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Alzheimer's & Dementia : the Journal of... Jan 2023The primary aim of this paper is to improve the clinical interpretation of white matter hyperintensities (WMHs) and provide an overarching summary of methodological... (Meta-Analysis)
Meta-Analysis
White matter hyperintensities and longitudinal cognitive decline in cognitively normal populations and across diagnostic categories: A meta-analysis, systematic review, and recommendations for future study harmonization.
INTRODUCTION
The primary aim of this paper is to improve the clinical interpretation of white matter hyperintensities (WMHs) and provide an overarching summary of methodological approaches, allowing researchers to design future studies targeting current knowledge gaps.
METHODS
A meta-analysis and systematic review was performed investigating associations between baseline WMHs and longitudinal cognitive outcomes in cognitively normal populations, and populations with mild cognitive impairment (MCI), Alzheimer's disease (AD), and stroke.
RESULTS
Baseline WMHs increase the risk of cognitive impairment and dementia across diagnostic categories and most consistently in MCI and post-stroke populations. Apolipoprotein E (APOE) genotype and domain-specific cognitive changes relating to strategic anatomical locations, such as frontal WMH and executive decline, represent important considerations. Meta-analysis reliability was assessed using multiple methods of estimation, and results suggest that heterogeneity in study design and reporting remains a significant barrier.
DISCUSSION
Recommendations and future directions for study of WMHs are provided to improve cross-study comparison and translation of research into consistent clinical interpretation.
Topics: Humans; White Matter; Reproducibility of Results; Magnetic Resonance Imaging; Cognitive Dysfunction; Alzheimer Disease
PubMed: 35319162
DOI: 10.1002/alz.12642 -
Disease Markers 2022Rising studies indicate that the apolipoprotein E (APOE) gene is related to the susceptibility of ischemic stroke (IS). However, certain consensus is limited by the lack... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Rising studies indicate that the apolipoprotein E (APOE) gene is related to the susceptibility of ischemic stroke (IS). However, certain consensus is limited by the lack of a large sample size of researches. This meta-analysis was performed to explore the potential association between the APOE gene and IS.
METHODS
To identify relevant case control studies in English publications by October 2020, we searched PubMed, Embase, Web of Science, and the Cochrane Library. Pooled odds ratios (ORs) with fixed- or random-effect models and corresponding 95% confidence intervals (CIs) were calculated to analyze potential associations.
RESULTS
A total of 55 researches from 32 countries containing 12207 IS cases and 27742 controls were included. The association between APOE gene 4 mutation and IS was confirmed (4 vs. 3 allele: pooled OR = 1.374, 95% CI, 1.214-1.556; 2/4 vs. 3/3: pooled OR = 1.233, 95% CI, 1.056-1.440; 3/4 vs. 3/3: pooled OR = 1.340, 95% CI, 1.165-1.542; 4/4 vs. 3/3: pooled OR = 1.833, 95% CI, 1.542-2.179; and APOE 4 carriers vs. non-4 carriers: pooled OR = 1.377; 95% CI, 1.203-1.576). Interestingly, APOE 4 mutation showed a dose-response correlation with IS risk (4/4 vs. 2/4: pooled OR = 1.625; 95% CI, 1.281-2.060; 4/4 vs. 3/4: pooled OR = 1.301; 95% CI, 1.077-1.571). Similar conclusions were drawn in the small artery disease (SAD) subtype, but not in large artery atherosclerosis (LAA) or in cardioaortic embolism (CE), by subgroup analysis.
CONCLUSIONS
These observations reveal that specific APOE 4 mutation was significantly associated with the risk of IS in a dose-dependent manner, while APOE 4 mutation was related to SAD subtype onset without a cumulative effect.
Topics: Apolipoprotein E4; Humans; Ischemic Stroke; Polymorphism, Genetic; Risk Factors
PubMed: 35154509
DOI: 10.1155/2022/1407183 -
Frontiers in Aging Neuroscience 2021Possession of one or two e4 alleles of the apolipoprotein E () gene is associated with cognitive decline and dementia risk. Some evidence suggests that physical activity...
INTRODUCTION
Possession of one or two e4 alleles of the apolipoprotein E () gene is associated with cognitive decline and dementia risk. Some evidence suggests that physical activity may benefit carriers of the e4 allele differently.
METHOD
We conducted a systematic review and meta-analysis of studies which assessed differences in the association between physical activity and: lipid profile, Alzheimer's disease pathology, brain structure and brain function in healthy adults. Searches were carried out in PubMed, SCOPUS, Web of Science and PsycInfo.
RESULTS
Thirty studies were included from 4,896 papers screened. Carriers of the e4 allele gained the same benefit from physical activity as non-carriers on most outcomes. For brain activation, e4 carriers appeared to gain a greater benefit from physical activity on task-related and resting-state activation and resting-state functional connectivity compared to non-carriers. analysis identified possible compensatory mechanisms allowing e4 carriers to maintain cognitive function.
DISCUSSION
Though there is evidence suggesting physical activity may benefit e4 carriers differently compared to non-carriers, this may vary by the specific brain health outcome, perhaps limited to brain activation. Further research is required to confirm these findings and elucidate the mechanisms.
PubMed: 35153725
DOI: 10.3389/fnagi.2021.815439 -
Acta Neuropathologica Communications Jan 2022The initiation, anatomic pattern, and extent of tau spread in traumatic brain injury (TBI), and the mechanism by which TBI leads to long-term tau pathology, remain...
Association between single moderate to severe traumatic brain injury and long-term tauopathy in humans and preclinical animal models: a systematic narrative review of the literature.
BACKGROUND
The initiation, anatomic pattern, and extent of tau spread in traumatic brain injury (TBI), and the mechanism by which TBI leads to long-term tau pathology, remain controversial. Some studies suggest that moderate to severe TBI is sufficient to promote tau pathology; however, others suggest that it is simply a consequence of aging. We therefore conducted a systematic narrative review of the literature addressing whether a single moderate to severe head injury leads to long-term development of tauopathy in both humans and animal models.
METHODS
Studies considered for inclusion in this review assessed a single moderate to severe TBI, assessed tau pathology at long-term timepoints post-injury, comprised experimental or observational studies, and were peer-reviewed and published in English. Databases searched included: PUBMED, NCBI-PMC, EMBASE, Web of Science, Academic Search Premiere, and APA Psychnet. Search results were uploaded to Covidence®, duplicates were removed, and articles underwent an abstract and full-text screening process. Data were then extracted and articles assessed for risk of bias.
FINDINGS
Of 4,150 studies screened, 26 were eligible for inclusion, of which 17 were human studies, 8 were preclinical animal studies, and 1 included both human and preclinical animal studies. Most studies had low to moderate risk of bias. Most human and animal studies (n = 12 and 9, respectively) suggested that a single moderate to severe TBI resulted in greater development of long-term tauopathy compared to no history of head injury. This conclusion should be interpreted with caution, however, due to several limitations: small sample sizes; inconsistencies in controlling for confounding factors that may have affected tau pathology (e.g., family history of dementia or neurological illnesses, apolipoprotein E genotype, etc.), inclusion of mostly males, and variation in reporting injury parameters.
INTERPRETATION
Results indicate that a single moderate to severe TBI leads to greater chronic development of tauopathy compared to no history of head injury. This implies that tau pathology induced may not be transient, but can progressively develop over time in both humans and animal models. Targeting these tau changes for therapeutic intervention should be further explored to elucidate if disease progression can be reversed or mitigated.
Topics: Animals; Brain; Brain Injuries, Traumatic; Disease Models, Animal; Humans; Tauopathies
PubMed: 35101132
DOI: 10.1186/s40478-022-01311-0 -
JAMA Neurology Mar 2022After more than a decade of research and development of clinical trials testing anti-β-amyloid monoclonal antibodies (mAbs), extensive experience has been gained... (Review)
Review
IMPORTANCE
After more than a decade of research and development of clinical trials testing anti-β-amyloid monoclonal antibodies (mAbs), extensive experience has been gained regarding the effects of these treatments in patients with Alzheimer disease (AD). On the verge of an expected large-scale introduction in the clinical setting after the recent US Food and Drug Administration approval of aducanumab, shared knowledge regarding amyloid-related imaging abnormalities (ARIAs) is of paramount importance.
OBJECTIVE
To summarize available evidence on ARIAs from randomized clinical trials (RCTs) testing anti-β-amyloid mAbs in patients with AD and to provide a comprehensive update about risk factors, clinical correlates, and implications for withholding and reinitiating treatment.
EVIDENCE REVIEW
In this systematic review, a literature search of MEDLINE/PubMed, Embase, and Cochrane Library and a search of ClinicalTrials.gov were conducted through September 15, 2021. Publications describing RCTs, secondary analyses of RCT data, and case reports of ARIAs were included. Strengths of clinical data were graded according to the Oxford Centre for Evidence-Based Medicine.
FINDINGS
Twenty-two RCTs, 11 secondary analyses of RCTs, and 1 case report, including in total 15 508 adult patients (8483 women [54.7%]; mean [SD] age, 69.6 [8.3] years) were selected for inclusion. Signal alterations that included parenchymal edema and sulcal effusion leading to transient hyperintensities on fluid-attenuated inversion recovery and T2-weighted sequences were termed ARIA-E, whereas those consisting of hemosiderin deposits, including parenchymal microhemorrhages and leptomeningeal superficial siderosis, were termed ARIA-H. Apolipoprotein E (ApoE) ε4 genotype was the main risk factor for both ARIA types; ARIA-E incidence was further associated with treatment dose, affecting the 55% of ApoE ε4 carriers in the high-dose aducanumab treatment group. Both ARIA types manifested early during study course, and symptomatic cases accounted for the 6.1% to 39.3% of ARIA-E cases at higher treatment doses across RCTs, whereas ARIA-H cases were generally asymptomatic. Most ARIA-E cases resolved with treatment withholding, although corticosteroid administration was required anecdotally. ARIA-E recurrence after dose reinitiation or adjustment varied from 13.8% to 25.6% across RCTs.
CONCLUSIONS AND RELEVANCE
Evidence suggests that ARIAs are frequent, mostly asymptomatic collateral events of amyloid-modifying therapies, highlighting the need for standardized clinical and neuroradiological management protocols in real-world clinical settings.
Topics: Aged; Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Amyloidogenic Proteins; Amyloidosis; Apolipoprotein E4; Female; Humans; Male
PubMed: 35099507
DOI: 10.1001/jamaneurol.2021.5205 -
Cerebrovascular Diseases (Basel,... 2022Previous studies reported inconsistent results regarding associations between apolipoprotein E (APOE) polymorphism and clinical outcomes after ischemic stroke (IS),... (Meta-Analysis)
Meta-Analysis
BACKGROUNDS
Previous studies reported inconsistent results regarding associations between apolipoprotein E (APOE) polymorphism and clinical outcomes after ischemic stroke (IS), intracerebral hemorrhage (ICH), or subarachnoid hemorrhage (SAH). Thus, the study was designed to make a systematic review and meta-analysis regarding the association between APOE polymorphism and clinical outcome after IS, ICH, and SAH.
METHODS
To identify studies eligible for this meta-analysis, we searched for articles published before August 2021 in the databases (PubMed, Web of Science, and Google Scholar). We used STATA 12.0 software to compute hazard ratios (HRs) and their 95% confidence intervals (CIs) regarding APOE polymorphism and clinical outcome after IS, ICH, and SAH.
RESULTS
Meta-analysis showed no significant association between APOE polymorphism and functional outcome after IS with fixed effects models (ε4 carrier vs. non-ε4 carrier: HR, 1.00; 95% CI: 0.83-1.21, I2 = 29.4%, p = 0.183; ε2 carrier vs. non-ε2 carrier: HR, 0.92; 95% CI: 0.72-1.16, I2 = 15.6%, p = 0.307). Meta-analysis showed that ICH patients carrying ε4 allele have increased risk of poor outcome in Caucasian population with fixed effects models (ε4 carrier vs. non-ε4 carrier: HR, 1.75; 95% CI: 1.19-2.57, I2 = 0.0%, p = 0.543). Meta-analysis showed no significant association between APOE polymorphism and functional outcomes after SAH with random effects models (ε4 carrier vs. non-ε4 carrier: HR, 1.51; 95% CI: 0.80-2.84, I2 = 57.1%, p = 0.022).
CONCLUSIONS
In conclusion, the present study demonstrated APOE ε4 carriers show worse functional outcomes after ICH, but not after IS or SAH. More large-scale studies were critical to explore the association between APOE polymorphism and clinical outcome after IS, ICH, and SAH.
Topics: Apolipoproteins E; Cerebral Hemorrhage; Genetic Predisposition to Disease; Genotype; Hemorrhagic Stroke; Humans; Ischemic Stroke; Subarachnoid Hemorrhage
PubMed: 34915479
DOI: 10.1159/000520053 -
The Journal of Nutrition, Health & Aging 2021Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease. The strongest genetic risk factor for sporadic AD is carriage of the ε4 allele of the...
Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease. The strongest genetic risk factor for sporadic AD is carriage of the ε4 allele of the Apolipoprotein E (APOE) gene. Strategies to slow the progression of AD, including dietary interventions, may be modified by the pathogenic effect of this polymorphism. Our objective in this review was to determine the extent and quality of the literature investigating how dietary factors and interventions interact with the APOE ε4 genotype to impact cognitive decline in AD. To that end, we performed a systematic scoping review of published English-language articles involving human subjects. We found evidence suggesting that adherence to a Mediterranean diet may reduce cognitive decline among APOE ε4 carriers, whereas ketogenic agents appear to be ineffective. Diets high in saturated fats may be particularly harmful for APOE ε4 carriers. We identified several topics, including the use of ω-3 fatty acid and antioxidant supplements, for which additional high level evidence is needed.
Topics: Alleles; Alzheimer Disease; Apolipoprotein E4; Cognitive Dysfunction; Diet; Genotype; Humans; Neurodegenerative Diseases
PubMed: 34866144
DOI: 10.1007/s12603-021-1705-4 -
Neuropathology and Applied Neurobiology Apr 2022The pathological processes leading to synapse loss, neuronal loss, brain atrophy and gliosis in Alzheimer's disease (AD) and their relation to vascular disease and... (Review)
Review
The pathological processes leading to synapse loss, neuronal loss, brain atrophy and gliosis in Alzheimer's disease (AD) and their relation to vascular disease and immunological changes are yet to be fully explored. Amyloid-β (Aβ) aggregation, vascular damage and altered immune response interact at the blood-brain barrier (BBB), affecting the brain endothelium and fuelling neurodegeneration. The aim of the present systematic literature review was to critically appraise and to summarise the published evidence on the clinical correlations and pathophysiological concepts of BBB damage in AD, focusing on human data. The PubMed, Cochrane, Medline and Embase databases were searched for original research articles, systematic reviews and meta-analyses, published in English language from 01/2000 to 07/2021, using the keywords Alzheimer*, amyloid-β or β-amyloid or abeta and BBB. This review shows that specific changes of intercellular structures, reduced expression of transendothelial carriers, induction of vasoactive mediators and activation of both astroglia and monocytes/macrophages characterise BBB damage in human AD and AD models. BBB dysfunction on magnetic resonance imaging takes place early in the disease course in AD-specific brain regions. The toxic effects of Aβ and apolipoprotein E (ApoE) are likely to induce a non-cerebral-amyloid-angiopathy-related degeneration of endothelial cells, independently of cerebrovascular disease; however, some of the observed structural changes may just arise with age. Small vessel disease, ApoE, loss of pericytes, proinflammatory signalling and cerebral amyloid angiopathy enhance BBB damage. Novel therapeutic approaches for AD, including magnetic resonance-guided focused ultrasound, aim to open the BBB, potentially leading to an improved drainage of Aβ along perivascular channels and increased elimination from the brain. In vitro treatments with ApoE-modifying agents yielded promising effects on modulating BBB function. Reducing cardiovascular risk factors represents one of the most promising interventions for dementia prevention at present. However, further research is needed to elucidate the connection of BBB damage and tau pathology, the role of proinflammatory mediators in draining macromolecules and cells from the cerebral parenchyma, including their contribution to cerebral amyloid angiopathy. Improved insight into these pathomechanisms may allow to shed light on the role of Aβ deposition as a primary versus a secondary event in the complex pathogenesis of AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Blood-Brain Barrier; Brain; Cerebral Amyloid Angiopathy; Endothelial Cells; Humans
PubMed: 34823269
DOI: 10.1111/nan.12782 -
The European Respiratory Journal Mar 2022Obstructive sleep apnoea and the related intermittent hypoxia (IH) are widely recognised as risk factors for incident cardiovascular diseases. Numerous studies support... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Obstructive sleep apnoea and the related intermittent hypoxia (IH) are widely recognised as risk factors for incident cardiovascular diseases. Numerous studies support the deleterious vascular impact of IH in rodents but an overall interpretation is challenging owing to heterogeneity in rodent species investigated and the severity and duration of IH exposure. To clarify this major issue, we conducted a systematic review and meta-analysis to quantify the impact of IH on systemic artery structure and function depending on the different IH exposure designs.
METHODS
We searched PubMed, Embase and Web of Science, and included 125 articles in a meta-analysis, among them 112 using wild-type rodents and 13 using apolipoprotein E knockout (ApoE) mice. We used the standardised mean difference (SMD) to compare results between studies.
RESULTS
IH significantly increased mean arterial pressure (+13.90 (95% CI 11.88-15.92) mmHg), and systolic and diastolic blood pressure. Meta-regressions showed that mean arterial pressure change was associated with strain and year of publication. IH altered vasodilation in males but not in females and increased endothelin-1-induced but not phenylephrine-induced vasoconstriction. Intima-media thickness significantly increased upon IH exposure (SMD 1.10 (95% CI 0.58-1.62); absolute values +5.23 (2.81-7.84) µm). This increase was observed in mice but not in rats and was negatively associated with age. Finally, IH increased atherosclerotic plaque size in ApoE mice (SMD 1.08 (95% CI 0.80-1.37)).
CONCLUSIONS
Our meta-analysis established that IH, independently of other confounders, has a strong effect on vascular structure and physiology. Our findings support the interest of identifying and treating sleep apnoea in routine cardiology practice.
Topics: Animals; Blood Pressure; Carotid Intima-Media Thickness; Disease Models, Animal; Female; Humans; Hypoxia; Male; Mice; Rats; Rodentia
PubMed: 34413154
DOI: 10.1183/13993003.00866-2021 -
Journal of Alzheimer's Disease : JAD 2021The global race-dependent association of Alzheimer's disease (AD) and apolipoprotein E (APOE) genotype is not well understood. Transethnic analysis of APOE could clarify... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The global race-dependent association of Alzheimer's disease (AD) and apolipoprotein E (APOE) genotype is not well understood. Transethnic analysis of APOE could clarify the role of genetics in AD risk across populations.
OBJECTIVE
This study aims to determine how race and APOE genotype affect the risks for AD.
METHODS
We performed a systematic search of PubMed, Embase, Web of Science, and the Cochrane Library since 1993 to Aug 25, 2020. A total of 10,395 reports were identified, and 133 were eligible for analysis with data on 77,402 participants. Studies contained AD clinical diagnostic and APOE genotype data. Homogeneous data sets were pooled in case-control analyses. Odds ratios and 95% confidence intervals for developing AD were calculated for populations of different races and APOE genotypes.
RESULTS
The proportion of APOE genotypes and alleles differed between populations of different races. Results showed that APOEɛ4 was a risk factor for AD, whereas APOEɛ2 protected against it. The effects of APOEɛ4 and ɛ2 on AD risk were distinct in various races, and they were substantially attenuated among Black people. Sub-group analysis found a higher frequency of APOEɛ4/ɛ4 and lower frequency of APOEɛ3/ɛ3 among early-onset AD than late-onset AD in a combined group and different races.
CONCLUSION
Our meta-analysis suggests that the association of APOE genotypes and AD differ among races. These results enhance our understanding of APOE-related risk for AD across race backgrounds and provide new insights into precision medicine for AD.
Topics: Alleles; Alzheimer Disease; Apolipoprotein E2; Apolipoprotein E4; Apolipoproteins E; Genotype; Humans; Racial Groups
PubMed: 34334408
DOI: 10.3233/JAD-210549