Data from our 4-year longitudinal study entitled "Brain changes and risk factors causing impaired mobility" have shown important relations among 24-hour systolic BP, progression of white matter hyperintensity (WMH) lesions and impaired mobility. Hence, in this application, we are proposing a randomized trial to reduce 24- hour ambulatory systolic BP (24ASBP) to 2 levels (usual vs. intensive ABP control) to mitigate the brain changes (WMHs) that are associated with impaired mobility. An increasing body of knowledge has related WMH to functional deterioration of mobility, urinary control and cognition. In baseline data from the precursor to this proposal we performed hypothesis-driven evaluations of WMH within brain regions (rWMH) known to be critical to mobility, cognition or voiding. These studies confirmed an association between rWMH and functional assessments suggesting that specific WM damage was linked to impaired function. While the 3 studies used different rWMHs (function dependent), a subsequent pooled analysis using rWMHs important for function demonstrated powerful correlations between rWMH and global WMH (tWMH) with r values of 0.5-0.9 for 8 of 10 structures). The tWMH predicted functional measures of mobility, executive function/processing speed and urinary function nearly as well as the best regional measures. The tWMH independently explains 5-11% of the variability for mobility, executive function/processing speed, and urinary incontinence severity and is a sensitive (r = 0.7-0.8) predictor of functional decline. Odds of decline in each of the 3 functional domains increased 1.5 to 2.4 fold with each 1% increase in tWMH. Ambulatory BP (ABP) data (but not clinic BP data) showed that in those subjects whose initial and 2 year 24-h systolic BP was <130 mmHg, significantly less WMH was observed than those whose 24-h systolic BP was >140 mmHg. Increases in ABP and WMH were significantly linked to less effective mobility documented by slower usual and maximal gait velocity and increased turn and stair descent time. Cognitive function was also diminished in the group with higher ABPs. Thus, small differences in 24-h systolic BP (10 mmHg), considered within the normotensive range for this age group, can result in clinically relevant differences in the accrual of tWMH and results in decreases in mobility and some aspects of cognitive function. The goal of the present proposal is to assess causality between 24-h systolic BP and reductions in mobility, cognitive and urinary function associated with WMH changes in brain as well as microstructural integrity as determined by diffusion tensor imaging in older people. The study will determine the impact of reducing the 24-h systolic BP to a goal of <125 mmHg (intensive BP control) vs. a goal of <140 mmHg (standard BP control). This separation of the ABP levels should achieve >10 mmHg differences between the groups that we believe is a key factor for reducing mobility impairment associated with WMH in older patients with systolic hypertension. This will be the first trial to study the ability to slow progression of WMHs to halt the resultant functional impairment by intensive reduction of ABP.
Ambulatory BP (ABP) data (but not clinic BP data) showed that in those subjects whose initial and 2-year 24-h systolic BP was <130 mmHg, significantly lower white matter hyperintensity volume and better mobility was noted (faster gait velocity, decreased turn and stair descent time) than those whose 24-h systolic BP was >140 mmHg. The goal of the present proposal is to assess causality between 24-h systolic BP and reductions in mobility, associated with WMH in older people. The study will determine the impact of reducing the 24-h systolic BP to a goal of <125 mmHg (intensive BP control) vs. a goal of <140 mmHg (standard BP control).
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