[show abstract][hide abstract] ABSTRACT: Objective: End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy REFVIDunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype. Methods: Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n = 2,100, Stage 1) were examined in ischemic stroke (n = 4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases, 55,000 controls) was used for replication (Stage 3). Results: Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (p < 5 × 10(-8) ) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (p = 2.6 × 10(-186) ), rs10665 with FVII (p = 2.4 × 10(-47) ), and rs505922 in the ABO gene with both von Willebrand factor (p = 4.7 × 10(-57) ) and factor VIII (p = 1.2 × 10(-36) ). In Stage 2, the 23 independent SNPs were examined in stroke cases/noncases using MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Wellcome Trust Case Control Consortium 2 collections. SNP rs505922 was nominally associated with ischemic stroke (odds ratio = 0.94, 95% confidence interval = 0.88-0.99, p = 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), p = 0.001, a finding specific to large-vessel and cardioembolic stroke (p = 0.001 and p = < 0.001, respectively) but not seen with small-vessel stroke (p = 0.811). Interpretation: ABO gene variants are associated with large-vessel and cardioembolic stroke but not small-vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype. Ann Neurol 2013.
Annals of Neurology 01/2013; 73(1):16-31. · 11.19 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND AND PURPOSE: Recently, a novel locus at 17q25 was associated with white matter hyperintensities (WMH) on MRI in stroke-free individuals. We aimed to replicate the association with WMH volume (WMHV) in patients with ischemic stroke. If the association acts by promoting a small vessel arteriopathy, it might be expected to also associate with lacunar stroke. METHODS: We quantified WMH on MRI in the stroke-free hemisphere of 2588 ischemic stroke cases. Association between WMHV and 6 single-nucleotide polymorphisms at chromosome 17q25 was assessed by linear regression. These single-nucleotide polymorphisms were also investigated for association with lacunar stroke in 1854 cases and 51 939 stroke-free controls from METASTROKE. Meta-analyses with previous reports and a genetic risk score approach were applied to identify other novel WMHV risk variants and uncover shared genetic contributions to WMHV in community participants without stroke and ischemic stroke. RESULTS: Single-nucleotide polymorphisms at 17q25 were associated with WMHV in ischemic stroke, the most significant being rs9894383 (P=0.0006). In contrast, there was no association between any single-nucleotide polymorphism and lacunar stroke. A genetic risk score analysis revealed further genetic components to WMHV shared between community participants without stroke and ischemic stroke. CONCLUSIONS: This study provides support for an association between the 17q25 locus and WMH. In contrast, it is not associated with lacunar stroke, suggesting that the association does not act by promoting small-vessel arteriopathy or the same arteriopathy responsible for lacunar infarction.
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes. METHODS: We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls. FINDINGS: We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10(-16)) and ZFHX3 (p=2·28×10(-8)), and for large-vessel stroke at a 9p21 locus (p=3·32×10(-5)) and HDAC9 (p=2·03×10(-12)). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p<5×10(-6). However, we were unable to replicate any of these novel associations in the replication cohort. INTERPRETATION: Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes. FUNDING: Wellcome Trust, UK Medical Research Council (MRC), Australian National and Medical Health Research Council, National Institutes of Health (NIH) including National Heart, Lung and Blood Institute (NHLBI), the National Institute on Aging (NIA), the National Human Genome Research Institute (NHGRI), and the National Institute of Neurological Disorders and Stroke (NINDS).
The Lancet Neurology 10/2012; 11(11):951-962. · 23.92 Impact Factor
[show abstract][hide abstract] ABSTRACT: Genome-wide association studies (GWAS) have not consistently detected replicable genetic risk factors for ischemic stroke, potentially due to etiological heterogeneity of this trait. We performed GWAS of ischemic stroke and a major ischemic stroke subtype (large artery atherosclerosis, LAA) using 1,162 ischemic stroke cases (including 421 LAA cases) and 1,244 population controls from Australia. Evidence for a genetic influence on ischemic stroke risk was detected, but this influence was higher and more significant for the LAA subtype. We identified a new LAA susceptibility locus on chromosome 6p21.1 (rs556621: odds ratio (OR) = 1.62, P = 3.9 × 10(-8)) and replicated this association in 1,715 LAA cases and 52,695 population controls from 10 independent population cohorts (meta-analysis replication OR = 1.15, P = 3.9 × 10(-4); discovery and replication combined OR = 1.21, P = 4.7 × 10(-8)). This study identifies a genetic risk locus for LAA and shows how analyzing etiological subtypes may better identify genetic risk alleles for ischemic stroke.
[show abstract][hide abstract] ABSTRACT: Ischemic stroke (IS) shares many common risk factors with coronary artery disease (CAD). We hypothesized that genetic variants associated with myocardial infarction (MI) or CAD may be similarly involved in the etiology of IS. To test this hypothesis, we evaluated whether single-nucleotide polymorphisms (SNPs) at 11 different loci recently associated with MI or CAD through genome-wide association studies were associated with IS.
Meta-analyses of the associations between the 11 MI-associated SNPs and IS were performed using 6865 cases and 11 395 control subjects recruited from 9 studies. SNPs were either genotyped directly or imputed; in a few cases a surrogate SNP in high linkage disequilibrium was chosen. Logistic regression was performed within each study to obtain study-specific βs and standard errors. Meta-analysis was conducted using an inverse variance weighted approach assuming a random effect model.
Despite having power to detect odds ratio of 1.09-1.14 for overall IS and 1.20-1.32 for major stroke subtypes, none of the SNPs were significantly associated with overall IS and/or stroke subtypes after adjusting for multiple comparisons.
Our results suggest that the major common loci associated with MI risk do not have effects of similar magnitude on overall IS but do not preclude moderate associations restricted to specific IS subtypes. Disparate mechanisms may be critical in the development of acute ischemic coronary and cerebrovascular events.
[show abstract][hide abstract] ABSTRACT: Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10(-11); odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.
[show abstract][hide abstract] ABSTRACT: The aim of this article was to demonstrate that stroke diagnosis alone does not explain differences and variety in the functioning and disability of patients. We suggest that the International Classification of Functioning, Disability, and Health Brief Core Set for Stroke is a useful, brief, and functional instrument to produce a functioning profile for stroke patients.
This article reports the baseline results of a longitudinal study with 111 patients with stroke and their functioning profiles obtained with the International Classification of Functioning, Disability, and Health Brief Core Set for Stroke.
Most frequently reported problems in body functions were memory, muscle power functions, and attention functions. Walking activities, speaking, and understanding spoken messages are the main restricted and limited activities. Principal differences between capacity and performance (i.e., the impact of environment in performing the activities) were found in activities of self-care, such as washing oneself or dressing. Immediate family and health professionals are the main facilitators reported by patients.
The International Classification of Functioning, Disability, and Health Brief Core Set for Stroke reports accurately on the main problematic areas of functioning and activities of daily living of people after stroke. It is a brief and useful instrument to use in clinical practice and it can be proposed as a "starting point" to plan interventions and organize services for patients after stroke.
American journal of physical medicine & rehabilitation / Association of Academic Physiatrists 12/2011; 91(13 Suppl 1):S14-21. · 1.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: Superficial siderosis (SS) of the central nervous system is a rare disorder caused by chronic or recurrent hemorrhages into the subarachnoid space with hemosiderin and ferritin deposition, which leads to neuronal damage. The source of bleeding remains unknown in 50% of cases. Recently, attention has been focused on fluid-filled collection in the spinal canal, suggesting the presence of a dural defect which may be the bleeding point. We present a patient with SS and spinal extradural fluid collection due to midthoracic dural defect with spinal cord herniation. The reduction of the spinal cord herniation and the repair of the dural defect resulted in the disappearance of the fluid collection and cerebrospinal fluid abnormalities. The case here reported is, to our knowledge, the first case of spinal cord herniation presenting with SS and confirms the key role played by dural lacerations in the pathogenesis of both SS and spinal cord herniation. The search for dural lacerations should be one of the primary aims in patients with SS.
Journal of the neurological sciences 08/2011; 312(1-2):170-2. · 2.32 Impact Factor
[show abstract][hide abstract] ABSTRACT: Phakomatosis refers to several malformation syndromes with simultaneous involvement of the skin, the eye, and the central nervous system by developmental lesions. Speckled lentiginous nevus (SLN), a subtype of congenital melanocytic nevi, is usually an isolate, harmless finding. Here, we report the case of a 52-year-old woman with congenital left laterocervical SLN associated with an ipsilateral intracranial extra-axial cavernous angioma, a yet not described association to date. After revision of the literature, we suggest that both these lesions could be correlated in the setting of an atypical, yet unclassifiable form of phakomatosis, such as phakomatosis pigmentovascularis or SLN syndrome. We also propose that patients with bizarre, geometrical, pigmented or vascular cervicocranial skin lesions should undergo a thorough neurologic and ophthalmologic evaluation.
[show abstract][hide abstract] ABSTRACT: Stroke is a significant cause of long-term disability. Currently, once damage from a stroke is established little can be done to recover lost function. Cell transplantation emerged as possible alternative therapy, on the basis of animal studies showing that cells transplanted into the brain not only survive, but also lead to functional improvement in different neurodegenerative diseases. Stem cells have been tested in stroke patients as a possible treatment option. While initially stem cells seemed to work by a 'cell replacement' mechanism, it is emerging that cell therapy works mostly by providing trophic support to the injured tissue and brain, fostering both neurogenesis and angiogenesis. This review summarizes clinical studies on stem cell transplantation in stroke patients to evaluate the safety, feasibility of administration and tolerability of this experimental treatment. At present there is little evidence to assess the applicability of this treatment in stroke patients and well designed clinical trials are necessary to evaluate safety and toxicity as well as optimal cell type, route and time of delivery.
Current Vascular Pharmacology 02/2010; 8(1):29-34. · 2.82 Impact Factor
[show abstract][hide abstract] ABSTRACT: Studies in animal models of ischemic stroke have shown that stem cells transplanted into the brain can lead to functional improvement. However, to date, evidence for the benefits of stem cell transplantation in ischemic stroke patients is lacking.
To assess the efficacy and safety of stem cell transplantation compared with conventional treatments in patients with ischemic stroke.
We searched the Cochrane Stroke Group Trials Register (last searched February 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, Issue 3), MEDLINE (1966 to August 2008), EMBASE (1980 to August 2008), Science Citation Index (1900 to August 2008), and BIOSIS (1926 to August 2008). We handsearched potentially relevant conference proceedings, screened reference lists, and searched ongoing trials and research registers (last searched November 2008). We also contacted individuals active in the field and stem cell manufacturers (last contacted December 2008).
We included randomized controlled trials (RCTs) recruiting patients with ischemic stroke, in any phase of the disease, and an ischemic lesion confirmed by computerized tomography or magnetic resonance imaging scan. We included all types of stem cell transplantation regardless of cell source (autograft, allograft, or xenograft; embryonic, fetal, or adult; from brain or other tissues), route of cell administration (systemic or local), and dosage. The primary outcome was efficacy (assessed as combined functional outcome or disability and dependency) at longer follow-up (minimum six months). Secondary outcomes included post-procedure safety outcomes (death, worsening of neurological deficit, infections and neoplastic transformation).
Two review authors independently extracted data and assessed trial quality. We contacted study authors for additional information.
We identified three very small RCTs. Two are still awaiting classification because only subgroups of patients could be included in this meta-analysis and additional unpublished data are needed. The third trial randomized 30 patients to intravenous transplantation of autologous mesenchymal stem cell (10 participants) or reference group (20 participants) (five participants, initially randomized to the intervention group, refused the treatment and were allocated to the reference group) and found a statistically non-significant functional improvement in treated patients at longer follow-up. No adverse cell-related events were reported.
No large trials of stem cell transplantation have been performed in ischemic stroke patients and it is too early to know whether this intervention can improve functional outcome. Large, well-designed trials are needed.
[show abstract][hide abstract] ABSTRACT: Evidence is growing that some patients are not responsive to the antithrombotic action of aspirin. We prospectively evaluated the ability of aspirin resistance status, determined by PFA-100, to predict new thrombotic events in patients with stable ischemic cerebrovascular disease.
We studied 129 consecutive patients with stroke, transient ischemic attack (TIA) or vascular cognitive impairment. We assessed relationships between aspirin resistance, risk factors for ischemic cerebrovascular disease, and occurrence of new thrombotic events (composite of stroke, TIA, myocardial infarction, and cardiovascular death).
Aspirin resistance, found in 26 (20.1%) cases, was unrelated to any of the examined vascular risk factors. During mean follow-up of 56 months, new thrombotic events occurred in 19 patients (14.7%), four with aspirin resistance (15.4%) and 15 (14.6%) without aspirin resistance (p=1.00).
Aspirin resistance determined by PFA-100 does not predict new thrombotic events in patients with stable ischemic cerebrovascular disease.
Clinical neurology and neurosurgery 01/2009; 111(3):270-3. · 1.30 Impact Factor
[show abstract][hide abstract] ABSTRACT: The gene-encoding plasminogen activator inhibitor type 1 (PAI-1) has a common 4G/5G 'functional' polymorphism, and people homozygous for the 4G allele have higher PAI-1 plasma concentrations. The 4G/4G genotype is associated with increased risk of myocardial infarction but paradoxically protects against stroke. We hypothesized that this paradox may be explained via an effect of the PAI-1 polymorphism on plasma lipids.
We studied 71 consecutive Italian patients referred to our Institute for first stroke or vascular cognitive impairment. PAI-1 gene 4G/5G polymorphism, total plasma cholesterol, plasma triglycerides, sex, age, smoking, oral contraceptive use, statin therapy, hypertension, diabetes, and history of myocardial infarction were examined.
The 4G/4G genotype was significantly associated with high cholesterol (p = 0.003) but not with triglycerides (p = 0.39). Adjusted odds ratios were: 5.8 for 4G/4G vs. 4G/5G (95% CI, 3.1-23.0), and 15.9 for 4G/4G vs. 5G/5G (95% CI, 2.4-105.0).
This finding may explain the involvement of the PAI-1 polymorphism in the clustering of atherothrombotic risk factors, and why people with the 4G/4G genotype are at increased risk for myocardial infarction. Stroke is not so clearly related to hypercholesterolemia and other effects of the 4G/4G genotype (perhaps increased PAI-1 expression) may protect against stroke.
[show abstract][hide abstract] ABSTRACT: The Italian region of Lombardy, with its existing stroke centers and high-technology laboratories, provides a favorable context for studying monogenic diseases associated with stroke. The Lombardia GENS project was set up to create a regional network for the diagnosis of six monogenic diseases associated with stroke: CADASIL, Fabry disease, MELAS, familial and sporadic hemiplegic migraine, hereditary cerebral amyloid angiopathy and Marfan syndrome. The network comprises 36 stroke centers and seven high-technology laboratories, performing molecular analysis. In this context, all stroke/TIA patients fulfilling clinical criteria for monogenic diseases are currently being included in an ongoing study. Demographic, clinical and family data and diagnostic criteria are collected using standardized forms. On the basis of stroke incidence in Lombardy and the reported prevalence of the diseases considered, we expect, during the course of the study, to collect datasets and DNA samples from more than 200 stroke patients suspected of having monogenic diseases. This will allow evaluation of the regional burden and better phenotype characterization of monogenic diseases associated with stroke.