Publications by authors named "Christopher D Anderson"

199 Publications

Re-CHARGE-AF: Recalibration of the CHARGE-AF Model for Atrial Fibrillation Risk Prediction in Patients With Acute Stroke.

J Am Heart Assoc 2021 Oct 20:e022363. Epub 2021 Oct 20.

Department of Neurology Brigham and Women's Hospital Boston MA.

Background Performance of existing atrial fibrillation (AF) risk prediction models in poststroke populations is unclear. We evaluated predictive utility of an AF risk model in patients with acute stroke and assessed performance of a fully refitted model. Methods and Results Within an academic hospital, we included patients aged 46 to 94 years discharged for acute ischemic stroke between 2003 and 2018. We estimated 5-year predicted probabilities of AF using the Cohorts for Heart and Aging Research in Genomic Epidemiology for Atrial Fibrillation (CHARGE-AF) model, by recalibrating CHARGE-AF to the baseline risk of the sample, and by fully refitting a Cox proportional hazards model to the stroke sample (Re-CHARGE-AF) model. We compared discrimination and calibration between models and used 200 bootstrap samples for optimism-adjusted measures. Among 551 patients with acute stroke, there were 70 incident AF events over 5 years (cumulative incidence, 15.2%; 95% CI, 10.6%-19.5%). Median predicted 5-year risk from CHARGE-AF was 4.8% (quartile 1-quartile 3, 2.0-12.6) and from Re-CHARGE-AF was 16.1% (quartile 1-quartile 3, 8.0-26.2). For CHARGE-AF, discrimination was moderate (C statistic, 0.64; 95% CI, 0.57-0.70) and calibration was poor, underestimating AF risk (Greenwood-Nam D'Agostino chi-square, <0.001). Calibration with recalibrated baseline risk was also poor (Greenwood-Nam D'Agostino chi-square, <0.001). Re-CHARGE-AF improved discrimination (=0.001) compared with CHARGE-AF (C statistic, 0.74 [95% CI, 0.68-0.79]; optimism-adjusted, 0.70 [95% CI, 0.65-0.75]) and was well calibrated (Greenwood-Nam D'Agostino chi-square, =0.97). Conclusions Covariates from an established AF risk model enable accurate estimation of AF risk in a poststroke population after recalibration. A fully refitted model was required to account for varying baseline AF hazard and strength of associations between covariates and incident AF.
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http://dx.doi.org/10.1161/JAHA.121.022363DOI Listing
October 2021

Cerebral Small Vessel Disease and Depression Among Intracerebral Hemorrhage Survivors.

Stroke 2021 Sep 30:STROKEAHA121035488. Epub 2021 Sep 30.

Department of Neurology, Massachusetts General Hospital, Boston. (J.P.C., M.P., P.K., J.R.A., A.C., C.K., Z.D., K.S., C.D.A., M.E.G., S.M.G., J.R., A.V., A.B.).

Background And Purpose: Intracerebral hemorrhage (ICH) is an acute manifestation of cerebral small vessel disease (CSVD), usually cerebral amyloid angiopathy or hypertensive arteriopathy. CSVD-related imaging findings are associated with increased depression incidence in the general population. Neuroimaging may, therefore, provide insight on depression risk among ICH survivors. We sought to determine whether CSVD CT and magnetic resonance imaging markers are associated with depression risk (before and after ICH), depression remission, and effectiveness of antidepressant treatment.

Methods: We analyzed data from the single-center longitudinal ICH study conducted at Massachusetts General Hospital. Participants underwent CT and magnetic resonance imaging imaging and were followed longitudinally. We extracted information for neuroimaging markers of CSVD subtype and severity. Outcomes of interest included pre-ICH depression, new-onset depression after ICH, resolution of depressive symptoms, and response to antidepressant treatment.

Results: We followed 612 ICH survivors for a median of 47.2 months. Multiple CSVD-related markers were associated with depression risk. Survivors of cerebral amyloid angiopathy-related lobar ICH were more likely to be diagnosed with depression before ICH (odds ratio, 1.68 [95% CI, 1.14-2.48]) and after ICH (sub-hazard ratio, 1.52 [95% CI, 1.12-2.07]), less likely to achieve remission of depressive symptoms (sub-hazard ratio, 0.69 [95% CI, 0.51-0.94]), and to benefit from antidepressant therapy (=0.041). Cerebral amyloid angiopathy disease burden on magnetic resonance imaging was associated with depression incidence and treatment resistance (interaction =0.037), whereas hypertensive arteriopathy disease burden was only associated with depression incidence after ICH.

Conclusions: CSVD severity is associated with depression diagnosis, both before and after ICH. Cerebral amyloid angiopathy-related ICH survivors are more likely to experience depression (both before and after ICH) than patients diagnosed with hypertensive arteriopathy-related ICH, and more likely to report persistent depressive symptoms and display resistance to antidepressant treatment.
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http://dx.doi.org/10.1161/STROKEAHA.121.035488DOI Listing
September 2021

Predictive Accuracy of a Clinical and Genetic Risk Model for Atrial Fibrillation.

Circ Genom Precis Med 2021 Oct 31;14(5):e003355. Epub 2021 Aug 31.

Cardiovascular Research Center (S.K., L.-C.W., P.T.E., S.A.L.), Massachusetts General Hospital, Boston.

Background: Atrial fibrillation (AF) risk estimation using clinical factors with or without genetic information may identify AF screening candidates more accurately than the guideline-based age threshold of ≥65 years.

Methods: We analyzed 4 samples across the United States and Europe (derivation: UK Biobank; validation: FINRISK, Geisinger MyCode Initiative, and Framingham Heart Study). We estimated AF risk using the CHARGE-AF (Cohorts for Heart and Aging Research in Genomic Epidemiology AF) score and a combination of CHARGE-AF and a 1168-variant polygenic score (Predict-AF). We compared the utility of age, CHARGE-AF, and Predict-AF for predicting 5-year AF by quantifying discrimination and calibration.

Results: Among 543 093 individuals, 8940 developed AF within 5 years. In the validation sets, CHARGE-AF (C index range, 0.720-0.824) and Predict-AF (0.749-0.831) had largely comparable discrimination, both favorable to continuous age (0.675-0.801). Calibration was similar using CHARGE-AF (slope range, 0.67-0.87) and Predict-AF (0.65-0.83). Net reclassification improvement using Predict-AF versus CHARGE-AF was modest (net reclassification improvement range, 0.024-0.057) but more favorable among individuals aged <65 years (0.062-0.11). Using Predict-AF among 99 530 individuals aged ≥65 years across each sample, 70 849 had AF risk <5%, of whom 69 067 (97.5%) did not develop AF, whereas 28 681 had AF risk ≥5%, of whom 2264 (7.9%) developed AF. Of 11 379 individuals aged <65 years with AF risk ≥5%, 435 (3.8%) developed AF before age 65 years, with roughly half (46.9%) meeting anticoagulation criteria.

Conclusions: AF risk estimation using clinical factors may prioritize individuals for AF screening more precisely than the age threshold endorsed in current guidelines. The additional value of genetic predisposition is modest but greatest among younger individuals.
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http://dx.doi.org/10.1161/CIRCGEN.121.003355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8530935PMC
October 2021

Ethnic and Racial Variation in Intracerebral Hemorrhage Risk Factors and Risk Factor Burden.

JAMA Netw Open 2021 Aug 2;4(8):e2121921. Epub 2021 Aug 2.

Henry and Allison McCance Center for Brain Health and Center for Genomic Medicine, Massachusetts General Hospital, Boston.

Importance: Black and Hispanic individuals have an increased risk of intracerebral hemorrhage (ICH) compared with their White counterparts, but no large studies of ICH have been conducted in these disproportionately affected populations.

Objective: To examine the prevalence, odds, and population attributable risk (PAR) percentage for established and novel risk factors for ICH, stratified by ICH location and racial/ethnic group.

Design, Setting, And Participants: The Ethnic/Racial Variations of Intracerebral Hemorrhage Study was a case-control study of ICH among 3000 Black, Hispanic, and White individuals who experienced spontaneous ICH (1000 cases in each group). Recruitment was conducted between September 2009 and July 2016 at 19 US sites comprising 42 hospitals. Control participants were identified through random digit dialing and were matched to case participants by age (±5 years), sex, race/ethnicity, and geographic area. Data analyses were conducted from January 2019 to May 2020.

Main Outcomes And Measures: Case and control participants underwent a standardized interview, physical measurement for body mass index, and genotyping for the ɛ2 and ɛ4 alleles of APOE, the gene encoding apolipoprotein E. Prevalence, multivariable adjusted odds ratio (OR), and PAR percentage were calculated for each risk factor in the entire ICH population and stratified by racial/ethnic group and by lobar or nonlobar location.

Results: There were 1000 Black patients (median [interquartile range (IQR)] age, 57 [50-65] years, 425 [42.5%] women), 1000 Hispanic patients (median [IQR] age, 58 [49-69] years; 373 [37.3%] women), and 1000 White patients (median [IQR] age, 71 [59-80] years; 437 [43.7%] women). The mean (SD) age of patients with ICH was significantly lower among Black and Hispanic patients compared with White patients (eg, lobar ICH: Black, 62.2 [15.2] years; Hispanic, 62.5 [15.7] years; White, 71.0 [13.3] years). More than half of all ICH in Black and Hispanic patients was associated with treated or untreated hypertension (PAR for treated hypertension, Black patients: 53.6%; 95% CI, 46.4%-59.8%; Hispanic patients: 46.5%; 95% CI, 40.6%-51.8%; untreated hypertension, Black patients: 45.5%; 95% CI, 39.%-51.1%; Hispanic patients: 42.7%; 95% CI, 37.6%-47.3%). Lack of health insurance also had a disproportionate association with the PAR percentage for ICH in Black and Hispanic patients (Black patients: 21.7%; 95% CI, 17.5%-25.7%; Hispanic patients: 30.2%; 95% CI, 26.1%-34.1%; White patients: 5.8%; 95% CI, 3.3%-8.2%). A high sleep apnea risk score was associated with both lobar (OR, 1.68; 95% CI, 1.36-2.06) and nonlobar (OR, 1.62; 95% CI, 1.37-1.91) ICH, and high cholesterol was inversely associated only with nonlobar ICH (OR, 0.60; 95% CI, 0.52-0.70); both had no interactions with race and ethnicity. In contrast to the association between the ɛ2 and ɛ4 alleles of APOE and ICH in White individuals (eg, presence of APOE ɛ2 allele: OR, 1.84; 95% CI, 1.34-2.52), APOE alleles were not associated with lobar ICH among Black or Hispanic individuals.

Conclusions And Relevance: This study found sleep apnea as a novel risk factor for ICH. The results suggest a strong contribution from inadequately treated hypertension and lack of health insurance to the disproportionate burden and earlier onset of ICH in Black and Hispanic populations. These findings emphasize the importance of addressing modifiable risk factors and the social determinants of health to reduce health disparities.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.21921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8383133PMC
August 2021

Stroke Genetics: Turning Discoveries into Clinical Applications.

Stroke 2021 Aug 17;52(9):2974-2982. Epub 2021 Aug 17.

Department of Neurology, Brigham and Women's Hospital, Boston, MA (C.D.A.).

The field of medical and population genetics in stroke is moving at a rapid pace and has led to unanticipated opportunities for discovery and clinical applications. Genome-wide association studies have highlighted the role of specific pathways relevant to etiologically defined subtypes of stroke and to stroke as a whole. They have further offered starting points for the exploration of novel pathways and pharmacological strategies in experimental systems. Mendelian randomization studies continue to provide insights in the causal relationships between exposures and outcomes and have become a useful tool for predicting the efficacy and side effects of drugs. Additional applications that have emerged from recent discoveries include risk prediction based on polygenic risk scores and pharmacogenomics. Among the topics currently moving into focus is the genetics of stroke outcome. While still at its infancy, this field is expected to boost the development of neuroprotective agents. We provide a brief overview on recent progress in these areas.
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http://dx.doi.org/10.1161/STROKEAHA.121.032616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384143PMC
August 2021

Cellular responses at the application site of a high-density microarray patch delivering an influenza vaccine in a randomized, controlled phase I clinical trial.

PLoS One 2021 30;16(7):e0255282. Epub 2021 Jul 30.

Vaxxas Pty Ltd, Brisbane, Queensland, Australia.

Microarray patches (MAPs) have the potential to be a safer, more acceptable, easier to use and more cost-effective method for administration of vaccines when compared to the needle and syringe. Since MAPs deliver vaccine to the dermis and epidermis, a degree of local immune response at the site of application is expected. In a phase 1 clinical trial (ACTRN 12618000112268), the Vaxxas high-density MAP (HD-MAP) was used to deliver a monovalent, split inactivated influenza virus vaccine into the skin. HD-MAP immunisation led to significantly enhanced humoral responses on day 8, 22 and 61 compared with IM injection of a quadrivalent commercial seasonal influenza vaccine (Afluria Quadrivalent®). Here, the aim was to analyse cellular responses to HD-MAPs in the skin of trial subjects, using flow cytometry and immunohistochemistry. HD-MAPs were coated with a split inactivated influenza virus vaccine (A/Singapore/GP1908/2015 [H1N1]), to deliver 5 μg haemagglutinin (HA) per HD-MAP. Three HD-MAPs were applied to the volar forearm (FA) of five healthy volunteers (to achieve the required 15 μg HA dose), whilst five control subjects received three uncoated HD-MAPs (placebo). Local skin response was recorded for over 61 days and haemagglutination inhibition antibody titres (HAI) were assessed on days 1, 4, 8, 22, and 61. Skin biopsies were taken before (day 1), and three days after HD-MAP application (day 4) and analysed by flow-cytometry and immunohistochemistry to compare local immune subset infiltration. HD-MAP vaccination with 15 μg HA resulted in significant HAI antibody titres compared to the placebo group. Application of uncoated placebo HD-MAPs resulted in mild erythema and oedema in most subjects, that resolved by day 4 in 80% of subjects. Active, HA-coated HD-MAP application resulted in stronger erythema responses on day 4, which resolved between days 22-61. Overall, these erythema responses were accompanied by an influx of immune cells in all subjects. Increased cell infiltration of CD3+, CD4+, CD8+ T cells as well as myeloid CD11b+ CD11c+ and non-myeloid CD11b- dendritic cells were observed in all subjects, but more pronounced in active HD-MAP groups. In contrast, CD19+/CD20+ B cell counts remained unchanged. Key limitations include the use of an influenza vaccine, to which the subjects may have had previous exposure. Different results might have been obtained with HD-MAPs inducing a primary immune response. In conclusion, influenza vaccine administered to the forearm (FA) using the HD-MAP was well-tolerated and induced a mild to moderate skin response with lymphocytic infiltrate at the site of application.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255282PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323919PMC
July 2021

Magnesium and Intracranial Aneurysms: Not Only Acute Subarachnoid Hemorrhage.

Neurology 2021 07 22;97(4):157-158. Epub 2021 Jun 22.

From the Department of Neurology (J.P.), Jagiellonian University Medical College, Krakow, Poland; Department of Neurology (C.D.A.), Brigham and Women's Hospital, Boston, MA; and Program in Medical and Population Genetics (C.D.A.), Broad Institute, Cambridge, MA.

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http://dx.doi.org/10.1212/WNL.0000000000012247DOI Listing
July 2021

Deep Learning to Predict Cardiac Magnetic Resonance-Derived Left Ventricular Mass and Hypertrophy From 12-Lead ECGs.

Circ Cardiovasc Imaging 2021 06 15;14(6):e012281. Epub 2021 Jun 15.

Cardiovascular Disease Initiative (S.K., J.P.P., C.D.A., P.T.E., J.E.H., S.A.L.), Broad Institute of Harvard and the Massachusetts Institute of Technology, Cambridge.

Background: Classical methods for detecting left ventricular (LV) hypertrophy (LVH) using 12-lead ECGs are insensitive. Deep learning models using ECG to infer cardiac magnetic resonance (CMR)-derived LV mass may improve LVH detection.

Methods: Within 32 239 individuals of the UK Biobank prospective cohort who underwent CMR and 12-lead ECG, we trained a convolutional neural network to predict CMR-derived LV mass using 12-lead ECGs (left ventricular mass-artificial intelligence [LVM-AI]). In independent test sets (UK Biobank [n=4903] and Mass General Brigham [MGB, n=1371]), we assessed correlation between LVM-AI predicted and CMR-derived LV mass and compared LVH discrimination using LVM-AI versus traditional ECG-based rules (ie, Sokolow-Lyon, Cornell, lead aVL rule, or any ECG rule). In the UK Biobank and an ambulatory MGB cohort (MGB outcomes, n=28 612), we assessed associations between LVM-AI predicted LVH and incident cardiovascular outcomes using age- and sex-adjusted Cox regression.

Results: LVM-AI predicted LV mass correlated with CMR-derived LV mass in both test sets, although correlation was greater in the UK Biobank (r=0.79) versus MGB (r=0.60, P<0.001 for both). When compared with any ECG rule, LVM-AI demonstrated similar LVH discrimination in the UK Biobank (LVM-AI c-statistic 0.653 [95% CI, 0.608 -0.698] versus any ECG rule c-statistic 0.618 [95% CI, 0.574 -0.663], P=0.11) and superior discrimination in MGB (0.621; 95% CI, 0.592 -0.649 versus 0.588; 95% CI, 0.564 -0.611, P=0.02). LVM-AI-predicted LVH was associated with incident atrial fibrillation, myocardial infarction, heart failure, and ventricular arrhythmias.

Conclusions: Deep learning-inferred LV mass estimates from 12-lead ECGs correlate with CMR-derived LV mass, associate with incident cardiovascular disease, and may improve LVH discrimination compared to traditional ECG rules.
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http://dx.doi.org/10.1161/CIRCIMAGING.120.012281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217289PMC
June 2021

Rare Missense Functional Variants at and in Sporadic Intracerebral Hemorrhage.

Neurology 2021 May 24. Epub 2021 May 24.

Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK

ObjectiveTo test the genetic contribution of rare missense variants in and in which common variants are genetically associated with sporadic intracerebral hemorrhage (ICH), we performed rare variant analysis in multiple sequencing data for the risk for sporadic ICH.MethodsWe performed sequencing across 559Kbp at 13q34 including and among 2,133 individuals (1,055 ICH cases; 1,078 controls) in US-based and 1,492 individuals (192 ICH cases; 1,189 controls) from Scotland-based cohorts, followed by sequence annotation, functional impact prediction, genetic association testing, and thermodynamic modeling.ResultsWe identified 107 rare nonsynonymous variants in sporadic ICH, of which two missense variants, rs138269346 (COL4A1) and rs201716258 (COL4A2), were predicted to be highly functional and occurred in multiple ICH cases but not in controls from the US-based cohort. The minor allele of rs201716258 was also present in Scottish ICH patients, and rs138269346 was observed in two ICH-free controls with a history of hypertension and myocardial infarction. Rs138269346 was nominally associated with non-lobar ICH risk (P=0.05), but not with lobar ICH (P=0.08), while associations between rs201716258 and ICH subtypes were non-significant (P>0.12). Both variants were considered pathogenic based on minor allele frequency (<0.00035 in EUR), predicted functional impact ( or ), and modeling studies (substantially altered physical length and thermal stability of collagen).ConclusionsWe identified rare missense variants in / in association with sporadic ICH. Our annotation and simulation studies suggest that these variants are highly functional and may represent targets for translational follow-up.
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http://dx.doi.org/10.1212/WNL.0000000000012227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302151PMC
May 2021

Impact of Uncontrolled Hypertension at 3 Months After Intracerebral Hemorrhage.

J Am Heart Assoc 2021 06 15;10(11):e020392. Epub 2021 May 15.

Department of Neurology Massachusetts General Hospital Boston MA.

Background Survivors of intracerebral hemorrhage (ICH) are at high risk for recurrent stroke, which is associated with blood pressure control. Because most recurrent stroke events occur within 12 to 18 months of the index ICH, rapid blood pressure control is likely to be crucial. We investigated the frequency and prognostic impact of uncontrolled short-term hypertension after ICH. Methods and Results We analyzed data from Massachusetts General Hospital (n=1305) and the University of Hong Kong (n=523). We classified hypertension as controlled, undertreated, or treatment resistant at 3 months after ICH and determined the following: (1) the risk factors for uncontrolled hypertension and (2) whether hypertension control at 3 months is associated with stroke recurrence and mortality. We followed 1828 survivors of ICH for a median of 46.2 months. Only 9 of 234 (4%) recurrent strokes occurred before 3 months after ICH. At 3 months, 713 participants (39%) had controlled hypertension, 755 (41%) had undertreated hypertension, and 360 (20%) had treatment-resistant hypertension. Black, Hispanic, and Asian race/ethnicity and higher blood pressure at time of ICH increased the risk of uncontrolled hypertension at 3 months (all <0.05). Uncontrolled hypertension at 3 months was associated with recurrent stroke and mortality during long-term follow-up (all <0.05). Conclusions Among survivors of ICH, >60% had uncontrolled hypertension at 3 months, with undertreatment accounting for the majority of cases. The 3-month blood pressure measurements were associated with higher recurrent stroke risk and mortality. Black, Hispanic, and Asian survivors of ICH and those presenting with severe acute hypertensive response were at highest risk for uncontrolled hypertension.
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http://dx.doi.org/10.1161/JAHA.120.020392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483505PMC
June 2021

The Unique Fiber Anatomy of Middle Temporal Gyrus Default Mode Connectivity.

Oper Neurosurg (Hagerstown) 2021 06;21(1):E8-E14

Centre for Minimally Invasive Neurosurgery, Prince of Wales Private Hospital, Sydney, Australia.

Background: The middle temporal gyrus (MTG) is understood to play a role in language-related tasks such as lexical comprehension and semantic cognition. However, a more specific understanding of its key white matter connections could promote the preservation of these functions during neurosurgery.

Objective: To provide a detailed description of the underlying white matter tracts associated with the MTG to improve semantic preservation during neurosurgery.

Methods: Tractography was performed using diffusion imaging obtained from 10 healthy adults from the Human Connectome Project. All tracts were mapped between cerebral hemispheres with a subsequent laterality index calculated based on resultant tract volumes. Ten postmortem dissections were performed for ex vivo validation of the tractography based on qualitative visual agreement.

Results: We identified 2 major white matter bundles leaving the MTG: the inferior longitudinal fasciculus and superior longitudinal fasciculus. In addition to long association fibers, a unique linear sequence of U-shaped fibers was identified, possibly representing a form of visual semantic transfer down the temporal lobe.

Conclusion: We elucidate the underlying fiber-bundle anatomy of the MTG, an area highly involved in the brain's language network. Improved understanding of the unique, underlying white matter connections in and around this area may augment our overall understanding of language processing as well as the involvement of higher order cerebral networks like the default mode network in these functions.
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http://dx.doi.org/10.1093/ons/opab109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203421PMC
June 2021

Contribution of Racial and Ethnic Differences in Cerebral Small Vessel Disease Subtype and Burden to Risk of Cerebral Hemorrhage Recurrence.

Neurology 2021 05 21;96(20):e2469-e2480. Epub 2021 Apr 21.

From the Department of Neurology (J.P.C., J.R.A., A.R.-T., S.M., P.K., A.C., C.K., Z.D., K.S., M.E.G., A.V., C.D.A., S.M.G., J.R., A.B.), Hemorrhagic Stroke Research Program (J.P.C., J.R.A., A.R.-T., S.M., P.K., A.C., C.K, Z.D., K.S., M.E.G., A.V., C.D.A., S.M.G., J.R., A.B.), Henry and Allison McCance Center for Brain Health (J.P.C., J.R.A., P.K., C.K., C.D.A., J.R., A.B.), and Center for Genomic Medicine (J.R.A., S.M., P.K., C.K., C.D.A., J.R., A.B.), Massachusetts General Hospital, Boston; University of Lille (M.P.), Inserm, CHU Lille, U1172-LilNCog-Lille Neuroscience & Cognition, France; School of Medicine (A.R.-T.), University of California, Irvine; Department of Neurology and Rehabilitation Medicine (S.D., L.G., M.L.F., D.W.), University of Cincinnati, OH; Department of Biostatistics and Data Sciences (C.D.L.), Wake Forest University, Winston-Salem, NC; Department of Neurology (A.T.), Keck School of Medicine, University of Southern California; and Los Angeles County Department of Health Services (A.T.), CA.

Objective: Black and Hispanic survivors of intracerebral hemorrhage (ICH) are at higher risk of recurrent intracranial bleeding. MRI-based markers of chronic cerebral small vessel disease (CSVD) are consistently associated with recurrent ICH. We therefore sought to investigate whether racial/ethnic differences in MRI-defined CSVD subtype and severity contribute to disparities in ICH recurrence risk.

Methods: We analyzed data from the Massachusetts General Hospital ICH study (n = 593) and the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study (n = 329). Using CSVD markers derived from MRIs obtained within 90 days of index ICH, we classified ICH cases as cerebral amyloid angiopathy (CAA)-related, hypertensive arteriopathy (HTNA)-related, and mixed etiology. We quantified CSVD burden using validated global, CAA-specific, and HTNA-specific scores. We compared CSVD subtype and severity among White, Black, and Hispanic ICH survivors and investigated its association with ICH recurrence risk.

Results: We analyzed data for 922 ICH survivors (655 White, 130 Black, 137 Hispanic). Minority ICH survivors had greater global CSVD ( = 0.011) and HTNA burden ( = 0.021) on MRI. Furthermore, minority survivors of HTNA-related and mixed-etiology ICH demonstrated higher HTNA burden, resulting in increased ICH recurrence risk (all < 0.05).

Conclusions: We uncovered significant differences in CSVD subtypes and severity among White and minority survivors of primary ICH, with direct implication for known disparities in ICH recurrence risk. Future studies of racial/ethnic disparities in ICH outcomes will benefit from including detailed MRI-based assessment of CSVD subtypes and severity and investigating social determinants of health.
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http://dx.doi.org/10.1212/WNL.0000000000011932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205476PMC
May 2021

Hematoma Expansion in Intracerebral Hemorrhage With Unclear Onset.

Neurology 2021 05 1;96(19):e2363-e2371. Epub 2021 Apr 1.

From UO Neurologia (A.M.), Azienda Socio-Sanitaria Territoriale (ASST) Valcamonica, Esine, Italy; Neuroradiology Department (G. Boulouis), Centre Hospitalier Sainte-Anne, Paris, France; J.P. Kistler Stroke Research Center, Department of Neurology (A. Charidimou, Q.L., A.D.W., C.D.A., M.E.G., A.B., A.V., S.M.G., J.R., J.N.G.), Massachusetts General Hospital Stroke Research Center, Harvard Medical School, Boston; Dipartimento di Scienze Cliniche e Sperimentali, Clinica Neurologica (L.P., A. Pezzini, A. Padovani), Università degli Studi di Brescia; UO di Neurologia (P.C.), Istituto Clinico Fondazione Poliambulanza, Brescia; UOC Neurologia (V.D.G.), ASST Cremona; UC Malattie Cerebrovascolari e Stroke Unit (E.L., F.M., A. Cavallini) and UC Neurologia d'Urgenza (E.L., F.M., G.M.), IRCCS Fondazione Mondino, Pavia; Dipartimento di Dipartimento di Scienze Biomediche, Sperimentali e Cliniche, Neuroradiologia, Università degliStudi di Firenze (G. Busto, E.F.), and Stroke Unit (F.A., A.Z.), Ospedale Universitario Careggi, Firenze; UOC Neurologia e Rete Stroke, Metropolitana (L.B., S.G.), and Unità di Neuroradiologia (L.S.), IRCCS Istituto delle Scienze Neurologiche di Bologna, Ospedale Maggiore; Clinica Neurologica, Dipartimento di Scienze Biomediche e Chirurgico Specialistiche (M.L., I.C.), Università degli studi diFerrara, Ospedale Universitario S. Anna, Ferrara; Neurologia e Stroke Unit (E.C.), Ospedale di Circolo, ASST Settelaghi, Varese; Stroke Unit (M.G., M.M.), Neurologia Vascolare, ASST Spedali Civili, Brescia, Italy; Division of Neurocritical Care and Emergency Neurology, Department of Neurology (C.D.A., J.R., J.N.G.), Harvard Medical School, Henry and Allison McCance Center for Brain Health (C.D.A., J.R., J.N.G.), and Department of Emergency Medicine (J.N.G.), Massachusetts General Hospital, Boston.

Objective: To investigate the prevalence, predictors, and prognostic effect of hematoma expansion (HE) in patients with intracerebral hemorrhage (ICH) with unclear symptom onset (USO).

Methods: We performed a retrospective analysis of patients with primary spontaneous ICH admitted at 5 academic medical centers in the United States and Italy. HE (volume increase >6 mL or >33% from baseline to follow-up noncontrast CT [NCCT]) and mortality at 30 days were the outcomes of interest. Baseline NCCT was also analyzed for presence of hypodensities (any hypodense region within the hematoma margins). Predictors of HE and mortality were explored with multivariable logistic regression.

Results: We enrolled 2,165 participants, 1,022 in the development cohort and 1,143 in the replication cohort, of whom 352 (34.4%) and 407 (35.6%) had ICH with USO, respectively. When compared with participants having a clear symptom onset, patients with USO had a similar frequency of HE (25.0% vs 21.9%, = 0.269 and 29.9% vs 31.5%, = 0.423). Among patients with USO, HE was independently associated with mortality after adjustment for confounders (odds ratio [OR] 2.64, 95% confidence interval [CI] 1.43-4.89, = 0.002). This finding was similar in the replication cohort (OR 3.46, 95% CI 1.86-6.44, < 0.001). The presence of NCCT hypodensities in patients with USO was an independent predictor of HE in the development (OR 2.59, 95% CI 1.27-5.28, = 0.009) and replication (OR 2.43, 95% CI 1.42-4.17, = 0.001) population.

Conclusion: HE is common in patients with USO and independently associated with worse outcome. These findings suggest that patients with USO may be enrolled in clinical trials of medical treatments targeting HE.
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http://dx.doi.org/10.1212/WNL.0000000000011895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166446PMC
May 2021

Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies.

Lancet Neurol 2021 05 25;20(5):351-361. Epub 2021 Mar 25.

Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.

Background: The genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide mechanistic insights into the disease.

Methods: We did a pooled analysis of data from newly recruited patients with an MRI-confirmed diagnosis of lacunar stroke and existing genome-wide association studies (GWAS). Patients were recruited from hospitals in the UK as part of the UK DNA Lacunar Stroke studies 1 and 2 and from collaborators within the International Stroke Genetics Consortium. Cases and controls were stratified by ancestry and two meta-analyses were done: a European ancestry analysis, and a transethnic analysis that included all ancestry groups. We also did a multi-trait analysis of GWAS, in a joint analysis with a study of cerebral white matter hyperintensities (an aetiologically related radiological trait), to find additional genetic associations. We did a transcriptome-wide association study (TWAS) to detect genes for which expression is associated with lacunar stroke; identified significantly enriched pathways using multi-marker analysis of genomic annotation; and evaluated cardiovascular risk factors causally associated with the disease using mendelian randomisation.

Findings: Our meta-analysis comprised studies from Europe, the USA, and Australia, including 7338 cases and 254 798 controls, of which 2987 cases (matched with 29 540 controls) were confirmed using MRI. Five loci (ICA1L-WDR12-CARF-NBEAL1, ULK4, SPI1-SLC39A13-PSMC3-RAPSN, ZCCHC14, ZBTB14-EPB41L3) were found to be associated with lacunar stroke in the European or transethnic meta-analyses. A further seven loci (SLC25A44-PMF1-BGLAP, LOX-ZNF474-LOC100505841, FOXF2-FOXQ1, VTA1-GPR126, SH3PXD2A, HTRA1-ARMS2, COL4A2) were found to be associated in the multi-trait analysis with cerebral white matter hyperintensities (n=42 310). Two of the identified loci contain genes (COL4A2 and HTRA1) that are involved in monogenic lacunar stroke. The TWAS identified associations between the expression of six genes (SCL25A44, ULK4, CARF, FAM117B, ICA1L, NBEAL1) and lacunar stroke. Pathway analyses implicated disruption of the extracellular matrix, phosphatidylinositol 5 phosphate binding, and roundabout binding (false discovery rate <0·05). Mendelian randomisation analyses identified positive associations of elevated blood pressure, history of smoking, and type 2 diabetes with lacunar stroke.

Interpretation: Lacunar stroke has a substantial heritable component, with 12 loci now identified that could represent future treatment targets. These loci provide insights into lacunar stroke pathogenesis, highlighting disruption of the vascular extracellular matrix (COL4A2, LOX, SH3PXD2A, GPR126, HTRA1), pericyte differentiation (FOXF2, GPR126), TGF-β signalling (HTRA1), and myelination (ULK4, GPR126) in disease risk.

Funding: British Heart Foundation.
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http://dx.doi.org/10.1016/S1474-4422(21)00031-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062914PMC
May 2021

Anatomy and White Matter Connections of the Middle Frontal Gyrus.

World Neurosurg 2021 06 17;150:e520-e529. Epub 2021 Mar 17.

Centre for Minimally Invasive Neurosurgery, Prince of Wales Private Hospital, Sydney, New South Wales, Australia. Electronic address:

Background: The middle frontal gyrus (MFG) is involved in attention, working memory, and language-related processing. A detailed understanding of the subcortical white matter tracts connected within the MFG can facilitate improved navigation of white matter lesions in and around this gyrus and explain the postoperative morbidity after surgery. We aimed to characterize the fiber tracts within the MFG according to their connection to neuroanatomic structures through the use of diffusion spectrum imaging-based fiber tractography and validate the findings by gross anatomic dissection for qualitative visual agreement.

Methods: Tractography analysis was completed using diffusion imaging data from 10 healthy, adult subjects enrolled in the Human Connectome Project. We assessed the MFG as a whole component according to its fiber connectivity with other neural regions. Mapping was completed on all tracts within both hemispheres, with the resultant tract volumes used to calculate a lateralization index. A modified Klingler technique was used on 10 postmortem dissections to demonstrate the location and orientation of the major tracts.

Results: Two major connections of the MFG were identified: the superior longitudinal fasciculus, which connects the MFG to parts of the inferior parietal lobule, posterior temporal lobe, and lateral occipital cortex; and the inferior fronto-occipital fasciculus, which connected the MFG to the lingual gyrus and cuneus. Intra- and intergyral short association, U-shaped fibers were also identified.

Conclusions: Subcortical white matter pathways integrated within the MFG include the superior longitudinal fasciculus and inferior fronto-occipital fasciculus. The MFG is implicated in a variety of tasks involving attention and memory, making it an important cortical region. The postoperative neurologic outcomes related to surgery in and around the MFG could be clarified in the context of the anatomy of the fiber bundles highlighted in the present study.
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http://dx.doi.org/10.1016/j.wneu.2021.03.045DOI Listing
June 2021

Impact of hyperleptinemia during placental ischemia-induced hypertension in pregnant rats.

Am J Physiol Heart Circ Physiol 2021 05 12;320(5):H1949-H1958. Epub 2021 Mar 12.

Department of Surgery, The University of Mississippi Medical Center, Jackson, Mississippi.

The prevalence of preeclampsia and obesity have increased. Although obesity is a major risk factor for preeclampsia, the mechanisms linking these morbidities are poorly understood. Circulating leptin levels increase in proportion to fat mass. Infusion of this adipokine elicits hypertension in nonpregnant rats, but less is known about how hyperleptinemia impacts blood pressure during placental ischemia, an initiating event in the pathophysiology of hypertension in preeclampsia. We tested the hypothesis that hyperleptinemia during reduced uterine perfusion pressure (RUPP) exaggerates placental ischemia-induced hypertension. On () , Sprague-Dawley rats were implanted with osmotic mini-pumps delivering recombinant rat leptin (1 µg/kg/min iv) or vehicle concurrently with the RUPP procedure to induce placental ischemia or Sham. On , plasma leptin was elevated in Sham + Leptin and RUPP + Leptin. Leptin infusion did not significantly impact mean arterial pressure (MAP) in Sham. MAP was increased in RUPP + Vehicle vs. Sham + Vehicle. In contrast to our hypothesis, placental ischemia-induced hypertension was attenuated by leptin infusion. To examine potential mechanisms for attenuation of RUPP-induced hypertension during hyperleptinemia, endothelial-dependent vasorelaxation to acetylcholine was similar between Sham and RUPP; however, endothelial-independent vasorelaxation to the nitric oxide (NO)-donor, sodium nitroprusside, was increased in Sham and RUPP. These findings suggest that NO/cyclic guanosine monophosphate (cGMP) signaling was increased in the presence of hyperleptinemia. Plasma cGMP was elevated in Sham and RUPP hyperleptinemic groups compared with vehicle groups but plasma and vascular NO metabolites were reduced. These data suggest that hyperleptinemia during placental ischemia attenuates hypertension by compensatory increases in NO/cGMP signaling. Ours is the first study to examine the impact of hyperleptinemia on the development of placental ischemia-induced hypertension using an experimental animal model.
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http://dx.doi.org/10.1152/ajpheart.00724.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163645PMC
May 2021

Leveraging genetic data to elucidate the relationship between Covid-19 and ischemic stroke.

medRxiv 2021 Mar 1. Epub 2021 Mar 1.

Background: The relationship between coronavirus disease 2019 (Covid-19) and ischemic stroke is poorly defined. We aimed to leverage genetic data to investigate reported associations.

Methods: Genetic association estimates for liability to Covid-19 and cardiovascular traits were obtained from large-scale consortia. Analyses primarily focused on critical Covid-19, defined as hospitalization with Covid-19 requiring respiratory support or resulting in death. Cross-trait linkage disequilibrium score regression was used to estimate genetic correlations of critical Covid-19 with ischemic stroke, other related cardiovascular outcomes, and risk factors common to both Covid-19 and cardiovascular disease (body mass index, smoking and chronic inflammation, estimated using C-reactive protein). Mendelian randomization analysis was performed to investigate whether liability to critical Covid-19 was associated with increased risk of any of the cardiovascular outcomes for which genetic correlation was identified.

Results: There was evidence of genetic correlation between critical Covid-19 and ischemic stroke (r =0.29, FDR -value=4.65×10 ), body mass index (r =0.21, FDR- -value 6.26×10 ) and C-reactive protein (r =0.20, FDR- -value=1.35×10 ), but none of the other considered traits. In Mendelian randomization analysis, liability to critical Covid-19 was associated with increased risk of ischemic stroke (odds ratio [OR] per logOR increase in genetically predicted critical Covid-19 liability 1.03, 95% confidence interval 1.00-1.06, -value=0.03). Similar estimates were obtained when considering ischemic stroke subtypes. Consistent estimates were also obtained when performing statistical sensitivity analyses more robust to the inclusion of pleiotropic variants, including multivariable Mendelian randomization analyses adjusting for potential genetic confounding through body mass index, smoking and chronic inflammation. There was no evidence to suggest that genetic liability to ischemic stroke increased the risk of critical Covid-19.

Conclusions: These data support that liability to critical Covid-19 is associated with an increased risk of ischemic stroke. The host response predisposing to severe Covid-19 is likely to increase the risk of ischemic stroke, independent of other potentially mitigating risk factors.
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http://dx.doi.org/10.1101/2021.02.25.21252441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941632PMC
March 2021

Usefulness of Rhythm Monitoring Following Acute Ischemic Stroke.

Am J Cardiol 2021 05 20;147:44-51. Epub 2021 Feb 20.

Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts; Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

We characterized monitor utilization in stroke survivors and assessed associations with underlying clinical atrial fibrillation (AF) risk. We retrospectively analyzed consecutive patients with acute ischemic stroke 10/2018-6/2019 without prevalent AF and assessed the 6-month incidence of monitor utilization (Holter/ECG, event/patch, implantable loop recorder [ILR]) using Fine-Gray models accounting for the competing risk of death. We assessed for predictors of monitor utilization using cause-specific hazards regression adjusted for the Cohorts for Heart and Aging Research in Genomic Epidemiology AF (CHARGE-AF) score, stroke subtype, and discharge disposition. Of 493 patients with acute ischemic stroke (age 65±16; 47% women), the 6-month incidence of monitor utilization was 36.5% (95% CI 31.7, 41.3), and 6-month mortality was 13.6% (10.4, 16.8). Monitoring was performed with Holter/event (n = 107; 72.3%), ILR (n = 34; 23.0%) or both (n = 7; 4.7%). Monitoring was more likely after cryptogenic (hazard ratio [HR] 4.53 [3.22, 6.39]; 6-month monitor incidence 70.6%) and cardioembolic (HR 2.43 [1.28, 4.62]; incidence 47.7%) stroke, versus other/undocumented (incidence 22.7%). Among patients with cryptogenic stroke, the 6-month incidence of ILR was 27.5% [18.5, 36.5]. Monitoring was more likely after discharge home (HR 1.80 [1.29, 2.52]; incidence 46.1%) versus facility (incidence 24.9%). Monitoring was not associated with CHARGE-AF score (HR 1.08 per 1-SD increase [0.91, 1.27]), even though CHARGE-AF was associated with incident AF (HR 1.56 [1.03, 2.35]). In conclusion, rhythm monitors are utilized after one-third of ischemic strokes. Monitoring is more frequent after cryptogenic strokes, though ILR use is low. Monitor utilization is not associated with AF risk.
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http://dx.doi.org/10.1016/j.amjcard.2021.01.038DOI Listing
May 2021

Research Priorities in Atrial Fibrillation Screening: A Report From a National Heart, Lung, and Blood Institute Virtual Workshop.

Circulation 2021 Jan 25;143(4):372-388. Epub 2021 Jan 25.

Division of Cardiology and Duke Clinical Research Institute, Duke University Medical Center, Durham, NC (R.D.L., J.P.P., S.M.A.-K.).

Clinically recognized atrial fibrillation (AF) is associated with higher risk of complications, including ischemic stroke, cognitive decline, heart failure, myocardial infarction, and death. It is increasingly recognized that AF frequently is undetected until complications such as stroke or heart failure occur. Hence, the public and clinicians have an intense interest in detecting AF earlier. However, the most appropriate strategies to detect undiagnosed AF (sometimes referred to as subclinical AF) and the prognostic and therapeutic implications of AF detected by screening are uncertain. Our report summarizes the National Heart, Lung, and Blood Institute's virtual workshop focused on identifying key research priorities related to AF screening. Global experts reviewed major knowledge gaps and identified critical research priorities in the following areas: (1) role of opportunistic screening; (2) AF as a risk factor, risk marker, or both; (3) relationship between AF burden detected with long-term monitoring and outcomes/treatments; (4) designs of potential randomized trials of systematic AF screening with clinically relevant outcomes; and (5) role of AF screening after ischemic stroke. Our report aims to inform and catalyze AF screening research that will advance innovative, resource-efficient, and clinically relevant studies in diverse populations to improve the diagnosis, management, and prognosis of patients with undiagnosed AF.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.047633DOI Listing
January 2021

Metastatic Renal Cell Carcinoma to the Pancreas Presenting 25 Years After Nephrectomy.

Am Surg 2020 Dec 18:3134820947386. Epub 2020 Dec 18.

21693 University of Mississippi Medical Center, Jackson, MS, USA.

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http://dx.doi.org/10.1177/0003134820947386DOI Listing
December 2020

Automated Electronic Phenotyping of Cardioembolic Stroke.

Stroke 2021 01 10;52(1):181-189. Epub 2020 Dec 10.

Cardiovascular Research Center and Cardiac Arrhythmia Service (W.G., S.K., A.T.T.L., L.X.H., S.A.L.), Massachusetts General Hospital, Boston.

Background And Purpose: Oral anticoagulation is generally indicated for cardioembolic strokes, but not for other stroke causes. Consequently, subtype classification of ischemic stroke is important for risk stratification and secondary prevention. Because manual classification of ischemic stroke is time-intensive, we assessed the accuracy of automated algorithms for performing cardioembolic stroke subtyping using an electronic health record (EHR) database.

Methods: We adapted TOAST (Trial of ORG 10172 in Acute Stroke Treatment) features associated with cardioembolic stroke for derivation in the EHR. Using administrative codes and echocardiographic reports within Mass General Brigham Biobank (N=13 079), we iteratively developed EHR-based algorithms to define the TOAST cardioembolic stroke features, revising regular expression algorithms until achieving positive predictive value ≥80%. We compared several machine learning-based statistical algorithms for discriminating cardioembolic stroke using the feature algorithms applied to EHR data from 1598 patients with acute ischemic strokes from the Massachusetts General Hospital Ischemic Stroke Registry (2002-2010) with previously adjudicated TOAST and Causative Classification of Stroke subtypes.

Results: Regular expression-based feature extraction algorithms achieved a mean positive predictive value of 95% (range, 88%-100%) across 11 echocardiographic features. Among 1598 patients from the Massachusetts General Hospital Ischemic Stroke Registry, 1068 had any cardioembolic stroke feature within predefined time windows in proximity to the stroke event. Cardioembolic stroke tended to occur at an older age, with more TOAST-based comorbidities, and with atrial fibrillation (82.3%). The best model was a random forest with 92.2% accuracy and area under the receiver operating characteristic curve of 91.1% (95% CI, 87.5%-93.9%). Atrial fibrillation, age, dilated cardiomyopathy, congestive heart failure, patent foramen ovale, mitral annulus calcification, and recent myocardial infarction were the most discriminatory features.

Conclusions: Machine learning-based identification of cardioembolic stroke using EHR data is feasible. Future work is needed to improve the accuracy of automated cardioembolic stroke identification and assess generalizability of electronic phenotyping algorithms across clinical settings.
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http://dx.doi.org/10.1161/STROKEAHA.120.030663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769922PMC
January 2021

Clinical Application of a Novel Genetic Risk Score for Ischemic Stroke in Patients With Cardiometabolic Disease.

Circulation 2021 Feb 13;143(5):470-478. Epub 2020 Nov 13.

TIMI Study Group, Boston, MA (N.A.M., F.K.K., F.N., G.M.M., R.P.G., B.M.S., M.L.O'D., E.M.A., E.B., M.S.S., C.T.R.).

Background: Genome-wide association studies have identified single-nucleotide polymorphisms that are associated with an increased risk of stroke. We sought to determine whether a genetic risk score (GRS) could identify subjects at higher risk for ischemic stroke after accounting for traditional clinical risk factors in 5 trials across the spectrum of cardiometabolic disease.

Methods: Subjects who had consented for genetic testing and who were of European ancestry from the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation), SOLID-TIMI 52 (Stabilization of Plaques Using Darapladib), SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus), PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin), and FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) trials were included in this analysis. A set of 32 single-nucleotide polymorphisms associated with ischemic stroke was used to calculate a GRS in each patient and identify tertiles of genetic risk. A Cox model was used to calculate hazard ratios for ischemic stroke across genetic risk groups, adjusted for clinical risk factors.

Results: In 51 288 subjects across the 5 trials, a total of 960 subjects had an ischemic stroke over a median follow-up period of 2.5 years. After adjusting for clinical risk factors, a higher GRS was strongly and independently associated with increased risk for ischemic stroke ( trend=0.009). In comparison with individuals in the lowest third of the GRS, individuals in the middle and top tertiles of the GRS had adjusted hazard ratios of 1.15 (95% CI, 0.98-1.36) and 1.24 (95% CI 1.05-1.45) for ischemic stroke, respectively. Stratification into subgroups revealed that the performance of the GRS appeared stronger in the primary prevention cohort with an adjusted hazard ratio for the top versus lowest tertile of 1.27 (95% CI, 1.04-1.53), in comparison with an adjusted hazard ratio of 1.06 (95% CI, 0.81-1.41) in subjects with previous stroke. In an exploratory analysis of patients with atrial fibrillation and CHADS-VASc score of 2, high genetic risk conferred a 4-fold higher risk of stroke and an absolute risk equivalent to those with CHADS-VASc score of 3.

Conclusions: Across a broad spectrum of subjects with cardiometabolic disease, a 32-single-nucleotide polymorphism GRS was a strong, independent predictor of ischemic stroke. In patients with atrial fibrillation but lower CHADS-VASc scores, the GRS identified patients with risk comparable to those with higher CHADS-VASc scores.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.051927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856243PMC
February 2021

Association of Cerebral Small Vessel Disease and Cognitive Decline After Intracerebral Hemorrhage.

Neurology 2021 01 16;96(2):e182-e192. Epub 2020 Oct 16.

From U 1172-LilNCog-Lille Neuroscience and Cognition (M.P.), Université de Lille, Inserm, CHU Lille, France; Department of Neurology (M.P., L.S., L.X., A.C., T.P., S.S., C.K., K.S., S.M.G., C.D.A., M.E.G., J.R., A.V., A.B.), Hemorrhagic Stroke Research Program (L.S., A.C., S.M.G., C.D.A., M.E.G., J.R., A.V., A.B.), and Henry and Allison McCance Center for Brain Health (C.K., C.D.A., J.R., A.B.), Massachusetts General Hospital, Boston; Department of Neuroradiology (G.B.), Centre Hospitalier Sainte-Anne, Université Paris-Descartes, INSERM UMR 894, Paris, France; Department of Pharmacology, Faculty of Medicine (T.P.), Chulalongkorn University; and Chulalongkorn Stroke Center (T.P.), King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.

Objective: To determine whether MRI-based cerebral small vessel disease (CSVD) burden assessment, in addition to clinical and CT data, improved prediction of cognitive impairment after spontaneous intracerebral hemorrhage (ICH).

Methods: We analyzed data from ICH survivors enrolled in a single-center prospective study. We employed 3 validated CSVD burden scores: global, cerebral amyloid angiopathy (CAA)-specific, and hypertensive arteriopathy (HTNA)-specific. We quantified cognitive performance by administering the modified Telephone Interview for Cognitive Status test. We utilized linear mixed models to model cognitive decline rates, and survival models for new-onset dementia. We calculated CSVD scores' cutoffs to maximize predictive performance for dementia diagnosis.

Results: We enrolled 612 ICH survivors, and followed them for a median of 46.3 months (interquartile range 35.5-58.7). A total of 214/612 (35%) participants developed dementia. Higher global CSVD scores at baseline were associated with faster cognitive decline (coefficient -0.25, standard error [SE] 0.02) and dementia risk (sub-hazard ratio 1.35, 95% confidence interval 1.10-1.65). The global score outperformed the CAA and HTNA scores in predicting post-ICH dementia (all < 0.05). Compared to a model including readily available clinical and CT data, inclusion of the global CSVD score resulted in improved prediction of post-ICH dementia (area under the curve [AUC] 0.89, SE 0.02 vs AUC 0.81, SE 0.03, = 0.008 for comparison). Global CSVD scores ≥2 had highest sensitivity (83%) and specificity (91%) for dementia diagnosis.

Conclusions: A validated MRI-based CSVD score is associated with cognitive performance after ICH and improved diagnostic accuracy for predicting new onset of dementia.
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http://dx.doi.org/10.1212/WNL.0000000000011050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905779PMC
January 2021

Skin hydration dynamics investigated by electrical impedance techniques in vivo and in vitro.

Sci Rep 2020 10 14;10(1):17218. Epub 2020 Oct 14.

Biofilms - Research Center for Biointerfaces, Malmö University, Malmö, Sweden.

Skin is easily accessible for transdermal drug delivery and also attractive for biomarker sampling. These applications are strongly influenced by hydration where elevated hydration generally leads to increased skin permeability. Thus, favorable transdermal delivery and extraction conditions can be easily obtained by exploiting elevated skin hydration. Here, we provide a detailed in vivo and in vitro investigation of the skin hydration dynamics using three techniques based on electrical impedance spectroscopy. Good correlation between in vivo and in vitro results is demonstrated, which implies that simple but realistic in vitro models can be used for further studies related to skin hydration (e.g., cosmetic testing). Importantly, the results show that hydration proceeds in two stages. Firstly, hydration between 5 and 10 min results in a drastic skin impedance change, which is interpreted as filling of superficial voids in skin with conducting electrolyte solution. Secondly, a subtle impedance change is observed over time, which is interpreted as leveling of the water gradient across skin leading to structural relaxation/changes of the macromolecular skin barrier components. With respect to transdermal drug delivery and extraction of biomarkers; 1 h of hydration is suggested to result in beneficial and stable conditions in terms of high skin permeability and extraction efficiency.
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http://dx.doi.org/10.1038/s41598-020-73684-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557913PMC
October 2020

genotype, hypertension severity and outcomes after intracerebral haemorrhage.

Brain Commun 2019 14;1(1):fcz018. Epub 2019 Sep 14.

Henry and Allison McCance Center for Brain Health, MGH, Boston, MA, USA.

Intracerebral haemorrhage in the elderly is a severe manifestation of common forms of cerebral small vessel disease. Nearly 60% of intracerebral haemorrhage survivors will develop clinical manifestations of small vessel disease progression including recurrent haemorrhage, ischaemic stroke, dementia, late-life depression and gait impairment within 5 years. Blood pressure measurements following intracerebral haemorrhage are strongly associated with this risk. However, aggressive blood pressure lowering in the elderly carries substantial risks. In order to determine whether there might be an opportunity to select individuals at the highest risk for small vessel disease progression for aggressive blood pressure reduction, we investigated whether gene variants ɛ2/ɛ4 modify the association between blood pressure and small vessel disease clinical progression after intracerebral haemorrhage. We conducted a single-centre longitudinal study at a tertiary care referral centre (Massachusetts General Hospital in Boston, MA, USA), analysing 716 consecutive survivors of acute intracerebral haemorrhage, enrolled from January 2006 to December 2016. We conducted research interviews at the time of enrolment and obtained genotypes from peripheral venous blood samples. We followed patients longitudinally by means of validated phone-based research encounters, aimed at gathering measurements of systolic and diastolic blood pressure, as well as information on small vessel disease clinical outcomes (including recurrent haemorrhage, incident ischaemic stroke, incident dementia, incident depression and incident gait impairment). ε4 and systolic blood pressure were associated with the risk of recurrent haemorrhage, ischaemic stroke and post-haemorrhage dementia, depression and gait impairment (all  < 0.05). and systolic blood pressure interacted to increase the risk of recurrent haemorrhage, ischaemic stroke, dementia and gait impairment (all interaction  < 0.05). Among patients with elevated blood pressure following intracerebral haemorrhage (average systolic blood pressure 120-129 mmHg and diastolic blood pressure <80 mmHg) only those with one or more ε4 copies were at increased risk for one or more small vessel disease outcomes (hazard ratio = 1.97, 95% confidence interval 1.17-3.31). Among haemorrhage survivors with hypertension (stage 1 and beyond) genotype also stratified risk for all small vessel disease outcomes. In conclusion, genotype modifies the already strong association of hypertension with multiple small vessel disease clinical outcomes among intracerebral haemorrhage survivors. These data raise the possibility that genetic screening could inform blood pressure treatment goals in this patient population.
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http://dx.doi.org/10.1093/braincomms/fcz018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425529PMC
September 2019

Association of Selective Serotonin Reuptake Inhibitor Use After Intracerebral Hemorrhage With Hemorrhage Recurrence and Depression Severity.

JAMA Neurol 2020 Aug 31. Epub 2020 Aug 31.

Hemorrhagic Stroke Research Program, J. Philip Kistler Stroke Research Center, Boston, Massachusetts.

Importance: Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat poststroke depression but are associated with increased incidence of first-ever intracerebral hemorrhage (ICH) in the general population. The decision to treat ICH survivors with SSRIs must therefore balance potential risks of ICH recurrence with presumed benefits on depressive symptoms.

Objective: To determine whether SSRI use among survivors of primary ICH was associated with ICH recurrence and decreased severity of depressive symptoms.

Design, Setting, And Participants: Longitudinal ICH cohort study at a tertiary care center enrolling from January 2006 to December 2017, with follow-up for a median of 53.2 months (interquartile range, 42.3-61.2 months). The study included 1279 consenting individuals (1049 White, 89 Black, 77 Hispanic, and 64 other race/ethnicity) of 1335 eligible patients presenting with primary ICH and who were discharged alive from initial hospitalization for stroke.

Main Outcomes And Measures: We conducted univariable and multivariable analyses for ICH recurrence risk and depression severity, including subset analyses for patients with 1 or more of the following characteristics associated with high ICH recurrence risk: (1) lobar ICH; (2) presence of the apolipoprotein ε2/ε4 gene variants; (3) prior history of ICH/TIA/ischemic stroke; and (4) Black or Hispanic race/ethnicity.

Results: Mean age of study participants was 71.3 years, with 602 women (47%); of the 1279 participants, 1049 were White, 89 were Black, 77 were Hispanic, and 64 were other race/ethnicity. SSRI exposure was associated with both ICH recurrence (subhazard ratio [SHR], 1.31; 95% CI, 1.08-1.59) and resolution of post-ICH depression (SHR, 1.53; 95% CI, 1.12 2.09). Among those individuals at high risk for recurrent ICH, SSRIs were associated with further elevation in risk for ICH recurrence (SHR, 1.79; 95% CI, 1.22-2.64) compared with all other survivors of ICH (SHR, 1.20; 95% CI, 1.01-1.42; P = .008 for comparison of effect sizes). The association of SSRI with reduced depressive symptoms did not differ between high those at high risk for recurrent ICH and all other ICH survivors.

Conclusions And Relevance: Selective serotonin reuptake inhibitor exposure after ICH is associated with both improvement in depressive symptoms and increased risk of recurrent hemorrhagic stroke. Clinical history, neuroimaging data, and genetic biomarkers may help to identify survivors of ICH more likely to safely tolerate SSRI use.
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http://dx.doi.org/10.1001/jamaneurol.2020.3142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489430PMC
August 2020

Pancreatic Lymphatic Malformation : An Unusual Cause of Abdominal Pain.

Am Surg 2020 Jul 29:3134820940254. Epub 2020 Jul 29.

21693 Department of Surgery, University of Mississippi Medical Center School of Medicine, Jackson, MS, USA.

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http://dx.doi.org/10.1177/0003134820940254DOI Listing
July 2020

Malignant Somatic Transformation of a Teratoma 15 Years Following Completion Therapy for a Germ Cell Tumor.

Am Surg 2020 May;86(5):527-528

21693 Department of Surgery, University of Mississippi Medical Center School of Medicine, Jackson, MS, USA.

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http://dx.doi.org/10.1177/0003134820919738DOI Listing
May 2020

Abdominal Pregnancy, an Unusual Cause of Ischemic Small Bowel Obstruction.

Am Surg 2020 May;86(5):511-512

21693 Department of Surgery, University of Mississippi Medical Center School of Medicine, Jackson, MS, USA.

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http://dx.doi.org/10.1177/0003134820919726DOI Listing
May 2020
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