Age Of Stroke Onset Research Articles

Abstract 95: Associations of Ischemic Stroke With Known Stroke Susceptibility Loci Vary by Age

Objective: The goal of this study was to test whether the strength of association of stroke-associated genetic variants differs by age of stroke onset. Background: In the MEGASTROKE GWAS study, 55 variants were robustly associated with ischemic stroke in predominantly older populations. Yet limited research has been carried out to date to understand how these genetic associations are modified by age, which could provide clues to the underlying biological mechanisms of these associations. Methods: Analyses were based on 16,000 stroke cases of European ancestry identified from the Stroke Genetics Network (SiGN) and Early Onset Ischemic Stroke Consortium and 24,838 stroke-free controls. We tested if the associations of each variant with stroke differed by age using two complementary approaches. First, we used a case-control logistic regression model testing for the associations of stroke with variant, age, and a variant*age interaction term and second, we used a case-only approach, testing for an association of variant with age of stroke onset. All analyses were adjusted for sex and population structure. Results: We identified six variants whose associations were significantly modified by age (p ≤ 0.001) by either analysis; 5 variants by the case-control analysis and 4 variants by the case-only analysis. Among these were 2 variants at the ABO locus that have been previously shown to be more strongly associated with early compared to late onset stroke, tagging blood groups A and O, respectively, and a variant in WNT2B that has previously been associated with early, but not late, onset ischemic stroke in a small case-control study. Conclusions: Six out of 55 variants previously associated with ischemic stroke in large GWAS studies show differential effects by age, with the stroke risk allele more strongly associated with early onset stroke for 5 variants or more strongly associated with older onset stroke (1 variant). Future work is needed to understand the reasons for this age dependency. Disclosures: None. Study Supported By: R01NS100178, R01NS105150, R01NS114045

Biological Age Acceleration Is Lower in Women With Ischemic Stroke Compared to Men

Stroke onset in women occurs later in life compared with men. The underlying mechanisms of these differences have not been established. Epigenetic clocks, based on DNA methylation (DNAm) profiles, are the most accurate biological age estimate. Epigenetic age acceleration (EAA) measures indicate whether an individual is biologically younger or older than expected. Our aim was to analyze whether sexual dichotomy at age of stroke onset is conditioned by EAA. We used 2 DNAm datasets from whole blood samples of case-control genetic studies of ischemic stroke (IS), a discovery cohort of 374 IS patients (N women=163, N men=211), from GRECOS (Genotyping Recurrence Risk of Stroke) and SEDMAN (Dabigatran Study in the Early Phase of Stroke, New Neuroimaging Markers and Biomarkers) studies and a replication cohort of 981 IS patients (N women=411, N men=570) from BASICMAR register. We compared chronological age, 2 DNAm-based biomarkers of aging and intrinsic and extrinsic epigenetic age acceleration EAA (IEAA and extrinsic EAA, respectively), in IS as well as in individual IS etiologic subtypes. Horvath and Hannum epigenetic clocks were used to assess the aging rate. A proteomic study using the SOMAScan multiplex assay was performed on 26 samples analyzing 1305 proteins. Women present lower Hannum-extrinsic EAA values, whereas men have higher Hannum-extrinsic EAA values (women=-0.64, men=1.24, P=1.34×10-2); the same tendency was observed in the second cohort (women=-0.57, men=0.79, P=0.02). These differences seemed to be specific to cardioembolic and undetermined stroke subtypes. Additionally, 42 blood protein levels were associated with Hannum-extrinsic EAA (P<0.05), belonging to the immune effector process (P=1.54×10-6) and platelet degranulation (P<8.74×10-6) pathways. This study shows that sex-specific underlying biological mechanisms associated with stroke onset could be due to differences in biological age acceleration between men and women.

Genetic Factors, Brain Atrophy, and Response to Rehabilitation Therapy After Stroke

Objective Patients show substantial differences in response to rehabilitation therapy after stroke. We hypothesized that specific genetic profiles might explain some of this variance and, secondarily, that genetic factors are related to cerebral atrophy post-stroke. Methods The phase 3 ICARE study examined response to motor rehabilitation therapies. In 216 ICARE enrollees, DNA was analyzed for presence of the BDNF val66met and the ApoE ε4 polymorphism. The relationship of polymorphism status to 12-month change in motor status (Wolf Motor Function Test, WMFT) was examined. Neuroimaging data were also evaluated (n=127). Results Subjects were 61±13 years old (mean±SD) and enrolled 43±22 days post-stroke; 19.7% were BDNF val66met carriers and 29.8% ApoE ε4 carriers. Carrier status for each polymorphism was not associated with WMFT, either at baseline or over 12 months of follow-up. Neuroimaging, acquired 5±11 days post-stroke, showed that BDNF val66met polymorphism carriers had a 1.34-greater degree of cerebral atrophy compared to non-carriers (P=.01). Post hoc analysis found that age of stroke onset was 4.6 years younger in subjects with the ApoE ε4 polymorphism (P=.02). Conclusion Neither the val66met BDNF nor ApoE ε4 polymorphism explained inter-subject differences in response to rehabilitation therapy. The BDNF val66met polymorphism was associated with cerebral atrophy at baseline, echoing findings in healthy subjects, and suggesting an endophenotype. The ApoE ε4 polymorphism was associated with younger age at stroke onset, echoing findings in Alzheimer’s disease and suggesting a common biology. Genetic associations provide insights useful to understanding the biology of outcomes after stroke.

Abstract 9924: Polygenic Risk Score for PR Interval is Associated with Increased Risk of Ischemic Stroke

Atrial cardiomyopathy (AC) is an emerging risk factor for ischemic stroke (IS). We used polygenic risk scores (PRS) to study the association of the PR interval (PRI)-- an ECG marker for AC-- with IS and IS subtypes. We studied PRI, rather than other AC traits, because a validated multi-ethnic PRI-PRS exists. Methods: We calculated PRI-PRS for patients in the NINDS Stroke Genetics Network (SiGN) database, which contains well-characterized stroke patients and in which we have found an association of a PRS for atrial fibrillation with IS subtypes. We derived PRS for 10 GWAS thresholds after a clumping procedure to eliminate SNPs in linkage disequilibrium. SNPs were weighted by their beta coefficients from the GWAS summary statistics to generate PRS. We normalized by the number of SNPs included. We used logistic regression to compare PRI-PRS in stroke cases (n=13930) and non-stroke controls (n=49473). We controlled for sex and the first 10 principal components of genetic ancestry. We stratified by genetic ancestry and genotype platforms. Logistic regression analyses for each stratum were meta-analyzed using an inverse-variance weighting-based method, assuming fixed effects. Results and Conclusions: In the overall meta-analysis, PRI-PRS was weakly associated with increased risk of IS (p&lt;0.02, only for one GWAS threshold). PRI-PRS was associated with increased risk of IS due to small artery occlusion (SAO) (p=0.032 and 0.033, using GWAS of PRI p-value thresholds 0.05 and 0.005 respectively), but not with other IS subtypes. The SAO association may reflect the association of PRI and hypertension, a risk factor for SAO. In a secondary analysis of European strata, we observed a robust association (p&lt;0.02 across all GWAS thresholds) of the PRI-PRS with all IS in GEOS, which consists of younger onset strokes (age of stroke onset &lt; 50 years). PRI-PRS was also associated in GEOS (p&lt;0.01 across all GWAS thresholds) with the subtype of strokes of undetermined origin, which includes embolic strokes of unknown source (ESUS). PRI-PRS was also associated with large artery strokes at some GWAS thresholds in GEOS. Our results suggest that genetic risk for prolonged PRI is associated with SAO and may have more robust associations with other stroke subtypes in some populations.

Abstract P396: Hospital Management of Major Stroke Types in Urban and Rural China: Findings From a 11-Year Community-Based Studies Involving &gt;20,000 Hospitalized Stroke Cases

Background: Little is known about the contemporary use of hospital treatments for major stroke pathological types in urban and rural areas of China. Methods: The China Kadoorie Biobank recruited &gt;0.5 million adults (mean age 51 years, 59% women) during 2004-08 from ten (five urban, five rural) diverse areas in China. In-hospital medical records were retrieved from 20,229 participants (n=261 hospitals) hospitalised with a first-ever incident stroke over an 11-year follow-up period. Details of hospital management of stroke cases were analysed by sex, age of stroke onset, calendar year, hospital tier, region and other factors. Results: Among the 20,299 first-ever stroke cases, 17,306 (85%) had ischaemic stroke (IS; 7,123 non-lacunar, 6,690 lacunar and 3,493 silent lacunar), 2,623 (13%) had intracerebral haemorrhage (ICH), and 370 (2%) had subarachnoid haemorrhage (SAH). Among IS cases, anti-platelet treatment was used by 64% (65% non-lacunar, 66% lacunar, 56% silent lacunar), lipid-lowering by 50% (52% non-lacunar, 53% lacunar, 43% silent lacunar), blood pressure-lowering by about 42% of all IS subtypes, along with traditional Chinese medicines (TCM) by 59% (50% non-lacunar, 62% lacunar, 74% silent lacunar), with positive trends in use of these treatments by calendar year (Figure 1A), but inverse trends by hospital tier except TCM (Figure 1B). Approximately half of ICH (52.6%) or SAH (50.5%) cases received blood pressure-lowering medication, which did not vary significantly by area. A small proportion of cases with SAH had surgery to insert a coil (7.0%) or clip on aneurysm (5.7%). Interpretation: Among IS cases, use of antiplatelet, lipid-lowering and TCM increased in recent years and exceeded use of blood pressure-lowering treatment. In contrast, about half of all ICH and SAH cases used blood pressure-lowering treatments and there is significant under-use of surgery for SAH cases.

Abstract 91: Moyamoya Disease Susceptibility Gene, RNF213 p.R4810K Variant, is a Common Risk Factor for Atherothrombotic Brain Infarction in a Japanese Population

Background and Purpose: RNF213 has been identified as a susceptibility gene for moyamoya disease. The p.R4810K variant is found in about 80% of East Asian patients with moyamoya disease, and 20 - 25% of those with proximal intracranial arterial stenosis. In this study, we examined the association of RNF213 p.R4810K variant with non-cardioembolic stroke in a Japanese population. Methods: We analyzed 383 consecutive patients with acute non-cardioembolic stroke, who were admitted to the National Cerebral and Cardiovascular Center from June 2012 to May 2017 and participated in NCVC Biobank, and 1011 healthy local Japanese controls. Patients diagnosed with moyamoya disease were excluded. Written informed consent was obtained from all study participants. Odds ratios (OR) and 95% confidence intervals (CI) were adjusted for age, sex, and conventional risk factors for stroke. Results: The RNF213 p.R4810K variant was found in 5.2% of acute non-cardioembolic stroke patients and in 2.1% of healthy controls (adjusted OR 3.9, 95% CI 1.6 - 9.3, p=0.003). The mean age of stroke onset was lower in patients with the RNF213 p.R4810K variant than those without the variant (58.1±15.5 years vs. 69.1±13.2 years, p&lt;0.001). Among stroke subtypes, only atherothrombotic brain infarction (ATBI) was significantly associated with this variant (adjusted OR 11.5, 95% CI 3.4 - 36.2, p&lt;0.001, see also Table 1). When stratified by sex, these associations were more evident in women (Men: adjusted OR for ATBI 1.9, 95% CI 0.3 - 10.2, p=0.47; Women: adjusted OR for ATBI 58.0, 95% CI 10.3 - 327.3, p&lt;0.001, see also Table 1). Conclusion: The RNF213 p.R4810K variant is a genetic risk factor for non-cardioembolic stroke in Japan, especially for atherothrombotic brain infarction in women.

Trends in Age of First-Ever Stroke Following Increased Incidence and Life Expectancy in a Low-Income Chinese Population.

We investigated secular trends in the age of stroke onset and stroke incidence in a low-income population in rural China. The study population was recruited from a population-based stroke surveillance study conducted in a township in Tianjin, China, from 1992 to 2014. The trends in mean age and incidence of first-ever stroke were assessed by sex and stroke subtype. Risk factor surveys were conducted in the same population in both 1991 and 2011. A total of 1053 patients experienced first-ever stroke from 1992 to 2014. The mean age of stroke onset in men significantly decreased by 0.28 years annually overall, by 0.56 years for intracerebral hemorrhage, and by 0.22 years for ischemic stroke (P<0.05). However, a similar trend was not observed in women. The age-standardized first-ever stroke incidence in the same population significantly increased across sex and stroke subtypes, increased by 6.3% overall, 5.5% for men, 7.9% for women, 4.6% for intracerebral hemorrhage, and 7.3% for ischemic stroke (P<0.05) during 1992 to 2014. Concurrently, the prevalence of hypertension, diabetes mellitus, obesity, current smoking, and alcohol consumption increased significantly in young and middle-aged adults from 1991 to 2011. The age of stroke onset tends to be younger among low-income population in China after the dramatic increased incidence of stroke during the gradual extension of life expectancy of population in China. These findings suggested that stroke burden will continue to increase in the long time, unless the risk factors in low-income populations are effectively controlled.

Abstract TP178: Relationship Between Deprivation and Outcome for Stroke Patients: Data From the UK National Stroke Registry

Introduction: Previous studies have identified that social deprivation is associated with the onset of stroke, with people from areas of higher deprivation being more likely to have a stroke at a younger age. Methods: Data were extracted from the national stroke register (Sentinel Stroke National Audit Programme (SSNAP)) of adults with acute ischemic stroke treated in all hospitals in England and Wales from April 2013-March 2014. The patient’s zip code of residence was used to link the data with an index of multiple deprivation, which groups zip codes into quartiles of deprivation. Results: Of the 66798 adults with acute stroke discharged from 266 hospitals, deprivation data was available for 63007 patients (94.3%).The median age of stroke onset for the most deprived quartile was 5 years lower than for the least deprived quartile (74, 77, 79 and 79 years respectively, Kruskal-Wallis test p&lt;0.001). For patients in the most deprived quartiles compared to the least deprived, the rate of primary intracerebral hemorrhage was lower (9.9%, 10.5%, 10.7% and 11.7% respectively, chi2 p&lt;0.001), the rate of diabetes was higher (22.7%, 20.6%, 17.9% and 15.8%, chi2 p&lt;0.001), and the prevalence of congestive heart failure, hypertension and previous stroke/TIA were similar for all groups. The rate of atrial fibrillation (AF) prior to stroke was lower for more deprived patients (17.6%, 19.8%, 22.9% and 22.6%, chi2 p&lt;0.001), but the percentage of patients on anticoagulants if in AF was similar for all groups. Mortality at 30 days was lower in the most deprived group compared to the least deprived group (12.8%, 14.6%, 15.7% and 15.4%, chi2 p&lt;0.001). Conclusions: Patients living in more deprived areas have stroke at a younger age and are more likely to have a prior history of diabetes mellitus. Outcomes are similar for all groups but crude mortality at 30 days was lower for the most deprived group. This may be due to the lower median age of stroke onset, and the higher proportion of ischemic strokes. Predictive models for stroke outcome need to consider levels of deprivation and we are currently working on multivariable analysis to identify any independent effect of deprivation on mortality.

Sex differences in long-term outcomes among acute ischemic stroke patients with diabetes in China.

BackgroundDiabetes has been shown to be significantly associated with poor outcome after stroke. However, the sex differences in stroke outcome among patients with diabetes are unknown. Therefore, we aimed to assess the sex differences in long-term prognosis among acute ischemic stroke patients with diabetes.MethodsThe ischemic stroke patients with diabetes were recruited to this study between May 2005 and September 2014 in Tianjin, China. Sex differences in mortality, dependency (modified rank scale > 2), and recurrence at 3, 12, and 36 months after stroke were analyzed.ResultsA total of 2360 patients were recruited in this study. The age of stroke onset, National Institute of Health stroke scale (NIHSS), and modified rank scale (mRS) on admission were greater in women than in men (P < 0.05). Women were more likely to have hypertension, obesity, atrial fibrillation, and dyslipidemias. In contrast, men were more likely to have artery stenosis, current smoking, and alcohol consumption (P < 0.001). There was higher mortality in women than in men at 3 months (7.9 % vs 5.2 %), 12 months (12.2 % vs 8.2 %), and 36 months (21.9 % vs 16.1 %) after stroke; but no differences were found in dependency and recurrence. Sex differences were found in associated factors of outcomes by time-point. Trial of Org 10172 in Acute Stroke Treatment (TOAST) of large artery atherothrombosis (LAA), cardioembolism (CE), and smoking were risk factors of outcomes in women at short term and medium term; but atrial fibrillation (AF), obesity, and alcohol were risk factors of outcomes in men at medium term and long term.ConclusionsThese findings suggest that it is crucial to establish the individual scheme of therapy for every patient by different risk factors of stroke, strengthen the rehabilitation of stroke, and carry on the health education early for the secondary prevention of stroke in patients with diabetes mellitus (DM).

Age of stroke onset in men and women in the last 17 years: results of the RECCA registry

Age of stroke onset in men and women in the last 17 years: results of the RECCA registry

Determinants of White Matter Hyperintensity Burden Differ at the Extremes of Ages of Ischemic Stroke Onset

Age is a well-known risk factor for both stroke and increased burden of white matter hyperintensity (WMH), as detected on magnetic resonance imaging (MRI) scans. However, in patients diagnosed with ischemic stroke (IS), WMH volume (WMHv) varies significantly across age groups. We sought to examine the determinants of WMH burden across the ages of stroke onset with the goal to uncover potential age-specific stroke prevention targets. Adult subjects from an ongoing hospital-based cohort study of IS patients with admission brain MRI were categorized as having early (<55 years), late (>75 years), or average (55-75 years) age of stroke onset. WMHv was measured using a previously validated, MRI-based semi-automated method and normalized for linear regression analyses. Of 1008 IS subjects, 249 had early-onset stroke (24.7%), and 311 had late-onset stroke (30.9%). In multivariable analysis of WMHv using backward stepwise selection, only age (β = .02, P = .018), hypertension (β = .24, P = .049), and history of tobacco use (β = .38, P = .001) were independently associated with WMHv in patients with early-onset stroke, whereas male sex (β = -.30, P = .007), hyperlipidemia (β = -.27, P = .015), and current alcohol use (β = .23, P = .034) were independently associated with WMHv in patients with late-onset stroke. History of tobacco use is a strong independent predictor of WMH burden in patients with early-onset stroke, whereas age is no longer associated with WMHv in IS patients older than 75 years of age. These findings suggest that the major risk factors to target for stroke prevention differ across age groups and may be modifiable.

PRKCH 1425G/A Polymorphism Predicts Recurrence of Ischemic Stroke in a Chinese Population.

A recent genome-wide association study (GWAS) identified a nonsynonymous SNP (1425G/A) in PRKCH which was associated with increased risk of ischemic stroke. The purpose of this study was to examine whether this functional polymorphism is associated with stroke onset and prognosis in a Chinese population. We genotyped PRKCH 1425G/A using Improved Multiple Ligase Detection Reaction in 919 patients with ischemic stroke. Analyses of genotype association with onset and prognosis outcomes were assessed by the Kaplan-Meier method, the log-rank test, and the Cox proportional hazards models. PRKCH 1425G/A was not associated with age of stroke onset (P = 0.323). However, this functional polymorphism was significantly associated with risk of stroke recurrence in recessive models (hazard ratio [HR] = 2.23; 95% confidential interval [CI], 1.06 to 4.68; P = 0.014), and this effect was more predominant among smokers (HR = 3.67; 95% CI, 1.47-9.18; P = 0.005). Moreover, the variant genotypes of PRKCH 1425G/A are an independent prognostic factor for ischemic stroke in the final multivariate Cox regression model. Our findings show that PRKCH 1425G/A may be a useful biomarker for predicting the recurrence of ischemic stroke.

Chromosome 12p13 variants predict recurrence of ischaemic stroke in a Chinese population.

A recent genome-wide association study identified two genetic variants (rs12425791 and rs11833579) on chromosome 12p13 that confer risk of ischaemic stroke. The purpose of this study was to examine whether these two polymorphisms are associated with stroke onset and prognosis in a Chinese population. rs12425791 and rs11833579 were genotyped using the improved multiple ligase detection reaction in 913 patients with ischaemic stroke. Analyses of genotype association with onset and prognosis outcomes were evaluated by the Kaplan-Meier method, the log-rank test and Cox proportional hazards models. rs12425791 and rs11833579 were not associated with age of stroke onset (P=0.786 and 0.340, respectively). However, these two polymorphisms were significantly associated with risk of stroke recurrence, especially for the large-artery atherosclerosis (LAA) subtype, in recessive models [hazard ratio (HR)2.52; 95% confidence interval (CI) 1.04-6.12 for rs12425791; HR2.13; 95% CI 1.03-4.40 for rs11833579]. The combined genotype of these two single-nucleotide polymorphisms showed a locus-dosage effect on recurrence of LAA subtype and was an independent prognostic factor for LAA subtype in the final multivariate Cox regression model. These findings indicated that rs12425791 and rs11833579 on chromosome 12p13 may be useful biomarkers for predicting the prognosis of patients with the LAA subtype of ischaemic stroke.

Abstract T P130: Determinants of White Matter Hyperintensity Burden Differ at the Extremes of Age of Ischemic Stroke Onset

Background: White matter hyperintensity (WMH) detected on MRI scans of patients with acute ischemic stroke (AIS) is associated with greater risk of infarct progression, poor post-stroke outcomes, and recurrent stroke. Age is strongly linked to risk of stroke and WMH. We hypothesized that determinants of WMH severity differ across the lifetime and sought to test it in a prospective cohort of AIS patients with early (&lt;55 years), late (&gt;75 years) versus average age of stroke onset. Methods: Clinical characteristics as well as laboratory and radiographic data were ascertained on admission for AIS in all consecutive patients ≥ 18 years. WMH volume (WMHv) was measured using a previously validated, semi-automated method, normalized for intracranial area, and natural log-transformed for univariate and multivariate linear regression analyses. Results: Of 754 AIS patients, 175 (23.2%) developed early-onset (mean age 46.4 ± 7.5 years) and 237 (31.4%) late-onset (mean age 82.1 ± 5.2 years) stroke. Median WMHv differed between the early-onset AIS (2.4cc, IQR 1.6 - 4.5), late-onset AIS (11cc, IQR 5.8 - 23.2) and average-age-of-onset stroke patients (mean age 65.6 ± 5.8 years, median WMHv 6.4cc, IQR 3.2 - 13.0). In univariate analysis, WMHv burden was associated with age (p = 0.03) and history of tobacco use (p = 6.6E-3) in early-onset AIS, with gender (p = 0.03) in late-onset AIS, versus age (p = 1.8E-8) and hyperlipidemia (p = 0.045) in average-age-of-onset AIS. Although backward stepwise selection confirmed male gender (ß = -0.26, p = 0.04) in late-onset AIS patients as well as age (ß = 0.05, p = 3.9E-8) and hyperlipidemia (ß = -0.26, p = 0.02) in patients with average age of AIS onset as predictors of WMHv, only tobacco use (ß = 0.35, p = 8.8E-3) remained an independent predictor of WMHv severity in early-onset AIS patients. Conclusions: Phenotypic determinants of WMH severity in AIS patients differ at the extremes of age of stroke onset, including a strong link between tobacco use in patients with early-onset stroke and burden of small cerebral vessel disease. While age remains a major risk factor for WMH, modifiable determinants - such as smoking - should be targeted in the future to reduce WMH and mitigate stroke risk in each age group.

Association of FunctionalVKORC1Promoter Polymorphism with Occurrence and Clinical Aspects of Ischemic Stroke in a Greek Population

Genetic factors are considered to play an important role in determining the susceptibility to the occurrence, clinical course, and functional outcome of an acute ischemic stroke (IS). Undercarboxylation of specific vitamin K-dependent proteins, due to genetic polymorphisms of VKORC1, can affect both vascular calcification and thrombogenicity. We sought to determine the association of VKORC1 −1639G > A polymorphism with IS incidence, age of onset, severity of disease, and functional outcome after an acute IS. VKORC1 −1639G > A polymorphism was determined in 145 consecutive patients with first ever IS and 145 age- and sex-matched control subjects of Greek Caucasian origin using PCR-RFLP. Stroke severity and functional outcome were assessed on admission and at one month after stroke, respectively. Frequency of VKORC1 −1639G > A genotypes did not differ between IS patients and controls (OR = 1.12, P = 0.51). Moreover, carriage of the A allele was not associated with age of stroke onset, severity of disease (Scandinavian stroke scale score 32.2 versus 32.9, resp., P = 0.96), or poor outcome at 1 month post-stroke (52.9 versus 64.4%, resp., P = 0.31). In conclusion, VKORC1 −1639G > A polymorphism is not a genetic determinant of IS occurrence, age of onset, severity, or functional outcome of disease in a Greek population.

Abstract 2373: Childhood Stroke Impairs Functional Behavior

BACKGROUND: Stroke can affect children with long-term impairment of intellectual ability and increased risk of attention deficits and psychiatric disorders. Although limited studies in the literature suggest that stroke can chronically impair functional behavior and social adaptation, these functional outcomes have received little attention. We performed a pilot case-control study to examine the hypothesis that pediatric stroke impairs adaptive behavior, and we addressed the secondary hypotheses that stroke volume and location predict impaired functional behavior. METHODS: Children ages 6-15 years who had neonatal or childhood onset arterial ischemic stroke were identified by chart review at the Nationwide Children’s (Columbus, OH, USA) and Royal Children’s Hospital (Melbourne, Australia). Subjects were included if they could complete the test battery. Age- and gender-matched children who had asthma were selected as controls. Stroke cases were assessed with the Pediatric Stroke Outcome Measure and had an MRI brain scan after the acute phase of stroke. Cases and controls underwent functional assessments at least one year after the incident stroke. The battery of tests and ratings included the Wechsler Abbreviated Scales of Intelligence, WISC-IV Processing Speed Index, Child Behavior Checklist, Adaptive Behavior Assessment System, and Child &amp; Adolescent Scale of Participation. Infarct volumes were measured by manual segmentation. RESULTS: The sample included 10 children with perinatal stroke, 26 with acquired childhood stroke, and 15 controls. Median age at assessment was 8.7 yrs (IQR 6.9-11.9) and median time after presentation was 5.1 yrs (IQR 2.8-7.4). The median PSOM for stroke cases was 1 (range 0-8.0) and for controls was 0 (range 0-1). Stroke was significantly associated with lower levels of multiple daily living skills (p range 0.001-0.025), functional academics (p=0.048), and self-care (p=0.020), as well as a trend toward impaired school participation (p=0.064), but was not associated with impaired intellectual functioning or behavioral adjustment. Larger Infarcts showed a trend association with higher PSOM total scores (p=0.091). Infarcts that involved both cortex and subcortical parenchyma were associated with poorer daily living skills (p range 0.005-0.052) and a trend toward impaired home community participation (p=0.079). Age of stroke onset was not associated with impairments. Conclusions: Stroke causes deficits that may not be appreciated by standard IQ screening or report of overt behavior disorders. These deficits can affect daily living skills and result in impaired adaptive behavior. Strokes involving both cortex and subcortex, as a proxy for more extensive strokes, may be particularly associated with impaired adaptive behavior. These results are “best case” estimates because our study excluded mentally retarded or grossly impaired children.

Abstract 2531: Gene Pathway Analysis In Young- Vs. Old-onset Ischemic Stroke

BACKGROUND AND PURPOSE: Ischemic stroke is a heterogeneous complex disease that results from the interaction between numerous genetic and environmental risk factors. Stroke heritability is approximately 40% in the overall population, similar to that of cancer, although there may be important differences in the etiologies of young (&lt;49 years old) versus older onset ischemic stroke. The goal of this study was to conduct a mechanistic genome-wide association (GWA) analysis contrasting the gene pathways involved in young- and old-onset stroke. METHODS: Our analysis included 946 young subjects (448 ischemic stroke subjects and 498 age and sex matched controls, mean age of stroke onset 41 years) and 2558 older subjects (1070 ischemic stroke subjects and 1488 controls, mean age of stroke onset 66.5 years). All subjects were of European ancestry. The young onset cases and controls were genotyped by Illumina Omni1-Quad array with imputation up to 1.8 M SNPs and the old onset cases and controls by a combination of 550 v1 and v3 as well as 610 Illumina arrays with imputation up to 5.0 M SNPs. Single SNP association testing was performed within each contributing study by logistic regression adjusting for age, sex and population structure. Numbers of genes assigned with significant SNPs (P&lt;=0.0001) were 18 and 25 with young- and old-onset groups, respectively, which were used as an input to pathway analysis by the Pathway Studio (Ariadne Genomics, Co.) RESULTS: SNP-level analyses did not reveal any significant associations with each group that met Bonferroni adjusted thresholds for statistical significance. In analyzing the ‘suggestively associated SNPs’, protein-protein interaction pathway analysis in the young-onset group revealed a strong segregation of significant hub proteins (CAT, RUNX1, and EIF4E) with more than 100 connections, while in the old-onset group the interaction networks were dispersed without much segregation. We observed that protein-protein interaction networks have a power-law connectivity distribution in both young- and old-onset groups. We identified 3 significant and focused pathways, ROS metabolism, melanogenesis, and IGF1R-&gt;CdEBPA/FOXO1A signaling, enriched for young-onset stroke (P&lt;0.04). In the old-onset group, 10 pathways were identified involving broader signaling pathways. CONCLUSIONS: Young-onset stroke may involve genetic predisposition characterized by a few distinct and finite pathways. Our data suggests that young onset stroke may involve a few pathways that relate to a small number of key hub proteins, including ROS metabolism, melanogenesis, and IGF1R-&gt;CEBPA/FOXO1A signaling. Our analysis is consistent with the hypothesis that different pathways may be involved in young versus old onset stroke.

The Author Response: The Supernumerary Phantom Limb and Phantom Limb Pain in Stroke: Localization and Management Concerns

The supernumerary phantom limb is the problem of perception of body scheme (1), and phantom limb pain is one type of central pain, defined as central neuropathic pain caused by lesions or dysfunction in the central nervous system (brain, brainstem, and spinal cord) (2). Central pain is a neurological disorder that is rather common although difficult to treat, causing unrelenting suffering and disability (3). Diagnosis of central pain that may occur following stroke is complicated by cognitive and speech limitations as well as by depression, anxiety and sleep disturbances. Localized brain lesions causing central pain and their management have not been established clearly. Kiefer et al. (4) reported that the phantom limb pain is difficult to treat compared to conventional pain, and repetitive transcranial magnetic stimulation (rTMS) have shown to respond to drug resistant neurogenic pain (3, 5). The mechanism of cortical stimulation for the relief of pain is based on the excitability modification of neuronal activity intimately involved in the neural circuits responsible for perception and pain processing. Lefaucheur et al. (5) studied whether neurogenic pain relief by rTMS depended on the origin or the site of pain. The most favorable conditions were trigeminal nerve lesion, facial pain, and absence of severe sensory loss within the painful zone. The worst conditions were brainstem stroke, limb pain, and severe sensory loss. Basbaum et al. (6) described various descending modulatory pathways in the brainstem acting on pain transmission. Patients with brainstem stroke could have damage on these structures, leading to the inefficacy of corticothalamic descending control triggered by rTMS. The patients in our case report had the supernumerary phantom limb and phantom limb pain after brainstem stroke (7). We chose multimodal sensory neurocognitive rehabilitation and anticonvulsants (pregabalin) instead of rTMS (1). The purported age difference between poststroke patients, who developed central poststroke pain and those who did not, is a subject of some debate in the literature. Anderson et al. (8) found no disparity in age between the patients that went on to develop central poststroke pain (n = 87) versus those that did not (n = 120). Bowsher (9) found a significant difference in age of stroke onset between 130 central pain patients (median age 57 yr) and the whole stroke population (median age 75 yr). No studies on the relationship of demographic characteristics and phantom limb pain have been published. Both patients in our case report are middle-aged, highly educated, and have median socioeconomic status. In addition, the patients did not have psychotic symptoms (hallucination, delusion), therefore psychiatric consultation about supernumerary phantom limb was thought to be unnecessary. Subsequent larger and randomized studies are needed to examine the relationship between demographic characteristics (age, sex, education level), personality characteristics and central pain including phantom limb pain. We really appreciate the comments by Dr. Das, and further evaluation is needed for the brain localization of body scheme and the management of central pain.

Effect of Radical Scavenger N-Tert-Butyl-α-Phenylnitrone on Stroke in a Rat Model Using a Telemetric System

We used malignant stroke-prone spontaneously hypertensive rats (M-SHRSP) as a stroke model to explore the effects of the radical scavenger N-tert-butyl-alpha-phenylnitrone (PBN) on stroke. PBN was administrated in drinking water to M-SHRSP. Circadian rhythms in heart rate, blood pressure, and locomotive activity in M-SHRSP were monitored with a telemetric system, in addition to measurement of water intake and body weight. Stroke-onset was assessed by changes in neurological symptoms, water intake, and body weight. Circadian rhythms were basically the same between PBN-treated and control rats several days after stroke onset. Significant differences were seen in blood pressure, relative weight of brain and water intake, heart rate, and locomotive activity between two groups. As a result, no significant difference in age of stroke onset was seen between PBN-treated and control rats, but PBN-treated rats displayed prolonged mean life spans. PBN might be effective in prolonging life span.