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Carotid Intima-Media Thickness and Midlife Cognitive Function-
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Impact of Race and Social Disparities in the Bogalusa Heart Study
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E.J. Wright, B. Grund, K. Robertson, B.J. Brew, M. Roediger, M.P. Bain, F. Drummond, M.J. Vjecha, J. Hoy, C. Miller, A.C. Penalva de Oliveira, W. Pumpradit, J.C. Shlay, W. El-Sadr, R.W. Price
August 11, 2010.
Conclusions: In this HIV-positive population with high CD4 cell counts, neurocognitive impairment was associated with prior CVD. Lower neurocognitive performance was associated with prior CVD, hypertension, and hypercholesterolemia, but not conventional HAD risk factors. The contribution of CVD and cardiovascular risk factors to the neurocognition of HIV-positive populations warrants further investigation.
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Neurology 2022
Glossary
AD = Alzheimer disease; ADRD = AD and related dementias; BHS = Bogalusa Heart Study; BMI = body mass index; BP = blood pressure; c-IMT = carotid intima-media thickness; CARDIA = Coronary Artery Risk Development in Young Adults; CVRF = cardiovascular risk factors; DBP = diastolic BP; GCS = global cognitive z score; HDL = high-density lipoprotein; LCC = left common carotid; LIC = left internal carotid; NP = neuropsychological; RCB = right carotid bulb; RCC = right common carotid; SBP = systolic BP; WAIS-IV = Wechsler Adult Intelligence Scale 4th edition; WRAT = Wide Range Achievement Test.
Our study shows that subclinical atherosclerosis is associated with worse cognitive function in midlife independently of major CVRFs cardiovascular risk factors]. The association is buffered by education, and this effect may be stronger among Black compared to White participants. These findings reinforce the importance of establishing primary preventive measures as early as midlife, a critical time window for the initiation of early dementia pathology, and suggest that subclinical atherosclerosis may be a potential target in efforts to prevent cognitive decline.
Our results show that midlife c-IMT is an independent predictor of global cognitive function in midlife. This finding extends from previous studies examining these re-lationships in late life, when the pathophysiologic processes that lead to dementia may have already been well estab-lished. The association between c-IMT composite and GCS was independent of major risk factors (age, sex, race, SBP, glucose level, BMI, smoking status, non-HDL cholesterol, triglycerides, use of hypertension medication, and achieved education). Achieved education appeared to buffer the ef-fect of c-IMT on midlife cognitive function; however, the strength of this buffering effect may differ by race. We also found differences based on the cognitive domain tested, with executive function having the strongest association. These findings support the hypothesis that subclinical atherosclerosis is associated with cognitive performance as early as midlife and raise the possibility of preventing atherosclerotic disease to maintain cognitive function.
Our results also showed a buffered association between c-IMT and global cognitive function after adjustment for achieved education. Educationhas always played a key role in understanding the potential mechanisms of protection from dementia and drivers of racial disparities in ADRD prevalence.30,38,39 Previous studies showed modified effects by education when looking at the association between certain risk factors and AD prevalence.40 Indeed, recent literature suggests that higher education levels may increase cognitive reserve, the adaptability to sustain better cognitive function despite brain pa-thology, and therefore buffer the association between known CVRFs and brain pathology.41-44 Furthermore, it is recognized that the quality of education and literacy differs across geographic regions and is a potential explanation for racial disparities in cognitive performance.45 Individuals from segregated racial and rural communities in the southern United States are likely exposed to poorer quality of education.39,46 As a result, self-reported years of educa-tion may overestimate the achieved learning. Thus, the use of language domain tests as indicators of education is proposed as a method to obtain more accurate results.26,27,47 Consistent with this concept, our findings suggest that a higher education offers a protective effect on cognitive performance as early as midlife.
We found that independently of major CVRFs, the association between c-IMT and GCS was significant only among those with lower language cognitive domain z score, our indicator for achieved education. In addition, we found that independently of major CVRFs, the point estimate was larger in Black participants and was more attenuated by education compared to White participants.
Driven by an array of social and behavioral determinants, health disparities are one of the primary causes of the high burden of cardiovascular disease among Black Americans and, in conjunction with educational level, are some of the most robust risk factors accounting for race and ethnic differences for the risk of ADRD [alzheimers dementia].48,49 In line with this model, our sub-group analyses showed that Black participants had higher levels of CVRFs, including SBP and triglycerides, poorer educational level, income, homeownership, and health access. They also had greater intima-media thickness in bilateral common carotids, regions that have been shown to be more affected by the hypertensive hypertrophic response. In comparison, we did not find racial differences in carotid bulb segments, regions exposed to constant turbulent flow and more prone to atherosclerotic plaque formation.50 These findings are important given that studies have shown associ-ations between upper quintiles of c-IMT thickness and Alz-heimer dementia but not with carotid plaque.8
After the GCS was disaggregated into specific underlying cognitive domains, our results showed a stronger effect of subclinical atherosclerosis on executive function and verbal episodic memory. These results are in line with previous findings of c-IMT as a predictor of poorer memory, a com-mon preclinical deficit in AD,e2 independently of other significant risk factors in late life.e1 We also found a negative association between c-IMT and executive function that was independent of achieved education and CVRFs. As a whole, the data described above suggest that measurable cognitive decline, perhaps linked to the eventual emergence of de-mentia, may begin in midlife rather than late life.e3
A growing body of evidence shows that in late life, atherosclerosis of brain-supplying arteries, particularly the carotid arteries, is associated with subclinical injury of white matter, cognitive impairments, and dementia.
This study examines the relationship between subclinical atherosclerosis, represented by c-IMT, and cognitive function among Black and White participants from a rural community-based cohort of middle-aged adults located in the southern city of Bogalusa, Louisiana. We hypothesized that individuals with lower c-IMT would have better cognitive performance in midlife.
The Bogalusa Heart Study (BHS) is a longitudinal cohort dedicated to the study of the natural history of cardiovascular disease among White and Black individuals in the rural city of Bogalusa, Louisiana.18 Between 1973 and 2016, the BHS has conducted 9 child and 11 adult examinations of participants enrolled from childhood, prospectively collecting repeated, longitudinal measurements.18
Discussion
Subclinical atherosclerosis, measured as c-IMT, was associated with worse midlife cognitive function, independently of major CVRFs [cardiovascular risk factors]. The association was buffered by education and may be stronger among Black than White participants, likely due to corresponding structural and social determinants. These findings underscore the importance of establishing preventive measures in midlife and suggest subclinical atherosclerosis as a potential target to prevent cognitive decline.
Compared to White participants, Black women and men had significantly lower educational level (p < 0.001), less annual income (p < 0.001), lower rates of homeownership, and lower rates of private health insurance (p < 0.05). White men reported higher rates of employment (71.2%) compared to Black men (46.2%) (p < 0.001) (Table 1).
Cardiometabolic Risk Factors
Race and sex differences were found for BP, cholesterol, and triglyceride levels. The mean SBP and diastolic BP (DBP) were significantly higher in Black participants (SBP p < 0.05, DBP p < 0.05); SBP was also higher in men (White men p < 0.001, Black men p < 0.05). Atherogenic lipoprotein, the non-HDL level, was significantly higher in White men compared to Black men (p = 0.018). Triglyceride levels were significantly higher in White participants. Among White participants, men had higher triglyceride levels than women (p < 0.05). Black women reported more hypertension medication use com-pared to White women and Black men (Table 1).
c-IMT Measurements
Far-wall c-IMT measurements± are displayed in full detail in eTable 2, links.lww.com/WNL/B843. Black participants had higher RCC and LCC thickness compared to White partici-pants. Black women had thicker LCC, LIC, RCB, RCC, and c-IMT composite measures compared to White women. Significant sex differences were found among White partici-pants, with men having greater intima-media thickness in all carotid sections (Figure 1).
c-IMT Measurements and Cognitive Function
After adjustment for cardiovascular risk factors (CVRFs) and achieved education, our results show that c-IMT composite ≥50th percentile (0.87 mm) was inversely associated with GCS (standardized B ±SE-0.39 ± 0.18, p = 0.03). In subgroup analyses by race, after adjustment for CVRFs, we found a larger point estimate in Black participants (B ±SE-1.25 ± 0.45, p = 0.005) compared to White participants (B ±SE-0.92 ± 0.35, p = 0.008). However, the effect was not persistent after adjustment for achieved education (Black individuals: B ±SE -0.40 ± 0.30, p = 0.187; White individuals: B ±SE -0.39 ± 0.23, p = 0.09) (Table 2). The interaction between c-IMT composite ≥50th and the achieved education indicator (language cogni-tive domain z score) was significant (p = 0.03), and stratified analysis by achieved education showed a significant association between c-IMT composite and GCS among those in the 2 lower quartiles of language cognitive domain z score (B ±SE -0.81 ± 0.33, p = 0.013) independently of major CVRFs. Ad-ditional analysis using self-reported educational level instead of other education indicators is shown in eTable 3, links.lww. com/WNL/B843. Analysis excluding language from the GCS did not change the interpretation of results (eTable 4).
Greater c-IMT had the most impact on executive function and episodic memory. The c-IMT composite ≥50th percentile (0.87 mm) was independently associated with poorer cognitive performance in episodic memory (B ±SE-0.23 ± 0.10, p = 0.015) and with poorer performance in executive function. (B ±SE -0.33 ± 0.06, p < 0.001) (Table 3). In subgroup analyses, the effect on episodic memory performance remained significant in Black and White participants after adjustment for CVRFs (Black participants: B ±SE-0.45 ± 0.17, p = 0.008; White participants: B ±SE -0.29 ± 0.13, p = 0.028) but not after adjustment for achieved education. The effects on executive function remained significant among Black participants after adjustment for CVRFs (B ±SE -0.35± 0.12, p = 0.026) but not after adjustment for achieved education (B ±SE-0.16 ± 0.14, p = 0.272). In White participants, the association was independent of CVRFs and achieved education (B ±SE-0.40 ± 0.11, p < 0.001) (eTa-ble 5, links.lww.com/WNL/B843).
Abstract
Background and Objectives
Carotid intima-media thickness (c-IMT) is a measurement of atherosclerosis, a progressive disease that develops as early as childhood and has been linked with cognitive impairment and dementia in the elderly. However, the relationship between c-IMT and midlife cognitive function and the race and social disparities in this relationship remain unclear. We examined the association between c-IMT and cognitive function in midlife among Black and White participants from a semirural community-based cohort in Bogalusa, Louisiana.
Methods
In this cross-sectional analysis of participants from the Bogalusa Heart Study, linear regression models were used to determine the association between c-IMT dichotomized above the 50th percentile (>0.87 mm), an a demographically standardized global cognitive score (GCS), and individual cognitive domain-based z scores. Stratified analyses were performed to evaluate the impact of race and the individual’s education status.
Results
A total of 1,217 participants (age 48 ± 5.28 years) were included; 66% (804) self-identified as White, and 34% (413) self-identified as Black. Of those, 58% (708) were women, and 42%(509) were men. Having a c-IMT ≥50th percentile was inversely associated with GCS (B ±SE -0.39 ± 0.18, p = 0.03), independently of cardiovascular risk factors (CVRFs) and achieved education. The effect remained significant in Black and White participants after adjustment for CVRFs (Black participants: B ±SE -1.25 ± 0.45, p = 0.005; White participants: B ±SE-0.92 ± 0.35, p = 0.008) but not for education. The interaction between c-IMT ≥50th percentile and education was significant (p = 0.03), and stratified analysis showed an association with GCS among those with lower achieved education (B ±SE -0.81 ± 0.33, p = 0.013) independently of major CVRFs.
For decades, the leading cause of morbidity and mortality in the United States has been heart disease. As life expectancy increases, age-related diseases, including Alzheimer disease (AD) and AD-related dementias (ADRD), are increasing in prevalence.1-3 The vascular hypothesis provides substantial evidence supporting its essential role in understanding the development of AD and ADRD.4 Therefore, identifying modifiable risk factors shared by these conditions in a race-specific fashion and determining the critical time windows to prevent and delay the onset of ADRD are important.
The human brain can be affected by vascular dysfunction through diverse mechanisms.5 Changes in arterial structure, including arterial stiffening and atherosclerosis of large arteries, can alter the normal blood flow to the brain.6,7 As a consequence, microvascular ischemic disease and cerebral hypoperfusion are accompanied by a cascade of inflammatory response and endothelial dysfunction with subsequent alter-ations to the permeability of the blood-brain barrier.5,6 These mechanisms have been shown to cause neuronal damage and neurodegeneration and thus can serve as markers for pathologic events in the chronological ordering of emergence of AD and ADRD.4 A growing body of evidence shows that in late life, atherosclerosis of brain-supplying arteries, particularly the carotid arteries, is associated with subclinical injury of white matter, cognitive impairments, and dementia.7-10
Carotid intima-media thickness (c-IMT) is a subclinical indicator of atherosclerosis, a disease recognizable as early as childhood.11 Assessed by noninvasive ultrasound, c-IMT has been established as a robust predictor of subsequent vascular events12 and has been associated with cognitive performance in older adults.10,13 Recent evidence suggests that midlife increased c-IMT is associated with worse cog-nitive performance and dementia diagnoses later in life.14,15 However, the c-IMT-related effects on midlife cognitive function have not been well studied. Moreover, social and behavioral factors have been major drivers of inequalities in cardiovascular disease and dementia prevalence, and previous studies have shown higher dementia incidences among Black populations.16,17
This study examines the relationship between subclinical atherosclerosis, represented by c-IMT, and cognitive function among Black and White participants from a rural community-based cohort of middle-aged adults located in the southern city of Bogalusa, Louisiana. We hypothesized that individuals with lower c-IMT would have better cognitive performance in midlife.
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