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Vascular cognitive impairment (VCI), including vascular dementia, is the second most common dementia after Alzheimer's disease. Despite its prevalence, the genetic etiology of sporadic VCI is largely unknown. We conducted a systematic review of all published genetic association studies of forms of sporadic VCI prior to 6 July 2012. An initial pool of 229 gene association studies yielded 104 papers (72 polymorphisms from 47 genes) that met inclusion criteria for analysis. Systematic meta-analysis was conducted on 6 polymorphisms (which had 3 or more published case-control cohorts from 69 papers) in the APOE, ACT, ACE, MTHFR, PON1, and PSEN-1 genes. Associations of increased risk for VCI were found for APOE ε4 (1.818 (95% CI = 1.611-2.053), p < 0.001; n = 3,554 cases, n = 12,277 controls) and MTHFR rs1801133 (1.323 (95% CI = 1.061-1.650) p = 0.013); n = 659 cases, n = 981 controls). There was marginal evidence of a protective effect for APOE ε2 (0.885 (95% CI = 0.783-0.999), p = 0.048; n = 3,320 cases, n = 10,786 controls). This systematic study of all published genetic association studies of sporadic VCI supports MTHFR and APOE as susceptibility genes for VCI. It also shows the utility of meta-analysis as a tool to identify potential candidate genes from numerous individual small-scale studies of diseases where sample recruitment may be limited for a variety of practical reasons. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) regulates systemic and cerebral blood flow and is dysregulated in dementia. The major aim of this study was to determine if RAS signalling is dysregulated in vascular dementia. We measured markers of RAS signalling in white matter underlying the frontal and occipital cortex in neuropathologically confirmed cases of vascular dementia (n = 42), Alzheimer's disease (n = 50), mixed AD/VaD (n = 50) and age-matched controls (n = 50). All cases were stratified according to small vessel disease (SVD) severity across both regions. ACE-1 and ACE-2 protein and activity was measured by ELISA and fluorogenic peptide assays respectively, and angiotensin peptide (Ang-II, Ang-III and Ang-(1-7)) levels were measured by ELISA. ACE-1 protein level and enzyme activity, and Ang-II and Ang-III, were elevated in the white matter in vascular dementia in relation to SVD severity. ACE-1 and Ang-II protein levels were inversely related to MAG:PLP1 ratio, a biochemical marker of brain tissue oxygenation that when reduced indicates cerebral hypoperfusion, in a subset of cases. ACE-2 level was elevated in frontal white matter in vascular dementia. Ang-(1-7) level was elevated across all dementia groups compared to age-matched controls but was not related to SVD severity. RAS signalling was not altered in the white matter in Alzheimer's disease. In the overlying frontal cortex, ACE-1 protein was reduced and ACE-2 protein increased in vascular dementia, whereas angiotensin peptide levels were unchanged. These data indicate that RAS signalling is dysregulated in the white matter in vascular dementia and may contribute to the pathogenesis of small vessel disease., (© 2024 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

The renin-angiotensin system (RAS) is dysregulated in Alzheimer's disease (AD). In this study, we have explored the hypothesis that an -age--related imbalance in brain RAS is a trigger for RAS dysregulation in AD. We characterized RAS gene expression in the frontal cortex from (i) a cohort of normal aging (n = 99, age range = 19-96 years) and (ii) a case-control cohort (n = 209) including AD (n = 66), mixed dementia (VaD + AD; n = 50), pure vascular dementia (VaD; n = 42), and age-matched controls (n = 51). The AD, mixed dementia, and age-matched controls were further stratified by Braak tangle stage (BS): BS0-II (n = 48), BSIII-IV (n = 44), and BSV-VI (n = 85). Gene expression was calculated by quantitative PCR (qPCR) for ACE1, AGTR1, AGTR2, ACE2, LNPEP, and MAS1 using the 2-∆∆Cq method, after adjustment for reference genes (RPL13 and UBE2D2) and cell-specific calibrator genes (NEUN, GFAP, PECAM). ACE1 and AGTR1, markers of classical RAS signaling, and AGTR2 gene expression were elevated in normal aging and gene expression in markers of protective downstream regulatory RAS signaling, including ACE2, MAS1, and LNPEP, were unchanged. In AD and mixed dementia, AGTR1 and AGTR2 gene expression were elevated in BSIII-IV and BSV-VI, respectively. MAS1 gene expression was reduced at BSV-VI and was inversely related to parenchymal Aβ and tau load. LNPEP gene expression was specifically elevated in VaD. These data provide novel insights into RAS signaling in normal aging and dementia., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Traumatic brain injury (TBI) is a major health concern and leading cause of death and disability in young adults in the United Kingdom and worldwide; however, there is a paucity of disease modifying therapies for the treatment of TBI. This review investigates the potential of the renin-angiotensin system (RAS) as a treatment pathway for TBI in adults. Relevant electronic databases were searched on December 18, 2019, and updated May 16, 2021. All English language articles with adult human or animal populations investigating RAS drugs as an intervention for TBI or reporting genetic evidence relevant to the RAS and TBI were screened. Eighteen pre-clinical randomized controlled trials (RCTs) ( n  = 2269) and two clinical cohort studies ( n  = 771) were included. Meta-analyses of six pre-clinical RCTs ( n  = 99) indicated that candesartan improved neurological function over the short term (< 7 days: standardized mean difference [SMD] 0.61, 95% confidence interval [CI] 0.19-1.03, I2 = 0%) and over the long term (≥ 7 days: SMD 1.06, 95% CI 0.38; 1.73, I2 = 0%) post-TBI. Findings were similar for most secondary outcomes. There was a suggestion of benefit from other RAS-targeting drugs, although evidence was limited because there were few small studies. There was insufficient evidence to enable strong assessment of these drugs on mortality post-TBI. We conclude that angiotensin-receptor blockers, especially candesartan, show positive outcomes post-TBI in pre-clinical studies with moderate quality of evidence (Grading of Recommendations Assessment, Development and Evaluation [GRADE]). More research into the effect of regulatory-RAS targeting drugs is needed. Clinical trials of candesartan following TBI are recommended, because there is strong and consistent evidence of neuroprotection shown by these pre-clinical studies.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.

Introduction: Progress in understanding and management of vascular cognitive impairment (VCI) has been hampered by lack of consensus on diagnosis, reflecting the use of multiple different assessment protocols. A large multinational group of clinicians and researchers participated in a two-phase Vascular Impairment of Cognition Classification Consensus Study (VICCCS) to agree on principles (VICCCS-1) and protocols (VICCCS-2) for diagnosis of VCI. We present VICCCS-2., Methods: We used VICCCS-1 principles and published diagnostic guidelines as points of reference for an online Delphi survey aimed at achieving consensus on clinical diagnosis of VCI., Results: Six survey rounds comprising 65-79 participants agreed guidelines for diagnosis of VICCCS-revised mild and major forms of VCI and endorsed the National Institute of Neurological Disorders-Canadian Stroke Network neuropsychological assessment protocols and recommendations for imaging., Discussion: The VICCCS-2 suggests standardized use of the National Institute of Neurological Disorders-Canadian Stroke Network recommendations on neuropsychological and imaging assessment for diagnosis of VCI so as to promote research collaboration., (Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Introduction: Numerous diagnostic criteria have tried to tackle the variability in clinical manifestations and problematic diagnosis of vascular cognitive impairment (VCI) but none have been universally accepted. These criteria have not been readily comparable, impacting on clinical diagnosis rates and in turn prevalence estimates, research, and treatment., Methods: The Vascular Impairment of Cognition Classification Consensus Study (VICCCS) involved participants (81% academic researchers) from 27 countries in an online Delphi consensus study. Participants reviewed previously proposed concepts to develop new guidelines., Results: VICCCS had a mean of 122 (98-153) respondents across the study and a 67% threshold to represent consensus. VICCCS redefined VCI including classification of mild and major forms of VCI and subtypes. It proposes new standardized VCI-associated terminology and future research priorities to address gaps in current knowledge., Discussion: VICCCS proposes a consensus-based updated conceptualization of VCI intended to facilitate standardization in research., (Copyright © 2016 the Alzheimer's Association. All rights reserved.)

There are no generally accepted protocols for post-mortem assessment in cases of suspected vascular cognitive impairment. Neuropathologists from seven UK centres have collaborated in the development of a set of vascular cognitive impairment neuropathology guidelines (VCING), representing a validated consensus approach to the post-mortem assessment and scoring of cerebrovascular disease in relation to vascular cognitive impairment. The development had three stages: (i) agreement on a sampling protocol and scoring criteria, through a series of Delphi method surveys; (ii) determination of inter-rater reliability for each type of pathology in each region sampled (Gwet's AC2 coefficient); and (iii) empirical testing and validation of the criteria, by blinded post-mortem assessment of brain tissue from 113 individuals (55 to 100 years) without significant neurodegenerative disease who had had formal cognitive assessments within 12 months of death. Fourteen different vessel and parenchymal pathologies were assessed in 13 brain regions. Almost perfect agreement (AC2 > 0.8) was found when the agreed criteria were used for assessment of leptomeningeal, cortical and capillary cerebral amyloid angiopathy, large infarcts, lacunar infarcts, microhaemorrhage, larger haemorrhage, fibrinoid necrosis, microaneurysms, perivascular space dilation, perivascular haemosiderin leakage, and myelin loss. There was more variability (but still reasonably good agreement) in assessment of the severity of arteriolosclerosis (0.45-0.91) and microinfarcts (0.52-0.84). Regression analyses were undertaken to identify the best predictors of cognitive impairment. Seven pathologies-leptomeningeal cerebral amyloid angiopathy, large infarcts, lacunar infarcts, microinfarcts, arteriolosclerosis, perivascular space dilation and myelin loss-predicted cognitive impairment. Multivariable logistic regression determined the best predictive models of cognitive impairment. The preferred model included moderate/severe occipital leptomeningeal cerebral amyloid angiopathy, moderate/severe arteriolosclerosis in occipital white matter, and at least one large infarct (area under the receiver operating characteristic curve 77%). The presence of 0, 1, 2 or 3 of these features resulted in predicted probabilities of vascular cognitive impairment of 16%, 43%, 73% or 95%, respectively. We have developed VCING criteria that are reproducible and clinically predictive. Assuming our model can be validated in an independent dataset, we believe that this will be helpful for neuropathologists in reporting a low, intermediate or high likelihood that cerebrovascular disease contributed to cognitive impairment.10.1093/brain/aww214&#95;video&#95;abstractaww214&#95;video&#95;abstract., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Vascular cognitive impairment (VCI), including its severe form, vascular dementia (VaD), is the second most common form of dementia. The genetic etiology of sporadic VCI remains largely unknown. We previously conducted a systematic review and meta-analysis of all published genetic association studies of sporadic VCI prior to 6 July 2012, which demonstrated that APOE (ɛ4, ɛ2) and MTHFR (rs1801133) variants were associated with susceptibility for VCI. De novo genotyping was conducted in a new independent relatively large collaborative European cohort of VaD (nmax = 549) and elderly non-demented samples (nmax = 552). Where available, genotype data derived from Illumina's 610-quad array for 1210 GERAD1 control samples were also included in analyses of genes examined. Associations were tested using the Cochran-Armitage trend test: MTHFR rs1801133 (OR = 1.36, 95% CI 1.16-1.58, p = <0.0001), APOE rs7412 (OR = 0.62, 95% CI 0.42-0.90, p = 0.01), and APOE rs429358 (OR = 1.59, 95% CI 1.17-2.16, p = 0.003). Association was also observed with APOE epsilon alleles; ɛ4 (OR = 1.85, 95% CI 1.35-2.52, p = <0.0001) and ɛ2 (OR = 0.67, 95% CI 0.46-0.98, p = 0.03). Logistic regression and Bonferroni correction in a subgroup of the cohort adjusted for gender, age, and population maintained the association of APOE rs429358 and ɛ4 allele.

Interest exists in identifying the factors that specifically contribute to the increased prevalence of cardiovascular disease observed in psychiatric disease. The apolipoprotein-E (APOE) gene codes for a protein that has a key role in metabolism of cholesterol and triglycerides, with increased levels of apoE found in specific areas of post-mortem schizophrenic brains. This study investigated whether apoE variants influence the prevalence of cardiovascular risk factors (obesity, diabetes and dyslipidaemia), in patients receiving antipsychotic treatment, due to extension of the risk seen in the general population, but also due to the role of the APOE gene in mediating antipsychotic-induced side effects. Seven polymorphisms (rs741780, rs483082, rs429358, rs7412, rs10119, rs439401 and rs405509) were genotyped in 427 American Caucasian patients who were either receiving, or had been prescribed risperidone. Our results support the hypothesis that APOE gene variants influence the prevalence of diabetes and possibly overweight in psychiatric patients. Unfortunately, due to the cross sectional nature of this study, the contribution of antipsychotic treatment was not determined. These associations warrant prospective study to assess interaction between APOE gene variants and the propensity of antipsychotics to induce cardiovascular risk factors.