Kevin S. King

White Matter Hyperintensities: Use of Aortic Arch Pulse Wave Velocity to Predict Volume Independent of Other Cardiovascular Risk Factors

PURPOSE To evaluate the relationship between pulse wave velocity (PWV) from the aortic arch and subsequent cerebral microvascular disease independent of other baseline cardiovascular risk factors among the participants in the multiethnic Dallas Heart Study. MATERIALS AND METHODS Each subject gave written consent to participate in this HIPAA-compliant, institutional review board-approved prospective study. Aortic arch PWV was measured with phase-contrast magnetic resonance (MR) imaging in a population sample (n = 1270) drawn from the probability-based Dallas Heart Study. Seven years later, the volume of white matter hyperintensities (WMHs) was determined from brain MR images. Linear regression was conducted with aortic arch PWV, 15 other cardiovascular risk factors, and age, sex, and ethnicity included as predictors of WMH. The authors implemented a smoothly clipped absolute deviation-penalized variable selection method to evaluate an optimal predictive risk factor model. RESULTS Aortic arch PWV helped predict WMH volume independent of the other demographic and cardiovascular risk factors (regression coefficient: 0.29; standard error: 0.06; 95% confidence interval: 0.17, 0.42; P < .0001). The optimal predictor variables of subsequent WMH volume adjusted for sex and ethnicity included aortic arch PWV, age, systolic blood pressure, hypertension treatment, and congestive heart failure. The authors estimated that a 1% increase in aortic arch PWV (in meters per second) is related to a 0.3% increase in subsequent WMH volume (in milliliters) when all other variables in the model are held constant. CONCLUSION Aortic arch PWV measured with phase-contrast MR imaging is a highly significant independent predictor of subsequent WMH volume, with a higher standardized effect than any other cardiovascular risk factor assessed except for age. In an optimal predictive model of subsequent WMH burden, aortic arch PWV provides a distinct contribution along with systolic blood pressure, hypertension treatment, congestive heart failure, and age.

Association of Depressive Symptoms with Hippocampal Volume in 1936 Adults

Hippocampal atrophy is reported in major depressive disorder (MDD). However, sample sizes were generally modest, and participant characteristics, including age, differed between studies. This study used a community sample to examine relationships between current depressive symptom severity and hippocampal volume across the adult lifespan. A total of 1936 adults with magnetic resonance images of the brain and Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR) scores were included. Brain volumes were quantified using the FSL program. Multiple linear regressions were performed using left, right, and total hippocampal volume as criterion variables, and predictor variables of QIDS-SR total, total brain volume, age, gender, education, psychotropic medications, alcohol use, and race/ethnicity. Post hoc analyses were conducted in participants with QIDS-SR scores ⩾11 (moderate or greater depressive symptom severity) and <11, and older and younger adults. In the primary analysis (sample as a whole) QIDS-SR was inversely associated with total hippocampal volume (b=−0.044, p=0.032, (CI−0.019 to −0.001)) but not with left or right hippocampal volume evaluated individually. In participants with QIDS-SR scores of <11, hippocampal volumes were not associated with QIDS-SR scores. In those with QIDS-SR scores ⩾11 total, right, and left hippocampal volumes were modestly, but significantly, associated with QIDS-SR scores. The association between QIDS-SR scores and the hippocampal volume was much stronger in older persons. Findings suggest smaller hippocampal volumes among those with greater reported depressive symptom severity—an association that is strongest in people with at least moderate depressive symptom levels.

Genetic, anatomic, and clinical determinants of human serum sterol and vitamin D levels

Significance Cholesterol is the major sterol in blood and in excess causes cardiovascular disease. In addition to cholesterol, numerous other sterols of unknown function and pathogenicity circulate in the bloodstream. Here, we use chemical methods to screen for over 60 different sterols and sterol derivatives in the sera of 3,230 clinically well-characterized individuals. Twenty-seven sterols and two sterol derivatives (vitamin D2 and D3) were routinely detected in vastly different amounts in a majority of individuals. Genes, ethnicity, gender, age, clinical phenotype, and anatomy were identified as significant sources of interindividual variation in these lipid metabolites. An unknown fraction of the genome participates in the metabolism of sterols and vitamin D, two classes of lipids with diverse physiological and pathophysiological roles. Here, we used mass spectrometry to measure the abundance of >60 sterol and vitamin D derivatives in 3,230 serum samples from a well-phenotyped patient population. Twenty-nine of these lipids were detected in a majority of samples at levels that varied over thousands of fold in different individuals. Pairwise correlations between sterol and vitamin D levels revealed evidence for shared metabolic pathways, additional substrates for known enzymes, and transcriptional regulatory networks. Serum levels of multiple sterols and vitamin D metabolites varied significantly by sex, ethnicity, and age. A genome-wide association study identified 16 loci that were associated with levels of 19 sterols and 25-hydroxylated derivatives of vitamin D (P < 10−7). Resequencing, expression analysis, and biochemical experiments focused on one such locus (CYP39A1), revealed multiple loss-of-function alleles with additive effects on serum levels of the oxysterol, 24S-hydroxycholesterol, a substrate of the encoded enzyme. Body mass index, serum lipid levels, and hematocrit were strong phenotypic correlates of interindividual variation in multiple sterols and vitamin D metabolites. We conclude that correlating population-based analytical measurements with genotype and phenotype provides productive insight into human intermediary metabolism.

Effect of Leukocyte Telomere Length on Total and Regional Brain Volumes in a Large Population-Based Cohort

IMPORTANCE Telomere length has been associated with dementia and psychological stress, but its relationship with human brain size is unknown. OBJECTIVE To determine if peripheral blood telomere length is associated with brain volume. DESIGN, SETTING, AND PARTICIPANTS Peripheral blood leukocyte telomere length and brain volumes were measured for 1960 individuals in the Dallas Heart Study, a population-based, probability sample of Dallas County, Texas, residents, with a median (25th-75th percentile) age of 50 (42-58) years. Global and 48 regional brain volumes were assessed from the automated analysis of magnetic resonance imaging. MAIN OUTCOMES AND MEASURES Telomere length and global and regional brain volumes. RESULTS Leukocyte telomere length was associated with total cerebral volume (β [SE], 0.06 [0.01], P <.001) including white and cortical gray matter volume (β [SE], 0.04 [0.01], P = .002; β [SE], 0.07 [0.02], P <.001, respectively), independent of age, sex, ethnicity, and total intracranial volume. While age was associated with the size of most subsegmental regions of the cerebral cortex, telomere length was associated with certain subsegmental regions. Compared with age, telomere length (TL) explained a sizeable proportion of the variance in volume of the hippocampus, amygdala, and inferior temporal region (hippocampus: βTL [SE], 0.08 [0.02], R2, 0.91% vs βage [SE], -0.16 [0.02], R2, 3.80%; amygdala: βTL [SE], 0.08 [0.02], R2, 0.78% vs βage [SE],-0.19 [0.02], R2,4.63%; inferior temporal: βTL [SE], 0.07 [0.02], R2, 0.92% vs βage [SE], -0.14 [0.02], R2, 3.98%) (P <.001 for all). The association of telomere length and the size of the inferior and superior parietal, hippocampus, and fusiform regions was stronger in individuals older than 50 years than younger individuals (inferior parietal: β>50 [SE], 0.13 [0.03], P <.001 vs β≤50 [SE], 0.02 [0.02], P = .51, P for interaction = .001; superior parietal: β>50 [SE], 0.11 [0.03], P <.001 vs β≤50 [SE], 0.01 [0.02], P = .71, P for interaction = .004; hippocampus: β>50 [SE], 0.10 [0.03], P = .004 vs β≤50 [SE], 0.05 [0.02], P = .07, P for interaction = .04; fusiform: β>50 [SE], 0.09 [0.03], P = .002, β≤50 [SE], 0.03 [0.02], P = .31, P for interaction = .03). The volume of the hippocampus, amygdala, superior and inferior temporal, precuneus, lateral orbitofrontal, posterior cingulate, thalamus and ventral diencephalon were independently associated with telomere length after adjustment for all covariates (age, gender, ethnicity, total intracranial volume, body mass index, blood pressure, diabetes, smoking status, and APOE genotype). CONCLUSIONS AND RELEVANCE To our knowledge, this is the first population-based study to date to evaluate telomere length as an independent predictor of global and regional brain size. Future studies are needed to determine how telomere length and anatomic structural changes are related to cognitive function, dementia, and psychological disease.

MR Imaging of Hippocampal Asymmetry at 3T in a Multiethnic, Population-Based Sample: Results from the Dallas Heart Study

BACKGROUND AND PURPOSE: Asymmetry of the hippocampus is regarded as an important clinical finding, but limited data on hippocampal asymmetry are available for the general population. Here we present hippocampal asymmetry data from the Dallas Heart Study determined by automated methods and its relationship to age, sex, and ethnicity. MATERIALS AND METHODS: 3D magnetization-prepared rapid acquisition of gradient echo MR imaging was performed in 2082 DHS-2 participants. The MR images were analyzed by using 2 standard automated brain-segmentation programs, FSL-FIRST and FreeSurfer. Individuals with imaging errors, self-reported stroke, or major structural abnormalities were excluded. Statistical analyses were performed to determine the significance of the findings across age, sex, and ethnicity. RESULTS: At the 90th percentile, FSL-FIRST demonstrated hippocampal asymmetry of 9.8% (95% CI, 9.3%–10.5%). The 90th percentile of hippocampal asymmetry, measured by the difference in right and left hippocampi volume and the larger hippocampus, was 17.9% (95% CI, 17.0%–19.1%). Hippocampal asymmetry increases with age (P = .0216), men have greater asymmetry than women as shown by FSL-FIRST (P = .0036), but ethnicity is not significantly correlated with asymmetry. To confirm these findings, we used FreeSurfer. FreeSurfer showed asymmetry of 4.4% (95% CI, 4.3%–4.7%) normalized to total volume and 8.5% (95% CI, 8.3%–9.0%) normalized by difference/larger hippocampus. FreeSurfer also showed that hippocampal asymmetry increases with age (P = .0024) and that men had greater asymmetry than women (P = .03). CONCLUSIONS: There is a significant degree of hippocampal asymmetry in the population. The data provided will aid in the research, diagnosis, and treatment of temporal lobe epilepsy and other neurologic disease.

Effect of Normal Aging Versus Hypertension, Abnormal Body Mass Index, and Diabetes Mellitus on White Matter Hyperintensity Volume

Background and Purpose— The natural history of white matter hyperintensity (WMH) progression resulting from normal aging versus comorbid vascular insults remains unclear. Therefore we investigated age-related differences in WMH volumes among a group with comorbid hypertension, abnormal body mass index, and diabetes mellitus to a normal aging group drawn from the same population lacking any of these comorbidities. Methods— WMH volumes were acquired using 3T MRI for 2011 Dallas Heart Study participants. The slope of the WMH versus age regression was compared between normal and comorbidity groups <50 and ≥50 years of age where a change in slope was demonstrated. Results— Aging was linearly associated with greater log WMH volume for both normal (P=0.02) and comorbidity (P<0.0001) groups. Beyond 50 years of age, more rapid increases in WMH volumes for age were seen in the group with comorbidities (P<0.0001) but not in the normal group (P=0.173). The between-group difference in slope of expected WMH for age was significantly greater in the comorbidity groups ≥50 years of age (P=0.0008) but not <50 years of age (P=0.752). Conclusions— After 50 years of age, but not before, comorbid hypertension, obesity, and diabetes mellitus were associated with significantly larger WMH volumes for age compared with a normal aging group lacking these conditions. These results support the assertion that age-related differences in WMH volumes are significantly increased in the presence of comorbidities, but the effect is only detectable after 50 years of age.

Cardiovascular Risk Factors Associated with Smaller Brain Volumes in Regions Identified as Early Predictors of Cognitive Decline

PURPOSE To determine in a large multiethnic cohort the cardiovascular and genetic risk factors associated with smaller volume in the hippocampus, precuneus, and posterior cingulate, and their association with preclinical deficits in cognitive performance in patients younger and older than 50 years. MATERIALS AND METHODS The institutional review board approved the study and all participants provided written informed consent. Eligible for this study were 1629 participants (700 men and 929 women; mean age, 50.0 years ± 10.2 [standard deviation]) drawn from the population-based Dallas Heart Study who underwent laboratory and clinical analysis in an initial baseline visit and approximately 7 years later underwent brain magnetic resonance imaging with automated volumetry and cognitive assessment with the Montreal Cognitive Assessment (MoCA). Regression analysis showed associations between risk factors and segmental volumes, and associations between these volumes with cognitive performance in participants younger and older than 50 years. RESULTS Lower hippocampal volume was associated with previous alcohol consumption (standardized estimate, -0.04; P = .039) and smoking (standardized estimate, -0.04; P = .048). Several risk factors correlated with lower total brain, posterior cingulate, and precuneus volumes. Higher total (standardized estimate, 0.06; P = .050), high-density lipoprotein (standardized estimate, 0.07; P = .003), and low-density lipoprotein (standardized estimate, 0.04; P = .037) cholesterol levels were associated with larger posterior cingulate volume, and higher triglyceride levels (standardized estimate, 0.06; P = .004) were associated with larger precuneus volume. Total MoCA score was associated with posterior cingulate volume (standardized estimate, 0.13; P = .001) in younger individuals and with hippocampal (standardized estimate, 0.06; P < .05) and precuneus (standardized estimate, 0.08; P < .023) volumes in older adults. CONCLUSION Smaller volumes in specific brain regions considered to be early markers of dementia risk were associated with specific cardiovascular disease risk factors and cognitive deficits in a predominantly midlife multiethnic population-based sample. Additionally, the risk factors most associated with these brain volumes differed in participants younger and older than 50 years, as did the association between brain volume and MoCA score.

Automated quantification of white matter disease extent at 3 T: Comparison with volumetric readings

To develop and validate an algorithm to automatically quantify white matter hyperintensity (WMH) volume.

Association of 3.0-T Brain Magnetic Resonance Imaging Biomarkers With Cognitive Function in the Dallas Heart Study

IMPORTANCE Understanding the relationships between age-related changes in brain structure and cognitive function has been limited by inconsistent methods for assessing brain imaging, small sample sizes, and racially/ethnically homogeneous cohorts with biased selection based on risk factors. These limitations have prevented the generalizability of results from brain morphology studies. OBJECTIVE To determine the association of 3.0-T structural brain magnetic resonance (MR) imaging measurements with cognitive function in the multiracial/multiethnic, population-based Dallas Heart Study. DESIGN, SETTING, AND PARTICIPANTS Whole-brain, 2-dimensional, fluid-attenuated inversion recovery and 3-dimensional, magnetization-prepared, rapid acquisition with gradient echo MR imaging at 3.0 T was performed in 1645 Dallas Heart Study participants (mean [SD] age, 49.9 [10.5] years; age range, 19-85 years) who received both brain MR imaging and cognitive screening with the Montreal Cognitive Assessment between September 18, 2007, and December 28, 2009. Measurements were obtained for white matter hyperintensity volume, total brain volume, gray matter volume, white matter volume, cerebrospinal fluid volume, and hippocampal volume. Linear regression and a best predictive model were developed to determine the association of MR imaging biomarkers with the Montreal Cognitive Assessment total score and domain-specific questions. MAIN OUTCOMES AND MEASURES High-resolution anatomical MR imaging was used to quantify brain volumes. Scores on the screening Montreal Cognitive Assessment were used for cognitive assessment in participants. RESULTS After adjustment for demographic variables, total brain volume (P < .0001, standardized estimate [SE] = .1069), gray matter volume (P < .0001, SE = .1156), white matter volume (P = .008, SE = .0687), cerebrospinal fluid volume (P = .012, SE = -.0667), and hippocampal volume (P < .0001) were significantly associated with cognitive performance. A best predictive model identified gray matter volume (P < .001, SE = .0021), cerebrospinal fluid volume (P = .01, SE = .0024), and hippocampal volume (P = .004, SE = .1017) as 3 brain MR imaging biomarkers significantly associated with the Montreal Cognitive Assessment total score. Questions specific to the visuospatial domain were associated with the most brain MR imaging biomarkers (total brain volume, gray matter volume, white matter volume, cerebrospinal fluid volume, and hippocampal volume), while questions specific to the orientation domain were associated with the least brain MR imaging biomarkers (only hippocampal volume). CONCLUSIONS AND RELEVANCE Brain MR imaging volumes, including total brain volume, gray matter volume, cerebrospinal fluid volume, and hippocampal volume, were independently associated with cognitive function and may be important early biomarkers of risk for cognitive insult in a young multiracial/multiethnic population. A best predictive model indicated that a combination of multiple neuroimaging biomarkers may be more effective than a single brain MR imaging volume measurement.

Fully automated tool to identify the aorta and compute flow using phase-contrast MRI: Validation and application in a large population based study

To assess if fully automated localization of the aorta can be achieved using phase contrast (PC) MR images.