Griswold, Michael

Background Diffusion tensor imaging measures of white matter ( WM ) microstructural integrity appear to provide earlier indication of WM injury than WM hyperintensities; however, risk factors for poor WM microstructural integrity have not been established. Our study quantifies the association between vascular risk factors in midlife and late life with measures of late‐life WM microstructural integrity. Methods and Results We used data from 1851 participants in ARIC (Atherosclerosis Risk in Communities Study) who completed 3‐T magnetic resonance imaging, including diffusion tensor imaging, as part of the ARIC Neurocognitive Study (ARIC‐NCS). We quantified the association among lipids, glucose, and blood pressure from the baseline ARIC visit (1987–1989, ages 44–65, midlife) and visit 5 of ARIC (2011–2013, ages 67–90, late life, concurrent with ARIC‐NCS) with regional and overall WM mean diffusivity and fractional anisotropy obtained at ARIC visit 5 for ARIC participants. We also considered whether these associations were independent of or modified by WM hyperintensity volumes. We found that elevated blood pressure in midlife and late life and elevated glucose in midlife, but not late life, were associated with worse late‐life WM microstructural integrity. These associations were independent of the degree of WM hyperintensity, and the association between glucose and WM microstructural integrity appeared stronger for those with the least WM hyperintensity. There was little support for an adverse association between lipids and WM microstructural integrity. Conclusions Hypertension in both midlife and late life and elevated glucose in midlife are related to worse WM microstructural integrity in late life.

432 Background: In clinical trials and clinical practice, tumor response assessment with computed tomography (CT) defines critical end points in patients with metastatic disease treated with systemic agents. Methods to reduce errors and improve efficiency in tumor response assessment could improve patient care. Methods: Eleven readers from 10 different institutions independently categorized tumor response according to three different therapeutic response criteria using paired baseline and initial post-therapy CT studies from 20 randomly selected patients with metastatic renal cell carcinoma treated with sunitinib as part of a completed phase III multi-institutional study. Images were evaluated with a manual tumor response evaluation method (standard-of-care) and with computer-assisted response evaluation (CARE) that included stepwise guidance, interactive error-identification and correction methods, automated tumor metric extraction, calculations, response categorization, and data/image archival. A cross-over design, patient randomization, and two-week washout period were used to reduce recall bias. Comparative effectiveness metrics included error rate and mean patient evaluation time. Results: The standard-of-care method was on average associated with one or more errors in 30.5% (6.1/20) of patients while CARE had a 0.0% (0.0/20) error rate (p<0.001). The most common errors were related to data transfer and arithmetic calculation. In patients with errors, the median number of error types was 1 (range 1-3). Mean patient evaluation time with CARE was twice as fast as the standard-of-care method (6.4 vs. 13.1 minutes, p<0.001). Conclusions: Computer-assisted tumor response evaluation reduced errors and time of evaluation, indicating better overall effectiveness than manual tumor response evaluation methods that are the current standard-of-care.

Background: The association of central arterial stiffness and pressure pulsatility with mild cognitive impairment (MCI) and dementia is not well characterized in the population-based setting. Objective: The aim of this study was to quantify the cross-sectional association of arterial stiffness and pressure pulsatility with MCI and dementia among 4,461 older white and black adults from the population-based Atherosclerosis Risk in Communities Study-Neurocognitive Study. Methods: We used race-stratified multinomial logistic regression to evaluate associations of percentile cut points of carotid-femoral pulse wave velocity, central systolic blood pressure, central pulse pressure, and pulse pressure amplification with MCI and dementia versus no cognitive impairment. Results: Among whites, those with carotid-femoral pulse wave velocity or central systolic blood pressure ≥75th percentile had a higher prevalence of MCI compared to participants <75th percentile (conditional odds ratio (OR); 95% confidence interval (CI): 1.27 (1.02, 1.56) and 1.28 (1.04, 1.57), respectively) and those with central pulse pressure ≥75th percentile had a higher prevalence of MCI (OR 1.27 (95% CI: 1.03, 1.58)) and dementia (OR 1.76 (95% CI: 1.06, 2.92) compared to participants <75th percentile. Also among whites, those with pulse pressure amplification ≤25th percentile had a higher prevalence of dementia compared to participants >25th percentile (OR 1.65; (95% CI: 1.01, 2.70). Weaker associations were seen among black participants. Conclusion: Higher arterial stiffness and pulsatility were associated with MCI and dementia in white participants. Longitudinal characterization of the observed associations is warranted to assess whether arterial stiffness and pressure pulsatility predict MCI and dementia among older adults.

Objectives To quantify associations between inflammatory biomarkers and hippocampal volume ( HV ) and to examine effect modification according to sex, race, and age. Design Cross‐sectional analyses using generalized estimating equations to account for familial clustering; standardized β ‐coefficients adjusted for age, sex, race, and education. Setting Community cohorts in Jackson, Mississippi and Rochester, Minnesota. Participants The Genetic Epidemiology Network of Arteriopathy study. Measurements C‐reactive protein ( CRP ), interleukin‐6 ( IL ‐6), and soluble tumor necrosis factor receptors 1 ( sTNFR ‐1) and 2 ( sTNFR ‐2) from peripheral blood were measured in a sample of 773 non‐Hispanic whites (61% women, aged 60.2 ± 9.8) and 514 African Americans (70% women, aged 63.9 ± 8.1) who also underwent brain magnetic resonance imaging. Biomarkers were standardized and compared according to sex, race and age with HV. Results In the full sample, higher sTNFR ‐1 and sTNFR ‐2 were associated with smaller HV . Each standard deviation ( SD ) increase in sTNFR ‐1 was associated with 59.1 mm 3 (95% confidence interval ( CI ) = −101.4 to −16.7 mm 3 ) smaller HV and each SD increase in sTNFR ‐2 associated with 48.8 mm 3 (95% CI = −92.2 to −5.3 mm 3 ) smaller HV . Relationships were stronger for sTNFR ‐2 in men ( HV = −116.6 mm 3 for each SD increase, 95% CI = −201.0 to −32.1) than women ( HV = −26.0 per SD increase, 95% CI = −72.4–20.5) and sTNFR ‐1 in non‐Hispanic whites ( HV = −84.7 mm 3 per SD increase, 95% CI = −142.2 to −27.1) than African Americans ( HV = −14.1 mm 3 per SD increase, 95% CI = −78.3–50.1). Associations between IL ‐6 or CRP and HV were not supported. Conclusion Higher levels of sTNFR s were associated cross‐sectionally with smaller hippocampi. Longitudinal data are needed to determine whether these biomarkers may help to identify risk of late‐life cognitive impairment.

Objectives To examine associations between inflammation and physical function and potential mediation by white matter hyperintensities ( WMH s) in African Americans ( AA s) and European Americans ( EA s). Design Cross‐sectional analysis using linear and logistic models with generalized estimating equations to account for family clustering, reporting results as regression coefficients (β) and odds ratios ( OR s) adjusted for education, alcohol, exercise, body mass index, hypertension, diabetes mellitus, heart disease, cognition, ankle–brachial index, race (site), and supported interactions. Setting Genetic Epidemiology Network of Arteriopathy‐Genetics of Microangiopathic Brain Injury Study cohort. Participants AA and EA sibships with two or more siblings with hypertension before age 60 (N = 1,960; 65% female, 51% AA , aged 26–91, 50% obese, 72% hypertensive). Measurements Inflammation (C‐reactive protein ( CRP ), interleukin‐6 ( IL 6), soluble tumor necrosis factor receptors ( sTNFR s) 1 and 2, WMH volume (cm 3 ) according to magnetic resonance imaging), walking speed (cm/s) over 25 feet, and mobility difficulty (any self‐reported difficulty walking half a mile). Results In separate models, inflammatory markers were associated with walking speed ( sTNFR 1: β = −2.74, P < .001; sTNFR 2: β = −1.23, P = .03; CRP : β = −1.95, P = .001; IL 6: β = −1.24, P = .03) and mobility difficulty ( sTNFR 1: OR = 1.36, P = .001; sTNFR 2: OR = 1.25, P = .005; CRP : OR = 1.22, P = .005; IL 6: OR = 1.18, P = .02); the association between WMH volume and sTNFR 1 in AA (β = 0.07, P = .06) did not reach typical statistical thresholds. WMH volume was associated with walking speed in AA (β = −3.17, P = .02) but not with mobility difficulty ( OR = 1.10, P = .54). Adjusting for WMH did not change associations. Conclusion In young, middle‐aged, and older adults with prevalent cardiovascular risk factors, multiple inflammatory biomarkers were associated with slower walking speed independent of microvascular disease in the brain. There was little evidence of mediation by brain WMH volume. Inflammation may contribute to physical function impairments through pathways other than brain microvascular disease, particularly in AA s.

AbstractIntroductionThe impact of blood pressure on brain volumes may be time‐dependent or pattern‐dependent.MethodsOf 1678 participants from the Atherosclerosis Risk in Communities Neurocognitive Study, we quantified the association between measures and patterns of blood pressure over three time points (∼24 or ∼15 years prior and concurrent with neuroimaging) with late life brain volumes.ResultsHigher diastolic blood pressure ∼24 years prior, higher systolic and pulse pressure ∼15 years prior, and consistently elevated or rising systolic blood pressure from ∼15 years prior to concurrent with neuroimaging, but not blood pressures measured concurrent with neuroimaging, were associated with smaller volumes. The pattern of hypertension ∼15 years prior and hypotension concurrent with neuroimaging was associated with smaller volumes in regions preferentially affected by Alzheimer's disease (e.g., hippocampus: −0.27 standard units, 95% CI: −0.51, −0.03).DiscussionHypertension 15 to 24 years prior is relevant to current brain volumes. Hypertension followed by hypotension appears particularly detrimental.

Background and Purpose— The relationships between cerebrovascular lesions visible on imaging and cognition are complex. We explored the possibility that the cerebral cortical volume mediated these relationships. Methods— Total of 1906 nondemented participants (59% women; 25% African–American; mean age, 76.6 years) in the Atherosclerosis Risk in Communities (ARIC) study underwent cognitive assessments, risk factor assessments, and quantitative MRI for white matter hyperintensities (WMH) and infarcts. The Freesurfer imaging analysis pipeline was used to determine regional cerebral volumes. We examined the associations of cognitive domain outcomes with cerebral volumes (hippocampus and separate groups of posterior and frontal cortical regions of interest) and cerebrovascular imaging features (presence of large or small cortical/subcortical infarcts and WMH volume). We performed mediation pathway analyses to assess the hypothesis that hippocampal and cortical volumes mediated the associations between cerebrovascular imaging features and cognition. Results— In unmediated analyses, WMH and infarcts were both associated with worse psychomotor speed/executive function. In mediation analyses, WMH and infarct associations on psychomotor speed/executive function were significantly attenuated, but not abolished, by the inclusion of the posterior cortical regions of interest volume in the models, and the infarcts on psychomotor speed/executive function association were attenuated, but not abolished, by inclusion of the frontal cortical regions of interest volume. Conclusions— Both WMH and infarcts were associated with cortical volume, and both lesions were also associated with cognitive performance, implying shared pathophysiological mechanisms. Although cross-sectional, our findings suggest that WMH and infarcts could be proxies for clinically covert processes that directly damage cortical regions. Microinfarcts are 1 candidate for such a clinically covert process.

Background— QRS prolongation is associated with adverse outcomes in mostly white populations, but its clinical significance is not well established for other groups. We investigated the association between QRS duration and mortality in African Americans. Methods and Results— We analyzed data from 5146 African Americans in the Jackson Heart Study stratified by QRS duration on baseline 12-lead ECG. We defined QRS prolongation as QRS≥100 ms. We assessed the association between QRS duration and all-cause mortality using Cox proportional hazards models and reported the cumulative incidence of heart failure hospitalization. We identified factors associated with the development of QRS prolongation in patients with normal baseline QRS. At baseline, 30% (n=1528) of participants had QRS prolongation. The cumulative incidences of mortality and heart failure hospitalization were greater with versus without baseline QRS prolongation: 12.6% (95% confidence interval [CI], 11.0–14.4) versus 7.1% (95% CI, 6.3–8.0) and 8.2% (95% CI, 6.9–9.7) versus 4.4% (95% CI, 3.7–5.1), respectively. After risk adjustment, QRS prolongation was associated with increased mortality (hazard ratio, 1.27; 95% CI, 1.03–1.56; P =0.02). There was a linear relationship between QRS duration and mortality (hazard ratio per 10 ms increase, 1.06; 95% CI, 1.01–1.12). Older age, male sex, prior myocardial infarction, lower ejection fraction, left ventricular hypertrophy, and left ventricular dilatation were associated with the development of QRS prolongation. Conclusions— QRS prolongation in African Americans was associated with increased mortality and heart failure hospitalization. Factors associated with developing QRS prolongation included age, male sex, prior myocardial infarction, and left ventricular structural abnormalities.