Amyloid pathology and vascular risk are associated with distinct patterns of cerebral white matter hyperintensities: A multicenter study in 3132 memory clinic patients.

INTRODUCTION: White matter hyperintensities (WMH) are associated with key dementia etiologies, in particular arteriolosclerosis and amyloid pathology. We aimed to identify WMH locations associated with vascular risk or cerebral amyloid-ß1-42 (Aß42)-positive status. METHODS: Individual patient data (n = 3,132; mean age 71.5 ± 9 years; 49.3% female) from 11 memory clinic cohorts were harmonized. WMH volumes in 28 regions were related to a vascular risk compound score (VRCS) and Aß42 status (based on cerebrospinal fluid or amyloid positron emission tomography), correcting for age, sex, study site, and total WMH volume. RESULTS: VRCS was associated with WMH in anterior/superior corona radiata (B = 0.034/0.038, p < 0.001), external capsule (B = 0.052, p < 0.001), and middle cerebellar peduncle (B = 0.067, p < 0.001), and Aß42-positive status with WMH in posterior thalamic radiation (B = 0.097, p < 0.001) and splenium (B = 0.103, p < 0.001). DISCUSSION: Vascular risk factors and Aß42 pathology have distinct signature WMH patterns. This regional vulnerability may incite future studies into how arteriolosclerosis and Aß42 pathology affect the brain's white matter. HIGHLIGHTS: Key dementia etiologies may be associated with specific patterns of white matter hyperintensities (WMH). We related WMH locations to vascular risk and cerebral Aß42 status in 11 memory clinic cohorts. Aß42 positive status was associated with posterior WMH in splenium and posterior thalamic radiation. Vascular risk was associated with anterior and infratentorial WMH. Amyloid pathology and vascular risk have distinct signature WMH patterns.

Sex Differences in Poststroke Cognitive Impairment: A Multicenter Study in 2343 Patients With Acute Ischemic Stroke.

BACKGROUND: Poststroke cognitive impairment (PSCI) occurs in about half of stroke survivors. Cumulative evidence indicates that functional outcomes of stroke are worse in women than men. Yet it is unknown whether the occurrence and characteristics of PSCI differ between men and women. METHODS: Individual patient data from 9 cohorts of patients with ischemic stroke were harmonized and pooled through the Meta-VCI-Map consortium (n=2343, 38% women). We included patients with visible symptomatic infarcts on computed tomography/magnetic resonance imaging and cognitive assessment within 15 months after stroke. PSCI was defined as impairment in ≥1 cognitive domains on neuropsychological assessment. Logistic regression analyses were performed to compare men to women, adjusted for study cohort, to obtain odds ratios for PSCI and individual cognitive domains. We also explored sensitivity and specificity of cognitive screening tools for detecting PSCI, according to sex (Mini-Mental State Examination, 4 cohorts, n=1814; Montreal Cognitive Assessment, 3 cohorts, n=278). RESULTS: PSCI was found in 51% of both women and men. Men had a lower risk of impairment of attention and executive functioning (men: odds ratio, 0.76 [95% CI, 0.61-0.96]), and language (men: odds ratio, 0.67 [95% CI, 0.45-0.85]), but a higher risk of verbal memory impairment (men: odds ratio, 1.43 [95% CI, 1.17-1.75]). The sensitivity of Mini-Mental State Examination (<25) for PSCI was higher for women (0.53) than for men (0.27; P=0.02), with a lower specificity for women (0.80) than men (0.96; P=0.01). Sensitivity and specificity of Montreal Cognitive Assessment (<26.) for PSCI was comparable between women and men (0.91 versus 0.86; P=0.62 and 0.29 versus 0.28; P=0.86, respectively). CONCLUSIONS: Sex was not associated with PSCI occurrence but affected domains differed between men and women. The latter may explain why sensitivity of the Mini-Mental State Examination for detecting PSCI was higher in women with a lower specificity compared with men. These sex differences need to be considered when screening for and diagnosing PSCI in clinical practice.

White Matter Hyperintensity Volume and Poststroke Cognition: An Individual Patient Data Pooled Analysis of 9 Ischemic Stroke Cohort Studies.

BACKGROUND: White matter hyperintensities (WMH) are associated with cognitive dysfunction after ischemic stroke. Yet, uncertainty remains about affected domains, the role of other preexisting brain injury, and infarct types in the relation between WMH burden and poststroke cognition. We aimed to disentangle these factors in a large sample of patients with ischemic stroke from different cohorts. METHODS: We pooled and harmonized individual patient data (n=1568) from 9 cohorts, through the Meta VCI Map consortium (www.metavcimap.org). Included cohorts comprised patients with available magnetic resonance imaging and multidomain cognitive assessment <15 months poststroke. In this individual patient data meta-analysis, linear mixed models were used to determine the association between WMH volume and domain-specific cognitive functioning (Z scores; attention and executive functioning, processing speed, language and verbal memory) for the total sample and stratified by infarct type. Preexisting brain injury was accounted for in the multivariable models and all analyses were corrected for the study site as a random effect. RESULTS: In the total sample (67 years [SD, 11.5], 40% female), we found a dose-dependent inverse relationship between WMH volume and poststroke cognitive functioning across all 4 cognitive domains (coefficients ranging from -0.09 [SE, 0.04, P=0.01] for verbal memory to -0.19 [SE, 0.03, P<0.001] for attention and executive functioning). This relation was independent of acute infarct volume and the presence of lacunes and old infarcts. In stratified analyses, the relation between WMH volume and domain-specific functioning was also largely independent of infarct type. CONCLUSIONS: In patients with ischemic stroke, increasing WMH volume is independently associated with worse cognitive functioning across all major domains, regardless of old ischemic lesions and infarct type.

Strategic white matter hyperintensity locations for cognitive impairment: A multicenter lesion-symptom mapping study in 3525 memory clinic patients.

INTRODUCTION: Impact of white matter hyperintensities (WMH) on cognition likely depends on lesion location, but a comprehensive map of strategic locations is lacking. We aimed to identify these locations in a large multicenter study. METHODS: Individual patient data (n = 3525) from 11 memory clinic cohorts were harmonized. We determined the association of WMH location with attention and executive functioning, information processing speed, language, and verbal memory performance using voxel-based and region of interest tract-based analyses. RESULTS: WMH in the left and right anterior thalamic radiation, forceps major, and left inferior fronto-occipital fasciculus were significantly related to domain-specific impairment, independent of total WMH volume and atrophy. A strategic WMH score based on these tracts inversely correlated with performance in all domains. DISCUSSION: The data show that the impact of WMH on cognition is location-dependent, primarily involving four strategic white matter tracts. Evaluation of WMH location may support diagnosing vascular cognitive impairment. HIGHLIGHTS: We analyzed white matter hyperintensities (WMH) in 3525 memory clinic patients from 11 cohorts The impact of WMH on cognition depends on location We identified four strategic white matter tracts A single strategic WMH score was derived from these four strategic tracts The strategic WMH score was an independent determinant of four cognitive domains.

Enhancing Cognitive Performance Prediction through White Matter Hyperintensity Connectivity Assessment: A Multicenter Lesion Network Mapping Analysis of 3,485 Memory Clinic Patients.

Introduction: White matter hyperintensities of presumed vascular origin (WMH) are associated with cognitive impairment and are a key imaging marker in evaluating cognitive health. However, WMH volume alone does not fully account for the extent of cognitive deficits and the mechanisms linking WMH to these deficits remain unclear. We propose that lesion network mapping (LNM), enables to infer if brain networks are connected to lesions, and could be a promising technique for enhancing our understanding of the role of WMH in cognitive disorders. Our study employed this approach to test the following hypotheses: (1) LNM-informed markers surpass WMH volumes in predicting cognitive performance, and (2) WMH contributing to cognitive impairment map to specific brain networks. Methods & results: We analyzed cross-sectional data of 3,485 patients from 10 memory clinic cohorts within the Meta VCI Map Consortium, using harmonized test results in 4 cognitive domains and WMH segmentations. WMH segmentations were registered to a standard space and mapped onto existing normative structural and functional brain connectome data. We employed LNM to quantify WMH connectivity across 480 atlas-based gray and white matter regions of interest (ROI), resulting in ROI-level structural and functional LNM scores. The capacity of total and regional WMH volumes and LNM scores in predicting cognitive function was compared using ridge regression models in a nested cross-validation. LNM scores predicted performance in three cognitive domains (attention and executive function, information processing speed, and verbal memory) significantly better than WMH volumes. LNM scores did not improve prediction for language functions. ROI-level analysis revealed that higher LNM scores, representing greater disruptive effects of WMH on regional connectivity, in gray and white matter regions of the dorsal and ventral attention networks were associated with lower cognitive performance. Conclusion: Measures of WMH-related brain network connectivity significantly improve the prediction of current cognitive performance in memory clinic patients compared to WMH volume as a traditional imaging marker of cerebrovascular disease. This highlights the crucial role of network effects, particularly in attentionrelated brain regions, improving our understanding of vascular contributions to cognitive impairment. Moving forward, refining WMH information with connectivity data could contribute to patient-tailored therapeutic interventions and facilitate the identification of subgroups at risk of cognitive disorders.

Retinal pathology as biomarker for cognitive impairment and Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia. Furthermore, over the last few decades, there has been a shift towards identifying earlier stages of AD, which include mild cognitive impairment (MCI). Improved methods of screening and early detection are essential to identify cognitively normal individuals who have a high risk of developing MCI and AD, so that interventions can be developed to delay the progression of specific disease-related pathologies. Thus far, novel biomarkers that have been examined include structural and functional neuroimaging as well as biochemical analysis of cerebrospinal fluid. However, in spite of these efforts, there is still an urgent need for unravelling additional novel biomarkers for AD and MCI. As the retina shares many features with the brain, including embryological origin, anatomical (such as microvascular bed) and physiological characteristics (such as blood-tissue barrier), it has been suggested that the retina may provide an easily accessible and non-invasive way of examining pathology in the brain. While most AD-related pathology occurs in the brain, the disease has also been reported to affect different regions of the retina, including the macular region and optic disc. Studies have suggested that retinal pathology, such as deposits in the macular region, decreased retinal nerve fibre thickness, and optic disc cupping and retinal microvascular abnormalities may be related to AD and cognitive impairment. This article presents a review of current literature on retinal involvement in AD and MCI.

Deep-learning retinal vessel calibre measurements and risk of cognitive decline and dementia.

Previous studies have explored the associations of retinal vessel calibre, measured from retinal photographs or fundus images using semi-automated computer programs, with cognitive impairment and dementia, supporting the concept that retinal blood vessels reflect microvascular changes in the brain. Recently, artificial intelligence deep-learning algorithms have been developed for the fully automated assessment of retinal vessel calibres. Therefore, we aimed to determine whether deep-learning-based retinal vessel calibre measurements are predictive of risk of cognitive decline and dementia. We conducted a prospective study recruiting participants from memory clinics at the National University Hospital and St. Luke's Hospital in Singapore; all participants had comprehensive clinical and neuropsychological examinations at baseline and annually for up to 5 years. Fully automated measurements of retinal arteriolar and venular calibres from retinal fundus images were estimated using a deep-learning system. Cox regression models were then used to assess the relationship between baseline retinal vessel calibre and the risk of cognitive decline and developing dementia, adjusting for age, gender, ethnicity, education, cerebrovascular disease status, hypertension, hyperlipidemia, diabetes, and smoking. A total of 491 participants were included in this study, of whom 254 developed cognitive decline over 5 years. In multivariable models, narrower retinal arteriolar calibre (hazard ratio per standard deviation decrease = 1.258, P = 0.008) and wider retinal venular calibre (hazard ratio per standard deviation increase = 1.204, P = 0.037) were associated with increased risk of cognitive decline. Among participants with cognitive impairment but no dementia at baseline (n = 212), 44 progressed to have incident dementia; narrower retinal arteriolar calibre was also associated with incident dementia (hazard ratio per standard deviation decrease = 1.624, P = 0.021). In summary, deep-learning-based measurement of retinal vessel calibre was associated with risk of cognitive decline and dementia.

Network impact score is an independent predictor of post-stroke cognitive impairment: A multicenter cohort study in 2341 patients with acute ischemic stroke.

BACKGROUND: Post-stroke cognitive impairment (PSCI) is a common consequence of stroke. Accurate prediction of PSCI risk is challenging. The recently developed network impact score, which integrates information on infarct location and size with brain network topology, may improve PSCI risk prediction. AIMS: To determine if the network impact score is an independent predictor of PSCI, and of cognitive recovery or decline. METHODS: We pooled data from patients with acute ischemic stroke from 12 cohorts through the Meta VCI Map consortium. PSCI was defined as impairment in ≥ 1 cognitive domain on neuropsychological examination, or abnormal Montreal Cognitive Assessment. Cognitive recovery was defined as conversion from PSCI < 3 months post-stroke to no PSCI at follow-up, and cognitive decline as conversion from no PSCI to PSCI. The network impact score was related to serial measures of PSCI using Generalized Estimating Equations (GEE) models, and to PSCI stratified according to post-stroke interval (<3, 3-12, 12-24, >24 months) and cognitive recovery or decline using logistic regression. Models were adjusted for age, sex, education, prior stroke, infarct volume, and study site. RESULTS: We included 2341 patients with 4657 cognitive assessments. PSCI was present in 398/844 patients (47%) <3 months, 709/1640 (43%) at 3-12 months, 243/853 (28%) at 12-24 months, and 208/522 (40%) >24 months. Cognitive recovery occurred in 64/181 (35%) patients and cognitive decline in 26/287 (9%). The network impact score predicted PSCI in the univariable (OR 1.50, 95%CI 1.34-1.68) and multivariable (OR 1.27, 95%CI 1.10-1.46) GEE model, with similar ORs in the logistic regression models for specified post-stroke intervals. The network impact score was not associated with cognitive recovery or decline. CONCLUSIONS: The network impact score is an independent predictor of PSCI. As such, the network impact score may contribute to a more precise and individualized cognitive prognostication in patients with ischemic stroke. Future studies should address if multimodal prediction models, combining the network impact score with demographics, clinical characteristics and other advanced brain imaging biomarkers, will provide accurate individualized prediction of PSCI. A tool for calculating the network impact score is freely available at https://metavcimap.org/features/software-tools/lsm-viewer/.

Associations of retinal microvascular signs and intracranial large artery disease.

BACKGROUND AND PURPOSE: Intracranial large artery disease (ICLAD) is a major cause of ischemic stroke. Retinal microvascular changes are associated with stroke, including small vessel cerebral disease and extracranial carotid disease. We examined the relationship between ICLAD and retinal microvascular changes. METHODS: This is a prospective cohort of 802 acute ischemic stroke patients. Retinal changes were assessed from photographs by graders masked to clinical data. ICLAD was evaluated using prespecified criteria. RESULTS: ICLAD was not associated with ipsilateral retinal arteriolar/venular caliber, focal arteriolar narrowing, or arteriovenous nicking. Severe enhanced arteriolar light reflex was independently associated with any ICLAD (P=0.006) and severe ICLAD (P<0.001). CONCLUSIONS: Enhanced arteriolar light reflex, but not retinal vessel caliber, was related to ICLAD. These data suggest that retinal microvascular signs have specific associations with large cerebral vessel disease.

Strategic infarct locations for post-stroke cognitive impairment: a pooled analysis of individual patient data from 12 acute ischaemic stroke cohorts.

BACKGROUND: Post-stroke cognitive impairment (PSCI) occurs in approximately half of people in the first year after stroke. Infarct location is a potential determinant of PSCI, but a comprehensive map of strategic infarct locations predictive of PSCI is unavailable. We aimed to identify infarct locations most strongly predictive of PSCI after acute ischaemic stroke and use this information to develop a prediction model. METHODS: In this large-scale multicohort lesion-symptom mapping study, we pooled and harmonised individual patient data from 12 cohorts through the Meta-analyses on Strategic Lesion Locations for Vascular Cognitive Impairment using Lesion-Symptom Mapping (Meta VCI Map) consortium. The identified cohorts (as of Jan 1, 2019) comprised patients with acute symptomatic infarcts on CT or MRI (with available infarct segmentations) and a cognitive assessment up to 15 months after acute ischaemic stroke onset. PSCI was defined as performance lower than the fifth percentile of local normative data, on at least one cognitive domain on a multidomain neuropsychological assessment or on the Montreal Cognitive Assessment. Voxel-based lesion-symptom mapping (VLSM) was used to calculate voxel-wise odds ratios (ORs) for PSCI that were mapped onto a three-dimensional brain template to visualise PSCI risk per location. For the prediction model of PSCI risk, a location impact score on a 5-point scale was derived from the VLSM results on the basis of the mean voxel-wise coefficient (ln[OR]) within each patient's infarct. We did combined internal-external validation by leave-one-cohort-out cross-validation for all 12 cohorts using logistic regression. Predictive performance of a univariable model with only the location impact score was compared with a multivariable model with addition of other clinical PSCI predictors (age, sex, education, time interval between stroke onset and cognitive assessment, history of stroke, and total infarct volume). Testing of visual ratings was done by three clinicians, and accuracy, inter-rater reliability, and intra-rater reliability were assessed with Cohen's weighted kappa. FINDINGS: In our sample of 2950 patients (mean age 66·8 years [SD 11·6]; 1157 [39·2%] women), 1286 (43·6%) had PSCI. We achieved high lesion coverage of the brain in our analyses (86·9%). Infarcts in the left frontotemporal lobes, left thalamus, and right parietal lobe were strongly associated with PSCI (after false discovery rate correction, q<0·01; voxel-wise ORs >20). On cross-validation, the location impact score showed good correspondence, based on visual assessment of goodness of fit, between predicted and observed risk of PSCI across cohorts after adjusting for cohort-specific PSCI occurrence. Cross-validations showed that the location impact score by itself had similar performance to the combined model with other PSCI predictors, while allowing for easy visual assessment. Therefore the univariable model with only the location impact score was selected as the final model. Correspondence between visual ratings and actual location impact score (Cohen's weighted kappa: range 0·88-0·92), inter-rater agreement (0·85-0·87), and intra-rater agreement (for a single rater, 0·95) were all high. INTERPRETATION: To the best of our knowledge, this study provides the first comprehensive map of strategic infarct locations associated with risk of PSCI. A location impact score was derived from this map that robustly predicted PSCI across cohorts. Furthermore, we developed a quick and reliable visual rating scale that might in the future be applied by clinicians to identify individual patients at risk of PSCI. FUNDING: The Netherlands Organisation for Health Research and Development.

Ethnicity does not affect the homocysteine-lowering effect of B-vitamin therapy in Singaporean stroke patients.

BACKGROUND AND PURPOSE: Increased total homocysteine (tHcy) is a risk factor for stroke. This study examines whether the efficacy of B-vitamins in reducing tHcy is modified by ethnicity in a Singaporean ischemic stroke population. METHODS: 505 patients (419 Chinese, 41 Malays and 45 Indians) with ischemic stroke were randomized to receive placebo or B-vitamins. Fasting blood samples collected at baseline and 1 year were assayed for tHcy. MTHFR polymorphisms were genotyped. RESULTS: Ethnicity did not independently determine tHcy at baseline. The magnitude of tHcy reduction by B-vitamin treatment was consistent across ethnic groups (Chinese -3.8+/-4.5, Malay -4.9+/-4.2, and Indian -3.3+/-3.6 micromol/L) despite ethnic differences in MTHFR genotype and baseline folic acid (FA) and vitamin B(12) (vitB(12)) concentrations. CONCLUSIONS: Ethnicity does not appear to affect the tHcy-lowering effect of B-vitamins, despite differences in dietary intake and prevalence of MTHFR polymorphisms. This suggests that the effect of B-vitamins in lowering tHcy is generalizable across Asian populations. However, due to relatively small numbers of non-Chinese studied, confirmation in other populations is required.

The Meta VCI Map consortium for meta-analyses on strategic lesion locations for vascular cognitive impairment using lesion-symptom mapping: Design and multicenter pilot study.

INTRODUCTION: The Meta VCI Map consortium performs meta-analyses on strategic lesion locations for vascular cognitive impairment using lesion-symptom mapping. Integration of data from different cohorts will increase sample sizes, to improve brain lesion coverage and support comprehensive lesion-symptom mapping studies. METHODS: Cohorts with available imaging on white matter hyperintensities or infarcts and cognitive testing were invited. We performed a pilot study to test the feasibility of multicenter data processing and analysis and determine the benefits to lesion coverage. RESULTS: Forty-seven groups have joined Meta VCI Map (stroke n = 7800 patients; memory clinic n = 4900; population-based n = 14,400). The pilot study (six ischemic stroke cohorts, n = 878) demonstrated feasibility of multicenter data integration (computed tomography/magnetic resonance imaging) and achieved marked improvement of lesion coverage. DISCUSSION: Meta VCI Map will provide new insights into the relevance of vascular lesion location for cognitive dysfunction. After the successful pilot study, further projects are being prepared. Other investigators are welcome to join.

Is routine retinal examination useful in patients with acute ischemic stroke?

BACKGROUND AND PURPOSE: Patients with ischemic stroke have a high prevalence of hypertension and diabetes, which are major risk factors for potentially blinding retinal diseases. We studied the prevalence of retinal diseases, and the need for an ophthalmology referral, among persons with acute ischemic stroke. METHODS: We conducted a prospective study of 300 consecutive patients with acute ischemic stroke. Retinal photographs were taken and assessed in a masked fashion. Patients were advised and referred if they required an ophthalmology evaluation. RESULTS: Of the 286 patients with gradable photographs, retinal abnormalities were detected in 59%. Ophthalmology evaluation was advised for 3% of patients on an urgent basis and 28% on a nonurgent basis and resulted in either acute treatment or active follow-up for all who were subsequently reviewed. CONCLUSIONS: Patients with acute ischemic stroke have a high prevalence of retinal abnormalities. This study suggests that a routine retinal examination may provide an opportunity to detect potentially vision-threatening retinal diseases.

Improving detection of dementia in Asian patients with low education: combining the Mini-Mental State Examination and the Informant Questionnaire on Cognitive Decline in the Elderly.

BACKGROUND/AIMS: Previous work combining the Mini-Mental State Examination (MMSE) and Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) has been conducted in western populations. We ascertained, in an Asian population, (1) the best method of combining the tests, (2) the effects of educational level, and (3) the effect of different dementia etiologies. METHODS: Data from 576 patients were analyzed (407 nondemented controls, 87 Alzheimer's disease and 82 vascular dementia patients). Sensitivity, specificity and AUC values were obtained using three methods, the 'And' rule, the 'Or' rule, and the 'weighted sum' method. RESULTS: The 'weighted sum' rule had statistically superior AUC and specificity results, while the 'Or' rule had the best sensitivity results. The IQCODE outperformed the MMSE in all analyses. Patients with no education benefited more from combined tests. There was no difference between Alzheimer's disease and vascular dementia populations in the predictive value of any of the combined methods. CONCLUSION: We recommend that the IQCODE be used to supplement the MMSE whenever available and that the 'weighted sum' method be used to combine the MMSE and the IQCODE, particularly in populations with low education. As the study population selected may not be representative of the general population, further studies are required before generalization to nonclinical samples.

South Asian patients with ischemic stroke: intracranial large arteries are the predominant site of disease.

BACKGROUND AND PURPOSE: South Asians are the most prevalent ethnic group in the world. Intracranial disease is the most common vascular lesion worldwide. METHODS: We prospectively studied 200 consecutive ethnic South Asian patients with acute ischemic stroke in Singapore. RESULTS: Intracranial large-artery disease was prevalent among 54% of all stroke subtypes and was independently associated with hypertension and higher serum erythrocyte sedimentation rate. CONCLUSIONS: Among ethnic South Asian patients with ischemic stroke, intracranial large arteries are the predominant site of disease.

Intracranial large artery disease among OCSP subtypes in ethnic South Asian ischemic stroke patients.

The site of vascular stenosis correlates well with the Oxfordshire Community Stroke Project (OCSP) classification among Caucasians, but not among ethnic Chinese patients. We prospectively studied 205 consecutive ethnic South Asian ischemic stroke patients to investigate the prevalence of intracranial large artery disease determined by transcranial color-coded doppler and magnetic resonance angiography among OCSP subtypes. The distribution of OCSP subtypes was 7% total anterior circulation infarction (TACI), 17% partial anterior circulation infarction (PACI), 14% posterior circulation infarction (POCI) and 62% lacunar infarction (LACI). Significant intracranial large artery disease was common among all OCSP subtypes; 79% with TACI, 47% PACI, 65% POCI and 44% LACI. This is similar to ethnic Chinese data and is likely due to the predominance of intracranial disease over extracranial disease. Clinical axioms using OSCP subtypes based on Caucasian data may be misleading if applied to ethnic South Asians.

High plasma cyst(e)ine level may indicate poor clinical outcome in patients with acute stroke: possible involvement of hydrogen sulfide.

Cysteine is known to cause neuronal cell death and has been reported to be elevated in brain ischemia, but it has not been studied in clinical stroke. In this study, we correlated plasma levels of cyst(e)ine with long-term clinical outcome at 3 months in acute stroke. Patients were classified into 3 groups at 3 months as follows: good outcome (Rankin 0-1, n = 11), poor outcome (Rankin 2-5, n = 20), and dead (n = 5). Their plasma cyst(e)ine levels within 24 hours of stroke onset were 61 +/- 12, 67 +/- 9, and 82 +/- 14 micromol/L (standard deviation), respectively. The correlation between early plasma cyst(e)ine levels and long-term clinical outcome assessed at 3 months is significant with p < 0.001. None of the other 4 amino acids studied showed any significant correlation. Cyst(e)ine was also significantly elevated in patients who had early stroke deterioration (p < 0.02). Dose-dependent administration of cysteine increased the infarct volume by approximately 30% in a rat stroke model. This effect of cysteine was abolished by aminooxyacetic acid, an inhibitor of the enzyme cystathionine beta-synthase that converts cysteine to hydrogen sulfide (H2S), indicating that this novel neuromodulator may be acting as a mediator of ischemic brain damage. Raised plasma cyst(e)ine in patients with stroke may reflect increased production of H2S in the brain and thus predispose to poor outcome in clinical stroke. Inhibition of H2S formation may therefore be a novel approach in acute stroke therapy.

Hydrogen sulfide is a mediator of cerebral ischemic damage.

BACKGROUND AND PURPOSE: We observed recently that elevated plasma cysteine levels are associated with poor clinical outcome in acute stroke patients. In a rat stroke model, cysteine administration increased the infarct volume apparently via its conversion to hydrogen sulfide (H2S). We therefore investigated the effects of H2S and the inhibition of its formation on stroke. METHODS: Cerebral ischemia was studied in a rat stroke model created by permanent occlusion of the middle cerebral artery (MCAO). The resultant infarct volume was measured 24 hours after occlusion. RESULTS: Administration of sodium hydrosulfide (NaHS, an H2S donor) significantly increased the infarct volume after MCAO. The NaHS-induced increase in infarct volume was abolished by the administration of dizolcilpine maleate (an N-methyl-d-aspartate receptor channel blocker). MCAO caused an increase in H2S level in the lesioned cortex as well as an increase in the H2S synthesizing activity. Administration of 4 different inhibitors of H2S synthesis reduced MCAO-induced infarct volume dose dependently. The potency of these inhibitors in effecting neuroprotection in vivo appeared to parallel their potency as inhibitors of H2S synthesis in vitro. It also appeared that most of the H2S synthesizing activity in the cortex results from the action of cystathionine beta-synthase. CONCLUSIONS: The present results strongly suggest that H2S plays a part in cerebral ischemic damage after stroke. Inhibition of H2S synthesis should be investigated for its potential as a novel neuroprotective stroke therapy.

Methylenetetrahydrofolate reductase polymorphisms and homocysteine-lowering effect of vitamin therapy in Singaporean stroke patients.

BACKGROUND AND PURPOSE: Increased plasma total homocysteine (tHcy) levels are a risk factor for stroke and can be reduced with vitamin therapy. However, data on the tHcy-lowering effects of vitamins are limited largely to white populations. Thus, we aimed to determine in Singaporean patients with recent stroke: (1) the efficacy of vitamin therapy (folic acid, vitamin B12, and B6) on lowering tHcy, and (2) whether efficacy is modified by Methylenetetrahydrofolate reductase (MTHFR) gene polymorphism(s). METHODS: A total of 443 eligible patients were recruited after presenting with ischemic stroke within the past 7 months. Patients were randomized to receive either placebo or vitamins. Fasting blood samples collected at baseline and at 1 year were assayed for levels of plasma tHcy. Patients were genotyped for MTHFR C677T and A1298C polymorphisms. RESULTS: Mean baseline tHcy was similar in the 2 groups (placebo 13.7 micromol/L; vitamins 14.0 micromol/L; P=0.70). At 1 year, mean tHcy was 14.5 micromol/L in the placebo group compared with 10.7 micromol/L in the vitamin group (difference 3.8 micromol/L; 95% CI, 2.8 to 4.8 micromol/L; P<0.0001). MTHFR C677T genotype was an independent determinant of tHcy levels at baseline (P=0.005), but A1298C was not (P=0.08). Neither polymorphism significantly influenced the effect of vitamin therapy on tHcy at 1 year. The magnitude of the reduction in tHcy levels at 1 year with vitamin therapy was similar, irrespective of MTHFR genotypes. CONCLUSIONS: Vitamin therapy reduces mean tHcy levels by 3.8 micromol/L in the Singaporean stroke population studied. MTHFR C677T but not A1298C is independently associated with tHcy levels at baseline, and neither impacts the tHcy-lowering effect of vitamins used in this study.