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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 -
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 -
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 -
Preventive Nutrition and Food Science Dec 2023Plant sterols/stanols are effective cholesterol-lowering agents. However, it is unclear whether the apolipoprotein E () genetic variants influence it. We investigated... (Review)
Review
Plant sterols/stanols are effective cholesterol-lowering agents. However, it is unclear whether the apolipoprotein E () genetic variants influence it. We investigated whether genetic variants modulate the responses of blood lipids to dietary intervention plant sterols/stanols in adults and if the intervention dose and duration, as well as the age and status of participants, influence this effect. Randomized clinical trials were identified by searching databases in the Cochrane Library. Random-effect models were used to estimate the pooled effect size of each outcome of interest total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein cholesterol, and triglycerides. Meta-regression and subgroup analysis were used to investigate the effects of potential modifiers on the outcomes of interest. Eleven articles were selected from 3,248 retrieved abstracts. Plant sterol/stanol intervention was associated with a more significant reduction in LDL levels in the E3 group [-0.251 mmol/L; 95% confidence interval (95% CI), -0.488 to -0.015] compared with both the E4 and E2 groups. In E4 carriers, the plant sterol/stanol intervention dose and duration resulted in a larger decrease in LDL levels (-0.088027 mmol/L; 95% CI, -0.154690 to -0.021364). In conclusion, genetic variants affected the response of blood LDL levels to supplementation with plant sterols/stanols, as individuals with E3 variant showed significantly decreased LDL levels compared with the other genotypes. However, future studies recruiting participants according to their genetic variants are needed to confirm our conclusion.
PubMed: 38188084
DOI: 10.3746/pnf.2023.28.4.377 -
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 -
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 -
Association of apolipoprotein E genotypes with epilepsy risk: A systematic review and meta-analysis.Epilepsy & Behavior : E&B Sep 2019The objective of this study was to identify the association between certain genotypes or alleles of the APOE (Apolipoprotein E) gene and the epilepsy risk. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The objective of this study was to identify the association between certain genotypes or alleles of the APOE (Apolipoprotein E) gene and the epilepsy risk.
METHODS
All studies on human APOE genotypes associated with epilepsy were included. Separate meta-analyses were conducted between the patients with epilepsy and the control group from the following three aspects: ε4 carriers or ε2 carriers vs ε3/ε3 (the ε2/ε4 genotype was excluded), ε4 carriers vs ε2 carriers, and five genotypes vs ε3/ε3. The subgroup analysis was conducted on the ethnicity, the control group was healthy or not, and type of epilepsy.
RESULTS
Nine studies with 2210 individuals were included. Compared with ε3/ε3 genotype, ε4 carriers increased the epilepsy risk (odds ratios [ORs]: 1.27; 95% confidence intervals [CI]: 1.01 to 1.59; P = 0.042), while ε2 carriers had no association with epilepsy risk (OR: 0.88; 95% CI: 0.66 to 1.18; P = 0.184). The risk of epilepsy was 1.45 times greater in ε4 carriers compared with ε2 carriers (OR: 1.45; 95% CI: 1.02 to 2.04; P = 0.037). When the number of APOE ε4 allele increased, the ORs increased progressively (no ε4 alleles, OR: 0.88, 95% CI: 0.66 to 1.18; one ε4 allele, OR: 1.25, 95% CI: 0.99 to 1.57; two ε4 alleles, OR: 1.84, 95% CI: 0.83 to 4.10). Apolipoprotein E ε4 carriers had a higher epilepsy risk in the population without primary diseases (OR: 1.43; 95% CI: 1.09 to 1.88), and a higher risk in Asian populations (OR: 1.67; 95% CI: 1.12 to 2.49).
CONCLUSIONS
Apolipoprotein E ε4 allele genotype was associated with an increased epilepsy risk, which was more prominent in the Asian and the population without primary diseases. These findings may be used to guide the directions of prevention and treatment on epilepsy. Larger clinical studies are needed.
Topics: Alleles; Apolipoproteins E; Asian People; Epilepsy; Genetic Predisposition to Disease; Genotype; Heterozygote; Humans; Risk Factors
PubMed: 31299529
DOI: 10.1016/j.yebeh.2019.06.015 -
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 -
European Archives of Psychiatry and... Aug 2021The objective is to understand genetic predisposition to delirium. Following PRISMA guidelines, we undertook a systematic review of studies involving delirium and... (Meta-Analysis)
Meta-Analysis
The objective is to understand genetic predisposition to delirium. Following PRISMA guidelines, we undertook a systematic review of studies involving delirium and genetics in the databases of Pubmed, Scopus, Cochrane Library and PsycINFO, and performed a meta-analysis when appropriate. We evaluated 111 articles, of which 25 were finally included in the analysis. The studies were assessed by two independent researchers for methodological quality using the Downs and Black Tool and for genetic analysis quality. We performed a meta-analysis of 10 studies of the Apolipoprotein E (APOE) gene, obtaining no association with the presence of delirium (LOR 0.18, 95% CI - 0.10-0.47, p = 0.21). Notably, only 5 out of 25 articles met established criteria for genetic studies (good quality) and 6 were of moderate quality. Seven studies found an association with APOE4, the dopamine transporter gene SCL6A3, dopamine receptor 2 gene, glucocorticoid receptor, melatonin receptor and mitochondrial DNA haplotypes. One genome-wide association study found two suggestive long intergenic non-coding RNA genes. Five studies found no association with catechol-o-methyltransferase, melatonin receptor or several interleukins genes. The studies were heterogenous in establishing the presence of delirium. Future studies with large samples should further specify the delirium phenotype and deepen our understanding of interactions between genes and other biological factors.
Topics: Delirium; Genetic Predisposition to Disease; Humans
PubMed: 33779822
DOI: 10.1007/s00406-021-01255-x -
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