Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activity-dependent neuroprotective protein (ADNP) is essential for brain formation. Peptide activity scanning identified NAP (NAPVSIPQ) as a small active fragment of ADNP that provides neuroprotection at very low concentrations. In cell culture, NAP has demonstrated protection against toxicity associated with the beta-amyloid peptide, N-methyl-D-aspartate, electrical blockade, the envelope protein of the AIDS virus, dopamine, H2O2, nutrient starvation and zinc overload. NAP has also provided neuroprotection in animal models of apolipoprotein E deficiency, cholinergic toxicity, closed head injury, stroke, middle aged anxiety and cognitive dysfunction. NAP binds to tubulin and facilitates microtubule assembly leading to enhanced cellular survival that is associated with fundamental cytoskeletal elements. A liquid-chromatography, mass spectrometry assay demonstrated that NAP reaches the brain after either intravenous or intranasal administration. In a battery of toxicological tests including repeated dose toxicity in rats and dogs, cardiopulmonary tests in dogs, and functional behavioral assays in rats, no adverse side effects were observed with NAP concentrations that were approximately 500-fold higher than the biologically active dose. A Phase Ia clinical trial in the US assessed the tolerability and pharmacokinetics of intranasal administration of NAP in sequential ascending doses. The results supported the safety and tolerability of a single dose of NAP administered at up to 15 mg intranasally. Furthermore, dosing was recently completed for a second Phase I clinical trial in healthy adults and elderly volunteers with an intravenous formulation of NAP. NAP is poised for further clinical development targeting several indications, including Alzheimer's disease.
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PMID:NAP: research and development of a peptide derived from activity-dependent neuroprotective protein (ADNP). 1661 35

Data concerning the treatment of lipoprotein disturbances in patients with cerebrovascular disease (CVD) are less robust than those for coronary heart disease (CHD), raising clinical questions as to which is the appropriate therapeutic approach to stroke patients. Although observational cohort studies have failed to demonstrate an association between lipoprotein disorders and stroke incidence, recently completed trials of subjects at risk for CHD have shown that statins reduce not only the risk of myocardial infarction and death, but also that of brain infarction and transient ischemic attacks. At present, it seems reasonable to conclude that stroke patients with undesirable lipid profiles who have a history of CHD should receive specific treatment for the lipid disorder. Recommendations are more problematic for stroke patients with lipid disorder but no history of CHD. Furthermore, many of the risk factors for CVD and vascular dementia (VaD), including serum total cholesterol (TC), lipoprotein(a), diabetes, atrial fibrillation, hypertension, apolipoprotein E levels, and atherosclerosis, have also been shown to increase the risk of Alzheimer's disease (AD). In a recent study, we estimated the prevalence, incidence and rate of progression of Mild Cognitive Impairment (MCI) to dementia, and correlated vascular risk factors with incident MCI and its progression to dementia. We evaluated 2963 individuals from the population-based sample of 5632 subjects 65-84 years old of the Italian Longitudinal Study on Aging, with a 3.5-year follow-up. We found a progression rate to dementia (all causes) of 3.8/100 person-years. Furthermore, age was a risk factor for incident MCI, while education was protective, and serum TC evidenced a non-significant borderline trend for a protective effect. There was a non-significant trend for stroke as a risk factor of progression of MCI to dementia. In conclusion, in our population, among MCI patients who progressed to dementia, 60% progressed to AD and 33% to VaD. Vascular risk factors and CVD may influence the development of MCI and the rate of progression to dementia.
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PMID:Cerebrovascular disease in the elderly: lipoprotein metabolism and cognitive decline. 1670 84

Stroke is a heterogeneous multifactorial disease and is thought to have a polygenic basis. Case-control studies on gene sequence variations have identified a number of potential genetic predisposition factors, but due to the conflicting results, uncertainty remains on the effect of these polymorphisms on risk for the development of stroke. To qualitatively and quantitatively assess the risk associated with different gene polymorphisms for stroke in Asian populations, we comprehensively searched and identified all the studies of association. Clinically overt case-control studies were selected only if neuroimaging had been used as the confirmatory measure for diagnosis of stroke. We performed a meta-analysis of the three most investigated genes, viz., methylenetetrahydrofolate reductase (MTHFR), apolipoprotein E (ApoE) and angiotensin-converting enzyme (ACE). Statistically significant association with stroke were identified for C677T polymorphism of MTHFR [random effects odds ratio (OR) = 1.47, 95% confidence interval (95% CI) 1.19, 1.82; P = 0.0004] and marginally significant association was detected with allele epsilon 4 of ApoE (random effects OR = 1.47, 95% CI 1.00, 2.15; P = 0.049). The sensitivity analysis (exclusion of studies with controls not in Hardy-Weinberg equilibrium) revealed a significant association of stroke with the MTHFR C677T and ApoE epsilon 4 alleles but showed no association with ACE gene insertion/deletion polymorphism.
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PMID:Association of gene polymorphism with genetic susceptibility to stroke in Asian populations: a meta-analysis. 1717 Dec 28

Two patients presented with subarachnoid hemorrhage (SAH) associated with both intracranial dissecting and saccular aneurysms. Case 1, a 48-year-old woman, had a saccular aneurysm of the right internal carotid artery and dissecting aneurysms of the bilateral vertebral arteries. Case 2, a 52-year-old man, had three saccular aneurysms in the anterior circulation and a dissecting aneurysm of the unilateral vertebral artery. A saccular aneurysm was responsible for the SAH in both patients. Ruptured saccular aneurysms were treated with surgical clipping and unruptured dissecting aneurysms remained untreated. SAH recurred due to bleeding from an untreated dissecting aneurysm 4 days after the initial SAH in Case 1. Triple-H therapy, which causes increased hemodynamic stress, was not administered for symptomatic cerebral vasospasm after SAH in Case 2, because of the risk of bleeding from the untreated dissecting aneurysm, and the patient suffered cerebral infarction. The risk factors for this rare association are unclear, but both patients were smokers and had hypocholesterolemia including low apolipoprotein E levels. The clinical management of patients with SAH and both dissection and saccular aneurysms is complicated. Asymptomatic dissecting aneurysm has a benign clinical course in general, but hemodynamic stress related to stroke may induce abrupt development of dissecting aneurysms. Prophylactic obliteration during the acute stage of SAH may provide better outcomes if the unruptured dissecting lesion appears as obvious aneurysmal dilatation or pearl-and-string sign and is safely treatable with endovascular trapping.
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PMID:Subarachnoid hemorrhage in the presence of both intracranial dissecting and saccular aneurysms--two case reports. 1731 43

When properly controlled, Ca2+ fluxes across the plasma membrane and between intracellular compartments play critical roles in fundamental functions of neurons, including the regulation of neurite outgrowth and synaptogenesis, synaptic transmission and plasticity, and cell survival. During aging, and particularly in neurodegenerative disorders, cellular Ca2+-regulating systems are compromised resulting in synaptic dysfunction, impaired plasticity and neuronal degeneration. Oxidative stress, perturbed energy metabolism and aggregation of disease-related proteins (amyloid beta-peptide, alpha-synuclein, huntingtin, etc.) adversely affect Ca2+ homeostasis by mechanisms that have been elucidated recently. Alterations of Ca2+-regulating proteins in the plasma membrane (ligand- and voltage-gated Ca2+ channels, ion-motive ATPases, and glucose and glutamate transporters), endoplasmic reticulum (presenilin-1, Herp, and ryanodine and inositol triphosphate receptors), and mitochondria (electron transport chain proteins, Bcl-2 family members, and uncoupling proteins) are implicated in age-related neuronal dysfunction and disease. The adverse effects of aging on neuronal Ca2+ regulation are subject to modification by genetic (mutations in presenilins, alpha-synuclein, huntingtin, or Cu/Zn-superoxide dismutase; apolipoprotein E isotype, etc.) and environmental (dietary energy intake, exercise, exposure to toxins, etc.) factors that may cause or affect the risk of neurodegenerative disease. A better understanding of the cellular and molecular mechanisms that promote or prevent disturbances in cellular Ca2+ homeostasis during aging may lead to novel approaches for therapeutic intervention in neurological disorders such as Alzheimer's and Parkinson's diseases and stroke.
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PMID:Calcium and neurodegeneration. 1732 89

There is evidence that most forms of ischaemic stroke (IS) result from synergistic effects of the modifiable predisposing factors and multiple genes. In the present work, we report results of case-control study of IS association with apolipoprotein E gene (APOE) (promoter and coding polymorphisms) and lipoprotein lipase gene (LPL) (presence/absence of a HindIII cutting site). We studied 107 unrelated patients of Yakut ethnicity (69 men and 38 women, mean age 58.4+/-11.5 years) with first-ever IS in carotid/middle cerebral artery regions. The control group included 101 subjects of the same ethnicity (61 men and 40 women, mean age 57.6+/-11.6 years) free of clinically detectable cerebrovascular disease, and without any history of stroke. A positive association of IS with APOE -427T allele (p=0.0012, OR=3.99) and -427T/T genotype (p=0.0005, OR=4.96) and a negative association with -427C allele (p=0.0012, OR=0.25), -427T/C genotype (p=0.0003, OR=0.18), epsilon2 allele (p=0.018, OR=0.35), epsilon2/3 genotype (p=0.017, OR=0.28) and -491A/-427C/epsilon2 haplotype (p=0.0026, OR=0.18) were observed. For atherothrombotic subgroup the same allele and genotype associations were found plus association with APOE -491A allele (p=0.026, OR=3.98). No reliable IS associations were found with LPL T+495G (HindIII) polymorphism. An association of APOE promoter polymorphisms (A-491T, T-427C) with an IS is shown in our study for the first time. Our study provides evidence for the role of APOE gene as a prognostic genetic marker for IS, especially for its atherothrombotic subtype.
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PMID:Polymorphism of apolipoprotein E (APOE) and lipoprotein lipase (LPL) genes and ischaemic stroke in individuals of Yakut ethnicity. 1732 17

The association between apolipoprotein E (ApoE) polymorphism and stroke is still controversial. This study investigated the potential association between ApoE genotypes and stroke subtypes, and risk factors for ischaemic stroke in Greek patients hospitalized with their first-ever ischaemic stroke. One hundred patients (70 men and 30 women; mean age +/- SD 60.7 +/-9.8 years) were included in the study. The control group comprised 96 age- and sex-matched healthy volunteers. Cerebral infarction was classified as atherothrombotic, cardioembolic or lacunar small-vessel stroke. The three common ApoE alleles (E2, E3 and E4) were determined using the semi-nested polymerase chain reaction. No significant difference in the ApoE alleles was found between patients and controls. Similarly, there was no significant association between ApoE alleles and stroke subtypes, common risk factors for ischaemic stroke and neck vessel stenosis. Although the sample size was small, these results do not support a role for ApoE polymorphism in the pathogenesis of ischaemic stroke.
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PMID:Apolipoprotein E and first-ever ischaemic stroke in Greek hospitalized patients. 1740 64

The relationship between structural variants of the apolipoprotein E gene, APOE epsilon2/epsilon3/epsilon4, and dementia is well established, whereas the relationship of plasma apoE levels with dementia is less clear. Plasma apoE levels are under tight genetic control but vary widely within the various genotypes indicating that the APOE epsilon2/epsilon3/epsilon4 locus explains only a small fraction of this variation. Here we studied the association of plasma apolipoprotein E (apoE) levels with cognitive function in the elderly population at large. Within the Leiden 85-plus Study, a prospective population-based study of subjects aged 85 years, we measured plasma apoE level and genotype at base line. During a 5-year follow-up period, cognitive function was annually assessed using the Mini Mental State Examination (MMSE) and a standardized neuropsychological test battery. Among epsilon3epsilon3 carriers (n = 324), high plasma apoE levels associated with impaired global cognitive function (-1.10 points change in MMSE score per one standard deviation increase of plasma apoE level, P = 0.001), as well as lower attention (P = 0.064), speed and memory function (all P < 0.05). Adjustment for cardiovascular risk factors and exclusion of all subjects who suffered a stroke did not materially change the associations. Similar estimates were obtained in epsilon3epsilon4 carriers (n = 100), but not in epsilon2epsilon3 carriers (n = 90). We conclude that in old age, in non-epsilon2-allele carriers, high plasma apoE levels are associated with cognitive impairments, independent of genotype, cardiovascular risk factors, and stroke.
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PMID:Plasma levels of apolipoprotein E and cognitive function in old age. 1746 Jan 73

A relationship between apolipoprotein E (Apo E) genotype and stroke was previously suggested, but with inconsistent results. We investigated the relationships among serum lipid levels, Apo E alleles and genotypes, and stroke risk factors in 216 stroke patients and 282 age- and sex-matched controls. Fasting blood samples were collected for total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride level determination and for genomic DNA extraction. Apo was genotyped by polymerase chain reaction-restriction fragment length polymorphism (Cfo I) analysis. Increasing levels of total cholesterol, LDL-C, HDL-C, and triglycerides were associated with elevated stroke risk and was more pronounced in Apo E4-carrying subjects than in E3- and/or E2-carrying subjects. Apo 3 was significantly lower (0.546 vs 0.736; P < .001), whereas Apo 4 was higher in the stroke patients (0.370 vs 0.181; P < .001); Apo 2 was present at low but comparable frequencies. The prevalence of E3/E3 was lower and that of E4-containing phenotypes (E3/E4 and homozygous E4/E4) was higher in the stroke patients. The prevalence of the E4-containing phenotypes were significantly higher in ischemic versus hemorrhagic (P < .001) and in small-vessel versus large-vessel stroke cases (P < .001), and was associated with increased need for statin drugs (P = .040). Logistic regression models, after adjusting for potentially confounding variables including lipid profile, age, and sex, showed an significant association of apo 4 genotype with risk of stroke (P = .033). Our findings indicate that Apo 4 is an independent risk factor associated with an altered lipid profile in this study population.
J Stroke Cerebrovasc Dis
PMID:Association of apolipoprotein E gene polymorphism with ischemic stroke involving large-vessel disease and its relation to serum lipid levels. 1768 12

Oral anticoagulant treatment for secondary prevention after cerebral ischaemia of presumed arterial origin is associated with a higher bleeding rate than cardioembolic stroke. This discrepancy is only partly explained by known bleeding risk factors. Haemostatic genetic variants and AB0 blood group may be involved. We performed a nested casecontrol study in patients with cerebral ischaemia of presumed arterial origin on anticoagulant treatment (International Normalized Ratio between 3.0-4.5). All 34 cases with non-fatal haemorrhage (10 intracranial and 24 extracranial) and 68 control patients on anticoagulant treatment without such a bleeding were selected from the SPIRIT study. AB0 blood group and 11 haemostatic genetic variants were investigated. The Thr312Ala variant of the alpha fibrinogen gene was associated with a decreased bleeding risk (odds ratio (OR) 0.3 for Ala/Ala and Thr/Ala versus Thr/Thr genotype; 95% CI 0.1-0.8). Factor V Leiden was associated with an increased bleeding risk (OR 11.6; 95% CI 1.3-103). The APOE2 allele (OR 0.5; 95% CI 0.2-1.7) and the Tyr204Phe variant in the factor XIII subunit A (OR 2.1; 0.9-5) had nonsignificant relationships with bleeding risk. AB0 blood group and 7 other genetic variants in coagulation factors II and XIII, vitamin K epoxide reductase complex, beta fibrinogen and apolipoprotein E were not related with the risk of haemorrhage. The Ala312Thr variant in the alpha fibrinogen gene is associated with a decreased and factor V Leiden with an increased bleeding risk in patients on anticoagulant treatment after cerebral ischaemia of presumed arterial origin.
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PMID:Haemostatic genetic variants, ABO blood group and bleeding risk during oral anticoagulant treatment after cerebral ischaemia of arterial origin. 1799 14


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