Moderately elevated plasma homocysteine, MTHFR genotype and risk for stroke, vascular dementia and alzheimer's disease in northern ireland

BACKGROUND AND PURPOSE: Elevated plasma homocysteine level has been associated with increased risk for cardiovascular and cerebrovascular disease. Variation in the levels of this amino acid has been shown to be due to nutritional status and methylenetetrahydrofolate reductase (MTHFR) genotype. METHODS: Under a case-control design we compared fasting levels of homocysteine and MTHFR genotypes in groups of subjects consisting of stroke, vascular dementia (VaD), and Alzheimer disease patients and normal controls from Northern Ireland. RESULTS: A significant increase in plasma homocysteine was observed in all 3 disease groups compared with controls. This remained significant after allowance for confounding factors (age, sex, hypertension, cholesterol, smoking, creatinine, and nutritional measures). MTHFR genotype was not found to influence homocysteine levels, although the T allele was found to increase risk for VaD and perhaps dementia after stroke. CONCLUSIONS: We report that moderately high plasma levels of homocysteine are associated with stroke, VaD, and Alzheimer disease. This is not due to vascular risk factors, nutritional status, or MTHFR genotype

Neuroprotective actions of a histidine analogue in models of ischemic stroke.

Histidine is a naturally occurring amino acid with antioxidant properties, which is present in low amounts in tissues throughout the body. We recently synthesized and characterized histidine analogues related to the natural dipeptide carnosine, which selectively scavenge the toxic lipid peroxidation product 4-hydroxynonenal (HNE). We now report that the histidine analogue histidyl hydrazide is effective in reducing brain damage and improving functional outcome in a mouse model of focal ischemic stroke when administered intravenously at a dose of 20 mg/kg, either 30 min before or 60 min and 3 h after the onset of middle cerebral artery occlusion. The histidine analogue also protected cultured rat primary neurons against death induced by HNE, chemical hypoxia, glucose deprivation, and combined oxygen and glucose deprivation. The histidine analogue prevented neuronal apoptosis as indicated by decreased production of cleaved caspase-3 protein. These findings suggest a therapeutic potential for HNE-scavenging histidine analogues in the treatment of stroke and related neurodegenerative conditions.

Training of Reaching in Stroke Survivors With Severe and Chronic Upper Limb Paresis Using a Novel Nonrobotic Device: A Randomized Clinical Trial

Background and Purpose—Severe upper limb paresis is a major contributor to disability after stroke. This study investigated the efficacy of a new nonrobotic training device, the Sensorimotor Active Rehabilitation Training (SMART) Arm, that was used with or without electromyography-triggered electrical stimulation of triceps brachii to augment elbow extension, permitting stroke survivors with severe paresis to practice a constrained reaching task.

Methods—A single-blind, randomized clinical trial was conducted with 42 stroke survivors with severe and chronic paresis. Thirty-three participants completed the study, of whom 10 received training using the SMART Arm with electromyography-triggered electrical stimulation, 13 received training using the SMART Arm alone, and 10 received no intervention (control). Training consisted of 12 1-hour sessions over 4 weeks. The primary outcome measure was “upper arm function,” item 6 of the Motor Assessment Scale. Secondary outcome measures included impairment measures; triceps muscle strength, reaching force, modified Ashworth scale; and activity measures: reaching distance and Motor Assessment Scale. Assessments were administered before (0 weeks) and after training (4 weeks) and at 2 months follow-up (12 weeks).

Results—Both SMART Arm groups demonstrated significant improvements in all impairment and activity measures after training and at follow-up. There was no significant difference between these 2 groups. There was no change in the control group.

Conclusions—Our findings indicate that training of reaching using the SMART Arm can reduce impairment and improve activity in stroke survivors with severe and chronic upper limb paresis, highlighting the benefits of intensive task-oriented practice, even in the context of severe paresis.

The impact of newly identified loci on coronary heart disease, stroke and total mortality in the MORGAM prospective cohorts

Recently, genome wide association studies (GWAS) have identified a number of single nucleotide polymorphisms (SNPs) as being associated with coronary heart disease (CHD). We estimated the effect of these SNPs on incident CHD, stroke and total mortality in the prospective cohorts of the MORGAM Project. We studied cohorts from Finland, Sweden, France and Northern Ireland (total N=33,282, including 1,436 incident CHD events and 571 incident stroke events). The lead SNPs at seven loci identified thus far and additional SNPs (in total 42) were genotyped using a case-cohort design.We estimated the effect of the SNPs on disease history at baseline, disease events during follow-up and classic risk factors. Multiple testing was taken into account using false discovery rate (FDR) analysis. SNP rs1333049 on chromosome 9p21.3 was associated with both CHD and stroke (HR5=.20, 95% CI 1.08-1.34 for incident CHD events and 1.15, 0.99-1.34 for incident stroke). SNP rs11670734 (19q12) was associated with total mortality and stroke. SNP rs2146807 (10q11.21) showed some association with the fatality of acute coronary event. SNP rs2943634 (2q36.3) was associated with high density lipoprotein (HDL) cholesterol and SNPs rs599839, rs4970834 (1p13.3) and rs17228212 (15q22.23) were associated with non-HDL cholesterol. SNPs rs2943634 (2q36.3) and rs12525353 (6q25.1) were associated with blood pressure. These findings underline the need for replication studies in prospective settings and confirm the candidacy of several SNPs that may play a role in the etiology of cardiovascular disease.

Training-induced changes in the pattern of triceps to biceps activation during reaching tasks after chronic and severe stroke

This exploratory study was undertaken to investigate the mechanisms that contributed to improvements in upper limb function following a novel training program. Surface electromyography (EMG) was used to examine training-induced changes in the pattern of triceps and biceps activation during reaching tasks in stroke survivors with severe paresis in the chronic stage of recovery. The EMG data were obtained in the context of a single blind randomised clinical trial conducted with 42 stroke survivors with minimal upper limb muscle activity and who were more than 6 months post-stroke. Of the 33 participants who completed the study, 10 received training of reaching using a non-robotic upper limb training device, the SMART Arm, with EMG triggered functional electrical stimulation (EMG-stim), 13 received training of reaching using the SMART Arm alone, and 10 received no intervention. Each intervention group engaged in 12 1-h training sessions over a 4-week period. Clinical and laboratory measures of upper limb function were administered prior to training (0 weeks), at completion (4 weeks) and 2 months (12 weeks) after training. The primary outcome measure was 'upper arm function' which is Item 6 of the Motor Assessment Scale (MAS). Laboratory measures consisted of two multijoint reaching tasks to assess 'maximum isometric force' and 'maximum distance reached'. Surface EMG was used to monitor triceps brachii and biceps brachii during the two reaching tasks. To provide a comparison with normal values, seven healthy adults were tested on one of the reaching tasks according to the same procedure. Study findings demonstrated a statistically significant improvement in upper limb function for stroke participants in the two training groups compared to those who received no training however no difference was found between the two training groups. For the reaching tasks, all stroke participants, when compared to normal healthy adults, exhibited lower triceps and biceps activation and a lower ratio of triceps to biceps activation. Following training, stroke participants demonstrated increased triceps activation and an increased ratio of triceps to biceps activation for the task that was trained. Better performance was associated with greater triceps activation and a higher ratio of triceps to biceps activation. The findings suggest that increased activation of triceps as an agonist and an improved coordination between triceps and biceps could have mediated the observed changes in arm function. The changes in EMG activity were small relative to the changes in arm function indicating that factors, such as the contribution of other muscles of reaching, may also be implicated.