Incidence of neurodegenerative and cerebrovascular diseases associated with antihypertensive drug classes.
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ABSTRACT:
SUBMITTER: Harrison PJ
PROVIDER: S-EPMC7611720 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundHypertension in midlife is associated with increased risk of Alzheimer disease and vascular dementia late in life. In addition, some antihypertensive drugs have been proposed to have cognitive benefits, independent of their effect on hypertension. Consequently, there is potential to repurpose antihypertensive drugs for the prevention of dementia. This study systematically compared seven antihypertensive drug classes for this purpose, using the Clinical Practice Research Datalink.MethodsWe assessed treatments for hypertension in an instrumental variable analysis to address potential confounding and reverse causation. We used physicians' prescribing preference as an ordinal instrument, defined by the physicians' last seven prescriptions. Participants considered were new antihypertensive users between 1996 and 2016, aged 40 and over.ResultsWe analyzed 849,378 patients, with total follow up of 5,497,266 patient-years. We estimated that β-adrenoceptor blockers and vasodilator antihypertensives conferred small protective effects-for example, β-adrenoceptor blockers were associated with 13 (95% confidence interval = 6, 20) fewer cases of any dementia per 1000 treated compared with other antihypertensives.ConclusionsWe estimated small differences in the effects of antihypertensive drug classes on dementia outcomes. We also show that the magnitude of the differences between drug classes is smaller than that previously reported. Future research should look to implement other causal analysis methods to address biases in conventional observational research, with the ultimate aim of triangulating the evidence concerning this hypothesis.
| S-EPMC7523578 | biostudies-literature
Project description:ObjectiveWe employed Mendelian randomization to explore whether the effects of blood pressure (BP) and BP-lowering through different antihypertensive drug classes on stroke risk vary by stroke etiology.MethodsWe selected genetic variants associated with systolic and diastolic BP and BP-lowering variants in genes encoding antihypertensive drug targets from genome-wide association studies (GWAS) on 757,601 individuals. Applying 2-sample Mendelian randomization, we examined associations with any stroke (67,162 cases; 454,450 controls), ischemic stroke and its subtypes (large artery, cardioembolic, small vessel stroke), intracerebral hemorrhage (ICH, deep and lobar), and the related small vessel disease phenotype of white matter hyperintensities (WMH).ResultsGenetic predisposition to higher systolic and diastolic BP was associated with higher risk of any stroke, ischemic stroke, and ICH. We found associations between genetically determined BP and all ischemic stroke subtypes with a higher risk of large artery and small vessel stroke compared to cardioembolic stroke, as well as associations with deep, but not lobar ICH. Genetic proxies for calcium channel blockers, but not β-blockers, were associated with lower risk of any stroke and ischemic stroke. Proxies for calcium channel blockers showed particularly strong associations with small vessel stroke and the related radiologic phenotype of WMH.ConclusionsThis study supports a causal role of hypertension in all major stroke subtypes except lobar ICH. We find differences in the effects of BP and BP-lowering through antihypertensive drug classes between stroke subtypes and identify calcium channel blockade as a promising strategy for preventing manifestations of cerebral small vessel disease.
| S-EPMC7455321 | biostudies-literature
Project description:Background: Homocysteine (Hcy) is a toxic amino acid and hyperhomocysteinemia (HHcy) was reported to be associated with both cerebrovascular disease and neurodegenerative disease. Our aim was to assess the causal link between plasma Hcy level and cerebrovascular and neurodegenerative diseases through a Mendelian randomization (MR) study. Methods: A two-sample MR study was performed to infer the causal link. We extracted the genetic variants (SNPs) associated with plasma Hcy level from a large genome-wide association study (GWAS) meta-analysis. The main MR analysis was performed using the inverse variance-weighted method. Additional analyses were further performed using MR-Egger intercept and Cochran's Q statistic to detect the heterogeneity or pleiotropy of our findings. Results: Thirteen Hcy-associated SNPs were selected as instrumental variables. The results showed evidence of a causal link between plasma Hcy level and ischemic stroke (IS) caused by small artery occlusion (SAS, OR = 1.329, 95% CI 1.047-1.612, p = 0.048). Meanwhile, there was no evidence of association between plasma Hcy level and other types of IS, transient ischemic attack (TIA), or neurodegenerative disease. The MR-Egger intercept test indicated no evidence of directional pleiotropy. Results of additional MR analysis indicated that blood pressure (BP) and type 2 diabetes mellitus (T2DM) serve as influencers in the association. Conclusion: The MR study found a little causal link between plasma Hcy level and SAS. The link is likely to be influenced by other risk factors like BP and T2DM.
| S-EPMC8047106 | biostudies-literature
Project description:Major depressive and bipolar disorders predispose to atherosclerosis, and there is accruing data from animal model, epidemiological, and genomic studies that commonly used antihypertensive drugs may have a role in the pathogenesis or course of mood disorders. In this study, we propose to determine whether antihypertensive drugs have an impact on mood disorders through the analysis of patients on monotherapy with different classes of antihypertensive drugs from a large hospital database of 525?046 patients with follow-up for 5 years. There were 144?066 eligible patients fulfilling the inclusion criteria: age 40 to 80 years old at time of antihypertensive prescription and medication exposure >90 days. The burden of comorbidity assessed by Charlson and Elixhauser scores showed an independent linear association with mood disorder diagnosis. The median time to hospital admission with mood disorder was 847 days for the 299 admissions (641?685 person-years of follow-up). Patients on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers had the lowest risk for mood disorder admissions, and compared with this group, those on ?-blockers (hazard ratio=2.11; [95% confidence interval, 1.12-3.98]; P=0.02) and calcium antagonists (2.28 [95% confidence interval, 1.13-4.58]; P=0.02) showed higher risk, whereas those on no antihypertensives (1.63 [95% confidence interval, 0.94-2.82]; P=0.08) and thiazide diuretics (1.56 [95% confidence interval, 0.65-3.73]; P=0.32) showed no significant difference. Overall, our exploratory findings suggest possible differential effects of antihypertensive medications on mood that merits further study: calcium antagonists and ?-blockers may be associated with increased risk, whereas angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may be associated with a decreased risk of mood disorders.
| S-EPMC5058642 | biostudies-literature
Project description:BackgroundNeurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis, Parkinson's disease (PD), spinal cerebellar ataxias, and spinal and bulbar muscular atrophy are described by slow and selective degeneration of neurons and axons in the central nervous system (CNS) and constitute one of the major challenges of modern medicine. Computeraided or in silico drug design methods have matured into powerful tools for reducing the number of ligands that should be screened in experimental assays.MethodsIn the present review, the authors provide a basic background about neurodegenerative diseases and in silico techniques in the drug research. Furthermore, they review the various in silico studies reported against various targets in neurodegenerative diseases, including homology modeling, molecular docking, virtual high-throughput screening, quantitative structure activity relationship (QSAR), hologram quantitative structure activity relationship (HQSAR), 3D pharmacophore mapping, proteochemometrics modeling (PCM), fingerprints, fragment-based drug discovery, Monte Carlo simulation, molecular dynamic (MD) simulation, quantum-mechanical methods for drug design, support vector machines, and machine learning approaches.ResultsDetailed analysis of the recently reported case studies revealed that the majority of them use a sequential combination of ligand and structure-based virtual screening techniques, with particular focus on pharmacophore models and the docking approach.ConclusionNeurodegenerative diseases have a multifactorial pathoetiological origin, so scientists have become persuaded that a multi-target therapeutic strategy aimed at the simultaneous targeting of multiple proteins (and therefore etiologies) involved in the development of a disease is recommended in future.
| S-EPMC6080098 | biostudies-literature
Project description:Dementia resulting from small vessel diseases (SVDs) of the brain is an emerging epidemic for which there is no treatment. Hypertension is the major risk factor for SVDs, but how hypertension damages the brain microcirculation is unclear. Here, we show that chronic hypertension in a mouse model progressively disrupts on-demand delivery of blood to metabolically active areas of the brain (functional hyperemia) through diminished activity of the capillary endothelial cell inward-rectifier potassium channel, Kir2.1. Despite similar efficacy in reducing blood pressure, amlodipine, a voltage-dependent calcium-channel blocker, prevented hypertension-related damage to functional hyperemia whereas losartan, an angiotensin II type 1 receptor blocker, did not. We attribute this drug class effect to losartan-induced aldosterone breakthrough, a phenomenon triggered by pharmacological interruption of the renin-angiotensin pathway leading to elevated plasma aldosterone levels. This hypothesis is supported by the finding that combining losartan with the aldosterone receptor antagonist eplerenone prevented the hypertension-related decline in functional hyperemia. Collectively, these data suggest Kir2.1 as a possible therapeutic target in vascular dementia and indicate that concurrent mineralocorticoid aldosterone receptor blockade may aid in protecting against late-life cognitive decline in hypertensive patients treated with angiotensin II type 1 receptor blockers.
| S-EPMC8439604 | biostudies-literature
Project description:Neurodegenerative diseases (NDs) including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease are incurable and affect millions of people worldwide. The development of treatments for this unmet clinical need is a major global research challenge. Computer-aided drug design (CADD) methods minimize the huge number of ligands that could be screened in biological assays, reducing the cost, time, and effort required to develop new drugs. In this review, we provide an introduction to CADD and examine the progress in applying CADD and other molecular docking studies to NDs. We provide an updated overview of potential therapeutic targets for various NDs and discuss some of the advantages and disadvantages of these tools.
| S-EPMC8124449 | biostudies-literature
Project description:BACKGROUND:Uncertainty remains about the optimal monotherapy for hypertension, with current guidelines recommending any primary agent among the first-line drug classes thiazide or thiazide-like diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, dihydropyridine calcium channel blockers, and non-dihydropyridine calcium channel blockers, in the absence of comorbid indications. Randomised trials have not further refined this choice. METHODS:We developed a comprehensive framework for real-world evidence that enables comparative effectiveness and safety evaluation across many drugs and outcomes from observational data encompassing millions of patients, while minimising inherent bias. Using this framework, we did a systematic, large-scale study under a new-user cohort design to estimate the relative risks of three primary (acute myocardial infarction, hospitalisation for heart failure, and stroke) and six secondary effectiveness and 46 safety outcomes comparing all first-line classes across a global network of six administrative claims and three electronic health record databases. The framework addressed residual confounding, publication bias, and p-hacking using large-scale propensity adjustment, a large set of control outcomes, and full disclosure of hypotheses tested. FINDINGS:Using 4·9 million patients, we generated 22?000 calibrated, propensity-score-adjusted hazard ratios (HRs) comparing all classes and outcomes across databases. Most estimates revealed no effectiveness differences between classes; however, thiazide or thiazide-like diuretics showed better primary effectiveness than angiotensin-converting enzyme inhibitors: acute myocardial infarction (HR 0·84, 95% CI 0·75-0·95), hospitalisation for heart failure (0·83, 0·74-0·95), and stroke (0·83, 0·74-0·95) risk while on initial treatment. Safety profiles also favoured thiazide or thiazide-like diuretics over angiotensin-converting enzyme inhibitors. The non-dihydropyridine calcium channel blockers were significantly inferior to the other four classes. INTERPRETATION:This comprehensive framework introduces a new way of doing observational health-care science at scale. The approach supports equivalence between drug classes for initiating monotherapy for hypertension-in keeping with current guidelines, with the exception of thiazide or thiazide-like diuretics superiority to angiotensin-converting enzyme inhibitors and the inferiority of non-dihydropyridine calcium channel blockers. FUNDING:US National Science Foundation, US National Institutes of Health, Janssen Research & Development, IQVIA, South Korean Ministry of Health & Welfare, Australian National Health and Medical Research Council.
| S-EPMC6924620 | biostudies-literature
Project description:Neurodegenerative diseases of the central nervous system are characterised by pathogenetic cellular and molecular changes in specific areas of the brain that lead to the dysfunction and/or loss of explicit neuronal populations. Despite exhibiting different clinical profiles and selective neuronal loss, common features such as abnormal protein deposition, dysfunctional cellular transport, mitochondrial deficits, glutamate excitotoxicity and inflammation are observed in most, if not all, neurodegenerative disorders, suggesting converging pathways of neurodegeneration. We have generated comparative genome-wide gene expression data for Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, multiple sclerosis, Parkinson’s disease and schizophrenia using an extensive cohort of well characterised post-mortem CNS tissues. The analysis of whole genome expression patterns across these major disorders offers an outstanding opportunity not only to look into exclusive disease specific changes, but more importantly to uncover potential common molecular pathogenic mechanisms that could be targeted for therapeutic gain. Surprisingly, no dysregulated gene that passed our selection criteria was found in common across all 6 diseases using our primary method of analysis. However, 61 dysregulated genes were shared when comparing five and four diseases. Our analysis indicates firstly the involvement of common neuronal homeostatic, survival and synaptic plasticity pathways. Secondly, we report changes to immunoregulatory and immunomodulatory pathways in all diseases. Our secondary method of analysis confirmed significant up-regulation of a number of genes in diseases presenting degeneration and showed that somatostatin was downregulated in all 6 diseases. The latter is supportive of a general role for neuroinflammation in the pathogenesis and/or response to neurodegeneration. Unravelling the detailed nature of the molecular changes regulating inflammation in the CNS is key to the development of novel therapeutic approaches for these chronic conditions. A total of 113 cases were selected retrospectively on the basis of a confirmed clinical and neuropathological diagnosis and snap-frozen brain blocks were provided by various tissue banks within the BrainNet Europe network. Total RNA was extracted from dissected snap-frozen tissue (< 100 mg) by the individual laboratories according to a BNE optimised common protocol using the RNeasy(r) tissue lipid mini kit (Qiagen Ltd, Crawley, UK) according to the manufacturer's instructions, and was stored at -80C until further use. Gene expression analysis was performed on the RNA samples using the Illumina whole genome HumanRef8 v2 BeadChip (Illumina, London, UK). All the labelling and hybridisation of the samples was carried out in a single experiment by the Imperial College group to reduce the technical variability. RNA samples were prepared for array analysis using the Illumina TotalPrep(tm)-96 RNA Amplification Kit (Ambion/Applied Biosystems, Warrington, UK). Finally, the BeadChips we re scanned using the Illumina BeadArray Reader. The data was extracted using BeadStudio 3.2 (Illumina). Data normalisation and gene differential expression analyses were conducted using the Rosetta error models available in the Rosetta Resolver(r) system (Rosetta Biosoftware, Seattle, Wa, USA). Two samples presented very low signal expression most likely due to hybridization problems and did not pass the quality control test. They are not represented here. One of the 2 samples was a replicate, therefore there was loss of only 1 case bringing the grand total of cases used to 112 (total of samples of 118 including 6 replicates).
2011-01-29 | E-GEOD-26927 | biostudies-arrayexpress
Project description:Change in empathy is an increasingly recognised symptom of neurodegenerative diseases and contributes to caregiver burden and patient distress. Empathy impairment has been associated with brain atrophy but its relationship to white matter hyperintensities (WMH) is unknown. We aimed to investigate the relationships amongst WMH, brain atrophy, and empathy deficits in neurodegenerative and cerebrovascular diseases. Five hundred thirteen participants with Alzheimer's disease/mild cognitive impairment, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), Parkinson's disease, or cerebrovascular disease (CVD) were included. Empathy was assessed using the Interpersonal Reactivity Index. WMH were measured using a semi-automatic segmentation and FreeSurfer was used to measure cortical thickness. A heterogeneous pattern of cortical thinning was found between groups, with FTD showing thinning in frontotemporal regions and CVD in left superior parietal, left insula, and left postcentral. Results from both univariate and multivariate analyses revealed that several variables were associated with empathy, particularly cortical thickness in the fronto-insulo-temporal and cingulate regions, sex (female), global cognition, and right parietal and occipital WMH. Our results suggest that cortical atrophy and WMH may be associated with empathy deficits in neurodegenerative and cerebrovascular diseases. Future work should consider investigating the longitudinal effects of WMH and atrophy on empathy deficits in neurodegenerative and cerebrovascular diseases.
| S-EPMC9213606 | biostudies-literature