinically important (mean difference (MD) -0.92 Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) points (range 0 to 70), 95% confidence interval (CI) -1.44 to -0.40; high-certainty evidence). Donepezil 10 mg (MD -2.21 ADAS-Cog points, 95% CI -3.07 to -1.35; moderate-certainty evidence) and galantamine 16 to 24 mg (MD -2.01 ADAS-Cog point, 95%CI -3.18 to -0.85; moderate-certainty evidence) probably also improve cognition, although the larger effect estimates still may not be clinically important. With low certainty, there may be little to no effect of rivastigmine 3 to 12 mg daily on cognition (MD 0.03 ADAS-Cog points, 95% CI -3.04 to 3.10; low-certainty evidence). Adverse events reported in the studies included nausea and/or vomiting, diarrhoea, dizziness, headache, and hypertension. The results showed that there was probably little to no difference between donepezil 5 mg and placebo in the number of adverse events (odds ratio (OR) 1.22, 95% CI 0.94 to 1.58; moderate-certainty evidence), but there were slightly more adverse events with donepezil 10 mg than with placebo (OR 1.95, 95% CI 1.20 to 3.15; high-certainty evidence). The effect of rivastigmine 3 to 12 mg on adverse events was very uncertain (OR 3.21, 95% CI 0.36 to 28.88; very low-certainty evidence). Galantamine 16 to 24 mg is probably associated with a slight excess of adverse events over placebo (OR 1.57, 95% CI 1.02 to 2.43; moderate-certainty evidence). In the network meta-analysis (NMA), we included cognition to represent benefit, and adverse events to represent harm. All drugs ranked above placebo for cognition and below placebo for adverse events. We found donepezil 10 mg to rank first in terms of benefit, but third in terms of harms, when considering the network estimates and quality of evidence. Galantamine was ranked second in terms of both benefit and harm. Rivastigmine had the lowest ranking of the cholinesterase inhibitors in both benefit and harm NMA estimates, but this may reflect possibly inadequate doses received by some trial participants and small trial sample sizes.
AUTHORS' CONCLUSIONS
We found moderate- to high-certainty evidence that donepezil 5 mg, donepezil 10 mg, and galantamine have a slight beneficial effect on cognition in people with VCI, although the size of the change is unlikely to be clinically important. Donepezil 10 mg and galantamine 16 to 24 mg are probably associated with more adverse events than placebo. The evidence for rivastigmine was less certain. The data suggest that donepezil 10 mg has the greatest effect on cognition, but at the cost of adverse effects. The effect is modest, but in the absence of any other treatments, people living with VCI may still wish to consider the use of these agents. Further research into rivastigmine is needed, including the use of transdermal patches.
Topics: Activities of Daily Living; Bias; Cholinesterase Inhibitors; Cognition; Dementia, Vascular; Donepezil; Galantamine; Humans; Network Meta-Analysis; Nootropic Agents; Physical Functional Performance; Placebos; Randomized Controlled Trials as Topic; Rivastigmine
PubMed: 33704781
DOI: 10.1002/14651858.CD013306.pub2 -
Journal of Alzheimer's Disease : JAD 2021Previous studies have identified dementia as a risk factor for death from coronavirus disease 2019 (COVID-19). However, it is unclear whether Alzheimer's disease (AD) is...
Previous studies have identified dementia as a risk factor for death from coronavirus disease 2019 (COVID-19). However, it is unclear whether Alzheimer's disease (AD) is an independent risk factor for COVID-19 case fatality rate. In a retrospective cohort study, we identified 387,841 COVID-19 patients through TriNetX. After adjusting for demographics and comorbidities, we found that AD patients had higher odds of dying from COVID-19 compared to patients without AD (Odds Ratio: 1.20, 95%confidence interval: 1.09-1.32, p < 0.001). Interestingly, we did not observe increased mortality from COVID-19 among patients with vascular dementia. These data are relevant to the evolving COVID-19 pandemic.
Topics: Alzheimer Disease; COVID-19; Dementia, Vascular; Humans; Retrospective Studies; Risk Factors
PubMed: 34690147
DOI: 10.3233/JAD-215161 -
Journal of the American Heart... Aug 2023Background The knowledge gap regarding whether the correlation between atrial fibrillation (AF) and dementia in observational studies is causation or driven by other...
Background The knowledge gap regarding whether the correlation between atrial fibrillation (AF) and dementia in observational studies is causation or driven by other shared risk factors remains substantially unfilled. Methods and Results We performed a comprehensive 2-sample Mendelian randomization study to evaluate the causal effect of AF on overall dementia and its subtypes, including vascular dementia, Alzheimer dementia, Lewy body dementia, and frontotemporal dementia. The primary results in inverse variance-weighted analyses were further validated by various Mendelian randomization sensitivity analyses. Additionally, we conducted multivariable Mendelian randomization to examine 10 candidate mediators of the causal association of AF and dementia. Genetic predisposition to AF was modestly associated with an increased risk of overall dementia (odds ratio, 1.140 [95% CI, 1.023-1.271]; =0.018) and strongly associated with vascular dementia (odds ratio, 1.350 [95% CI, 1.076-1.695]; =0.010). Genetically predicted AF indicated neutral effects on Alzheimer dementia, Lewy body dementia, and frontotemporal dementia. In multivariable Mendelian randomization analysis, the total effect of AF on overall dementia was remarkably attenuated by adjusting for genetic effect for ischemic stroke (odds ratio, 1.068 [95% CI, 0.953-1.197]; =0.259) and low cardiac output (odds ratio, 1.046 [95% CI, 0.926-1.181]; =0.475), indicating that the causal association of genetically predicted AF with dementia was potentially mediated by ischemic stroke and low cardiac output. The causal effect of genetically predicted AF on dementia was independent of cerebral small-vessel disease and brain volume phenotypes. Conclusions Our findings provided novel evidence supporting the causal effect of genetically predicted AF on dementia mediated by ischemic stroke and low cardiac output. Future clinical trials are warranted to evaluate the potential role of appropriate AF management in dementia prevention.
Topics: Humans; Atrial Fibrillation; Alzheimer Disease; Dementia, Vascular; Lewy Body Disease; Mendelian Randomization Analysis; Frontotemporal Dementia; Cardiac Output, Low; Ischemic Stroke; Polymorphism, Single Nucleotide; Genome-Wide Association Study
PubMed: 37548160
DOI: 10.1161/JAHA.123.029623 -
Neurology Oct 2022Leisure activities are major components of modifiable and healthy lifestyles and are proposed to help prevent the development of dementia. This study aimed to assess the... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND OBJECTIVES
Leisure activities are major components of modifiable and healthy lifestyles and are proposed to help prevent the development of dementia. This study aimed to assess the effects of different types of leisure activities, including cognitive, physical, and social activities, on the incidence of all-cause dementia (ACD), Alzheimer disease (AD), and vascular dementia (VD).
METHODS
We performed a systematic review and meta-analysis of the Cochrane, PubMed, Embase, and Web of Science databases to identify longitudinal studies that examined associations between leisure activities and dementia. Relative risks (RRs) and 95% CIs were pooled using random-effects meta-analysis. Subgroup analyses were used to estimate potential effect modifiers. The study was registered with PROSPERO (CRD42019116857).
RESULTS
A total of 38 longitudinal studies, with 2,154,818 participants at baseline, 74,700 ACD cases, 2,848 AD cases, and 1,423 VD cases during follow-up, were included in the meta-analysis. The subgroup analyses showed that physical (RR 0.83, 95% CI 0.78-0.88), cognitive (RR 0.77; 95% CI 0.68-0.87), and social (RR 0.93; 95% CI 0.87-0.99) activities were associated with a decreased incidence of ACD. In addition, physical (RR 0.87; 95% CI 0.78-0.96) and cognitive (RR 0.66; 95% CI 0.52-0.85) activities were related to a reduced risk of AD. Physical activity (RR 0.67; 95% CI 0.53-0.85) was associated with a lower incidence of VD.
DISCUSSION
Our findings suggest that leisure activities are inversely associated with a risk of ACD, AD, and VD.
Topics: Humans; Dementia; Risk Factors; Alzheimer Disease; Dementia, Vascular; Leisure Activities
PubMed: 35948447
DOI: 10.1212/WNL.0000000000200929 -
JAMA Network Open Dec 2022In recent decades, there has been increased interest in the possible adverse neurological effects of 5α-reductase inhibitors (5-ARIs), which have been used mainly for...
IMPORTANCE
In recent decades, there has been increased interest in the possible adverse neurological effects of 5α-reductase inhibitors (5-ARIs), which have been used mainly for benign prostatic hyperplasia and androgenic alopecia. Numerous studies and reports have indicated associations of 5-ARIs with depression and suicide. However, most of these studies had methodological shortcomings, and very little is known about the potential association of 5-ARIs with dementia.
OBJECTIVE
To investigate the association of 5-ARI use with all-cause dementia, Alzheimer disease, vascular dementia, depression, and suicide.
DESIGN, SETTING, AND PARTICIPANTS
This Swedish register-based cohort study included 2 236 876 men aged 50 to 90 years between July 1, 2005, and December 31, 2018. Statistical analyses were performed from September 15, 2021, to May 25, 2022.
MAIN OUTCOMES AND MEASURES
A diagnosis of all-cause dementia, Alzheimer disease, vascular dementia, depression, or completed suicide.
EXPOSURES
A recorded prescription in the Swedish national prescription register of finasteride or dutasteride and duration of use.
RESULTS
Of 2 236 876 men (median age at the start of follow-up, 55 years [IQR, 50-65 years] and at treatment initiation, 73 years [IQR, 66-80 years]), 70 645 (3.2%) started finasteride treatment, and 8774 (0.4%) started dutasteride treatment. Men taking finasteride or dutasteride were at increased risk of all-cause dementia (finasteride: hazard ratio [HR], 1.22 [95% CI, 1.17-1.28]; dutasteride: HR, 1.10 [95% CI, 1.01-1.20]), Alzheimer disease (finasteride: HR, 1.20 [95% CI, 1.10-1.31]; dutasteride: HR, 1.28 [95% CI, 1.09-1.50]), vascular dementia (finasteride: HR, 1.44 [95% CI, 1.30-1.58]; dutasteride: HR, 1.31 [95% CI, 1.08-1.59]), and depression (finasteride: HR, 1.61 [95% CI, 1.48-1.75]; dutasteride: HR, 1.68 [95% CI, 1.43-1.96]). However, the magnitude of the association decreased over time, and the findings became statistically nonsignificant with continuous exposures over 4 years, except for depression, which showed a constant risk over time, with no differences between finasteride and dutasteride. In contrast, 5-ARIs were not associated with suicide (finasteride: HR, 1.22 [95% CI, 0.99-1.49]; dutasteride: HR, 0.98 [95% CI, 0.62-1.54]).
CONCLUSIONS AND RELEVANCE
This cohort study found that, while men receiving 5-ARI treatment showed a higher risk for dementia in the initial periods after starting treatment, the decreasing magnitude of the association over time suggested that the risk may be, entirely or in part, due to increased dementia detection among patients with benign prostate enlargement. Both finasteride and dutasteride were similarly associated with depression with a constant risk over time, while neither drug was associated with suicide. Prescribing clinicians and potential users should be aware of the possible risks for depression associated with 5-ARI use.
Topics: Humans; Male; 5-alpha Reductase Inhibitors; Alzheimer Disease; Cohort Studies; Dementia, Vascular; Depression; Dutasteride; Finasteride; Prostatic Hyperplasia; Retrospective Studies; Suicide; Antineoplastic Agents
PubMed: 36547981
DOI: 10.1001/jamanetworkopen.2022.48135 -
Annals of Neurology May 2020
Topics: Alzheimer Disease; Atherosclerosis; Dementia, Vascular; Humans
PubMed: 32154602
DOI: 10.1002/ana.25715