Ihab Hajjar

Hypertension and Cerebral Vasoreactivity: A Continuous Arterial Spin Labeling Magnetic Resonance Imaging Study

Hypertension is associated with microvascular and macrovascular brain injury but its direct influence on the cerebral circulation is not fully clear. Our objective was to investigate the association of hypertension with global and regional cerebral vasoreactivity to CO2 using continuous arterial spin labeling MRI, independent of stroke and white matter hyperintensities. Participants (n=62; mean age: 66.7±1.0 years, 55% women, 84% white, 65% hypertension, 47% stroke) underwent arterial spin labeling perfusion MRI during normal breathing, 5% CO2 rebreathing, and hyperventilation, as well as 24-hour ambulatory blood pressure monitoring. Vasoreactivity was the slope of the regression between cerebral perfusion and end-tidal CO2. White matter hyperintensity volumes were quantified. Nighttime dipping was calculated as the percentage decline in nighttime/daytime blood pressure. After accounting for stroke and white matter hyperintensity volume, hypertensive participants had lower global vasoreactivity (1.11±0.13 versus 0.43±0.1 mL/100 g per minute per millimeter of mercury; P=0.0012). Regionally, this was significant in the frontal, temporal, and parietal lobes. Higher mean systolic blood pressure was associated with lower vasoreactivity (decreased by 0.11 U/10-mm Hg increase in systolic blood pressure; P=0.04), but nighttime dipping was not (P=0.2). The magnitude of decrease in vasoreactivity in hypertension without stroke was comparable to the magnitude of decrease in vasoreactivity in stroke without hypertension. Hypertension has a direct negative effect on the cerebrovascular circulation independent of white matter hyperintensities and stroke that is comparable to that seen with stroke. Because lower vasoreactivity is associated with poor outcomes, studies of the impact of antihypertensive on vasoreactivity are important.

Roles of Arterial Stiffness and Blood Pressure in Hypertension-Associated Cognitive Decline in Healthy Adults

Although there is strong evidence that hypertension leads to cognitive decline, especially in the executive domain, the relationship between blood pressure and cognition has been conflicted. Hypertension is characterized by blood pressure elevation and increased arterial stiffness. We aimed at investigating whether arterial stiffness would be superior to blood pressure in predicting cognitive decline and explaining the hypertension-executive decline association. A randomly selected asymptomatic population (n=591, age=49.2 years, 70% women, 27% black, and education=18 years) underwent annual vascular and cognitive assessments. Cognition was assessed using computerized versions commonly used cognitive tests, and principal component analysis was used for deriving cognitive scores for executive function, memory, and working memory. Arterial stiffness was measured by carotid–femoral pulse wave velocity (PWV). Higher PWV, but not blood pressure, was associated with a steeper decline in executive (P=0.0002), memory (P=0.05), and working memory (P=0.02) scores after adjusting for demographics, education, and baseline cognitive performance. This remained true after adjusting for hypertension. Hypertension was associated with greater decline in executive score (P=0.0029) and those with combined hypertension and elevated PWV (>7 m/s) had the greatest decline in executive score (P value hypertension×PWV=0.02). PWV explained the association between hypertension and executive function (P value for hypertension=0.0029 versus 0.24 when adjusting for PWV). In healthy adults, increased arterial stiffness is superior to blood pressure in predicting cognitive decline in all domains and in explaining the hypertension-executive function association. Arterial stiffness, especially in hypertension, may be a target in the prevention of cognitive decline.

Retinal Microvascular Signs and Functional Loss in Older Persons The Cardiovascular Health Study

Background and Purpose— We hypothesized that retinal microvascular signs are associated with executive dysfunction, slow gait, and depressive mood, which are characteristic features of microvascular disease affecting frontal subcortical regions of the brain. Methods— In the Cardiovascular Health Study, 1744 participants (mean age, 78) free of stroke had retinal photographs and carotid ultrasound during the 1997 to 1998 visit. We examined the cross-sectional association of retinal signs with the digit-symbol substitution test (DSST) score, gait speed, the Center for Epidemiologic Studies–Depression score, and depressive mood, defined as Center for Epidemiologic Studies–Depression score >9 or antidepressant use. Results— After adjusting for potential confounders, retinal signs were associated with lower DSST score (generalized arteriolar narrowing and arteriovenous nicking), slower gait (retinopathy), and depressive mood (generalized arteriolar narrowing). A higher number of retinal signs was associated with lower DSST score (−0.76 and −2.79 points for 1 sign and ≥2 signs versus none; P<0.001) and slower gait (−0.009 and −0.083 m/s; P=0.047), but not with the square root of Center for Epidemiologic Studies–Depression score (0.079 and −0.208; P=0.072). In addition, coexistence of retinal signs (generalized arteriolar narrowing and arteriovenous nicking) and carotid atherosclerosis was associated with lower DSST score compared with either process alone (P for interaction <0.01). Notably, further adjustment for ventricular size, white matter disease, and infarcts on MRI did not attenuate the association. Conclusions— Retinal signs are associated with executive dysfunction and slow gait, and possibly with depressive mood, suggesting a common process involving small vessels.

Proton Pump Inhibitors and Risk of Mild Cognitive Impairment and Dementia

To examine the risk associated with the use of proton pump inhibitors (PPIs) of conversion to mild cognitive impairment (MCI), dementia, and specifically Alzheimers disease (AD).

Apolipoprotein E, Carbon Dioxide Vasoreactivity, and Cognition in Older Adults: Effect of Hypertension

To investigate the associations between the apolipoprotein E (APOE) ε4 allele, carbon dioxide (CO2) vasoreactivity, and cognitive performance and to explore the effect of CO2 vasoreactivity and hypertension on the associations between APOE and cognition.

Modulation of Renin-Angiotensin System May Slow Conversion from Mild Cognitive Impairment to Alzheimer's Disease.

To assess the effect of modulation of the renin‐angiotensin system (RAS) on conversion to Alzheimers disease (AD) and cognitive decline in people with mild cognitive impairment (MCI) and the effect of the permeability of the blood–brain barrier (BBB) and race on the potential relationship between the RAS and AD.

Racial Disparity in Cognitive and Functional Disability in Hypertension and All-Cause Mortality

BACKGROUND Subjective cognitive and functional limitations are early markers of future dementia and physical disability. Hypertension may increase the risk of dementia; however, the magnitude and significance of subjective limitations in the hypertensive US population are unknown, particularly in African Americans who bear the greatest burden of hypertension. Our objectives were to assess the prevalence and racial disparity of subjective cognitive and functional limitations and their impact on mortality in the hypertensive US population. METHODS We analyzed data from the National Health and Nutrition Examination Survey (NHANES) collected between 1999 and 2010 (N = 28,477; 31% with hypertension; 11% African American), which included blood pressure measurement, self-reported cognitive and functional (physical and non-physical) limitations, and all-cause mortality. Complex survey regression models were used. RESULTS In the United States, 8% of the hypertensive population reported cognitive and 25% reported functional limitations (vs. 5.7% and 15% respectively in the non-hypertensive population, P < 0.0001). Hypertensive African Americans carried the highest burden of cognitive (11%, P = 0.01) and functional (27%, P = 0.03) limitations compared to non-hypertensive African Americans and to non-African Americans. All-cause mortality was significantly higher in hypertensive individuals who reported cognitive or functional limitations (P < 0.0001 for both) relative to those without either. CONCLUSIONS The prevalence of cognitive and functional disability is larger in the US hypertensive population compared to the non-hypertensive population. African Americans with hypertension carry a disproportionate burden of these limitations. Individuals with hypertension who report cognitive or functional symptoms have higher all-cause mortality and query about these symptoms should be part of hypertension evaluation.

Association of JNC-8 and SPRINT Systolic Blood Pressure Levels With Cognitive Function and Related Racial Disparity

Importance The Eighth Joint National Committee (JNC-8) recommended treating systolic blood pressure (SBP) to a target below 150 mm Hg in older adults, whereas data from the Systolic Blood Pressure Intervention Trial (SPRINT) suggested that a SBP level of lower than 120 mm Hg decreases cardiovascular event rates. Target SBP guidelines have not addressed the potential that black patients may have greater morbidity and mortality from hypertension, especially with regard to cognitive outcomes. The association of these discordant SBP targets with cognition and differences by race have not been systematically evaluated in the same population. Objectives To assess the long-term outcomes of the various recommended SBP levels and to determine if racial differences exist based on long-term cognitive trajectories. Design, Setting, and Participants A total of 1657 cognitively intact older adults receiving treatment for hypertension were studied from 1997 to 2007 in the Health Aging and Body Composition study. Data analysis was conducted from October 1, 2016, to January 1, 2017. Main Outcomes and Measures Cognition was assessed using the Modified Mini-Mental State Examination (3MSE) 4 times and the Digit Symbol Substitution Test (DSST) 5 times. At each visit, participants were classified as having an SBP level of 120 mm Hg or lower, 121 to 139 mm Hg, 140 to 149 mm Hg, or 150 mm Hg or higher based on the mean SBP level of 2 seated readings. Mixed models assessed the association of SBP levels with 10-year cognitive trajectories. The impact of race was tested using a race interaction term. Results During the 10-year study period, among the 1657 individuals (908 women and 784 black patients; mean [SE] age, 73.7 [0.1] years), there was a differential decrease in 3MSE and DSST scores by the SBP levels, with the greatest decrease in the group with SBP levels of 150 mm Hg or higher (adjusted decrease was 3.7 for 3MSE and 6.2 for DSST) and the lowest decrease in the group with SBP levels of 120 mm Hg or lower (adjusted decrease was 3.0 for 3MSE and 5.0 for DSST) (P < .001 for both). Compared with white patients, black patients had a greater difference between the higher and lower SBP levels in the decrease in cognition; adjusted differences between the group with SBP levels of 150 mm Hg or higher and the group with SBP levels of 120 mm Hg or lower were –0.05 in white patients and –0.08 in black patients for 3MSE (P = .03) and –0.07 in white patients and –0.13 in black patients for DSST (P = .05). Conclusions and Relevance For patients 70 years of age or older receiving treatment for hypertension, a SPRINT SBP level of 120 mm Hg or lower was not associated with worsening cognitive outcome and may be superior to the JNC-8 target for cognition. Lower SBP treatment levels may result in improved cognition in black patients.

Aldosterone, Cognitive Function, and Cerebral Hemodynamics in Hypertension and Antihypertensive Therapy

BACKGROUND Animal studies suggest that the renin-angiotensin-aldosterone system is involved in neurocognitive function and the response to antihypertensive therapy. We investigated the impact of circulating aldosterone and renin activity on cognition and cerebral hemodynamics at baseline and after antihypertensive therapy for 1 year. METHODS Participants were older adults (n = 47; mean age = 71 years) enrolled in a clinical trial. Routine antihypertensive medications were replaced with the study regimen to achieve a blood pressure <140/90 mm Hg. Executive function, memory, cerebral hemodynamics (blood flow velocity), CO2 vasoreactivity (measured using transcranial Doppler ultrasonography), plasma renin activity, and aldosterone were measured at baseline and at 6 and 12 months after the initiation of treatment. RESULTS At baseline, higher levels of circulating aldosterone were associated with lower blood flow velocity (β = -0.02; P = 0.03), lower CO2 vasoreactivity (β = -0.11; P = 0.007), and decreased autoregulation abilities (β = -0.09; P = 0.01). Those with higher levels of aldosterone at baseline demonstrated the greatest improvement in executive function (P = 0.014 for the aldosterone effect) and in CO2 vasoreactivity (P = 0.026 for the aldosterone effect) after 12 months of lowering blood pressure (<140/90 mm Hg). Plasma renin activity was not associated with any of the measures. CONCLUSIONS Higher levels of aldosterone may be associated with decreased cerebrovascular function in hypertension. Those with higher aldosterone levels may benefit the most from lowering blood pressure. The role of aldosterone in brain health warrants further investigation in a larger trial.

Racial Differences in Insular Connectivity and Thickness and Related Cognitive Impairment in Hypertension

Hypertensive African–Americans have a greater risk of cognitive impairment than hypertensive Caucasian–Americans. The neural basis of this increased risk is yet unknown. Neuroimaging investigations suggest that the normal neural activity comprises complex interactions between brain networks. Recent studies consistently demonstrate that the insula, part of the salience network, provides modulation effects (information flow) over the default-mode and central-executive networks in cognitively normal subjects, and argue that the modulation effect is declined in cognitive impairment. The purpose of this study is to examine the information flow at the nodes of three networks using resting state functional magnetic resonance imaging (MRI) data in cognitively impaired hypertensive individuals with the African–Americans and the Caucasian–Americans races, and to compare the thickness of impaired node between two racial groups. Granger causality methodology was used to calculate information flow between networks using resting state functional MRI data, and FreeSurfer was used to measure cortical thickness from T1-weighted structural images. We found that negative information flow of the insula in both African–Americans and Caucasian–Americans, which was in contrast with previously reported positive information flow in this region of normal individuals. Also, significantly greater negative information flow in insula was found in African–Americans than Caucasian–Americans (Wilcoxon rank sum; Z = 2.06; p < 0.05). Significantly, lower insula thickness was found in African–Americans compared with Caucasian–Americans (median = 2.797 mm vs. 2.897 mm) (Wilcoxon rank sum; Z = 2.09; p < 0.05). Finally, the insula thickness correlated with the global cognitive testing measured by Montreal cognitive assessment (Spearman’s correlation; r = 0.30; p < 0.05). These findings suggest that the insula is a potential biomarker for the racial disparity in cognitive impairment of hypertensive individuals.