The results support an association between high BP and risk of cognitive decline in MCI. Individuals with high BP readings on two or three annual assessments experienced greater slowing on TMT A and B than those with no high readings on any occasion, as well as a trend for greater worsening on Digit Span Backward. Intervening strokes did not explain these findings. The observation of a faster decline in naming ability was unexpected but could reflect the time demands of this measure, because individuals are penalized if their responses exceed 20 seconds. High systolic BP appeared to account for the results based on the higher percentage of persons with high systolic (63%) versus diastolic (20%) readings, but the importance of diastolic BP should not be dismissed, because its role could not be adequately evaluated due to its low frequency of occurrence. Examination of relationships with actual systolic BP levels, based on the number of occasions with clinically significant high readings or averaged values, also demonstrated vulnerability on tasks requiring rapid performance and set shifting (TMT A and B) and expressive language (naming). Moreover, CDR Sum declined more precipitously in those with two or three occasions of high systolic BP.
These results are consistent with the findings of a previous study that recently demonstrated an association between hypertension and risk for cognitive decline in a Chinese population,3
but unlike that study, which examined the risk of a change in diagnosis from MCI to Alzheimer's disease, the current study examined specific cognitive domains that are especially vulnerable. In addition, unlike the previous study, the participants in the current study were excluded if they had a previous history of stroke or transient ischemic attack. Thus, the results demonstrate the influence of a vascular risk factor on cognitive changes in the absence of overt clinical disease.
The results of studies examining hypertension as a risk factor for cognitive decline and Alzheimer's disease have been mixed, with two recent reviews13,37
concluding that the overall evidence is weak. The current study circumvented some of the methodological problems mentioned in these recent reviews that can hamper interpretation of many studies, including reliance on self-reported hypertension at baseline and reliance on a single BP reading at baseline. Studies that rely solely on self-reports of hypertension may incorrectly classify some participants. Findings from the National Health and Nutrition Examination Surveys, which indicate that, between 2005 and 2006, 7% of the U.S. population had systolic BP readings of 140 mmHg or diastolic BP readings of 90 mmHg or higher. Yet, no healthcare provider had told these individuals that they had high BP. These results highlight the unreliability of self-report data. Overall, only 78% of hypertensive adults were aware that they had this condi-tion.38
Moreover, studies that rely on a single reading at one time point do not take into account whether the status of individuals changes. For example, in the data from the current study, 43% of those who were normotensive at baseline had one or two high BP readings at year 2 and 3 visits. Such changes would result in the misclassification of individuals, weakening associations with cognitive performance and functional outcome.
A limitation of this study is that the follow-up period was short (2 years). Only 52% of the sample had complete cognitive data and BP readings at 3 years. Given the desire to study a homogenous population with equal length of follow-up, using data for the third year would have halved the sample size. An alternative approach of imputing missing data for the third year was deemed inadvisable given the amount of missing data that would need to be imputed. Further follow-up would allow clearer determination of whether the differences between the hypertensive and normotensive individuals persist over time. Two aspects of the findings for the cognitive test results increase confidence in their validity. First, participants with two or three high readings had greater worsening of cognition over time than those with no high readings, whereas those with only one high reading did not. This suggests a doseresponse relationship whereby only those with more-sustained uncontrolled BP showed an effect. Another source of confidence is that the pattern of impairments is consistent with the clinical phenotype of slow processing speed and set shifting difficulty reported in the literature.19–25
Another limitation of this study is that an established database was relied on, as opposed to the study being designed and therefore allowing a mediation model for the association between hypertension and cognitive decline to be tested. There are potentially many mechanisms through which high BP exerts a deleterious effect on the course of cognitive function, including disruption of cerebral white matter integrity and the greater risk for white matter infarcts, greater brain atrophy, and silent strokes.39–42
Brain imaging is not a required data element of the ADCs, but findings of greater cerebrovascular changes in those classified with high BP would clarify the mechanism of the observed relationships. Neuropathological studies have also demonstrated an association between uncontrolled hypertension and neurofibrillary tangles and neuritic plaques.43–45
Studies using in vivo amyloid imaging techniques and studies examining relationships between hypertension and associated measures of chronic inflammation, including serum interleukin-6 and C-reactive protein, would be of interest. Other possible mechanisms, including treatment with antihypertensive medications and cholinesterase inhibitors, may have been operative as well. These potential associations will await longitudinal studies to further elucidate mechanisms for cognitive decline.