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Nutrition Reviews Aug 2023In preclinical Alzheimer's disease (AD), the brain gradually becomes insulin resistant. As a result, brain glucose utilization is compromised, causing a cellular energy... (Meta-Analysis)
Meta-Analysis
CONTEXT
In preclinical Alzheimer's disease (AD), the brain gradually becomes insulin resistant. As a result, brain glucose utilization is compromised, causing a cellular energy deficit that leads to the accumulation of free radicals, which increases inflammation and damages neurons. When glucose utilization is impaired, ketone bodies offer an alternative energy source. Ketone bodies are synthesized from fats, obtained from either the diet or adipose tissue. Dietary medium-chain fatty acids (MCFAs), which are preferentially metabolized into ketone bodies, have the potential to supply the insulin-resistant brain with energy.
OBJECTIVE
This systematic review and meta-analysis aims to review the effect of MCFA supplements on circulating ketone bodies and cognition in individuals with subjective cognitive decline, mild cognitive impairment, and AD.
DATA SOURCES
A comprehensive search of electronic databases was performed on August 12, 2019, to retrieve all publications meeting the inclusion criteria. Alerts were then set to identify any publications after the search date up until January 31, 2021.
DATA EXTRACTION
Data were extracted by 2 authors and assessed by a third. In total, 410 publications were identified, of which 16 (n = 17 studies) met the inclusion criteria.
DATA ANALYSIS
All studies assessing change in levels of blood ketone bodies due to MCFA supplementation (n = 12) reported a significant increase. Cognition outcomes (measured in 13 studies), however, varied, ranging from no improvement (n = 4 studies) to improvement (n = 8 studies) or improvement only in apolipoprotein E allele 4 (APOE ε4) noncarriers (n = 2 studies). One study reported an increase in regional cerebral blood flow in APOE ε4 noncarriers and another reported an increase in energy metabolism in the brain.
CONCLUSION
MCFA supplementation increases circulating ketone body levels, resulting in increased brain energy metabolism. Further research is required to determine whether this MCFA-mediated increase in brain energy metabolism improves cognition.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO registration number CRD42019146967.
Topics: Humans; Alzheimer Disease; Apolipoprotein E4; Fatty Acids; Ketone Bodies; Insulin; Glucose
PubMed: 36633304
DOI: 10.1093/nutrit/nuac104 -
Sleep Medicine Jan 2023The glymphatic system is thought to be responsible for waste clearance in the brain. As it is primarily active during sleep, different components of sleep, subjective... (Review)
Review
OBJECTIVE
The glymphatic system is thought to be responsible for waste clearance in the brain. As it is primarily active during sleep, different components of sleep, subjective sleep quality, and sleep patterns may contribute to glymphatic functioning. This systematic review aimed at exploring the effect of sleep components, sleep quality, and sleep patterns on outcomes associated with the glymphatic system in healthy adults.
METHODS
PubMed®, Scopus, and Web of Science were searched for studies published in English until December 2021. Articles subjectively or objectively investigating sleep components (total sleep time, time in bed, sleep efficiency, sleep onset latency, wake-up after sleep onset, sleep stage, awakenings), sleep quality, or sleep pattern in healthy individuals, on outcomes associated with glymphatic system (levels of amyloid-β, tau, α-synuclein; cerebrospinal fluid, perivascular spaces; apolipoprotein E) were selected.
RESULTS
Out of 8359 records screened, 51 studies were included. Overall, contradictory findings were observed according to different sleep assessment method. The most frequently assessed sleep parameters were total sleep time, sleep quality, and sleep efficiency. No association was found between sleep efficiency and amyloid-β, and between slow-wave activity and tau. Most of the studies did not find any correlation between total sleep time and amyloid-β nor tau level. Opposing results correlated sleep quality with amyloid-β and tau.
CONCLUSIONS
This review highlighted inconsistent results across the studies; as such, the specific association between the glymphatic system and sleep parameters in healthy adults remains poorly understood. Due to the heterogeneity of sleep assessment methods and the self-reported data representing the majority of the observations, future studies with universal study design and sleep methodology in healthy individuals are advocated.
Topics: Adult; Humans; Amyloid beta-Peptides; Brain; Glymphatic System; Sleep; Sleep Wake Disorders
PubMed: 36481512
DOI: 10.1016/j.sleep.2022.11.012 -
The Journal of Gene Medicine Mar 2023In order to clarify the role of the maternal apolipoprotein E (ApoE) genotype and the risk of recurrent pregnancy loss (RPL), we herein performed an updated systematic... (Meta-Analysis)
Meta-Analysis
BACKGROUND
In order to clarify the role of the maternal apolipoprotein E (ApoE) genotype and the risk of recurrent pregnancy loss (RPL), we herein performed an updated systematic review and meta-analysis to reevaluate the evidence on this association.
METHODS
A comprehensive literature search was performed on PubMed, Web of Knowledge and the Cochrane library up to September 2022. Methodological study quality was assessed using the Newcastle-Ottawa Scale and the credibility of significant pooled odds ratios (ORs) was estimated by the false positive report probability and the Bayesian false discovery probability.
RESULTS
Twelve studies published from 2009 to 2022 fulfilled the inclusion criteria. In the overall analysis, the ε4 allele was found to confer an increased risk of RPL compared to the ε3 allele (OR 1.60, 95% CI 1.00-2.55, p = 0.049) and women carrying the ApoE ε4 allele displayed a higher risk of RPL compared with those carrying the ε2 and ε3 alleles (OR 1.75, 95% CI 1.06-2.87, p = 0.028). Subgroup analysis based on subjects' ethnicity revealed that these associations were restricted to the Asian population (ε4 allele vs. ε3 allele, OR 5.93, 95% CI 1.79-19.61, p = 0.004; ε4 allele carriers vs. carriers of ε2 and ε3 alleles, OR 8.42, 95% CI 1.47-48.12, p = 0.017). None of the associations detected were found to be noteworthy under false positive report probability or Bayesian false discovery probability at a prior probability of 0.001.
CONCLUSIONS
This updated meta-analysis highlights an association between maternal ApoE genotype and RPL risk in Asians, but not in Caucasians. Further case-control studies are warranted in women of Asian ancestry to exclude the possibility of false-positive findings.
Topics: Female; Humans; Abortion, Habitual; Apolipoproteins E; Bayes Theorem; Genotype; Heterozygote
PubMed: 36479790
DOI: 10.1002/jgm.3467 -
Stroke Jan 2023There are limited data regarding the prevalence of distinct clinical, neuroimaging and genetic markers among patients diagnosed with cerebral amyloid angiopathy-related... (Meta-Analysis)
Meta-Analysis
BACKGROUND
There are limited data regarding the prevalence of distinct clinical, neuroimaging and genetic markers among patients diagnosed with cerebral amyloid angiopathy-related inflammation (CAA-ri). We sought to determine the prevalence of clinical, radiological, genetic and cerebrospinal fluid biomarker findings in patients with CAA-ri.
METHODS
A systematic review and meta-analysis of published studies including patients with CAA-ri was conducted to determine the prevalence of clinical, neuroimaging, genetic and cerebrospinal fluid biomarker findings. Subgroup analyses were performed based on (1) prospective or retrospective study design and (2) CAA-ri diagnosis with or without available biopsy. We pooled the prevalence rates using random-effects models and assessed the heterogeneity using Cochran-Q and I-statistics.
RESULTS
We identified 4 prospective and 17 retrospective cohort studies comprising 378 patients with CAA-ri (mean age, 71.5 years; women, 52%). The pooled prevalence rates were as follows: cognitive decline at presentation 70% ([95% CI, 54%-84%]; I=82%), focal neurological deficits 55% ([95% CI, 40%-70%]; I=82%), encephalopathy 54% ([95% CI, 39%-68%]; I=43%), seizures 37% ([95% CI, 27%-49%]; I=65%), headache 31% ([95% CI, 22%-42%]; I=58%), T2/fluid-attenuated inversion recovery-hyperintense white matter lesions 98% ([95% CI, 93%-100%]; I=44%), lobar cerebral microbleeds 96% ([95% CI, 92%-99%]; I=25%), gadolinium enhancing lesions 54% ([95% CI, 42%-66%]; I=62%), cortical superficial siderosis 51% ([95% CI, 34%-68%]; I=77%) and lobar macrohemorrhage 40% ([95% CI, 11%-73%]; I=88%). The prevalence rate of the ApoE (Apolipoprotein E) ε4/ε4 genotype was 34% ([95% CI, 17%-53%]; I=76%). Subgroup analyses demonstrated no differences in these prevalence rates based on study design and diagnostic strategy.
CONCLUSIONS
Cognitive decline was the most common clinical feature. Hyperintense T2/fluid-attenuated inversion recovery white matter lesions and lobar cerebral microbleeds were by far the most prevalent neuroimaging findings. Thirty-four percent of patients with CAA-ri have homozygous ApoE ε4/ε4 genotype and scarce data exist regarding the cerebrospinal fluid biomarkers and its significance in these patients.
Topics: Humans; Female; Aged; Retrospective Studies; Genetic Markers; Prospective Studies; Cerebral Hemorrhage; Cerebral Amyloid Angiopathy; Neuroimaging; Inflammation; Magnetic Resonance Imaging
PubMed: 36453271
DOI: 10.1161/STROKEAHA.122.040671 -
Neuropsychology Review Dec 2023First-degree relatives of individuals with late-onset Alzheimer's disease (LOAD) are at increased risk for developing dementia, yet the associations between family... (Meta-Analysis)
Meta-Analysis Review
First-degree relatives of individuals with late-onset Alzheimer's disease (LOAD) are at increased risk for developing dementia, yet the associations between family history of LOAD and cognitive dysfunction remain unclear. In this quantitative review, we provide the first meta-analysis on the cognitive profile of unaffected first-degree blood relatives of LOAD-affected individuals compared to controls without a family history of LOAD. A systematic literature search was conducted in PsycINFO, PubMed /MEDLINE, and Scopus. We fitted a three-level structural equation modeling meta-analysis to control for non-independent effect sizes. Heterogeneity and risk of publication bias were also investigated. Thirty-four studies enabled us to estimate 218 effect sizes across several cognitive domains. Overall, first-degree relatives (n = 4,086, mean age = 57.40, SD = 4.71) showed significantly inferior cognitive performance (Hedges' g = -0.16; 95% CI, -0.25 to -0.08; p < .001) compared to controls (n = 2,388, mean age = 58.43, SD = 5.69). Specifically, controls outperformed first-degree relatives in language, visuospatial and verbal long-term memory, executive functions, verbal short-term memory, and verbal IQ. Among the first-degree relatives, APOE ɛ4 carriership was associated with more significant dysfunction in cognition (g = -0.24; 95% CI, -0.38 to -0.11; p < .001) compared to non-carriers (g = -0.14; 95% CI, -0.28 to -0.01; p = .04). Cognitive test type was significantly associated with between-group differences, accounting for 65% (R = .6499) of the effect size heterogeneity in the fitted regression model. No evidence of publication bias was found. The current findings provide support for mild but robust cognitive dysfunction in first-degree relatives of LOAD-affected individuals that appears to be moderated by cognitive domain, cognitive test type, and APOE ɛ4.
Topics: Humans; Middle Aged; Alzheimer Disease; Cognition; Cognitive Dysfunction; Cognition Disorders; Neuropsychological Tests; Apolipoproteins E
PubMed: 36057684
DOI: 10.1007/s11065-022-09555-2 -
Ageing Research Reviews Nov 2022Alzheimer's disease (AD) involves a series of pathological changes and some biomarkers were reported to assist in monitoring and predicting disease progression before... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Alzheimer's disease (AD) involves a series of pathological changes and some biomarkers were reported to assist in monitoring and predicting disease progression before the emergence of clinical symptoms. We aimed to identify prospective biomarkers and quantify their effect on AD progression.
METHODS
PubMed, EMBASE and Web of Science databases were searched for prospective cohort studies published up to October 2021. Eligible studies were included, and the available data were extracted. Meta-analyses were conducted based on random-effect models. Relative risk (RR) with 95% confidence interval (CI) was adopted as the final effect size.
RESULTS
Totally 48,769 articles were identified, of which 84 studies with 20 prospective biomarkers were included in meta-analyses. In the present study, 15 biomarkers were associated with AD progression, comprising CSF Aβ42 (RR=2.49, 95%CI=1.68-3.69), t-tau (RR=1.88, 95%CI=1.49-2.37), p-tau (RR=1.74, 95%CI=1.37-2.21), tau/Aβ42 ratio (RR=5.11, 95%CI=2.01-13.00); peripheral blood Aβ42/Aβ40 (RR=1.26, 95%CI=1.05-1.51), t-tau (RR=1.33, 95%CI=1.08-1.64), NFL (RR=1.75, 95%CI=1.07-2.87); whole, left and right hippocampal volume (HV) (whole: RR=1.65, 95%CI=1.39-1.95; left: RR=2.60, 95%CI=1.02-6.64; right: RR=1.43, 95%CI=1.23-1.66), entorhinal cortex (EC) volume (RR=1.69, 95%CI=1.24-2.30), medial temporal lobe atrophy (MTA) (RR=1.52, 95%CI=1.33-1.74), 18 F-FDG PET (RR=2.24, 95%CI=1.29-3.89), 11 C-labeled Pittsburgh Compound B PET (11 C-PIB PET) (RR=3.91, 95%CI=1.06-14.41); APOE ε4 (RR=2.16, 1.83-2.55). A total of 70 articles were included in the qualitative review, in which 61 biomarkers were additionally associated with AD progression.
CONCLUSION
CSF Aβ42, t-tau, p-tau, tau/Aβ42; peripheral blood t-tau, Aβ42/Aβ40, NFL; whole, left and right HV, EC volume, MTA, 18 F-FDG PET, 11 C-PIB PET; APOE ε4 may be promising prospective biomarkers for AD progression.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E4; Atrophy; Biomarkers; Humans; Prospective Studies; tau Proteins
PubMed: 35905816
DOI: 10.1016/j.arr.2022.101699 -
Multiple Sclerosis and Related Disorders Sep 2022Multiple sclerosis (MS) is a neuroinflammatory disorder commonly seen in young female adults. Cognitive impairment is one of the widespread symptoms of MS. In recent... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Multiple sclerosis (MS) is a neuroinflammatory disorder commonly seen in young female adults. Cognitive impairment is one of the widespread symptoms of MS. In recent years multiple studies sought the possible risk factors for MS-related cognitive deficit. Apolipoprotein E (ApoE) genotype is one of the genetic factors which correlated significantly with cognitive status and it is a well-known risk factor for Alzheimer's Disease. In this systematic review and meta-analysis, we collected the current evidence to evaluate the association between the ApoE genotype and the cognitive outcomes in patients with MS.
METHOD
Results of searches through Medline via PubMed, Scopus, and ISI web of science, as well as hand searching, were screened in the title/abstract and full-text stages. English observational studies in which the association between ApoE and cognitive outcomes, in patients with MS were included in this systematic review. Animal studies, conference abstracts, reviews, clinical trials, case reports, letters and withdrawn studies, were not included. Risk of bias was assessed using the Joanna Briggs Institute (JBI) critical appraisal tools and the meta-analysis was conducted with Comprehensive Meta-Analysis (CMA.2) software. The numbers of patients with impairment in both ApoE4+ and ApoE4- groups were utilized for the calculation of the odds ratios (ORs) with 95% confidence intervals (CI) and a 0.05 level of significance for p-value.
RESULT
Out of 224 results of searching, 13 studies met the eligibility criteria and were included in our systematic review, and 5 of them were included in the quantitative synthesis. Eleven studies assessed the cognitive status of patients with MS in two groups of ApoE4+ and ApoE4- while 2 rests, reported the rate of ApoE4+ patients in cognitively impaired and non-impaired groups. The phenotype of MS was only Relapsing-remitting multiple sclerosis (RRMS) in 3 studies and in the other 10 studies, it was a mixture of RRMS, clinically isolated syndrome (CIS), and progressive MS. Most of the reports did not find a significant association between ApoE genotype and cognitive outcomes in patients with MS. Contrary to the expectations, patients in ApoE4- group were more likely to have impairment in Judgment of Line Orientation (JLO) (OR: 0.405; 95% CI: 0.173 to 0.949, p-value:0.038), while ApoE4+ patients had more rate of impairment in SRT (OR:1.901; 95%CI: 1.237 to 2.920; p-value:0.003). Appropriate identifying and dealing with cofounding factors were the most common source of bias in our included studies.
CONCLUSION
ApoE may have a domain-specific association with cognitive impairment in MS patients. ApoE4 patients had more delayed responses to stimuli, but the rate of impaired visuospatial perception is lower in these patients. Based on the current evidence, there is a doubt about the clinical significance of this association.
Topics: Apolipoprotein E4; Apolipoproteins E; Cognition; Cognitive Dysfunction; Female; Genotype; Humans; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting
PubMed: 35803087
DOI: 10.1016/j.msard.2022.104011 -
PloS One 2022Although advanced age and presence of comorbidities significantly impact the variation observed in the clinical symptoms of COVID-19, it has been suggested that genetic... (Meta-Analysis)
Meta-Analysis
Although advanced age and presence of comorbidities significantly impact the variation observed in the clinical symptoms of COVID-19, it has been suggested that genetic variants may also be involved in the disease. Thus, the aim of this study was to perform a systematic review with meta-analysis of the literature to identify genetic polymorphisms that are likely to contribute to COVID-19 pathogenesis. Pubmed, Embase and GWAS Catalog repositories were systematically searched to retrieve articles that investigated associations between polymorphisms and COVID-19. For polymorphisms analyzed in 3 or more studies, pooled OR with 95% CI were calculated using random or fixed effect models in the Stata Software. Sixty-four eligible articles were included in this review. In total, 8 polymorphisms in 7 candidate genes and 74 alleles of the HLA loci were analyzed in 3 or more studies. The HLA-A*30 and CCR5 rs333Del alleles were associated with protection against COVID-19 infection, while the APOE rs429358C allele was associated with risk for this disease. Regarding COVID-19 severity, the HLA-A*33, ACE1 Ins, and TMPRSS2 rs12329760T alleles were associated with protection against severe forms, while the HLA-B*38, HLA-C*6, and ApoE rs429358C alleles were associated with risk for severe forms of COVID-19. In conclusion, polymorphisms in the ApoE, ACE1, TMPRSS2, CCR5, and HLA loci appear to be involved in the susceptibility to and/or severity of COVID-19.
Topics: Apolipoproteins E; COVID-19; Genetic Predisposition to Disease; HLA-A Antigens; Humans; Polymorphism, Genetic
PubMed: 35793369
DOI: 10.1371/journal.pone.0270627 -
Frontiers in Psychiatry 2022Resilience is broadly defined as the ability to maintain or regain functioning in the face of adversity and is influenced by both environmental and genetic factors. The...
Resilience is broadly defined as the ability to maintain or regain functioning in the face of adversity and is influenced by both environmental and genetic factors. The identification of specific genetic factors and their biological pathways underpinning resilient functioning can help in the identification of common key factors, but heterogeneities in the operationalisation of resilience have hampered advances. We conducted a systematic review of genetic variants associated with resilience to enable the identification of general resilience mechanisms. We adopted broad inclusion criteria for the definition of resilience to capture both human and animal model studies, which use a wide range of resilience definitions and measure very different outcomes. Analyzing 158 studies, we found 71 candidate genes associated with resilience. OPRM1 (Opioid receptor mu 1), NPY (neuropeptide Y), CACNA1C (calcium voltage-gated channel subunit alpha1 C), DCC (deleted in colorectal carcinoma), and FKBP5 (FKBP prolyl isomerase 5) had both animal and human variants associated with resilience, supporting the idea of shared biological pathways. Further, for OPRM1, OXTR (oxytocin receptor), CRHR1 (corticotropin-releasing hormone receptor 1), COMT (catechol-O-methyltransferase), BDNF (brain-derived neurotrophic factor), APOE (apolipoprotein E), and SLC6A4 (solute carrier family 6 member 4), the same allele was associated with resilience across divergent resilience definitions, which suggests these genes may therefore provide a starting point for further research examining commonality in resilience pathways.
PubMed: 35669264
DOI: 10.3389/fpsyt.2022.840120 -
Frontiers in Aging Neuroscience 2022Alzheimer's disease (AD) is a devastating neurodegenerative disorder with no cure, and available treatments are only able to postpone the progression of the disease....
BACKGROUND AND PURPOSE
Alzheimer's disease (AD) is a devastating neurodegenerative disorder with no cure, and available treatments are only able to postpone the progression of the disease. Mild cognitive impairment (MCI) is considered to be a transitional stage preceding AD. Therefore, prediction models for conversion from MCI to AD are desperately required. These will allow early treatment of patients with MCI before they develop AD. This study performed a systematic review and meta-analysis to summarize the reported risk prediction models and identify the most prevalent factors for conversion from MCI to AD.
METHODS
We systematically reviewed the studies from the databases of PubMed, CINAHL Plus, Web of Science, Embase, and Cochrane Library, which were searched through September 2021. Two reviewers independently identified eligible articles and extracted the data. We used the Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modeling Studies (CHARMS) checklist for the risk of bias assessment.
RESULTS
In total, 18 articles describing the prediction models for conversion from MCI to AD were identified. The dementia conversion rate of elderly patients with MCI ranged from 14.49 to 87%. Models in 12 studies were developed using the data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). C-index/area under the receiver operating characteristic curve (AUC) of development models were 0.67-0.98, and the validation models were 0.62-0.96. MRI, apolipoprotein E genotype 4 (APOE4), older age, Mini-Mental State Examination (MMSE) score, and Alzheimer's Disease Assessment Scale cognitive (ADAS-cog) score were the most common and strongest predictors included in the models.
CONCLUSION
In this systematic review, many prediction models have been developed and have good predictive performance, but the lack of external validation of models limited the extensive application in the general population. In clinical practice, it is recommended that medical professionals adopt a comprehensive forecasting method rather than a single predictive factor to screen patients with a high risk of MCI. Future research should pay attention to the improvement, calibration, and validation of existing models while considering new variables, new methods, and differences in risk profiles across populations.
PubMed: 35493941
DOI: 10.3389/fnagi.2022.840386