ORTHOSTATIC CHANGES IN BLOOD PRESSURE AND COGNITIVE STATUS IN THE ELDERLY : THE PRO . V . A STUDY Running title : Orthostatic blood pressure and cognitive status

Cognitive impairment (CI) and cognitive decline (CD) are common among older people and can be considered as conditions lying along a continuum from cognitively normal aging to dementia. Several factors are important for the onset of CI and CD, including female sex and the apolipoprotein Eε4 (apoEε4) genotype. Changes in blood pressure (BP) are associated with both CI and CD in older people. Hypertension might be implicated in the pathogenesis of poor cognition, and recent studies suggest that hypotension could be a risk factor for CI and CD too. This association has not been thoroughly investigated for orthostatic changes in BP, however. The type of orthostatic BP dysregulation most often studied is orthostatic hypotension, identifiable in ≈20% to 30% of individuals over 65 years of age. Although both orthostatic hypotension and poor cognitive status are common in the elderly, few studies have explored the potential longitudinal influence of orthostatic hypotension on cognitive function, and they have generated inconsistent findings. Some authors found orthostatic hypotension unassociated with CI or CD in geriatric patients, whereas others reported a significant link. Meanwhile, the possible relationship between orthostatic hypertension and cognitive status has never been considered, though this condition is a risk factor for several other negative outcomes in the elderly, such as cardiovascular diseases, essential hypertension, and mortality. We hypothesized that both orthostatic hypotension and orthostatic hypertension might carry a risk of being associated with cognitive deterioration. The aim of the present study was thus to explore whether postural changes in BP could predict Abstract—We studied a cohort of 1408 older subjects to explore whether postural changes in blood pressure (BP; defined as orthostatic hypoor hypertension) can predict the onset of cognitive deterioration. Orthostatic hypotension was defined as a drop of 20 mm Hg in systolic or 10 mm Hg in diastolic BP and orthostatic hypertension as a rise of 20 mm Hg in systolic BP. Orthostatic BP values were grouped into quintiles for secondary analyses. Two cognitive assessments were considered: (1) cognitive impairment, that is, Mini-Mental State Examination scores ≤24/30, and (2) cognitive decline (CD), that is, a 3-point decrease in Mini-Mental State Examination score from the baseline to the follow-up. At the baseline, the prevalence of orthostatic hypotension and hypertension was 18.3% and 10.9%, respectively. At the follow-up (4.4±1.2 years), 286 participants were found cognitively impaired and 138 had a CD. Using logistic regression analysis adjusted for potential baseline confounders, participants with orthostatic hypertension were at significantly higher risk of CD (odds ratio =1.50; 95% confidence intervals =1.26–1.78). Neither orthostatic hypotension nor orthostatic hypertension raised the risk of developing a cognitive impairment. Using quintiles of orthostatic BP values, we found that both decreases and increases in systolic and diastolic BP raised the risk of CD, but not of cognitive impairment. In conclusion, we found that orthostatic hypertension predicts the onset of CD, but not of cognitive impairment in the elderly, whereas orthostatic hypotension predicts neither of these conditions. Further studies are needed to confirm our findings. (Hypertension. 2016;68:427-435. DOI: 10.1161/HYPERTENSIONAHA.116.07334.) • Online Data Supplement