Impact of mean blood pressure and blood pressure variability after diagnosis of mild cognitive impairment and risk of dementia

Abstract Hypertension and increased blood pressure variability (BPV) are associated with the development of dementia. However, previous studies did not focus on the risk of dementia among participants with mild cognitive impairment (MCI) and controlled blood pressure level. To address this limitation, the authors performed a post‐hoc analysis of SPRINT MIND participants diagnosed with MCI (mean Montreal Cognitive Assessment score at diagnosis 16.1±3.1). The primary outcome was subsequent diagnosis of probable dementia. The exposure was mean blood pressure and BPV following MCI diagnosis until the end of follow‐up or a dementia event (mean follow‐up 2.6±1.2 years). The primary outcome occurred in 76/516 (14.7%) patients. The mean blood pressure was not significantly higher in participants who developed dementia. In the lowest quartile of BPV (systolic standard deviation), the rate of dementia was 8.5% (11/129), while in the highest quartile it was 21.7% (28/129). The highest quartile of systolic BPV had an adjusted hazard ratio for dementia of 2.73 (95% CI, 1.31–5.69) and for diastolic BPV it was 2.62 (95% CI, 1.26–5.47). In SPRINT MIND participants, the authors found that increased BPV after MCI diagnosis was associated with incident probable dementia during subsequent follow‐up.

dementia, we performed an analysis of the Systolic Blood Pressure Trial -Memory and Cognition in Decreased Hypertension (SPRINT MIND) cohort.

METHODS
We performed a post-hoc analysis of the SPRINT-MIND dataset. 17 SPRINT-MIND was an ancillary study to the parent SPRINT trial, which enrolled 9361 participants > 50 years old and with cardiovascular risk factors at 102 centers in the United States. SPRINT examined the benefit of a systolic blood pressure goal of < 120 versus < 140 on cardiovascular outcomes and, in the SPRINT MIND ancillary study, cognitive outcomes. Patients with dementia and a history of stroke were excluded from enrollment. We included participants enrolled in SPRINT MIND who had an outcome event of mild cognitive impairment (MCI) during the follow-up period and at least four blood pressure measurements subsequent to the MCI event and prior to a dementia outcome or study completion.
IRB approval was not required for the deidentified dataset, which is publicly available. 7 The primary outcome of our cohort study was incident probable dementia during the remainder of follow-up after MCI diagnosis. The determination of probable dementia and MCI in SPRINT MIND relied on both screening and adjudication at follow-up visits and planned cognitive testing at years 2 and 4, and study closeout when it was more than 1 year after the year four evaluation. 8 In the parent SPRINT trial, seated blood pressures were recorded by trained study personnel recorded at study visits according to a protocol. 9 The blood pressure used in the present study is a single value per visit that is the average of three seated blood pressures.
The study exposure was the mean blood pressure and BPV following MCI diagnosis until either the end of follow-up or a dementia event.
Because prior research has suggested that the adjudication of BPV improves with measurement using multiple methodologies, BPV was measured as standard deviation, coefficient of variation, residual standard deviation, average real variability, and successive variation. We fit a Cox proportional hazards model to the outcome of dementia. The Cox model was adjusted for age, sex, race, education, SPRINT randomization arm, history of cardiovascular disease, hypertension, diabetes, and mean blood pressure (except models fit to mean blood pressure). These covariates were selected based off prior research suggesting their possible confounding effects. 10,11 We verified the proportional hazards assumption of our Cox models by testing the Schoenfeld residuals.
In the Cox models fit to the outcome of dementia, we did not find an association for mean systolic or diastolic blood pressure. However, both systolic and diastolic BPV, as continuous variables and when comparing the highest to lowest quartile, were associated with dementia (

DISCUSSION
In hypertensive SPRINT MIND participants, we found that increased BPV after MCI diagnosis was associated with incident probable dementia during subsequent follow-up, independent of mean blood pressure. The effect of increased BPV on the risk of probable dementia was consistent for multiple different methodologic approaches to BPV measurement and for both systolic and diastolic BPV. Increased BPV has previously been associated with the development of dementia and MCI, 2,12 but the transition from MCI to dementia has not been fully explored. These hypothesis-generating results warrant replication because the reduction of BPV is not a recognized treatment target to reduce the burden of dementia and specific classes of antihypertensive medications, such as calcium channel blockers, have been shown to reduce BPV. 13 Our study has several important limitations. The most important is that this is a post hoc analysis that was not designed to answer the specific research question and, therefore, the results should be considered hypothesis-generating only. We also did not have uniform blood pressure measurements because they were dependent on study visits, which may have biased the results, although the number of measurements was not different in patients who developed dementia versus not. The limited number of blood pressure measurements after MCI diagnosis also prevented sensitivity analyses where we could explore the impact of using more blood pressure measurements to improve the precision of BPV's measurement. We were not able to examine neuroimaging mediators of the reported associations, such as white matter hyperintensity or cerebral atrophy, 6  final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.