Abstract BACKGROUND African Americans (AAs) are at high risk for hypertension (HTN) and poor blood pressure (BP) control. Persistently elevated BP contributes to cardiovascular morbidity. White matter hyperintensities (WMHs) are a definable magnetic resonance imaging (MRI) marker of cerebrovascular injury linked to impairments in higher level thinking (i.e., executive functions), memory formation, and speed of perceptual-motor processing. METHODS This subinvestigation evaluated neuropsychological functioning in association with WMH on brain MRIs in 23 otherwise-healthy hypertensive AAs participating in an NIH-funded study of the effects of vitamin D on BP and cardiac remodeling in AA patients 30–74 years of age with HTN and left ventricular hypertrophy. Neuropsychological assessment included psychomotor processing speed [(Symbol Digit Modality Test (SDMT) and Trail Making Test], executive functioning (Controlled Oral Word Association Test and Trail Making Test Part B), memory (Rey Auditory Verbal Learning Test), and fine motor functioning (Finger Tapping). RESULTS Significant correlations (P < 0.05) were found between volume of periventricular lesions and trails A (r = 0.51) and dominant hand finger tapping speed (r = −0.69) and between subcortical lesion volume and trails A (r = 0.60), both dominant (r = −0.62) and nondominant hand finger tapping speed (r = −0.76) and oral SDMT (r = −0.60); higher lesion volumes correlated to worse neuropsychological performance. CONCLUSIONS Psychomotor tests including the Trail Making Test and finger tapping speed are sensitive indicators of subclinical deficits in mental processing speed and could serve as early markers of deep subcortical cerebrovascular injury in otherwise-healthy individuals with uncontrolled chronic HTN. African American, blood pressure, cognition, hypertension, MRI, neuropsychology One of the known consequences of poor cardiovascular health is cerebrovascular disease (CVD), in its severe form, vascular dementia (VaD). VaD appears to have 2 distinct subtypes. The first is characterized by multi-infarct, strategic-infarct, or intracranial hemorrhage, with abrupt onset. The second includes VaD caused by sustained hypertension (HTN), impaired cerebral autoregulatory mechanisms, and subsequent subcortical small vessel disease, with an insidious onset mirroring the clinical course of other dementias. The latter, which develops in up to 67% of VaD cases,1 is particularly concerning as it is, by the time symptoms manifest, essentially irreversible. In less severe forms, cognitive deficit that is associated with small vessel ischemic disease is termed vascular-related mild cognitive impairment. Although dementia is commonly researched, there is a paucity of information in the literature regarding subthreshold forms of cognitive impairment that may be associated with CVD and how cognitive and behavioral changes may be related to neurological changes. Cardiovascular disease risk factors have been associated with cognitive and neuropathological changes in the absence of diagnosed dementia or acute stroke.2 Recent neuroimaging studies have concluded that the magnitude of cognitive impairment among patients with cardiovascular disease is significantly associated with neuropathological changes secondary to vascular damage.3 Slow progression of neuropsychological deficits has been linked to gradually progressive microvascular brain changes, specifically hypertensive arteriolar lipohyalinosis (cerebral microangiopathy) involving small penetrating vessels.4 Importantly, reversal of cognitive deficits associated with cerebrovascular compromise via treatment of HTN and other risk factors has been reported.4 To minimize morbidity and mortality as well as negative impact on productivity and quality of life, detection and treatment of such early, neuropathological manifestations is imperative. Leukoaraiosis, or white matter hyperintensities (WMHs), are abnormal cerebral white matter changes best seen on magnetic resonance imaging (MRI) of the brain, typically in the deep cerebral and periventricular areas.5 WMH can be caused by cardiovascular etiologies including direct occlusion from atherosclerosis or thromboembolic disorders and subclinical ischemia due to cerebral hypoperfusion. WMH have been associated with cognitive impairment, although the specific aspects of cognitive functioning that are affected and the strength of this relationship remains somewhat unclear. Although memory loss may be one of the most patent manifestations of neuropsychological impairment, it may not be the earliest or most salient feature of vascular-related cognitive decline. Rather, VaD has been associated with impairment in executive functioning, specifically, cognitive flexibility, planning, and inhibition, as well as slowed information processing speed and low mood. Prefrontal brain regions and subcortical areas are most vulnerable to vascular insufficiency given lower vasodilatory capacity vs. white matter found in other brain regions6; thus, neural circuits that involve these areas (i.e., frontal subcortical circuits) are the most vulnerable to changes in cerebrovascular patency. Consequently, early signs of cognitive deficit associated with cerebrovascular functioning are often dysexecutive (i.e., impairment in higher order thinking skills) or related to speed of information processing.7 Whereas several studies have shown the relation between cardiovascular risk factors, such as HTN, and cognitive function8,9 or abnormalities on neuroimaging,10,11 very little evidence has linked these 2 outcomes in this patient population. Additionally, the vast majority of this literature has focused on Caucasian individuals with very few studies examining African Americans (AAs). In general, AAs are at higher risk for cardiovascular risk factors12 and VaD,13 so detection of cognitive difficulties before the development of VaD would be most imperative for this population. Accordingly, this study was designed to evaluate cognitive function in AA patients with HTN and left ventricular hypertrophy, but no prior history of cardiovascular or CVD. Our specific aim was to explore within this population the relationship between neuropsychological test performance, particularly measures of executive functioning and processing speed, and subcortical and periventricular WMH as detected by MRI. METHODS This study was part of an ancillary NIH-funded longitudinal trial (5 R01 MD005849; Levy PI) of blood pressure (BP) control with or without vitamin D supplementation in asymptomatic, vitamin D–deficient AA patients with MRI-detected subclinical hypertensive heart disease. The study was approved by the local Institution Review Board at Wayne State University and was in accordance with the ethical standards set forth by the Institution Review Board for utilization of humans in research. Individuals between 30 and 74 years of age with poorly controlled chronic HTN were recruited from the emergency department, and enrolled in the study if they were found to have evidence of left ventricular hypertrophy on cardiac MRI. All patients received intensive BP control (uniform goal systolic BP <130 mm Hg), utilizing an evidence-based, standardized algorithm, for the duration of the study. MRI data were obtained using a 3T Siemens VERIO system (Siemens Medical Solutions, Erlangen, Germany) with a state-of-the-art 12 channel head and neck coil. The MRI protocol consisted of conventional clinical imaging sequences looking at general anatomy and function of the head and neck. Head sequences included: 3D susceptibility weighted imaging, T2 weighted imaging, 3D fluid-attenuated inversion recovery (FLAIR), 3D volumetric interpolated breath-hold examination precontrast and postcontrast, and perfusion weighted imaging. All scans were done using a body phase array/head/neck coil with the spine coil in place as well. Three-dimensional views of the data were created and volume rendered for viewing. WMH was evaluated from the FLAIR sequence using Signal Processing in Nuclear magnetic resonance (SPIN, SpinTech, Detroit, MI) software. This recently developed semiautomatic tool extracted WMH, including skull stripping, normalization that corrects for rf field inhomogeneities and local thresholding to exact the lesions. Using this approach, we were able to aggregate individual white matter lesion data and quantify the total volume with a high degree of precision and accuracy. Neuropsychological assessment included the Trail Making Test Parts A and B,14 as a measure of visual searching speed and cognitive flexibility, the Finger Oscillation Test (or Finger Tapping)15 as a measure of dominant and nondominant fine motor speed and control, the Symbol Digit Modalities Test (SDMT), Oral Trial,16 as a measure of visual attention, working memory, processing speed and integration (i.e., executive functioning), the Controlled Oral Word Association Test (COWAT)17 as a measure of lexical word generation, and the Rey Auditory Verbal Learning Test (RAVLT)18 total words recalled overall 5 trials as a measure of learning. Bivariate correlations were examined between the brain imaging/WMH variables and the neuropsychological variables, utilizing Hochberg multiple comparison adjustment to minimize the potential of capitalizing on chance associations between the variables. This substudy including both brain imaging and neuropsychological testing was an unfunded addition that was completed during the later portions of the parent study, thereby limiting the total number of participants available to complete data collection. Given the small sample size, there was not adequate power for further exploration of associations. RESULTS Twenty-three individuals completed both neuropsychological assessment and brain MRI. The mean age was 44.8 [SD = 9.6] years, mean systolic BP was 189.3 (SD = 20.3) mm Hg and mean diastolic BP was 108.8 (SD = 18.2) mm Hg. The mean performance of Trail Making Tests A and B (based on Mitroshina metanorms for 50-year-old male with 12 years of education) fell in the average range of functioning overall (T = 51 and 45, respectively), as did COWAT (T = 45), and SDMT oral (z = 0). Finger tapping, however, was borderline to mildly impaired based on the normative comparison (T = 32 dominant hand, T = 37 non-dominant hand). Correlations between the neuropsychological variables and the MRI findings of lesion burden in the periventricular and deep subcortical white matter are presented in Table 1. Using a traditional cutoff of P < 0.05, measures of psychomotor and mental processing speed (i.e., time to complete trails A, and the oral version of the SDMT) were significantly associated with increased lesion volume. Overall, learning showed a trend toward significance in relationship to both lesion types, and the correlation between trails B and deep subcortical lesion burden also trended toward significance. Table 1. Results from correlations between neuropsychological measures and white matter lesion volume Neuropsychological test Volume of periventricular lesions [r (P value)] Volume of deep white matter lesions [r (P value)] Trail Making Test A 0.51 (0.04) 0.60 (0.01) Trail Making Test B 0.35 (0.17) 0.49 (0.06) Finger Tapping Dominant Hand −0.69 (<0.01) −0.62 (0.01) Finger Tapping Nondominant Hand −0.42 (0.10) −0.76 (<0.01) Symbol Digit Modality Test −0.47 (0.06) −0.60 (0.02) Controlled Oral Word Association Test −0.36 (0.17) −0.23 (0.42) Rey Auditory Verbal Learning Test Total −0.43 (0.09) −0.48 (0.06) Neuropsychological test Volume of periventricular lesions [r (P value)] Volume of deep white matter lesions [r (P value)] Trail Making Test A 0.51 (0.04) 0.60 (0.01) Trail Making Test B 0.35 (0.17) 0.49 (0.06) Finger Tapping Dominant Hand −0.69 (<0.01) −0.62 (0.01) Finger Tapping Nondominant Hand −0.42 (0.10) −0.76 (<0.01) Symbol Digit Modality Test −0.47 (0.06) −0.60 (0.02) Controlled Oral Word Association Test −0.36 (0.17) −0.23 (0.42) Rey Auditory Verbal Learning Test Total −0.43 (0.09) −0.48 (0.06) Bold values represent P < 0.05. View Large Table 1. Results from correlations between neuropsychological measures and white matter lesion volume Neuropsychological test Volume of periventricular lesions [r (P value)] Volume of deep white matter lesions [r (P value)] Trail Making Test A 0.51 (0.04) 0.60 (0.01) Trail Making Test B 0.35 (0.17) 0.49 (0.06) Finger Tapping Dominant Hand −0.69 (<0.01) −0.62 (0.01) Finger Tapping Nondominant Hand −0.42 (0.10) −0.76 (<0.01) Symbol Digit Modality Test −0.47 (0.06) −0.60 (0.02) Controlled Oral Word Association Test −0.36 (0.17) −0.23 (0.42) Rey Auditory Verbal Learning Test Total −0.43 (0.09) −0.48 (0.06) Neuropsychological test Volume of periventricular lesions [r (P value)] Volume of deep white matter lesions [r (P value)] Trail Making Test A 0.51 (0.04) 0.60 (0.01) Trail Making Test B 0.35 (0.17) 0.49 (0.06) Finger Tapping Dominant Hand −0.69 (<0.01) −0.62 (0.01) Finger Tapping Nondominant Hand −0.42 (0.10) −0.76 (<0.01) Symbol Digit Modality Test −0.47 (0.06) −0.60 (0.02) Controlled Oral Word Association Test −0.36 (0.17) −0.23 (0.42) Rey Auditory Verbal Learning Test Total −0.43 (0.09) −0.48 (0.06) Bold values represent P < 0.05. View Large The largest associations (and the only associations of statistical significance after Hochberg multiple comparison adjustment19 to a cutoff of P < 0.004) were seen between fine motor speed (Finger Tapping test) and lesion volume. Motor speed in the dominant hand showed a strong negative association with periventricular lesion burden, whereas motor speed in the nondominant hand showed a strong negative association with deep subcortical lesion burden. DISCUSSION The findings presented here indicate that in a sample of AAs with uncontrolled HTN and subclinical left ventricular hypertrophy but no diagnosed CVD, there is a statistical association between periventricular and subcortical white matter lesion burden and psychomotor speed as measured by standard neuropsychological assessment tools. Although neuropsychological inefficiencies may be subclinical, the finding of medium-to-large effects in this underpowered exploratory study supports the importance of further investigation into the neuropsychological consequences of poorly controlled HTN. Neuropsychological tools may be important for early detection of subclinical consequences caused by HTN and monitoring of progression over time. Poor management of CVD risk occurs at a significant cost to society due to lost productivity and escalating health care needs as secondary consequences begin to manifest. Identification of early indicators of such develop consequences may allow for better patient education with regard to cognitive sequelae of risk factors like HTN and underscore the importance of aggressive management via health behavior change. These findings are largely consistent with previous literature examining vascular effects on cognition, but specifically focused on young or middle-age, asymptomatic AAs, thought to be the most at risk for going on to develop VaD.12,13 In studies investigating white matter lesion volume and cognition in other populations, executive function appears to be the most vulnerable domain.20 This study may illustrate that processing speed is actually the first cognitive domain to be subclinically impacted by white matter lesion burdens from uncontrolled HTN, with measures of executive functioning trending toward significance. Other studies that similarly have looked at hypertensive individuals without VaD found deficits in psychomotor speed, though more consistently the domains of memory, attention, and abstract reasoning are affected.7 Given that previous studies largely focused on Caucasian older adults and did not control for other cardiovascular risk factors, it is possible that younger AAs with HTN and subclinical hypertensive heart disease are more sensitive to deficits in psychomotor speed, or at least that this particular sample’s white matter lesions were more likely to impact processing speed. This study had several limitations, the most obvious being the small sample size. Greater power in the study may have allowed for detection of smaller effects and more complex interactions between the cognitive tests and the neuroimaging data. The sample size also limited the types of statistical analyses to correlation for a cross-sectional sample, making directionality and the predictive quality undeterminable. The generalizability of the sample to other populations is restricted, as all of the participants were urban-dwelling African Americans in the Detroit metropolitan area without a proper comparison group. Additionally, confounds such as age may have influenced these results, as both WMHs and poorer test performance are associated with older age, but could not be fully explored in this study due to the small sample. Notably, this study is novel in illustrating a relation between neuroimaging findings and cognition for a cohort of relatively young, asymptomatic AAs with chronic HTN, and in incorporating a full neuropsychological battery of tests spanning several cognitive domains, while also incorporating neuroimaging techniques. Future directions should include a larger sample size with a non-AA comparison group to detect smaller effects that may be mediated by race. Relations between neuropsychological functioning and day-to-day functional abilities (i.e., medication adherence, ability to drive safely) need to be further explored in this population as well. In sum, this study provides preliminary evidence that declines in cognitive function for individuals with HTN may be related to early structural changes in the brain before any symptoms are detectable on routine clinical examination. Earlier identification of these subtle cognitive deficits may help drive treatment of HTN in an effort to prevent future neuropsychiatric consequences, especially in at-risk populations. ACKNOWLEDGMENT The authors would like to acknowledge Demaris Pop and Sherry Vogel for their assistance with data collection. DISCLOSURE The authors A.B., E.M.H., R.D., and P.V. are supported by grant number 5R01MD005849 from NIH/NIMHD. 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American Journal of Hypertension – Oxford University Press
Published: Apr 17, 2018
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