Abstract 133: White Matter Hyperintensity and Cardiovascular Disease Outcomes: A Secondary Analysis of the SPRINT MIND Trial

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Adam H de Havenon ◽  
Tanya Turan ◽  
Sharon Yeatts ◽  
Rebecca Gottesman ◽  
Shyam Prabhakaran ◽  
...  
Keyword(s):  
White Matter ◽  
Primary Outcome ◽  
Stroke Risk ◽  
Secondary Analysis ◽  
White Matter Hyperintensity ◽  
Secondary Outcome ◽  
Cox Models ◽  
Disease Outcomes ◽  
Hazard Ratios ◽  
The Mean

Background: The Systolic Blood Pressure Intervention Trial (SPRINT) randomized patients to a goal SBP <120 mm Hg vs. <140 mm Hg . A subset of patients enrolled in SPRINT MIND, which performed a baseline MRI and measured white matter hyperintensity volume (WMHv). We evaluated the association between WMHv and cardiovascular events. Methods: The primary outcome was a composite of stroke, MI, ACS, decompensated CHF, or CVD death. The secondary outcome was stroke. The WMHv was divided into quartiles. We fit Cox models to the outcomes and report adjusted hazard ratios for the quartiles of WMHv, and stratified by SPRINT treatment arm. Results: Among 719 included patients, the mean WMHv in the quartiles was 0.34, 1.09, 2.61, and 10.8 mL. The primary outcome occurred in 51/719 (7.1%) and the secondary outcome in 10/719 (1.4%). The WMHv was associated with both outcomes (Table 1, Figure 1). After stratifying by treatment arm, we found the association persisted in the standard, but not intensive, treatment arm (Table 2). However, the interaction term between WMHv and treatment arm was not significant. Conclusions: We observed that degree of WMH was associated with CVD and stroke risk in SPRINT MIND. The risk may be attenuated in patients randomized to intensive BP lowering. Trials are needed to determine if intensive BP lowering can prospectively reduce the high cardiovascular risk in patients with WMH.

Abstract TMP99: White Matter Hyperintensity Progression and Subsequent Incident Stroke: A Secondary Analysis of the ACCORD Trial

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Adam H de Havenon ◽  
Sharon Yeatts ◽  
Rebecca Gottesman ◽  
Tanya Turan ◽  
Natalia Rost ◽  
...  
Keyword(s):  
Risk Factor ◽  
White Matter ◽  
Primary Outcome ◽  
Cox Model ◽  
Secondary Analysis ◽  
Exposure Period ◽  
White Matter Hyperintensity ◽  
Diabetic Patients ◽  
Cox Models ◽  
Recurrent Strokes

Introduction: Studies have shown that the volume of white matter hyperintensity (WMH) is a risk factor for stroke, but there are scarce data exploring the relationship between WMH progression on serial MRIs and subsequent risk of stroke. Hypothesis: We hypothesize that WMH progression in the ACCORD trial increases the risk of subsequent incident stroke. Methods: The exposure period was from baseline to month 40, during which an MRI was performed at both baseline and month 40. The primary outcome was incident ischemic stroke after the month 40 MRI until study completion. We fit Cox models to the primary outcome and included both the baseline and month 40 WMH volume as covariates, with the hazard ratio for the month 40 WMH volume of primary interest because it represents WMH progression in this model. Results: We included 497 patients, of whom 53.3% were male and the mean (SD) age was 62.7 (5.7) years at enrollment. Mean (SD) follow-up after the month 40 MRI was 5.2 (1.8) years. Incident stroke occurred in 17 (3.4%) patients, in whom 2 were recurrent strokes and 15 were first-ever strokes. WMH progression was associated with subsequent stroke in the Cox model (HR 1.27, 95% CI 1.03-1.57, p=0.024) and remained significant after adjusting for patient age, history of prior stroke, and cigarette smoking (HR 1.33, 95% CI 1.07-1.65, p=0.010). Conclusions: Although this preliminary analysis is underpowered, WMH progression, independent of absolute WMH burden, may be a risk factor for future stroke in diabetic patients. This novel finding could have translational implications - specifically that interventions which reduce the progression of WMH could, in turn, reduce future risk of stroke.

Abstract 42: Association of White Matter Hyperintensity Progression and Cognitive Decline: A Secondary Analysis of the ACCORDION MIND Study

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Adam H de Havenon ◽  
Sharon Yeatts ◽  
Rebecca Gottesman ◽  
Tanya Turan ◽  
Natalia Rost ◽  
...  
Keyword(s):  
White Matter ◽  
Verbal Learning ◽  
Secondary Analysis ◽  
Pressure Control ◽  
Epidemiological Studies ◽  
Adverse Outcomes ◽  
White Matter Hyperintensity ◽  
Diabetic Patients ◽  
Patients With Diabetes ◽  
The Mean

Introduction: Retrospective and epidemiological studies have shown that white matter hyperintensity (WMH) is associated with vascular dementia, but WMH progression on serial MRIs has not been examined in a prospective study of diabetic patients, who have a higher risk of the adverse outcomes associated with WMH including dementia. Methods: This is a secondary analysis of the Memory in Diabetes (MIND) substudy of the Action to Control Cardiovascular Risk in Diabetes Follow-on Study (ACCORDION). The primary outcome was 4 cognitive tests measured at a baseline visit and month 80 follow-up visit, including Rey’s Auditory Verbal Learning Test (RAVLT), Mini Mental Status Examination (MMSE), Stroop test, and Digit Symbol Coding (DSC). The primary predictor was WMH progression, represented as the WMH volume on the month 80 MRI with the baseline WMH volume included in the model. We predicted change in the cognitive scores by modelling their association with WMH progression. Results: We included 262 patients, with a mean (SD) baseline age of 62.7 (5.3) years and 56.1% male. The mean (SD) WMH volume on the baseline and month 80 MRIs was 1.9 (3.0) and 4.3 (6.0) mL, respectively. The change in WMH was significantly associated with the change in RAVLT score in the linear regression model (β Coef -0.132, p=0.029). (Table). The mean (SD) RAVLT at baseline and month 80 was 8.0 (2.4) and 8.5 (2.8). Conclusions: WMH progression in diabetic patients is associated with worse performance on memory testing over an 80 month period. Though preliminary and not able to account for location of WMH, our results are consistent with the hypothesis that WMH progression is harmful to cognition in diabetics. The SPRINT MIND trial recently reported that intensive blood pressure control attenuates WMH progression and development of mild cognitive impairment, but excluded patients with diabetes. Against this backdrop, our data suggest that diabetics should be included in future trials to reduce WMH progression.

Abstract MP14: White Matter Hyperintensity Progression, Macroalbuminuria, and Intensive Glycemic Control in Diabetics

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Varsha Muddasani ◽  
Nazanin Sheibani ◽  
Ka-ho Wong ◽  
Adam H De Havenon
Keyword(s):  
White Matter ◽  
Glycemic Control ◽  
Linear Regression ◽  
Secondary Analysis ◽  
White Matter Hyperintensity ◽  
Diabetic Patients ◽  
Intensive Glycemic Control ◽  
The Mean ◽  
Interaction Term

Introduction: White matter hyperintensity (WMH) is associated with a higher risk of stroke, dementia, and depression. Prior research has suggested that renal impairment and diabetes may predispose to the development of WMH. Here, we evaluated the association between WMH volume (WMHv), macroalbuminuria, and glycemic control in a cohort of diabetic patients. Methods: This is a secondary analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) dataset. The primary outcome is WMH progression in mL, evaluated by fitting linear regression to WMHv on the month 40 MRI and including the WMHv on the baseline MRI in the model. The primary predictors were incident macroalbuminuria, defined as new onset urinary albumin >300mg/day, and the ACCORD glucose randomization arm. Results: We included 502 patients. The mean (SD) WMHv at baseline was 2.1 (3.9) mL and at month 40 was 3.6 (5.7) mL. Twenty-three patients (4.6%) developed macroalbuminuria during the study period, who had a higher mean WMH progression (2.9 vs. 1.4 mL, p=0.012). In a linear regression model adjusted for mean systolic blood pressure during follow-up, macroalbuminuria was a significant predictor of WMH progression (Beta 1.20, 95% CI 0.17-2.22, p=0.022). In the same model, the interaction term between glucose randomization arm and macroalbuminuria was highly significant (Beta 3.38, 95% CI 1.20-5.57, p=0.003). The predicted follow-up WMHv for the interaction term are in Figure 1, showing that macroalbuminuria with intensive glycated hemoglobin reduction (goal A1c<6%) was associated with the most WMH progression. Conclusion: In diabetic patients, the development of macroalbuminuria was associated with WMH progression over 40 months, although only in patients assigned to intensive glycemic control. This finding is consistent with the adverse events seen in ACCORD with intensive glycemic control.

scholarly journals Using Ultrasound and Inflammation to Improve Prediction of Ischemic Stroke: A Secondary Analysis of the Multi-Ethnic Study of Atherosclerosis

2021 ◽  
pp. 37-43
Author(s):  
Hediyeh Baradaran ◽  
Alen Delic ◽  
Ka-Ho Wong ◽  
Nazanin Sheibani ◽  
Matthew Alexander ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Goodness Of Fit ◽  
Primary Outcome ◽  
Stroke Risk ◽  
Secondary Analysis ◽  
Predictor Variables ◽  
Baseline Model ◽  
Fit Statistics ◽  
Ischemic Stroke Risk

Introduction: Current ischemic stroke risk prediction is primarily based on clinical factors, rather than imaging or laboratory markers. We examined the relationship between baseline ultrasound and inflammation measurements and subsequent primary ischemic stroke risk. Methods: In this secondary analysis of the Multi-Ethnic Study of Atherosclerosis (MESA), the primary outcome is the incident ischemic stroke during follow-up. The predictor variables are 9 carotid ultrasound-derived measurements and 6 serum inflammation measurements from the baseline study visit. We fit Cox regression models to the outcome of ischemic stroke. The baseline model included patient age, hypertension, diabetes, total cholesterol, smoking, and systolic blood pressure. Goodness-of-fit statistics were assessed to compare the baseline model to a model with ultrasound and inflammation predictor variables that remained significant when added to the baseline model. Results: We included 5,918 participants. The primary outcome of ischemic stroke was seen in 105 patients with a mean follow-up time of 7.7 years. In the Cox models, we found that carotid distensibility (CD), carotid stenosis (CS), and serum interleukin-6 (IL-6) were associated with incident stroke. Adding tertiles of CD, IL-6, and categories of CS to a baseline model that included traditional clinical vascular risk factors resulted in a better model fit than traditional risk factors alone as indicated by goodness-of-fit statistics. Conclusions: In a multiethnic cohort of patients without cerebrovascular disease at baseline, we found that CD, CS, and IL-6 helped predict the occurrence of primary ischemic stroke. Future research could evaluate if these basic ultrasound and serum measurements have implications for primary prevention efforts or clinical trial inclusion criteria.

Abstract 47: Using Ultrasound and Inflammation to Improve Prediction of Ischemic Stroke: A Secondary Analysis of MESA

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Adam H de Havenon ◽  
Ka-Ho Wong ◽  
J Scott McNally ◽  
Jennifer Majersik
Keyword(s):  
Ischemic Stroke ◽  
Total Cholesterol ◽  
Primary Outcome ◽  
Epidemiologic Study ◽  
Secondary Analysis ◽  
Serum Marker ◽  
Patient Age ◽  
Cox Models ◽  
Patient Âgé

Background: The Multi-Ethnic Study of Atherosclerosis (MESA) is a large prospective epidemiologic study of the clinical factors that can predict transition from asymptomatic to symptomatic cardiovascular disease. Although prior studies have looked at ischemic stroke, they have not systematically examined the relationship between baseline ultrasound and inflammation measurements and subsequent primary stroke risk. Methods: The primary outcome is incident ischemic stroke during follow-up. The predictors are 9 ultrasound-derived measurements and 5 serum measurements related to inflammation. We fit Cox models to ischemic stroke and adjusted for patient age, hypertension, diabetes, total cholesterol, and smoking. Using DeLong’s method, we compared the AUC of the baseline adjusted model to the AUC of the model with predictor variables that were significant in the Cox models, to determine if they improved stroke prediction. Results: We included 6,095 patients with an average age of 61.9 years. The primary outcome of ischemic stroke was seen in 107 patients (1.8%) and the mean follow-up time was 7.7 years. In the Cox models, we found that small artery elasticity (SAE), carotid distensibility (CD), carotid stenosis (CS), and interleukin-6 (IL6) were associated with incident stroke. The AUC of the baseline model to predict stroke, which included patient age, hypertension, diabetes, total cholesterol, and smoking, was 0.745. When we added tertiles of SAE, CD, IL6 and categories of CS, the AUC improved to 0.765 (p=0.021 for difference). Conclusions: In a multiethnic cohort of patients without CVD at baseline, we found several ultrasound measurements and a serum marker of inflammation which predicted the occurrence of a primary ischemic stroke. Adding these basic ultrasound and serum measurements significantly improved the prediction of stroke, which could have implications for primary prevention efforts.

Abstract P622: Racial Variation in White Matter Hyperintensity Progression in the ACCORDION MIND Study

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Alison L Herman ◽  
Adam H De Havenon ◽  
Guido J Falcone ◽  
Shadi Yaghi ◽  
Shyam Prabhakaran ◽  
...  
Keyword(s):  
Blood Pressure ◽  
White Matter ◽  
Systolic Blood Pressure ◽  
White Matter Hyperintensity ◽  
Diabetic Patients ◽  
Patient Race ◽  
Black Patients ◽  
The Mean ◽  
White Patients

Introduction: White matter hyperintensities (WMH) are linked to cognitive decline and stroke. We hypothesized that Black race would be associated with greater WMH progression in the ACCORDION MIND trial. Methods: The primary outcome is WMH progression in mL, evaluated by fitting linear regression to WMH volume on the month 80 MRI and including the WMH volume on the baseline MRI. The primary predictor is patient race, with the exclusion of patients defined as “other” race. We also derived predicted probabilities of our outcome for systolic blood pressure (SBP) levels. Results: We included 276 patients who completed the baseline and month 80 MRI, of which 207 were white, 48 Black, and 21 Hispanic. During follow-up, the mean number of SBP, LDL, and A1c measurements per patient was 21, 8, and 15. The mean (SD) WMH progression was 3.3 (5.4) mL for blacks, 2.5 (3.2) mL for Hispanics, and 2.4 (3.3) mL for whites. In the multivariate regression model (Table 1), Black, compared to white, patients had significantly more WMH progression (β Coefficient 1.26, 95% CI 0.45-2.06, p=0.002). Hispanic, compared to white, patients did not have significantly different WMH progression (p=0.392), nor was there a difference when comparing Hispanic to Black patients (p=0.162). The predicted WMH progression was significantly higher for Black compared to white patients across a mean SBP of 117 to 139 mm Hg (Figure 1). Conclusions: Black diabetic patients in ACCORDION MIND have a higher risk of WMH progression than white patients across a normal range of systolic blood pressure.

A phase III trial of intramuscular recombinant interferon beta as treatment for exacerbating-remitting multiple sclerosis: design and conduct of study and baseline characteristics of patients

1995 ◽  
Vol 1 (2) ◽  
pp. 118-135 ◽  
Author(s):  
LD Jacobs ◽  
DL Cookfair ◽  
RA Rudick ◽  
RM Herndon ◽  
J R Richert ◽  
...  
Keyword(s):  
Primary Outcome ◽  
Interferon Beta ◽  
Outcome Measure ◽  
Primary Outcome Measure ◽  
Phase Iii ◽  
Secondary Outcome ◽  
Recombinant Interferon ◽  
Study Population ◽  
The Mean ◽  
Baseline Characteristics

The design and conduct of a randomized, double-blinded, placebo-controlled, multicenter, phase III study of recombinant interferon beta-1a (IFN-β-1a) as treatment for exacerbating-remitting MS are described, as are baseline characteristics of the study population. The purpose of the study was to determine if 6.0 × 106 IU (30 μg) of IFN-β-1a, administered by weekly intramuscular (i.m.) injections, was effective in delaying the onset of sustained disability. The primary outcome measure was time to onset of treatment failure, defined as a worsening on the Kurtzke Expanded Disability Status Scale (EDSS) of greater than or equal to 1.0 point compared with baseline, persisting for at least 6 months. An intent-to-treat design was used. The primary outcome measure was analyzed using the Mantel-Cox log-rank statistic and Kaplan-Meier survival curves. Secondary outcomes included quantitative measures of upper and lower extremity function, neuropsychological test performance, functional and quality of life assessments and several measures derived from annual brain MRI studies. Entry criteria included prestudy exacerbation rates of at least 0.67 per year and EDSS scores of 1.0–3.5. A total of 301 MS patients were randomly assigned to receive weekly i.m. injections of IFN-β-1a or placebo. The average age of the study population at entry was 37 years; 92% were Caucasian and 73% were women. The mean prestudy disease duration was 6.5 years, mean prestudy exacerbation rate was 1.2 per year and the mean EDSS score was 2.3. The randomization yielded well-balanced treatment arms. Various aspects of the study are discussed, including: (1) the decision to focus study design on sustained disability; (2) the rationale for the treatment regimen; (3) measures taken to assure the reliability of the primary outcome measure; and (4) a description of the secondary outcome measures.

Abstract 154: Diabetic Retinopathy and Risk of Stroke: A Secondary Analysis of Accord

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Ka-ho Wong ◽  
Cecilia Peterson ◽  
Rock Theodore ◽  
Kinga aitken ◽  
Michael Dela Cruz ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Primary Outcome ◽  
Cox Model ◽  
Secondary Analysis ◽  
Cox Models ◽  
Interaction Terms ◽  
Increased Risk ◽  
Microvascular Pathology ◽  
Fundus Photographs

Background: Diabetic retinopathy is a common microvascular complication of diabetes. Previous research has shown that the macrovascular complications of diabetes, including stroke, are often comorbid with shared and, possibly, synergistic pathology. Methods: This is a secondary analysis of the subgroup of patients who enrolled in the ACCORD Eye study of ACCORD. The primary outcome is stroke during follow-up. The primary predictor was presence of diabetic retinopathy on the Early Treatment Diabetic Retinopathy Study Severity Scale as assessed from seven-field stereoscopic fundus photographs at study baseline. We fit adjusted Cox models to the primary outcome to provide hazard ratios for stroke and included interaction terms with the ACCORD randomization arms. Results: We included 2,828 patients with a mean (SD) age of 62.1 years and 61.8% were male. The primary outcome of stroke was met by 117 patients during a mean (SD) of 5.4 (1.8) years of follow-up. Diabetic retinopathy was present in 874/2,828 (30.9%) of patients at baseline, and was more common in patients with stroke versus without stroke (41.0 vs 30.5%, p=0.016). In the Cox model, adjusted for baseline patient age, gender, race, total cholesterol, Hgb A1c, smoking, and randomization arm, we found that diabetic retinopathy remained associated with incident stroke (HR 1.60, 95% CI 1.10-2.32, p=0.015) (Figure 1). This association was not affected by randomization to the ACCORD glucose intervention (p=0.305), lipid intervention (p=0.546), or blood pressure intervention (p=0.422). Conclusion: Diabetic retinopathy is associated with an increased risk of stroke, which suggests that the microvascular pathology inherent to diabetic retinopathy has larger cardiovascular implications.

P–328 Dienogest significantly decreases the size of the cyst and alters Anti-Müllerian Hormone concentration in patients with endometrioma

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
E Karataş ◽  
B E Temiz ◽  
S Mumusoglu ◽  
H Yarali ◽  
G Bozdag
Keyword(s):  
Primary Outcome ◽  
Statistical Significance ◽  
Mean Difference ◽  
Secondary Outcome ◽  
Control Group ◽  
Significant Drop ◽  
Mean Size ◽  
The Mean ◽  
Respective Figure

Abstract Study question Does utilization of dienogest make any impact on the size of cyst and Anti-Müllerian Hormone (AMH) concentration in patients with endometrioma throughout 12-months? Summary answer Although dienogest makes a gradual reduction in the size of endometrioma cyst throughout 12-months, a significant drop in AMH serum concentration was also noticed. What is known already According to recent studies, pre-operative serum AMH levels might be illusively increased with parallel to the size of endometrioma which will be a misleading factor while deciding to operate the patient via cystectomy. Although dienogest is one of the medical options that might be commenced in patients with endometrioma cyst, there is limited data about its effect on the size of the endometrioma and hence serum AMH concentration throughout 12 months of follow up. Study design, size, duration The current observational cohort study was conducted among patients with endometrioma those treated with dienogest from January 2017 to January 2020. The primary outcome was alteration in diameter of endometrioma cyst at 6th and 12th months of treatment. Secondary outcome was alteration in serum AMH concentration in the same period. Of 104 patients treated with dienogest, 44 patients were excluded due to being treated with any type of surgical intervention during follow up period. Participants/materials, setting, methods A total of 60 patients were recruited for the final analysis. Of them, primary symptom was dysmenorrhea, chronic pelvic pain and menstrual irregularity in 16 (26.7%), 25 (41.7%) and 8 (13.3%) patients, respectively. Eighteen patients (30%) were asymptomatic. As 21 patients had bi-lateral endometrioma, size of the leading cyst was considered to be analyzed for the primary outcome measure. Paired-t test was used for comparison of numerical values and p ≤ 0.05 was taken as statistical significance. Main results and the role of chance The mean age was 31.5±8.0 years. In the time point when dienogest was started, the mean size of the endometrioma was 46.3±17.4 mm. The mean serum AMH concentration was 3.6±2.4 ng/ml. After 6 months of treatment, the mean size of the endometrioma decreased to 38.6±14.0 mm which corresponds to a mean difference of 7.8 mm (95% CI: 3.0 to 12.6; p: 0.003). The respective figure for AMH was 3.3±2.7 ng/ml which corresponds to a mean difference of 0.3 ng/ml (95% CI: –0.2 to 0.8; p: 0.23) at 6 months. After 12 months of treatment, the mean size of the endometrioma was 37.5±15.7 mm which corresponds to a mean difference of 8.9 mm (95% CI: 2.9 to 14.9; p: 0.005) at the end of 12 months. The respective figure for AMH was 2.7±1.9 ng/ml which corresponds to a mean difference of 0.9 ng/ml (95% CI: 0.1 to 1.7; p: 0.045) at the end of 12 months. The mean diameter of endometrioma and AMH concentration did not differ throughout the time period between 6th and 12th months of the treatment. Limitations, reasons for caution Although herein we present the largest data that depicts the alteration of endometrioma cyst and AMH concentration with the application of dienogest, the lack of control group is a limitation that avoids to perform any comparison. Wider implications of the findings: A shrinkage after commencement of treatment suggest that dienogest might present improvement in patients with endometrioma with respect to radiological findings, but further studies are required whether a decline in AMH concentration after 12 months refers to a genuine decrease in ovarian reserve or resolution of misleading high pre-treatment levels. Trial registration number not available

Abstract TMP58: Determinants of White Matter Hyperintensity in Acute Ischemic Stroke Patients: The MRI-GENIE Study

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Anne-Katrin Giese ◽  
Markus D Schirmer ◽  
Adrian V Dalca ◽  
Ramesh Sridharan ◽  
Lisa Cloonan ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Risk Factors ◽  
Ischemic Stroke ◽  
White Matter ◽  
Stroke Risk ◽  
Smoking Status ◽  
Vascular Risk Factors ◽  
White Matter Hyperintensity ◽  
Vascular Risk ◽  
Prior Stroke

Introduction: White matter hyperintensity (WMH) is a highly heritable trait and a significant contributor to stroke risk and severity. Vascular risk factors contribute to WMH severity; however, knowledge of the determinants of WMH in acute ischemic stroke (AIS) is still limited. Hypothesis: WMH volume (WMHv) varies across AIS subtypes and is modified by vascular risk factors. Methods: We extracted WMHv from the clinical MRI scans of 2683 AIS subjects from the MRI-Genetics Interface Exploration (MRI-GENIE) study using a novel fully-automated, volumetric analysis pipeline. Demographic data, stroke risk factors and stroke subtyping for the Causative Classification of Stroke (CCS) were performed at each of the 12 international study sites. WMHv was natural log-transformed for linear regression analyses. Results: Median WMHv was 5.7cm 3 (interquartile range (IQR): 2.2-12.8cm 3 ). In univariable analysis, age (63.1 ± 14.7 years, β=0.04, SE=0.002), prior stroke (10.2%, β=0.66, SE=0.08), hypertension (65.4%, β=0.75, SE=0.05), diabetes mellitus (23.1%, β=0.35, SE=0.06), coronary artery disease (17.6%, β=0.04, SE=0.002), and atrial fibrillation (14.6%, β=0.48, SE=0.07) were significant predictors of WMHv (all p<0.0001), as well as smoking status (52.2%, β=0.15, SE=0.05, p=0.005), race (16.5% Non-Caucasian, β=0.25, SE=0.07) and ethnicity (8.2% Hispanic, β=0.30, SE=0.11) (all p<0.01). In multivariable analysis, age (β=0.04, SE=0.002), prior stroke (β=0.56, SE=0.08), hypertension (β=0.33, SE=0.05), smoking status (β=0.16, SE=0.05), race (β=0.42, SE=0.06), and ethnicity (β=0.34, SE=0.09) were independent predictors of WMHv (all p<0.0001), as well as diabetes mellitus (β=0.13, SE=0.06, p=0.02). WMHv differed significantly (p<0.0001, unadjusted) across CCS stroke subtypes: cardioembolic stroke (8.0cm 3 , IQR: 4.2-15.4cm 3 ), large-artery stroke (6.9cm 3 , IQR: 3.1-14.7cm 3 ), small-vessel stroke (5.8cm 3 , IQR: 2.5-13.5cm 3 ), stroke of undetermined (4.7cm 3 , IQR: 1.6-11.0cm 3 ) or other (2.55cm 3 , IQR: 0.9-8.8cm 3 ) causes. Conclusion: In this largest-to-date, multicenter hospital-based cohort of AIS patients with automated WMHv analysis, common vascular risk factors contribute significantly to WMH burden and WMHv varies by CCS subtype.

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