Seth T. Lirette

Vascular Imaging Abnormalities and Cognition Mediation by Cortical Volume in Nondemented Individuals: Atherosclerosis Risk in Communities-Neurocognitive Study

The mechanisms by which cerebrovascular disease (CVD) causes cognitive impairment have been elusive. While the volume of infarcted tissue was an obvious initial candidate as a quantitative marker of pathology1, persons with clinically overt, large infarcts account for only a small fraction of cognitively impaired individuals with CVD2–5. The presence of even one visible lacunar infarct is associated with cognitive impairment or cognitive decline6–10, and the associations of white matter hyperintensities with cognition do not occur only with severe disease11–14. Because one or two lacunar infarcts or moderate WMH burden are themselves unlikely to be sufficient to damage enough cognitively eloquent grey matter or pathways, the associations of WMH and smaller infarcts with cognitive impairment imply that WMH or visible lacunes must be proxies for a more broadly distributed pathological process. We had the opportunity to conduct a large-scale clinical and imaging cross-sectional analysis of non-demented individuals in the Atherosclerosis Risk in Communities (ARIC) Neurocognitive Study cohort. We tested the hypothesis that the cognitive consequences of WMH and smaller infarcts are mediated by another pathophysiological process, specifically variations in regional cerebral cortical volume. Regional cortical volumes are a measure of neuronal and synaptic structural integrity. Our analyses do not require us to specify how visible subcortical cerebrovascular lesions cause loss of cortical volume, but microinfarcts are the most plausible candidate mechanism5, 15–18.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.

Association of high-density lipoprotein subclasses and incident coronary heart disease: The Jackson Heart and Framingham Offspring Cohort Studies

Aims We aimed to clarify the associations of high-density lipoprotein cholesterol (HDL-C) subclasses with incident coronary heart disease (CHD) in two large primary prevention cohorts. Methods We measured cholesterol at baseline from the two major HDL subfractions (larger, more buoyant HDL2 and smaller, denser HDL3) separated by density gradient ultracentrifugation in 4114 (mean age 53.8 years; 64% female) African American participants from the Jackson Heart Study and 818 (mean age 57.3 years, 52% female) predominantly Caucasian participants from the Framingham Offspring Cohort Study. Multivariable adjusted hazard ratios (HRs) for HDL-C and its subclasses were derived from Cox proportional hazards regression models to estimate associations with incident CHD events including myocardial infarction, CHD death, and revascularization. Analyses were performed for each cohort separately and as a combined population. Results In models adjusted for cardiovascular risk factors for the combined population, HDL3-C (HR 0.76 per SD increase; 95% confidence interval (CI), 0.62–0.94; p = 0.01), rather than HDL2-C (HR 0.88 per SD; 95% CI, 0.72–1.09; p = 0.24) drove the inverse association of HDL-C (HR 0.79 per SD; 95% CI, 0.64–0.98; p = 0.03) with CHD. Similar associations were seen in multivariable analyses within each cohort including after adjusting for apolipoprotein A1 in the Jackson Heart Study. Conclusion Smaller, denser HDL3-C levels are primarily responsible for the inverse association between HDL-C and incident CHD in this diverse group of primary prevention subjects. These findings have important implications ranging from considerations of HDL biology to interpretations of clinical trials utilizing HDL-C therapeutics.

Associations between inflammation and cognitive function in African Americans and European Americans

To examine associations between specific inflammatory biomarkers and cognitive function in African Americans (AAs) and European Americans (EAs) with prevalent vascular risk factors.

Remnant Lipoprotein Cholesterol and Incident Coronary Heart Disease: The Jackson Heart and Framingham Offspring Cohort Studies

Background Remnant lipoproteins (RLPs), the triglyceride‐enriched precursors to low‐density lipoprotein, are an emerging risk factor for coronary heart disease (CHD). We sought to determine the association of RLP cholesterol (RLP‐C) levels with incident CHD in 2 diverse, prospective, longitudinal observational US cohorts. Methods and Results We analyzed cholesterol levels from serum lipoprotein samples separated via density gradient ultracentrifugation in 4114 US black participants (mean age 53.8 years, 64% women) from the Jackson Heart Study and a random sample of 818 predominantly white participants (mean age 57.3 years, 52% women) from the Framingham Offspring Cohort Study. Multivariable‐adjusted hazard ratios (HRs) for RLP‐C (the sum of very low‐density lipoprotein3 cholesterol and intermediate‐density lipoprotein cholesterol) were derived to estimate associations with incident CHD events consisting of myocardial infarction, CHD death, and revascularizations for each cohort separately and as a combined population. There were 146 CHD events in the combined population. After adjustments for age, sex, body mass index, smoking, blood pressure, diabetes, and lipid‐lowering therapy for the combined population, RLP‐C (HR 1.23 per 1‐SD increase, 95% CI 1.06–1.42, P<0.01) and intermediate‐density lipoprotein cholesterol (HR 1.26 per 1‐SD increase, 95% CI 1.08–1.47, P<0.01) predicted CHD during an 8‐year follow‐up. Associations were attenuated by high‐density lipoprotein cholesterol and ultimately lost significance with inclusion of real low‐density lipoprotein cholesterol, which excludes Lp(a) and IDL cholesterol fractions. Similar associations were seen in multivariable analyses within each cohort. Conclusion RLP‐C levels are predictive of incident CHD in this diverse group of primary prevention subjects. Interventions aimed at reducing RLP‐C to prevent CHD warrant further intensive investigation. Clinical Trial Registration URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00415415.

Blood metabolite markers of cognitive performance and brain function in aging

We recently showed that Alzheimers disease patients have lower plasma concentrations of the phosphatidylcholines (PC16:0/20:5; PC16:0/22:6; and PC18:0/22:6) relative to healthy controls. We now extend these findings by examining associations between plasma concentrations of these PCs with cognition and brain function (measured by regional resting state cerebral blood flow; rCBF) in non-demented older individuals. Within the Baltimore Longitudinal Study of Aging neuroimaging substudy, participants underwent cognitive assessments and brain 15O-water positron emission tomography. Plasma phosphatidylcholines concentrations (PC16:0/20:5, PC16:0/22:6, and PC18:0/22:6), cognition (California Verbal Learning Test (CVLT), Trail Making Test A&B, the Mini-Mental State Examination, Benton Visual Retention, Card Rotation, and Fluencies—Category and Letter), and rCBF were assessed. Lower plasma phosphatidylcholine concentrations were associated with lower baseline memory performance (CVLT long delay recall task—PC16:0/20:5: −2.17–1.39−0.60 p = 0.001 (β with 95% confidence interval subscripts)) and lower rCBF in several brain regions including those associated with memory performance and higher order cognitive processes. Our findings suggest that lower plasma concentrations of PC16:0/20:5, PC16:0/22:6, and PC18:0/22:6 are associated with poorer memory performance as well as widespread decreases in brain function during aging. Dysregulation of peripheral phosphatidylcholine metabolism may therefore be a common feature of both Alzheimers disease and age-associated differences in cognition.

Effects of Age and Functional Status on the Relationship of Systolic Blood Pressure With Mortality in Mid and Late Life: The ARIC Study

Background. Impaired functional status attenuates the relationship of systolic blood pressure (SBP) with mortality in older adults but has not been studied in middle-aged populations. Method. Among 10,264 stroke-free Atherosclerosis Risk in Communities participants (mean age 62.8 [5.7] years; 6,349 [62%] younger [<65 years]; 5,148 [50%] men; 2,664 [26%] Black), function was defined as good function (GF) for those self-reporting no difficulty performing functional tasks and basic or instrumental tasks of daily living; all others were defined as impaired function (IF). SBP categories were normal (<120 mmHg), prehypertension (120–139 mmHg), and hypertension (≥140 mmHg). Mortality risk associated with SBP was estimated using adjusted Cox proportional hazard models with a triple interaction between age, functional status, and SBP. Results. Mean follow-up was 12.9 years with 2,863 (28%) deaths. Among younger participants, 3,017 (48%) had IF; 2,279 of 3,915 (58%) older participants had IF. Prehypertension (hazard ratio [HR] = 1.48 [1.03, 2.15] p = .04) and hypertension (HR = 1.97 [1.29, 3.03] p = .002) were associated with mortality in younger GF and older (≥65 years) GF participants (prehypertension HR = 1.21 [1.06, 1.37] p = .005; hypertension HR = 1.47 [1.36, 1.59] p < .001). Among IF participants, prehypertension was not associated with mortality in younger participants (HR = 0.99 [0.85, 1.15] p = .93) and was protective in older participants (HR = 0.87 [0.85, 0.90] p < .001). Hypertension was associated with mortality in younger IF participants (HR = 1.54 [1.30, 1.82] p < .001) but not in older IF participants (HR = 0.99 [0.87, 1.14] p = .93). Conclusions. Compared with younger and well-functioning persons, the additional contribution of blood pressure to mortality is much lower with older age and impaired function, particularly if both are present. Functional status and age could potentially inform optimal blood pressure targets.

Liver Surface Nodularity Score Allows Prediction of Cirrhosis Decompensation and Death

Purpose To determine whether use of the liver surface nodularity (LSN) score, a quantitative biomarker derived from routine computed tomographic (CT) images, allows prediction of cirrhosis decompensation and death. Materials and Methods For this institutional review board-approved HIPAA-compliant retrospective study, adult patients with cirrhosis and Model for End-Stage Liver Disease (MELD) score within 3 months of initial liver CT imaging between January 3, 2006, and May 30, 2012, were identified from electronic medical records (n = 830). The LSN score was measured by using CT images and quantitative software. Competing risk regression was used to determine the association of the LSN score with hepatic decompensation and overall survival. A risk model combining LSN scores (<3 or ≥3) and MELD scores (<10 or ≥10) was created for predicting liver-related events. Results In patients with compensated cirrhosis, 40% (129 of 326) experienced decompensation during a median follow-up period of 4.22 years. After adjustment for competing risks including MELD score, LSN score (hazard ratio, 1.38; 95% confidence interval: 1.06, 1.79) was found to be independently predictive of hepatic decompensation. Median times to decompensation of patients at high (1.76 years, n = 48), intermediate (3.79 years, n = 126), and low (6.14 years, n = 152) risk of hepatic decompensation were significantly different (P < .001). Among the full cohort with compensated or decompensated cirrhosis, 61% (504 of 830) died during the median follow-up period of 2.26 years. After adjustment for competing risks, LSN score (hazard ratio, 1.22; 95% confidence interval: 1.11, 1.33) and MELD score (hazard ratio, 1.08; 95% confidence interval: 1.06, 1.11) were found to be independent predictors of death. Median times to death of patients at high (0.94 years, n = 315), intermediate (2.79 years, n = 312), and low (4.69 years, n = 203) risk were significantly different (P < .001). Conclusion The LSN score derived from routine CT images allows prediction of cirrhosis decompensation and death. ©RSNA, 2016 Online supplemental material is available for this article.

Urinary CYP eicosanoid excretion correlates with glomerular filtration in African-Americans with chronic kidney disease.

Previous studies have indicated that cytochrome P450 (CYP) metabolites of arachidonic acid (AA), i.e., 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs), play an important role in the regulation of renal tubular and vascular function. The present study for the first time profiled HETEs and epoxygenase derived dihydroxyeicosatetraenoic acid diHETEs levels in spot urines and plasma in 262 African American patients from the University of Mississippi Chronic Kidney Disease Clinic and 31 African American controls. Significant correlations in eGFR and urinary 20-HETE/creatinine and 19-HETE/creatinine levels were observed. The eGFR increased by 17.47 [p=0.001] and 60.68 [(p=0.005]ml/min/for each ng/mg increase in 20-HETE and 19-HETE levels, respectively. Similar significant positive associations were found between the other urinary eicosanoids and eGFR and also with 19-HETE/urine creatinine concentration and proteinuria. We found that approximately 80% of plasma HETEs and 30% diHETEs were glucuronidated and the fractional excretion of 20-HETE was less than 1%. These results suggest that there is a significant hepatic source of urinary 20-HETE glucuronide and EETs with extensive renal biotransformation to metabolites which may play a role in the pathogenesis of CKD.

Stroke with intracranial stenosis is associated with increased platelet activation in sickle cell anemia

Overt stroke in sickle cell anemia (SCA) is associated with intracranial stenosis and thrombus formation. Platelet activation is critical for thrombus formation.

QUANTITATIVE IMPACT OF REMNANT LIPOPROTEINS ON RISK FOR HARD CHD EVENTS: A META-ANALYSIS OF THE FRAMINGHAM OFFSPRING AND JACKSON HEART STUDIES

Remnant lipoproteins (RLP) are an important emerging risk factor for coronary heart disease (CHD). Remnants are precursors to low-density lipoproteins and can be elevated if there is impaired triglyceride lipolysis, as observed in patients with metabolic syndrome and diabetes. Remnant particles