| 21. |
- Aldridge, Chad M., et al.
(författare)
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Genome-Wide Association Studies of 3 Distinct Recovery Phenotypes in Mild Ischemic Stroke
- 2024
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Ingår i: Neurology. - 1526-632X. ; 102:3
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVES: Stroke genetic research has made substantial progress in the past decade. Its recovery application, however, remains behind, in part due to its reliance on the modified Rankin Scale (mRS) score as a measure of poststroke outcome. The mRS does not map well to biological processes because numerous psychosocial factors drive much of what the mRS captures. Second, the mRS contains multiple disparate biological events into a single measure further limiting its use for biological discovery. This led us to investigate the effect of distinct stroke recovery phenotypes on genetic variation associations with Genome-Wide Association Studies (GWASs) by repurposing the NIH Stroke Scale (NIHSS) and its subscores. METHODS: In the Vitamin Intervention for Stroke Prevention cohort, we estimated changes in cognition, motor, and global impairments over 2 years using specific measures. We included genotyped participants with a total NIHSS score greater than zero at randomization and excluded those with recurrent stroke during the trial. A GWAS linear mixed-effects model predicted score changes, with participant as a random effect, and included initial score, age, sex, treatment group, and the first 5 ancestry principal components. RESULTS: In total, 1,270 participants (64% male) were included with a median NIHSS score of 2 (interquartile range [IQR] 1-3) and median age 68 (IQR 59-75) years. At randomization, 20% had cognitive deficits (NIHSS Cog-4 score >0) and 70% had ≥1 motor deficits (impairment score >1). At 2 years, these percentages improved to 7.2% with cognitive deficits and 30% with motor deficits. GWAS identified novel suggestive gene-impairment associations (p < 5e-6) for cognition (CAMK2D, EVX2, LINC0143, PTPRM, SGMS1, and SMAD2), motor (ACBD6, KDM4B, MARK4, PTPRS, ROBO1, and ROBO2), and global (MSR1 and ROBO2) impairments. DISCUSSION: Defining domain-specific stroke recovery phenotypes and using longitudinal clinical trial designs can help detect novel genes associated with chronic recovery. These data support the use of granular endpoints to identify genetic associations related to stroke recovery.
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| 22. |
- Anderson, Christopher D., et al.
(författare)
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Common Variants Within Oxidative Phosphorylation Genes Influence Risk of Ischemic Stroke and Intracerebral Hemorrhage
- 2013
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Ingår i: Stroke: a journal of cerebral circulation. - 1524-4628. ; 44:3, s. 612-619
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose-Previous studies demonstrated association between mitochondrial DNA variants and ischemic stroke (IS). We investigated whether variants within a larger set of oxidative phosphorylation (OXPHOS) genes encoded by both autosomal and mitochondrial DNA were associated with risk of IS and, based on our results, extended our investigation to intracerebral hemorrhage (ICH). Methods-This association study used a discovery cohort of 1643 individuals, a validation cohort of 2432 individuals for IS, and an extension cohort of 1476 individuals for ICH. Gene-set enrichment analysis was performed on all structural OXPHOS genes, as well as genes contributing to individual respiratory complexes. Gene-sets passing gene-set enrichment analysis were tested by constructing genetic scores using common variants residing within each gene. Associations between each variant and IS that emerged in the discovery cohort were examined in validation and extension cohorts. Results-IS was associated with genetic risk scores in OXPHOS as a whole (odds ratio [OR], 1.17; P=0.008) and complex I (OR, 1.06; P=0.050). Among IS subtypes, small vessel stroke showed association with OXPHOS (OR, 1.16; P=0.007), complex I (OR, 1.13; P=0.027), and complex IV (OR, 1.14; P=0.018). To further explore this small vessel association, we extended our analysis to ICH, revealing association between deep hemispheric ICH and complex IV (OR, 1.08; P=0.008). Conclusions-This pathway analysis demonstrates association between common genetic variants within OXPHOS genes and stroke. The associations for small vessel stroke and deep ICH suggest that genetic variation in OXPHOS influences small vessel pathobiology. Further studies are needed to identify culprit genetic variants and assess their functional consequences. (Stroke. 2013;44:612-619.)
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| 23. |
- Anderson, Christopher D., et al.
(författare)
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Genetic variants in CETP increase risk of intracerebral hemorrhage
- 2016
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Ingår i: Annals of Neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 80:5, s. 730-740
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: In observational epidemiologic studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH.METHODS: We performed 2 candidate-gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL-C as well as ICH risk.RESULTS: Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR] = 1.25, standard error [SE] = 0.06, p = 6.0 × 10(-4) ) with no heterogeneity across studies (I(2) = 0%). This association was replicated in patients of European ancestry (p = 0.03). A genetic score of CETP variants found to increase HDL-C by ∼2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR = 1.86, SE = 0.13, p = 1.39 × 10(-6) ).INTERPRETATION: Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted. Ann Neurol 2016;80:730-740.
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| 24. |
- Andersson, Anders, et al.
(författare)
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Hyperhomocysteinemia and changed plasma thiol redox status in chronic obstructive pulmonary disease
- 2001
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Ingår i: Clinical Chemistry and Laboratory Medicine. - 1434-6621. ; 39:3, s. 229-233
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Tidskriftsartikel (refereegranskat)abstract
- Reduced and total homocysteine, cysteine, glutathione and cysteinylglycine in plasma were investigated in 19 patients with chronic obstructive pulmonary disease and in 29 healthy subjects. The purpose was to examine the influence of pro-oxidant activity caused by the lung disease on the metabolism of homocysteine and other plasma thiols. We observed a decreased concentration of reduced glutathione and a decreased ratio of reduced/total glutathione in the patients compared to the healthy individuals, which supports the hypothesis of an association between free radicals and pathogenesis in some lung diseases. We also observed an increased total plasma homocysteine. The influence of a possible extracellular pro-oxidant activity on the concentration of total plasma homocysteine is discussed.
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| 25. |
- Andersson, Anders S, et al.
(författare)
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Vitamin supplementation normalizes total plasma homocysteine concentration but not plasma homocysteine redox status in patients with acute coronary syndromes and hyperhomocysteinemia.
- 2002
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Ingår i: Clinical Chemistry and Laboratory Medicine. - 1434-6621. ; 40:6, s. 554-558
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Tidskriftsartikel (refereegranskat)abstract
- Despite the growing evidence that elevated total homocysteine (tHcy) in plasma is a cardiovascular risk factor, the mechanism underlying the vascular injury is still unknown. Studies are difficult due to the fact that little is known about the formation of different homocysteine species in vivo. In the present study we have investigated the different fractions of tHcy in 21 patients with acute coronary syndromes and elevated concentration of plasma tHcy. A subgroup of the patients (n=16) was investigated before and after a 3 months study period with or without vitamin supplementation (folic acid 5 mg, pyridoxine 40 mg and cyanocobalamin 1 mg once daily). A major finding is that these patients had a lowered ratio (0.95%) between the concentration of reduced homocysteine (HcyH) and tHcy compared to controls (1.38%). A low ratio HcyH/tHcy in plasma in combination with elevated plasma tHcy concentrations might reflect increased oxidative activity or decreased reducing capacity in plasma from the patients. Another main finding in the present study is that, although vitamin supplementation of these patients normalized plasma tHcy, the ratio between HcyH and tHcy did not normalize. Since substantial evidence indicates that progression of arteriosclerosis is related to enhanced oxidant activity, the premature vascular disease associated with increased plasma tHcy concentration might be due to increased oxidative activity and the elevated plasma tHcy concentration may only reflect the increased oxidative stress.
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| 26. |
- Andgren, S, et al.
(författare)
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Time delay between symptom and surgery in patients with carotid artery stenosis.
- 2011
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Ingår i: Acta Neurologica Scandinavica. - : Hindawi Limited. - 1600-0404 .- 0001-6314. ; 124, s. 329-333
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Tidskriftsartikel (refereegranskat)abstract
- Andgren S, Sjöberg L, Norrving B, Lindgren A. Time delay between symptom and surgery in patients with carotid artery stenosis. Acta Neurol Scand: DOI: 10.1111/j.1600-0404.2010.01478.x. © 2011 John Wiley & Sons A/S. Objectives - Many severe strokes are preceded by warning signs such as a transient ischemic attack or stroke with minor deficits. Carotid endarterectomy (CEA) of a symptomatic carotid artery stenosis can prevent future strokes, but should be performed within 2 weeks after the initial symptom to maximize the benefit. The aim of this study was to determine the time delays between symptom and CEA. Methods- We performed a single center observational retrospective study at a tertiary stroke center. A total of 142 carotids in 139 patients with symptomatic stenoses between 2002 and 2006 were included. The main outcome measure was time between qualifying cerebrovascular symptom and CEA. Results - The median time between symptom and CEA was 26 days. The longest delays were between the last diagnostic examination and carotid conference, and between carotid conference and surgery. The median time was shorter for those who received emergency medical care (median 21 days) and for those who were admitted immediately to hospital (median 20 days). Conclusions - The time between symptom and surgery is often longer than desirable. There are several measures to improve the chain of procedures for patients with carotid artery stenosis. These may include omitting the formal carotid conference for uncomplicated cases and minimizing waiting time for surgery.
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| 27. |
- Appleton, Jason Philip, et al.
(författare)
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Improving the likelihood of neurology patients being examined using patient feedback
- 2015
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Ingår i: BMJ Quality Improvement Reports. - : BMJ. - 2050-1315. ; 4:1
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Tidskriftsartikel (refereegranskat)abstract
- We aimed to establish whether recall of elements of the neurological examination can be improved by use of a simple patient assessment score. In a previous study we demonstrated that in-patients referred to neurology at two United Kingdom (UK) hospitals were not fully examined prior to referral; we therefore designed a larger quality improvement report with 80% power to detect a 10% increase in tendon hammer or ophthalmoscope use following an educational intervention. In-patients referred to neurology over a four month period (in hospitals in the UK (10), Jordan (1), Sweden (2), and the United Arab Emirates (1)) were asked whether they recalled being examined with a tendon hammer (T), ophthalmoscope (O), and stethoscope (S) since admission. The results were disseminated to local medical teams using various techniques (including Grand Round presentations, email, posters, discounted equipment). Data were then collected for a further four month period post-intervention. Pre-intervention and post-intervention data were available for 11 centres with 407 & 391 patients in each arm respectively. Median age of patients was 51 (range 13-100) and 49 (range 16-95) years respectively, with 44.72% and 44.76% being male in each group. 264 patients (64.86%) recalled being examined with a tendon hammer in the pre-intervention arm, which significantly improved to 298 (76.21%) (p<0.001). Only 119 patients (29.24%) recollected examination with an ophthalmoscope pre-intervention, which significantly improved to 149 (38.11%)(p=0.009). The majority of patients (321 (78.87%)) pre-intervention recalled examination with a stethoscope, which significantly improved to 330 (84.4%) to a lesser extent (p=0.045). Results indicate that most patients are not fully examined prior to neurology referral yet a simple assessment score and educational intervention can improve recall of elements of the neurological examination and thus the likelihood of patients being examined neurologically. This is the largest and - to our knowledge - only study to assess this issue. This has implications for national neurological educators.
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| 28. |
- Appleton, Jason Philip, et al.
(författare)
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The TOS2 study: An international multi-centre audit assessing the standard of neurological examination
- 2015
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 1468-330X .- 0022-3050. ; 86:11
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Konferensbidrag (refereegranskat)abstract
- Having previously demonstrated that in-patients referred to neurology at two UK hospitals were not fully examined prior to referral, we designed an audit with 80% power to detect a 10% increase in tendon hammer or ophthalmoscope use following an educational intervention. In-patients referred to neurology over a 4 month period in the UK, Jordan, Sweden and the United Arab Emirates were asked whether they recalled examination with a Tendon hammer, Ophthalmoscope and Stethoscope since admission. Results were disseminated to local medical teams and data were collected for a further 4 months. Pre and post-intervention data were available for 11 centres with 407 and 391 patients in each arm. 264 patients (64.86%) recalled examination with a tendon hammer preintervention, which significantly improved to 298 (76.21%) (p
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| 29. |
- Arsava, E. M., et al.
(författare)
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The Causative Classification of Stroke system An international reliability and optimization study
- 2010
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Ingår i: Neurology. - 1526-632X. ; 75:14, s. 1277-1284
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Tidskriftsartikel (refereegranskat)abstract
- Background: Valid and reliable ischemic stroke subtype determination is crucial for well-powered multicenter studies. The Causative Classification of Stroke System (CCS, available at http://ccs.mgh.harvard.edu) is a computerized, evidence-based algorithm that provides both causative and phenotypic stroke subtypes in a rule-based manner. We determined whether CCS demonstrates high interrater reliability in order to be useful for international multicenter studies. Methods: Twenty members of the International Stroke Genetics Consortium from 13 centers in 8 countries, who were not involved in the design and development of the CCS, independently assessed the same 50 consecutive patients with acute ischemic stroke through reviews of abstracted case summaries. Agreement among ratings was measured by kappa statistic. Results: The kappa value for causative classification was 0.80 (95% confidence interval [ CI] 0.78-0.81) for the 5-subtype, 0.79 (95% CI 0.77-0.80) for the 8-subtype, and 0.70 (95% CI 0.69-0.71) for the 16-subtype CCS. Correction of a software-related factor that generated ambiguity improved agreement: kappa = 0.81 (95% CI 0.79-0.82) for the 5-subtype, 0.79 (95% CI 0.77-0.80) for the 8-subtype, and 0.79 (95% CI 0.78-0.80) for the 16-subtype CCS. The kappa value for phenotypic classification was 0.79 (95% CI 0.77-0.82) for supra-aortic large artery atherosclerosis, 0.95 (95% CI 0.93-0.98) for cardioembolism, 0.88 (95% CI 0.85-0.91) for small artery occlusion, and 0.79 (0.76-0.82) for other uncommon causes. Conclusions: CCS allows classification of stroke subtypes by multiple investigators with high reliability, supporting its potential for improving stroke classification in multicenter studies and ensuring accurate means of communication among different researchers, institutions, and eras. Neurology (R) 2010;75:1277-1284
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| 30. |
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