Publications by authors named "Rebecca F Gottesman"

319 Publications

Pre-Statistical Considerations for Harmonization of Cognitive Instruments: Harmonization of ARIC, CARDIA, CHS, FHS, MESA, and NOMAS.

J Alzheimers Dis 2021 Aug 24. Epub 2021 Aug 24.

Cognitive Health Services Research Program, University of Michigan Medical School, Ann Arbor, MI, USA.

Background: Meta-analyses of individuals' cognitive data are increasing to investigate the biomedical, lifestyle, and sociocultural factors that influence cognitive decline and dementia risk. Pre-statistical harmonization of cognitive instruments is a critical methodological step for accurate cognitive data harmonization, yet specific approaches for this process are unclear.

Objective: To describe pre-statistical harmonization of cognitive instruments for an individual-level meta-analysis in the blood pressure and cognition (BP COG) study.

Methods: We identified cognitive instruments from six cohorts (the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Coronary Artery Risk Development in Young Adults study, Framingham Offspring Study, Multi-Ethnic Study of Atherosclerosis, and Northern Manhattan Study) and conducted an extensive review of each item's administration and scoring procedures, and score distributions.

Results: We included 153 cognitive instrument items from 34 instruments across the six cohorts. Of these items, 42%were common across ≥2 cohorts. 86%of common items showed differences across cohorts. We found administration, scoring, and coding differences for seemingly equivalent items. These differences corresponded to variability across cohorts in score distributions and ranges. We performed data augmentation to adjust for differences.

Conclusion: Cross-cohort administration, scoring, and procedural differences for cognitive instruments are frequent and need to be assessed to address potential impact on meta-analyses and cognitive data interpretation. Detecting and accounting for these differences is critical for accurate attributions of cognitive health across cohort studies.
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http://dx.doi.org/10.3233/JAD-210459DOI Listing
August 2021

Brain White Matter Structure and Amyloid Deposition in Black and White Older Adults: The ARIC-PET Study.

J Am Heart Assoc 2021 Sep 25;10(17):e022087. Epub 2021 Aug 25.

Stroke Branch National Institute of Neurological Disorders and Stroke Intramural Research ProgramNIH Bethesda MD.

Background White matter abnormalities are a common feature of aging and Alzheimer disease, and tend to be more severe among Black individuals. However, the extent to which white matter abnormalities relate to amyloid deposition, a marker of Alzheimer pathology, remains unclear. This cross-sectional study examined the association of white matter abnormalities with cortical amyloid in a community sample of older adults without dementia and examined the moderating effect of race. Methods and Results Participants from the ARIC-PET (Atherosclerosis Risk in Communities-Positron Emission Tomography) study underwent brain magnetic resonance imaging, which quantified white matter hyperintensity volume and microstructural integrity using diffusion tensor imaging. Participants received florbetapir positron emission tomography imaging to measure brain amyloid. Associations between measures of white matter structure and elevated amyloid status were examined using multivariable logistic regression. Among 322 participants (43% Black), each SD increase in white matter hyperintensity volume was associated with a greater odds of elevated amyloid (odds ratio [OR], 1.37; 95% CI, 1.03-1.83) after adjusting for demographic and cardiovascular risk factors. In race-stratified analyses, a greater white matter hyperintensity volume was more strongly associated with elevated amyloid among Black participants (OR, 2.00; 95% CI, 1.15-3.50), compared with White participants (OR, 1.29; 95% CI, 0.89-1.89). However, the race interaction was not statistically significant ( interaction=0.09). We found no association between white matter microstructure and elevated amyloid. Conclusions The results suggest a modest positive relationship between white matter hyperintensity and elevated amyloid in older adults without dementia. Although the results indicate that this association is nonsignificantly stronger among Black participants, these findings will need to be confirmed or refuted using larger multiracial cohorts.
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http://dx.doi.org/10.1161/JAHA.121.022087DOI Listing
September 2021

Cognitive stimulation in the workplace, plasma proteins, and risk of dementia: three analyses of population cohort studies.

BMJ 2021 08 18;374:n1804. Epub 2021 Aug 18.

Department of Epidemiology and Public Health, University College London, London, UK.

Objectives: To examine the association between cognitively stimulating work and subsequent risk of dementia and to identify protein pathways for this association.

Design: Multicohort study with three sets of analyses.

Setting: United Kingdom, Europe, and the United States.

Participants: Three associations were examined: cognitive stimulation and dementia risk in 107 896 participants from seven population based prospective cohort studies from the IPD-Work consortium (individual participant data meta-analysis in working populations); cognitive stimulation and proteins in a random sample of 2261 participants from one cohort study; and proteins and dementia risk in 13 656 participants from two cohort studies.

Main Outcome Measures: Cognitive stimulation was measured at baseline using standard questionnaire instruments on active versus passive jobs and at baseline and over time using a job exposure matrix indicator. 4953 proteins in plasma samples were scanned. Follow-up of incident dementia varied between 13.7 to 30.1 years depending on the cohort. People with dementia were identified through linked electronic health records and repeated clinical examinations.

Results: During 1.8 million person years at risk, 1143 people with dementia were recorded. The risk of dementia was found to be lower for participants with high compared with low cognitive stimulation at work (crude incidence of dementia per 10 000 person years 4.8 in the high stimulation group and 7.3 in the low stimulation group, age and sex adjusted hazard ratio 0.77, 95% confidence interval 0.65 to 0.92, heterogeneity in cohort specific estimates I=0%, P=0.99). This association was robust to additional adjustment for education, risk factors for dementia in adulthood (smoking, heavy alcohol consumption, physical inactivity, job strain, obesity, hypertension, and prevalent diabetes at baseline), and cardiometabolic diseases (diabetes, coronary heart disease, stroke) before dementia diagnosis (fully adjusted hazard ratio 0.82, 95% confidence interval 0.68 to 0.98). The risk of dementia was also observed during the first 10 years of follow-up (hazard ratio 0.60, 95% confidence interval 0.37 to 0.95) and from year 10 onwards (0.79, 0.66 to 0.95) and replicated using a repeated job exposure matrix indicator of cognitive stimulation (hazard ratio per 1 standard deviation increase 0.77, 95% confidence interval 0.69 to 0.86). In analysis controlling for multiple testing, higher cognitive stimulation at work was associated with lower levels of proteins that inhibit central nervous system axonogenesis and synaptogenesis: slit homologue 2 (SLIT2, fully adjusted β -0.34, P<0.001), carbohydrate sulfotransferase 12 (CHSTC, fully adjusted β -0.33, P<0.001), and peptidyl-glycine α-amidating monooxygenase (AMD, fully adjusted β -0.32, P<0.001). These proteins were associated with increased dementia risk, with the fully adjusted hazard ratio per 1 SD being 1.16 (95% confidence interval 1.05 to 1.28) for SLIT2, 1.13 (1.00 to 1.27) for CHSTC, and 1.04 (0.97 to 1.13) for AMD.

Conclusions: The risk of dementia in old age was found to be lower in people with cognitively stimulating jobs than in those with non-stimulating jobs. The findings that cognitive stimulation is associated with lower levels of plasma proteins that potentially inhibit axonogenesis and synaptogenesis and increase the risk of dementia might provide clues to underlying biological mechanisms.
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http://dx.doi.org/10.1136/bmj.n1804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372196PMC
August 2021

Association of Midlife Plasma Amyloid-β Levels With Cognitive Impairment in Late Life: The ARIC Neurocognitive Study.

Neurology 2021 Sep 4;97(11):e1123-e1131. Epub 2021 Aug 4.

From the Departments of Medicine (K.J.S., A.T., B.G.W., M.E.G., T.H.M.) and Data Science (C.S., J.S.), University of Mississippi Medical Center, Jackson; Departments of Neurology (K.A.W.) and Epidemiology (A.R.S.), The Johns Hopkins University, Baltimore, MD; Mayo Clinic (S.Y.), Jacksonville, FL; Stroke Branch (R.F.G.), National Institute of Neurological Disorders and Stroke Intramural Program, National Institutes of Health, Bethesda, MD; and Departments of Health Sciences Research (M.M.M.) and Neurology (M.M.M., D.K.), Mayo Clinic, Rochester, MN.

Background And Objectives: To evaluate the association between midlife plasma amyloid-β (Aβ, Aβ, Aβ:Aβ) and risk of mild cognitive impairment (MCI) and dementia.

Methods: Plasma Aβ and Aβ were retrospectively measured with a fluorometric bead-based immunoassay in a subsample of the Atherosclerosis Risk in Communities cohort study. We investigated the relationship of plasma Aβ, Aβ, and Aβ:Aβ ratio measured in midlife and late life and the change from midlife to late life to risk of MCI, dementia, and combined MCI/dementia outcomes in late life (from 2011-2019). We used multinomial logistic regressions estimating relative risk ratios (RRRs) of these cognitive outcomes vs cognitively normal adjusted for age, sex, education, site-race, , hypertension, diabetes, and body mass index.

Results: A total of 2,284 participants were included (midlife mean age 59.2 ± 5.2, 57% female, 22% Black). Each doubling of midlife Aβ:Aβ was associated with 37% lower risk of MCI/dementia (RRR 0.63, 95% confidence interval [CI] 0.46-0.87), but only up to approximately the median (spline model threshold 0.20). Every 1-SD increase in plasma Aβ (10 pg/mL) was associated with 13% lower risk of MCI/dementia (RRR 0.87, 95% CI 0.77-0.98), whereas every 1-SD increase in plasma Aβ (67 pg/mL) was associated with 15% higher risk of MCI/dementia (RRR 1.15, 95% CI 1.01-1.29). Associations were comparable but slightly weaker statistically when models were repeated using late-life plasma Aβ predictors. Aβ and Aβ increased from midlife to late life, but changes were not associated with cognitive outcomes.

Discussion: Midlife measurement of plasma Aβ may have utility as a blood-based biomarker indicative of risk for future cognitive impairment.
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http://dx.doi.org/10.1212/WNL.0000000000012482DOI Listing
September 2021

Plasma proteins, cognitive decline, and 20-year risk of dementia in the Whitehall II and Atherosclerosis Risk in Communities studies.

Alzheimers Dement 2021 Aug 2. Epub 2021 Aug 2.

Department of Epidemiology and Public Health, University College London, London, UK.

Introduction: Plasma proteins affect biological processes and are common drug targets but their role in the development of Alzheimer's disease and related dementias remains unclear. We examined associations between 4953 plasma proteins and cognitive decline and risk of dementia in two cohort studies with 20-year follow-ups.

Methods: In the Whitehall II prospective cohort study proteins were measured using SOMAscan technology. Cognitive performance was tested five times over 20 years. Linkage to electronic health records identified incident dementia. The results were replicated in the Atherosclerosis Risk in Communities (ARIC) study.

Results: Fifteen non-amyloid/non-tau-related proteins were associated with cognitive decline and dementia, were consistently identified in both cohorts, and were not explained by known dementia risk factors. Levels of six of the proteins are modifiable by currently approved medications for other conditions.

Discussion: This study identified several plasma proteins in dementia-free people that are associated with long-term risk of cognitive decline and dementia.
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http://dx.doi.org/10.1002/alz.12419DOI Listing
August 2021

Comparing data-driven and hypothesis-driven MRI-based predictors of cognitive impairment in individuals from the Atherosclerosis Risk in Communities (ARIC) study.

Alzheimers Dement 2021 Jul 26. Epub 2021 Jul 26.

Divison of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

Introduction: A data-driven index of dementia risk based on magnetic resonance imaging (MRI), the Alzheimer's Disease Pattern Similarity (AD-PS) score, was estimated for participants in the Atherosclerosis Risk in Communities (ARIC) study.

Methods: AD-PS scores were generated for 839 cognitively non-impaired individuals with a mean follow-up of 4.86 years. The scores and a hypothesis-driven volumetric measure based on several brain regions susceptible to AD were compared as predictors of incident cognitive impairment in different settings.

Results: Logistic regression analyses suggest the data-driven AD-PS scores to be more predictive of incident cognitive impairment than its counterpart. Both biomarkers were more predictive of incident cognitive impairment in participants who were White, female, and apolipoprotein E gene (APOE) ε4 carriers. Random forest analyses including predictors from different domains ranked the AD-PS scores as the most relevant MRI predictor of cognitive impairment.

Conclusions: Overall, the AD-PS scores were the stronger MRI-derived predictors of incident cognitive impairment in cognitively non-impaired individuals.
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http://dx.doi.org/10.1002/alz.12427DOI Listing
July 2021

Mortality in Patients With Late-Onset Epilepsy: Results From the Atherosclerosis Risk in Communities Study.

Neurology 2021 Sep 19;97(11):e1132-e1140. Epub 2021 Jul 19.

From the Departments of Neurology (E.L.J., G.L.K.) and Epidemiology (R.F.G.), Johns Hopkins School of Medicine, Baltimore, MD; Department of Epidemiology (A.K.-N.), University of North Carolina at Chapel Hill; Department of Epidemiology (A.K.-N.), University of Kentucky, Lexington; Department of Neurology (A.D.L.), Massachusetts General Hospital; and Department of Neurology (R.S.), Brigham and Women's Hospital, Boston, MA.

Background And Objectives: To determine the risk of mortality and causes of death in persons with late-onset epilepsy (LOE) compared to those without epilepsy in a community-based sample, adjusting for demographics and comorbid conditions.

Methods: This is an analysis of the prospective Atherosclerosis Risk in Communities study, initiated in 1987-1989 among 15,792 mostly Black and White men and women in 4 US communities. We used Centers for Medicare & Medicaid Services fee-for-service claims codes to identify cases of incident epilepsy starting at or after age 67. We used Cox proportional hazards analysis to identify the hazard of mortality associated with LOE and to adjust for demographics and vascular risk factors. We used death certificate data to identify dates and causes of death.

Results: Analyses included 9,090 participants, of whom 678 developed LOE during median 11.5 years of follow-up after age 67. Participants who developed LOE were at an increased hazard of mortality compared to those who did not, with adjusted hazard ratio 2.39 (95% confidence interval 2.12-2.71). We observed excess mortality due to stroke, dementia, neurologic conditions, and end-stage renal disease in participants with compared to without LOE. Only 4 deaths (1.1%) were directly attributed to seizure-related causes.

Conclusions: Persons who develop LOE are at increased risk of death compared to those without epilepsy, even after adjusting for comorbidities. The majority of this excess mortality is due to stroke and dementia.
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http://dx.doi.org/10.1212/WNL.0000000000012483DOI Listing
September 2021

Cerebral Small-Vessel Disease in Individuals with a Family History of Coronary Heart Disease: The Atherosclerosis Risk in Communities Study.

Neuroepidemiology 2021 17;55(4):316-322. Epub 2021 Jun 17.

Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine (JHUSOM), Baltimore, Maryland, USA.

Introduction: The degree to which a family history of coronary heart disease (FHCHD) is associated with silent cerebral small-vessel disease (cSVD) among healthy adults, independent of prevalent CHD and traditional risk factors, is unknown.

Methods: The Atherosclerosis Risk in Communities (ARIC) study is a community-based cohort study with self-reported family history data and brain magnetic resonance imaging (ages 68-88). The association between markers of cSVD (lacunar infarcts and cerebral microbleeds), or log-transformed white matter hyperintensity (WMH) volume, and FHCHD, or the number of affected relatives was examined using separate adjusted logistic or linear regression models, respectively. Race interaction terms were evaluated.

Results: Of 1,639 participants without prevalent CHD (76 ± 5 years, 62% female, 29% black), 686 (42%) had FHCHD. There were higher odds of lacunar infarct (OR 1.40, 95% CI 1.07-1.84) among those with parental FHCHD and higher odds of microhemorrhages (lobar OR 1.86, 95% CI 1.13-3.06; subcortical OR 1.47, 95% CI 1.01-2.15) among those with sibling FHCHD. A greater number of any relative affected was associated with higher odds of lacunar infarct (OR 1.24, 95% CI 1.04-1.47) and lobar microhemorrhages (OR 1.31, 95% CI 1.05-1.64) but not subcortical microhemorrhages (OR 1.09, 95% CI 0.92-1.28). Odds of having a lacunar infarct were higher among blacks (p-interaction 0.04) with paternal FHCHD (OR 2.20, CI 1.35-3.58) than whites with paternal FHCHD (OR 1.17, CI 0.87-1.56). There was no association with WMH.

Discussion/conclusion: Markers of cSVD, specifically lacunar infarcts and microhemorrhages, appear to be associated with FHCHD, potentially representing shared mechanisms in different vascular beds, and perhaps a genetic propensity for vascular disease.
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http://dx.doi.org/10.1159/000516428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371924PMC
June 2021

Risk factors and outcomes of HIV-associated stroke in Zambia.

AIDS 2021 Jun 16. Epub 2021 Jun 16.

Department of Internal Medicine, University Teaching Hospital; Lusaka, Zambia Rush University Medical Center, Chicago, IL, USA Department of Internal Medicine, University of Zambia School of Medicine, Lusaka Zambia Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD USA.

Objective: To compare risk factors and clinical outcomes between people living with HIV (PLWH) and HIV-uninfected (HIV-) adults with stroke hospitalized in Zambia.

Methods: We retrospectively reviewed charts of all adults admitted to the University Teaching Hospital in Lusaka, Zambia with a clinical diagnosis of stroke between October 2018 and March 2019. Standardized data collection instruments were used to collect demographic, clinical, laboratory and imaging results. Comparison between individuals with and without HIV infection was made using t-tests for continuous parametric variables, Wilcoxon rank-sum tests for continuous non-parametric variables, and chi-square analyses for categorical variables.

Results: 272 adults with stroke were admitted of whom 58 (21%) were PLWH. Compared to HIV- participants, PLWH were younger (48 ± 14) years versus 62 ± 18) years, p < 0.001). PLWH were less likely to have hypertension (65% vs 83%, p = 0.003) and more likely to have no traditional cerebrovascular risk factors (34% vs 15%, p = 0.01). Deep vein thrombosis (DVT) (4% vs 1%, p = 0.04) was more common during hospitalization amongst PLWH, but there was no difference in in-hospital mortality (21% vs 23%, p = 0.65). Among PLWH with stroke, factors associated with in-hospital mortality were Glasgow Coma Scale (GCS) on admission (7 vs 10, p = 0.046), hypertension (92% vs 59%, p = 0.04) and fever (58% vs 13%, p = 0.003).

Conclusion: This Zambian cohort of PLWH and stroke is notable for being significantly younger with fewer traditional stroke risk factors but higher rates of DVT than their HIV-uninfected counterparts. GCS on admission, hypertension and fever were associated with in-hospital mortality.
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http://dx.doi.org/10.1097/QAD.0000000000002999DOI Listing
June 2021

Reflection on modern methods: shared-parameter models for longitudinal studies with missing data.

Int J Epidemiol 2021 Aug;50(4):1384-1393

Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.

A primary goal of longitudinal studies is to examine trends over time. Reported results from these studies often depend on strong, unverifiable assumptions about the missing data. Whereas the risk of substantial bias from missing data is widely known, analyses exploring missing-data influences are commonly done either ad hoc or not at all. This article outlines one of the three primary recognized approaches for examining missing-data effects that could be more widely used, i.e. the shared-parameter model (SPM), and explains its purpose, use, limitations and extensions. We additionally provide synthetic data and reproducible research code for running SPMs in SAS, Stata and R programming languages to facilitate their use in practice and for teaching purposes in epidemiology, biostatistics, data science and related fields. Our goals are to increase understanding and use of these methods by providing introductions to the concepts and access to helpful tools.
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http://dx.doi.org/10.1093/ije/dyab086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407871PMC
August 2021

Is post-stroke cognitive impairment all about real estate?

Nat Rev Neurol 2021 Aug;17(8):465-466

Stroke Branch, National Institute of Neurological Disorders and Stroke Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.

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http://dx.doi.org/10.1038/s41582-021-00526-4DOI Listing
August 2021

Prevalence of Disability Associated With Head Injury With Loss of Consciousness in Adults in the United States: A Population-Based Study.

Neurology 2021 07 26;97(2):e124-e135. Epub 2021 May 26.

From the Department of Neurology (A.L.C.S.), University of Pennsylvania Perelman School of Medicine, Philadelphia; Department of Epidemiology (D.W., R.F.G., E.S.), Johns Hopkins University Bloomberg School of Public Health; and Department of Neurology (R.F.G.), Johns Hopkins University School of Medicine, Baltimore, MD.

Objective: To provide nationally representative prevalence estimates of disability associated with prior head injury with loss of consciousness in the United States and to examine associations between prior head injury and disability.

Methods: This was a cross-sectional analysis of 7,390 participants ≥40 years of age in the 2011-2014 National Health and Nutrition Examination Surveys (NHANES). Head injury with loss of consciousness was assessed by self-report. Domains of disability were assessed with a standardized structured questionnaire and measured grip strength. Logistic and linear regression models adjusted for demographic, socioeconomic/behavioral, and medical comorbidity variables were used. Multiple imputation was used to account for missing covariate data.

Results: Mean age of participants was 58 years; 53% were female; 71% were non-Hispanic White; and 16% had a history of head injury with loss of consciousness. Overall, participants with a history of head injury had higher prevalence of disability in at least 1 domain of functioning compared to individuals without head injury (47.4% vs 38.6%, < 0.001), with the highest prevalence of disability in the domains of mobility and work productivity. In fully adjusted models, head injury was significantly positively associated with disability in all domains assessed on the standardized questionnaire (all < 0.05). Participants with head injury had greater grip strength (all < 0.05).

Conclusions: We found that 47.4% of individuals ≥40 years of age in the United States with a history of head injury are living with disability in at least 1 domain of functioning, corresponding to 11.4 million affected individuals. This significant burden of disability suggests that efforts are needed to improve functioning among individuals with head injury.
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http://dx.doi.org/10.1212/WNL.0000000000012148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279570PMC
July 2021

Cardiac Structure and Function Is Associated With Hemispatial Neglect Severity.

Front Neurol 2021 6;12:666257. Epub 2021 May 6.

Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States.

Hemispatial neglect is a debilitating consequence of right hemispheric ischemic stroke (RIS), with evidence that patient-level factors influence neglect severity. Study objective: Determine if cardiac function is associated with presence and severity of neglect, independent of infarct size. Two hundred and eighteen non-demented, RIS with cerebral MRI and echocardiography who completed ≥1 of 4 tests evaluating neglect were included. Age- and sex- adjusted Z-scores defined neglect with severity categorized as no neglect, neglect on one or neglect on ≥2 tests. The dependent variable was presence of neglect (multivariable logistic regression), or neglect severity (multinomial logistic regression). The association with left ventricular (LV) structure/function (independent variable) was evaluated using separate nested adjustment models. Patients were on average 61 yo (21-95), female (50%), black (53%), with an ejection fraction of 60% (IQR 20-75%). Fifty eight (27%) had neglect. Each 1 cm increase in LV systolic diameter was associated with a higher relative risk of having neglect on two tests compared to those with no neglect (RRR = 1.83, 95% CI 1.01-3.32), but not after adjusting for education and DWI volume (RRR = 1.68, 95% CI 0.89-3.19). Per 1 cm increase in left atrial (LA) diameter, the relative risk of having neglect on 2 tests vs. no neglect was over two times higher (95% CI 1.04-4.77), but lost significance in the final model (RRR = 1.73, 95% CI 0.76-3.94). We found an association between markers of diastolic dysfunction (enlarging LV, compensatory enlarging LA) and severity of neglect, suggesting that cardiac structure, and function affects not only lesion volume, but also the functional consequences of infarct volume.
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http://dx.doi.org/10.3389/fneur.2021.666257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134693PMC
May 2021

Coronary Revascularization and Cognitive Decline: The Patient or the Procedure?

JAMA 2021 05;325(19):1941-1942

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

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http://dx.doi.org/10.1001/jama.2021.5816DOI Listing
May 2021

Plasma amyloid β levels are driven by genetic variants near APOE, BACE1, APP, PSEN2: A genome-wide association study in over 12,000 non-demented participants.

Alzheimers Dement 2021 May 18. Epub 2021 May 18.

Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA.

Introduction: There is increasing interest in plasma amyloid beta (Aβ) as an endophenotype of Alzheimer's disease (AD). Identifying the genetic determinants of plasma Aβ levels may elucidate important biological processes that determine plasma Aβ measures.

Methods: We included 12,369 non-demented participants from eight population-based studies. Imputed genetic data and measured plasma Aβ1-40, Aβ1-42 levels and Aβ1-42/Aβ1-40 ratio were used to perform genome-wide association studies, and gene-based and pathway analyses. Significant variants and genes were followed up for their association with brain positron emission tomography Aβ deposition and AD risk.

Results: Single-variant analysis identified associations with apolipoprotein E (APOE) for Aβ1-42 and Aβ1-42/Aβ1-40 ratio, and BACE1 for Aβ1-40. Gene-based analysis of Aβ1-40 additionally identified associations for APP, PSEN2, CCK, and ZNF397. There was suggestive evidence for interaction between a BACE1 variant and APOE ε4 on brain Aβ deposition.

Discussion: Identification of variants near/in known major Aβ-processing genes strengthens the relevance of plasma-Aβ levels as an endophenotype of AD.
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http://dx.doi.org/10.1002/alz.12333DOI Listing
May 2021

Association of Coronary Artery Atherosclerosis With Brain White Matter Hyperintensity.

Stroke 2021 Aug 18;52(8):2594-2600. Epub 2021 May 18.

Department of Neurology (M.C.J., R.F.G., P.N.), Johns Hopkins University School of Medicine, Baltimore, MD.

[Figure: see text].
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http://dx.doi.org/10.1161/STROKEAHA.120.032674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316285PMC
August 2021

Association Between Intracerebral Hemorrhage and Subsequent Arterial Ischemic Events in Participants From 4 Population-Based Cohort Studies.

JAMA Neurol 2021 Jul;78(7):809-816

Clinical and Translational Neuroscience Unit, Feil Family Brain and Mind Research Institute, Department of Neurology, Weill Cornell Medicine, New York, New York.

Importance: Intracerebral hemorrhage and arterial ischemic disease share risk factors, to our knowledge, but the association between the 2 conditions remains unknown.

Objective: To evaluate whether intracerebral hemorrhage was associated with an increased risk of incident ischemic stroke and myocardial infarction.

Design, Setting, And Participants: An analysis was conducted of pooled longitudinal participant-level data from 4 population-based cohort studies in the United States: the Atherosclerosis Risk in Communities (ARIC) study, the Cardiovascular Health Study (CHS), the Northern Manhattan Study (NOMAS), and the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Patients were enrolled from 1987 to 2007, and the last available follow-up was December 31, 2018. Data were analyzed from September 1, 2019, to March 31, 2020.

Exposure: Intracerebral hemorrhage, as assessed by an adjudication committee based on predefined clinical and radiologic criteria.

Main Outcomes And Measures: The primary outcome was an arterial ischemic event, defined as a composite of ischemic stroke or myocardial infarction, centrally adjudicated within each study. Secondary outcomes were ischemic stroke and myocardial infarction. Participants with prevalent intracerebral hemorrhage, ischemic stroke, or myocardial infarction at their baseline study visit were excluded. Cox proportional hazards regression was used to examine the association between intracerebral hemorrhage and subsequent arterial ischemic events after adjustment for baseline age, sex, race/ethnicity, vascular comorbidities, and antithrombotic medications.

Results: Of 55 131 participants, 47 866 (27 639 women [57.7%]; mean [SD] age, 62.2 [10.2] years) were eligible for analysis. During a median follow-up of 12.7 years (interquartile range, 7.7-19.5 years), there were 318 intracerebral hemorrhages and 7648 arterial ischemic events. The incidence of an arterial ischemic event was 3.6 events per 100 person-years (95% CI, 2.7-5.0 events per 100 person-years) after intracerebral hemorrhage vs 1.1 events per 100 person-years (95% CI, 1.1-1.2 events per 100 person-years) among those without intracerebral hemorrhage. In adjusted models, intracerebral hemorrhage was associated with arterial ischemic events (hazard ratio [HR], 2.3; 95% CI, 1.7-3.1), ischemic stroke (HR, 3.1; 95% CI, 2.1-4.5), and myocardial infarction (HR, 1.9; 95% CI, 1.2-2.9). In sensitivity analyses, intracerebral hemorrhage was associated with arterial ischemic events when updating covariates in a time-varying manner (HR, 2.2; 95% CI, 1.6-3.0); when using incidence density matching (odds ratio, 2.3; 95% CI, 1.3-4.2); when including participants with prevalent intracerebral hemorrhage, ischemic stroke, or myocardial infarction (HR, 2.2; 95% CI, 1.6-2.9); and when using death as a competing risk (subdistribution HR, 1.6; 95% CI, 1.1-2.1).

Conclusions And Relevance: This study found that intracerebral hemorrhage was associated with an increased risk of ischemic stroke and myocardial infarction. These findings suggest that intracerebral hemorrhage may be a novel risk marker for arterial ischemic events.
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http://dx.doi.org/10.1001/jamaneurol.2021.0925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094038PMC
July 2021

Association of Carotid Intima-Media Thickness and Other Carotid Ultrasound Features With Incident Dementia in the ARIC-NCS.

J Am Heart Assoc 2021 May 17;10(9):e020489. Epub 2021 Apr 17.

Division of Epidemiology and Community Health School of Public Health University of Minnesota Minneapolis MN.

Background Increased carotid intima-media thickness, interadventitial diameter, presence of carotid plaque, and lower distensibility are predictors for cardiovascular disease. These indices likely relate to cerebrovascular disease, and thus may constitute a form of vascular contributions to dementia and Alzheimer disease-related dementia. Therefore, we assessed the relationship of carotid measurements and arterial stiffness with incident dementia in the ARIC (Atherosclerosis Risk in Communities) study. Methods and Results A total of 12 459 ARIC participants with carotid arterial ultrasounds in 1990 to 1992 were followed through 2017 for dementia. Dementia cases were identified using in-person and phone cognitive status assessments, hospitalization discharge codes, and death certificate codes. Cox proportional hazards models were used to estimate the hazard ratios (HRs) for incident dementia. Participants were aged 57±6 at baseline, 57% were women, and 23% were Black individuals. Over a median follow-up time of 24 years, 2224 dementia events were ascertained. After multivariable adjustments, the highest quintile of carotid intima-media thickness and interadventitial diameter in midlife was associated with increased risk of dementia (HR [95% CIs], 1.25 [1.08-1.45]; and 1.22 [1.04-1.43], respectively) compared with its respective lowest quintile. Presence of carotid plaque did not have a significant association with dementia (HR [95% CI], 1.06 [0.97-1.15]). Higher distensibility was associated with lower risk of dementia (HR [95% CI] highest versus lowest quintile, 0.76 [0.63-0.91]). Conclusions Greater carotid intima-media thickness, interadventitial diameter, and lower carotid distensibility are associated with an increased risk of incident dementia. These findings suggest that both atherosclerosis and carotid stiffness may be implicated in dementia risk.
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http://dx.doi.org/10.1161/JAHA.120.020489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200760PMC
May 2021

Cerebrovascular Disease and Cognitive Outcome in Patients with Cardiac Disease.

Semin Neurol 2021 Aug 13;41(4):463-472. Epub 2021 Apr 13.

Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.

The pace of understanding cognitive decline and dementia has rapidly accelerated over the past decade, with constantly evolving insights into the vascular contributions to cognitive impairment and dementia (VCID). Notably, more overlap has been discovered in the pathophysiology between what was previously understood to be Alzheimer's disease and VCID, leading to a heightened emphasis on disease prevention through early and aggressive control of vascular risk factors. One particularly vulnerable population may be those with cardiac disease, as they are at risk for cerebrovascular disease, which itself can lead to dementia, and increasing evidence supports cognitive impairment in disease processes such as heart failure and atrial fibrillation, independent of ischemic stroke, suggesting other potential mechanisms. In this article, we review the evidence supporting the relationship between cardiac disease, cerebrovascular disease, and cognitive decline and discuss the ongoing and future research efforts aimed at defining the important relationship between these entities.
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http://dx.doi.org/10.1055/s-0041-1726330DOI Listing
August 2021

White Matter Hyperintensity and Cardiovascular Disease Outcomes in the SPRINT MIND Trial.

J Stroke Cerebrovasc Dis 2021 Jun 3;30(6):105764. Epub 2021 Apr 3.

Departments of Neurology: University of Utah, MUSC, Johns Hopkins University, University of Chicago, MGH, 175 N. Medical Dr, Salt Lake City, UT 84132, USA. Electronic address:

Background: The Systolic Blood Pressure Intervention Trial (SPRINT) randomized patients to a goal systolic blood pressure (SBP) <120 mm Hg vs. <140 mm Hg. In a subset of participants, the SPRINT MIND ancillary study performed a baseline MRI and measured white matter hyperintensity volume (WMHv). In this secondary analysis, we evaluated the association between baseline WMHv and cardiovascular events during follow-up in the overall sample.

Methods: The primary outcome was the same as SPRINT, a composite of stroke, myocardial infarction, acute coronary syndrome, decompensated congestive heart failure, or cardiovascular death. We fit Cox models to the primary outcome and report adjusted hazard ratios (HR) for log-transformed WMHv and quartiles of WMHv.

Results: Among 717 participants, the median (IQR) baseline WMHv was 1.62 (0.66-3.98) mL. The primary outcome occurred in 51/719 (7.1%). The median WMHv was higher in patients with the primary outcome (3.40 mL versus 1.56 mL, p < 0.001). In adjusted models, WMHv as a log-transformed continuous variable was associated with the primary outcome (HR 1.44, 95% CI 1.15-1.80). The highest quartile of WMHv, compared to the lowest, was also independently associated with the primary outcome (HR 3.21, 95% CI 1.27-8.13).

Conclusions: We found that the baseline volume of WMH was associated with future CVD risk in SPRINT MIND. Prospective clinical trials with larger sample sizes than the current study are needed to determine whether intensive BP lowering can reduce the high cardiovascular risk in patients with WMH.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.105764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107132PMC
June 2021

Novel Score for Stratifying Risk of Critical Care Needs in Patients With Intracerebral Hemorrhage.

Neurology 2021 05 31;96(20):e2458-e2468. Epub 2021 Mar 31.

From the Department of Neurology (R.F., B.J.C., R.K., E.B.M., V.C.U., R.F.G.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology (A.A.), University of Miami, Miller School of Medicine, Jackson Memorial Health System, FL; and Department of Neurology (W.X.), Case Western Reserve University School of Medicine, University Hospitals Cleveland Medical Center, OH.

Objective: To develop a risk prediction score identifying patients with intracerebral hemorrhage (ICH) at low risk for critical care.

Methods: We retrospectively analyzed data of 451 patients with ICH between 2010 and 2018. The sample was randomly divided into a development and a validation cohort. Logistic regression was used to develop a risk score by weighting independent predictors of intensive care unit (ICU) needs according to strength of association. The risk score was tested in the validation cohort and externally validated in a dataset from another institution.

Results: The rate of ICU interventions was 80.3%. Systolic blood pressure (SBP), Glasgow Coma Scale (GCS) score, intraventricular hemorrhage (IVH), and ICH volume were independent predictors of critical care, resulting in the following point assignments for the Intensive Care Triaging in Spontaneous Intracerebral Hemorrhage (INTRINSIC) score: SBP 160 to 190 mm Hg (1 point), SBP >190 mm Hg (3 points); GCS 8 to 13 (1 point), GCS <8 (3 points); ICH volume 16 to 40 cm (1 point), ICH volume >40 cm (2 points); and presence of IVH (1 point), with values ranging between 0 and 9. Among patients with a score of 0 and no ICU needs during their emergency department stay, 93.6% remained without critical care needs. In an external validation cohort of patients with ICH, the INTRINSIC score achieved an area under the receiver operating characteristic curve of 0.823 (95% confidence interval 0.782-0.863). A score <2 predicted the absence of critical care needs with 48.5% sensitivity and 88.5% specificity, and a score <3 predicted the absence of critical care needs with 61.7% sensitivity and 83.0% specificity.

Conclusion: The INTRINSIC score identifies patients with ICH who are at low risk for critical care interventions.

Classification Of Evidence: This study provides Class II evidence that the INTRINSIC score identifies patients with ICH at low risk for critical care interventions.
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http://dx.doi.org/10.1212/WNL.0000000000011927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205477PMC
May 2021

Risk factors and outcomes of hospitalized stroke patients in Lusaka, Zambia.

J Neurol Sci 2021 May 18;424:117404. Epub 2021 Mar 18.

University of Zambia School of Medicine, Lusaka, Zambia; University Teaching Hospital, Lusaka, Zambia; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address:

Background: Limited data exists about stroke risk factors and outcomes in sub-Saharan African countries, including Zambia. We aim to fill this gap by describing features of hospitalized stroke patients at University Teaching Hospital (UTH), the national referral hospital in Lusaka, Zambia.

Methods: We conducted a retrospective study of consecutive adults with stroke admitted to UTH's inpatient neurology service from October 2018 to March 2019. Strokes were classified as ischemic or hemorrhagic based on CT scan results and unknown if CT scan was not obtained. Chi-square analyses and t-tests were used to compare characteristics between cohorts with differing stroke subtypes.

Results: Adults with stroke constituted 43% (n = 324) of all neurological admissions, had an average age of 60 ± 18 years, and 62% of the cohort was female. Stroke subtypes were 58% ischemic, 28% hemorrhagic, and 14% unknown. Hypertension was present in 80% of all strokes and was significantly associated with hemorrhagic stroke (p = 0.03). HIV was present in 18% of all strokes and did not significantly differ by stroke subtype. Diabetes (16%), heart disease (34%), atrial fibrillation (9%), and past medical history of stroke (22%) were all significantly more common in patients with ischemic stroke (p < 0.05). In-hospital mortality was 24% overall and highest among individuals with hemorrhagic strokes (33%, p = 0.005).

Conclusions: This Zambian stroke cohort is notable for its young age, significant HIV burden, high in-hospital mortality, and high rates of uncontrolled hypertension. Our results demonstrate Zambia's substantial stroke burden, significant contribution of HIV to stroke, and the need to improve primary stroke prevention.
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http://dx.doi.org/10.1016/j.jns.2021.117404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096704PMC
May 2021

Head injury and 25-year risk of dementia.

Alzheimers Dement 2021 Mar 9. Epub 2021 Mar 9.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health.

Introduction: Head injury is associated with significant morbidity and mortality. Long-term associations of head injury with dementia in community-based populations are less clear.

Methods: Prospective cohort study of 14,376 participants (mean age 54 years at baseline, 56% female, 27% Black, 24% with head injury) enrolled in the Atherosclerosis Risk in Communities (ARIC) Study. Head injury was defined using self-report and International Classification of Diseases, Ninth/Tenth Revision (ICD-9/10) codes. Dementia was defined using cognitive assessments, informant interviews, and ICD-9/10 and death certificate codes.

Results: Head injury was associated with risk of dementia (hazard ratio [HR] = 1.44, 95% confidence interval [CI] = 1.3-1.57), with evidence of dose-response (1 head injury: HR = 1.25, 95% CI = 1.13-1.39, 2+ head injuries: HR = 2.14, 95% CI = 1.86-2.46). There was evidence for stronger associations among female participants (HR = 1.69, 95% CI = 1.51-1.90) versus male participants (HR = 1.15, 95% CI = 1.00-1.32), P-for-interaction < .001, and among White participants (HR = 1.55, 95% CI = 1.40-1.72) versus Black participants (HR = 1.22, 95% CI = 1.02-1.45), P-for-interaction = .008.

Discussion: In this community-based cohort with 25-year follow-up, head injury was associated with increased dementia risk in a dose-dependent manner, with stronger associations among female participants and White participants.
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http://dx.doi.org/10.1002/alz.12315DOI Listing
March 2021

Sex Differences in Cognitive Decline Among US Adults.

JAMA Netw Open 2021 02 1;4(2):e210169. Epub 2021 Feb 1.

Cognitive Health Services Research Program, Department of Internal Medicine, University of Michigan, Ann Arbor.

Importance: Sex differences in dementia risk are unclear, but some studies have found greater risk for women.

Objective: To determine associations between sex and cognitive decline in order to better understand sex differences in dementia risk.

Design, Setting, And Participants: This cohort study used pooled analysis of individual participant data from 5 cohort studies for years 1971 to 2017: Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, and Northern Manhattan Study. Linear mixed-effects models were used to estimate changes in each continuous cognitive outcome over time by sex. Data analysis was completed from March 2019 to October 2020.

Exposure: Sex.

Main Outcomes And Measures: The primary outcome was change in global cognition. Secondary outcomes were change in memory and executive function. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition.

Results: Among 34 349 participants, 26 088 who self-reported Black or White race, were free of stroke and dementia, and had covariate data at or before the first cognitive assessment were included for analysis. Median (interquartile range) follow-up was 7.9 (5.3-20.5) years. There were 11 775 (44.7%) men (median [interquartile range] age, 58 [51-66] years at first cognitive assessment; 2229 [18.9%] Black) and 14 313 women (median [interquartile range] age, 58 [51-67] years at first cognitive assessment; 3636 [25.4%] Black). Women had significantly higher baseline performance than men in global cognition (2.20 points higher; 95% CI, 2.04 to 2.35 points; P < .001), executive function (2.13 points higher; 95% CI, 1.98 to 2.29 points; P < .001), and memory (1.89 points higher; 95% CI, 1.72 to 2.06 points; P < .001). Compared with men, women had significantly faster declines in global cognition (-0.07 points/y faster; 95% CI, -0.08 to -0.05 points/y; P < .001) and executive function (-0.06 points/y faster; 95% CI, -0.07 to -0.05 points/y; P < .001). Men and women had similar declines in memory (-0.004 points/y faster; 95% CI, -0.023 to 0.014; P = .61).

Conclusions And Relevance: The results of this cohort study suggest that women may have greater cognitive reserve but faster cognitive decline than men, which could contribute to sex differences in late-life dementia.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.0169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907956PMC
February 2021

Midlife Cardiovascular Risk Factors, Subclinical Atherosclerosis, and Cerebral Hypometabolism.

J Am Coll Cardiol 2021 02;77(7):899-901

Departments of Neurology and Epidemiology, Johns Hopkins University, Baltimore, Maryland, USA. Electronic address: https://twitter.com/gottesman_lab.

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http://dx.doi.org/10.1016/j.jacc.2020.12.046DOI Listing
February 2021

Common Medications and Intracerebral Hemorrhage: The ARIC Study.

J Am Heart Assoc 2021 02 15;10(5):e014270. Epub 2021 Feb 15.

Department of Neurology Johns Hopkins University School of Medicine Baltimore MD.

Background Antiplatelets, anticoagulants, and statins are commonly prescribed for various indications. The associations between these medications and the risk of intracerebral hemorrhage (ICH) and cerebral microbleeds (CMBs) are unclear. Methods and Results We performed a retrospective study of the ARIC (Atherosclerosis Risk in Communities) study cohort, recruited from 4 US communities in 1987 to 1989 with follow-up. In 2011 to 2013, a subset (N=1942) underwent brain magnetic resonance imaging with CMB evaluation. Time-varying and any antiplatelet, anticoagulant, or statin use was evaluated at subsequent study visits in participants not on each medication at baseline. To determine the hazard of ICH and odds of CMB by medication use, logistic and Cox proportional hazard models were built, respectively, adjusting for the propensity to take the medication, concomitant use of other medications, and cognitive, genetic, and radiographic data. Of 15 719 individuals during up to 20 years of follow-up, 130 participants experienced an ICH. The adjusted hazard of ICH was significantly lower among participants taking an antiplatelet at the most recent study visit before ICH versus nonusers (hazard ratio [HR], 0.53; 95% CI, 0.30-0.92). Statin users had a significantly lower hazard of an ICH compared with nonusers (adjusted HR, 0.13; 95% CI, 0.05-0.34). There was no association of CMB and antiplatelet, anticoagulant, or statin use in adjusted models. Conclusions In this US community-based study, antiplatelet and statin use were associated with lower ICH hazard, whereas no association was noted between CMBs and antiplatelets, anticoagulants, and statins. Further study is needed to understand the differential roles of these medications in cerebral microhemorrhages and macrohemorrhages.
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http://dx.doi.org/10.1161/JAHA.120.014270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174245PMC
February 2021

Recruiting Diverse Populations in Clinical Trials: How Do We Overcome Selection Bias?

Neurology 2021 03 10;96(11):509-510. Epub 2021 Feb 10.

From the Departments of Neurology and Epidemiology (R.F.G.), Johns Hopkins University School of Medicine, Baltimore, MD; and Departments of Neurology and Physical Medicine and Rehabilitation (R.H.), University of Pennsylvania, Philadelphia.

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http://dx.doi.org/10.1212/WNL.0000000000011639DOI Listing
March 2021

Generalizability of findings from a clinical sample to a community-based sample: A comparison of ADNI and ARIC.

Alzheimers Dement 2021 08 1;17(8):1265-1276. Epub 2021 Feb 1.

Department of Epidemiology, George Washington University, Washington, District of Columbia, USA.

Introduction: Clinic-based study samples, including the Alzheimer's Disease Neuroimaging Initiative (ADNI), offer rich data, but findings may not generalize to community-based settings. We compared associations in ADNI to those in the Atherosclerosis Risk in Communities (ARIC) study to assess generalizability across the two settings.

Methods: We estimated cohort-specific associations among risk factors, cognitive test scores, and neuroimaging outcomes to identify and quantify the extent of significant and substantively meaningful differences in associations between cohorts. We explored whether using more homogenous samples improved comparability in effect estimates.

Results: The proportion of associations that differed significantly between cohorts ranged from 27% to 34% across sample subsets. Many differences were substantively meaningful (e.g., odds ratios [OR] for apolipoprotein E ε4 on amyloid positivity in ARIC: OR = 2.8, in ADNI: OR = 8.6).

Discussion: A higher proportion of associations differed significantly and substantively than would be expected by chance. Findings in clinical samples should be confirmed in more representative samples.
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http://dx.doi.org/10.1002/alz.12293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359773PMC
August 2021

Periodontal Disease, Atrial Fibrillation and Stroke.

Am Heart J 2021 05 24;235:36-43. Epub 2021 Jan 24.

Department of Periodontology, University of North Carolina, Chapel Hill, NC.

Background: We recently described the association between periodontal disease (PD) and stroke risk.

Purpose: The purpose of this study was to test the association between PD, dental care utilization and incident atrial fibrillation (AF), as well as AF as a mediator to PD- stroke association.

Methods: In dental cohort of the Atherosclerosis Risk in Communities Study (ARIC), participants without prior AF underwent full-mouth periodontal measurements. PD was defined on an ordinal scale as healthy (referent), mild, moderate and severe. In ARIC main cohort, participants were classified as regular or episodic dental care users. These patients were followed for AF, over 17 years. Cox proportional hazards models adjusted for AF risk factors were used to study relationships between PD severity, dental care utilization and AF. Mediation analysis was used to test if AF mediated the PD- stroke association.

Results: In dental ARIC cohort, 5,958 were assessed without prior AF, 754 were found to have AF. Severe PD was associated with AF on both univariable (crude HR, 1.54; 95% CI, 1.26-1.87) and multivariable (adjusted HR, 1.31, 95% CI, 1.06-1.62) analyses. Mediation analysis suggested AF mediates the association between PD and stroke. In the main ARIC cohort, 9,666 participants without prior AF were assessed for dental care use, 1558 were found to have AF. Compared with episodic users, regular users had a lower risk for AF on univariable (crude HR, 0.82, 95% CI, 0.74-0.90) and multivariable (adjusted HR, 0.88, 95% CI, 0.78-0.99) analyses.

Conclusions: PD is associated with AF. The association may explain the PD-stroke risk. Regular users had a lower risk of incident AF compared with episodic users.
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http://dx.doi.org/10.1016/j.ahj.2021.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084947PMC
May 2021

Subclinical Vascular Disease Burden and Premature Mortality Among Middle-aged Adults: the Atherosclerosis Risk in Communities Study.

J Gen Intern Med 2021 07 19;36(7):2048-2054. Epub 2021 Jan 19.

Division of Geriatrics, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.

Background: Whether high burden of subclinical vascular disease (SVD) is associated with increased premature mortality among middle-aged adults is not adequately understood. The association of midlife SVD burden with premature mortality among middle-aged adults free of clinical cardiovascular disease (CVD) could provide further insights into stratifying premature death beyond clinical CVD.

Objective: To determine whether high burden of subclinical vascular disease is associated with increased premature mortality among middle-aged adults.

Design: We leveraged data from the Atherosclerosis Risk in Communities Study.

Participants: Thirteen thousand eight hundred seventy-six community-dwelling blacks and whites aged 45-64 years from the Atherosclerosis Risk in Communities Study.

Main Measures: Each SVD measure-ankle-brachial index, carotid intima-media thickness, and electrocardiogram-was scored 0 (no abnormalities), 1 (minor abnormalities), or 2 (major abnormalities). An index was constructed as the sum of three measures, ranging from 0 (lowest burden) to 6 (highest burden). We used the Cox proportional-hazards model to determine the association of SVD burden with premature mortality (death before age 70) among persons free of clinical CVD. We then tested the difference in point estimates between SVD and clinical CVD.

Key Results: Among persons without CVD, the premature death was 1.7, 2.1, 2.5, and 3.8 per 1000 person-years among those with an SVD score of 0 (lowest burden), 1, 2, and 3-6 (highest burden), respectively. After multivariable-adjustment, highest SVD burden (score = 3-6; HR = 1.47) was significantly associated with premature death among persons initially without CVD. In the model where persons with and without CVD were included, high SVD burden (score: 3-6 vs. 0) and CVD did not have hugely different association with premature death (HR = 1.49 vs. 1.68; P = 0.32 for comparison).

Conclusions: Midlife SVD burden was associated with premature mortality and it could stratify premature death beyond clinical CVD. It is important to take SVD into account when designing interventions for reducing premature mortality.
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http://dx.doi.org/10.1007/s11606-020-06398-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298717PMC
July 2021
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