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Anderson C.D.,Center for Human Genetic Research | Charidimou A.,Massachusetts General Hospital | Charidimou A.,University College London
Neurology | Year: 2015

The MRI era has provided vascular neurologists with a number of novel imaging markers that associate with clinical outcomes in stroke and cerebrovascular disease. Examples include periventricular white mater hyperintensities, lobar and deep cerebral microbleeds, cortical superficial siderosis, and cerebral microinfarcts.1,2 Recently, MRI-visible perivascular spaces (or Virchow-Robin spaces) have been associated with both deep and lobar intracerebral hemorrhage (ICH),3 and have therefore garnered increasing attention. Although classically thought of as extensions of the subarachnoid space coursing with penetrating cerebral vessels, evolving data suggest that Virchow-Robin spaces may actually be interstitial fluid-filled cavities and not contiguous with the subarachnoid space.4 While it is not yet clear whether all MRI-visible perivascular spaces carry the same risk implications across patient populations, their frequent coexistence on MRI and spatial association with incident ICH raise the hypothesis that they represent another imaging marker of cerebral small vessel disease and may therefore provide clues regarding the initiation and progression of related clinical and imaging phenotypes. © 2015 American Academy of Neurology.

Jaiswal S.,Harvard University | Jaiswal S.,Dana-Farber Cancer Institute | Fontanillas P.,The Broad Institute of MIT and Harvard | Flannick J.,CSIC - Biological Research Center | And 37 more authors.
New England Journal of Medicine | Year: 2014

Background The incidence of hematologic cancers increases with age. These cancers are associated with recurrent somatic mutations in specific genes. We hypothesized that such mutations would be detectable in the blood of some persons who are not known to have hematologic disorders.METHODS We analyzed whole-exome sequencing data from DNA in the peripheral-blood cells of 17, 182 persons who were unselected for hematologic phenotypes. We looked for somatic mutations by identifying previously characterized single-nucleotide variants and small insertions or deletions in 160 genes that are recurrently mutated in hematologic cancers. The presence of mutations was analyzed for an association with hematologic phenotypes, survival, and cardiovascular events.RESULTS Detectable somatic mutations were rare in persons younger than 40 years of age but rose appreciably in frequency with age. Among persons 70 to 79 years of age, 80 to 89 years of age, and 90 to 108 years of age, these clonal mutations were observed in 9.5% (219 of 2300 persons), 11.7% (37 of 317), and 18.4% (19 of 103), respectively. The majority of the variants occurred in three genes: DNMT3A, TET2, and ASXL1. The presence of a somatic mutation was associated with an increase in the risk of hematologic cancer (hazard ratio, 11.1; 95% confidence interval [CI], 3.9 to 32.6), an increase in all-cause mortality (hazard ratio, 1.4; 95% CI, 1.1 to 1.8), and increases in the risks of incident coronary heart disease (hazard ratio, 2.0; 95% CI, 1.2 to 3.4) and ischemic stroke (hazard ratio, 2.6; 95% CI, 1.4 to 4.8).CONCLUSIONS Age-related clonal hematopoiesis is a common condition that is associated with increases in the risk of hematologic cancer and in all-cause mortality, with the latter possibly due to an increased risk of cardiovascular disease. Copyright © 2014 Massachusetts Medical Society. All rights reserved.

Ciura V.A.,Massachusetts General Hospital | Brouwers H.B.,Center for Human Genetic Research | Brouwers H.B.,Hemorrhagic Stroke Research Group | Brouwers H.B.,ilip Kistler Stroke Research Center | And 13 more authors.
Stroke | Year: 2014

Background and Purpose-The computed tomography angiography (CTA) spot sign is a validated biomarker for poor outcome and hematoma expansion in intracerebral hemorrhage. The spot sign has proven to be a dynamic entity, with multimodal imaging proving to be of additional value. We investigated whether the addition of a 90-second delayed CTA acquisition would capture additional intracerebral hemorrhage patients with the spot sign and increase the sensitivity of the spot sign. Methods-We prospectively enrolled consecutive intracerebral hemorrhage patients undergoing first pass and 90-second delayed CTA for 18 months at a single academic center. Univariate and multivariate logistic regression were performed to assess clinical and neuroimaging covariates for relationship with hematoma expansion and mortality. Results-Sensitivity of the spot sign for hematoma expansion on first pass CTA was 55%, which increased to 64% if the spot sign was present on either CTA acquisition. In multivariate analysis the spot sign presence was associated with significant hematoma expansion: odds ratio, 17.7 (95% confidence interval, 3.7-84.2; P=0.0004), 8.3 (95% confidence interval, 2.0-33.4; P=0.004), and 12.0 (95% confidence interval, 2.9-50.5; P=0.0008) if present on first pass, delayed, or either CTA acquisition, respectively. Spot sign presence on either acquisitions was also significant for mortality. Conclusions-We demonstrate improved sensitivity for predicting hematoma expansion and poor outcome by adding a 90-second delayed CTA, which may enhance selection of patients who may benefit from hemostatic therapy. © 2014 American Heart Association, Inc.

Lieb W.,U.S. National Institutes of Health | Gona P.,U.S. National Institutes of Health | Larson M.G.,U.S. National Institutes of Health | Massaro J.M.,U.S. National Institutes of Health | And 13 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2010

Objective: Experimental evidence identified the osteoprotegerin (OPG)/receptor activator of nuclear factor-κB (RANK)/RANK ligand (RANKL) pathway as a candidate system modulating vascular remodeling and cardiovascular disease (CVD). Methods and Results: Serum concentrations of OPG and RANKL were measured in 3250 Framingham Study participants (54% women, 61±9 years). During a mean follow-up of 4.6 years, 143 (of 3084 free of CVD at baseline) participants developed a first CVD event, and 235 died. In multivariable models, OPG was associated with increased hazards for incident CVD and mortality (hazard ratio, 1.27; 95% CI, 1.04 to 1.54; and hazard ratio, 1.25; 95% CI, 1.07 to 1.47, per 1-SD increment in log-OPG, respectively). Log-OPG was positively related to multiple CVD risk factors, including age, smoking, diabetes, systolic blood pressure, and prevalent CVD. In a subsample (n=1264), the prevalence of coronary artery calcification, measured by computed tomography, increased nonsignificantly with OPG quartiles. RANKL concentrations displayed inverse associations with multiple CVD risk factors, including smoking, diabetes, and antihypertensive treatment, and were not related to coronary artery calcification or incident CVD or mortality. Conclusion: Our prospective data reinforce OPG as marker for CVD risk factor burden and predictor for CVD and mortality in the community. © 2010 American Heart Association, Inc.

Wu O.,Massachusetts General Hospital | Cloonan L.,Kistler Stroke Research Center | Mocking S.J.T.,Massachusetts General Hospital | Bouts M.J.R.J.,Massachusetts General Hospital | And 10 more authors.
Stroke | Year: 2015

Background and Purpose - Acute infarct volume, often proposed as a biomarker for evaluating novel interventions for acute ischemic stroke, correlates only moderately with traditional clinical end points, such as the modified Rankin Scale. We hypothesized that the topography of acute stroke lesions on diffusion-weighted magnetic resonance imaging may provide further information with regard to presenting stroke severity and long-term functional outcomes. Methods - Data from a prospective stroke repository were limited to acute ischemic stroke subjects with magnetic resonance imaging completed within 48 hours from last known well, admission NIH Stroke Scale (NIHSS), and 3-to-6 months modified Rankin Scale scores. Using voxel-based lesion symptom mapping techniques, including age, sex, and diffusion-weighted magnetic resonance imaging lesion volume as covariates, statistical maps were calculated to determine the significance of lesion location for clinical outcome and admission stroke severity. Results - Four hundred ninety subjects were analyzed. Acute stroke lesions in the left hemisphere were associated with more severe NIHSS at admission and poor modified Rankin Scale at 3 to 6 months. Specifically, injury to white matter (corona radiata, internal and external capsules, superior longitudinal fasciculus, and uncinate fasciculus), postcentral gyrus, putamen, and operculum were implicated in poor modified Rankin Scale. More severe NIHSS involved these regions, as well as the amygdala, caudate, pallidum, inferior frontal gyrus, insula, and precentral gyrus. Conclusions - Acute lesion topography provides important insights into anatomic correlates of admission stroke severity and poststroke outcomes. Future models that account for infarct location in addition to diffusion-weighted magnetic resonance imaging volume may improve stroke outcome prediction and identify patients likely to benefit from aggressive acute intervention and personalized rehabilitation strategies. © 2015 American Heart Association, Inc.

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