N-Terminal Pro Brain, N-Terminal Pro Atrial Natriuretic Peptides, and Dynamic Cerebral Autoregulation.

Background Elevated natriuretic peptides (NP) are associated with adverse cerebrovascular conditions including stroke, cerebral small vessel disease, and dementia. However, the mechanisms underlying these associations remain unclear. In this study, we examined the relationship of NT-proBNP (N-terminal pro brain NP) and NT-proANP (N-terminal pro atrial NP) with cerebrovascular function, measured by cerebral autoregulation. Methods and Results We included 154 participants (mean age 56±4 years old) from the CARDIA (Coronary Artery Risk Development in Young Adults) cohort. NT-proBNP and NT-proANP were measured in blood samples from the year 25 examination using electrochemiluminescence Immunoassay and enzyme-linked immunoassay, respectively. Dynamic cerebral autoregulation (dCA) was assessed at the year 30 examination by transcranial Doppler ultrasound, using transfer function analysis (phase and gain) of spontaneous blood pressure and flow velocity oscillations, where lower phase and higher gain reflect less efficient cerebral autoregulation. We used multivariable linear regression models adjusted for demographics, vascular risk factors, and history of kidney and cardiac diseases. Higher NT-proBNP levels at year 25 were associated with lower phase (ß [95% CI]=-5.30 lower degrees of phase [-10.05 to -0.54]) and higher gain (ß [95% CI]=0.06 higher cm/s per mm Hg of gain [0.004-0.12]) at year 30. Similarly, higher NT-proANP levels were associated with lower phase (ß [95% CI]=-9.08 lower degrees of phase [-16.46 to -1.70]). Conclusions Higher circulating levels of NT-proBNP and NT-proANP are associated with less efficient dCA 5 years later. These findings link circulating NP to cerebral autoregulation and may be one mechanism tying NP to adverse cerebrovascular outcomes.

Cumulative Blood Pressure Exposure, Basal Ganglia, and Thalamic Morphology in Midlife.

High blood pressure (BP) negatively affects brain structure and function. Hypertension is associated with white matter hyperintensities, cognitive and mobility impairment in late-life. However, the impact of BP exposure from young adulthood on brain structure and function in mid-life is unclear. Identifying early brain structural changes associated with BP exposure, before clinical onset of cognitive dysfunction and mobility impairment, is essential for understanding mechanisms and developing interventions. We examined the effect of cumulative BP exposure from young adulthood on brain structure in a substudy of 144 (61 female) individuals from the CARDIA (Coronary Artery Risk Development in Young Adults) study. At year 30 (Y30, ninth visit), participants (56±4 years old) completed brain magnetic resonance imaging and gait measures (pace, rhythm, and postural control). Cumulative systolic and diastolic BP (cumulative systolic blood pressure, cDBP) over 9 visits were calculated, multiplying mean values between 2 consecutive visits by years between visits. Surface-based analysis of basal ganglia and thalamus was achieved using FreeSurfer-initiated Large Deformation Diffeomorphic Metric Mapping. Morphometric changes were regressed onto cumulative BP to localize regions of shape variation. Y30 white matter hyperintensity volumes were small and positively correlated with cumulative BP but not gait. Negative morphometric associations with cumulative systolic blood pressure were seen in the caudate, putamen, nucleus accumbens, pallidum, and thalamus. A concave right medial putamen shape mediated the relationship between cumulative systolic blood pressure and stride width. Basal ganglia and thalamic morphometric changes, rather than volumes, may be earlier manifestation of gray matter structural signatures of BP exposure that impact midlife gait.

Cumulative Blood Pressure Exposure During Young Adulthood and Mobility and Cognitive Function in Midlife.

BACKGROUND: High blood pressure (BP) is a known risk factor for mobility and cognitive impairment in older adults. This study tested the association of cumulative BP exposure from young adulthood to midlife with gait and cognitive function in midlife. Furthermore, we tested whether these associations were modified by cerebral white matter hyperintensity (WMH) burden. METHODS: We included 191 participants from the CARDIA study (Coronary Artery Risk Development in Young Adults), a community-based cohort of young individuals followed over 30 years. Cumulative BP was calculated as the area under the curve (mm Hg×years) from baseline up to year 30 examination. Gait and cognition were assessed at the year 30 examination. Cerebral WMH was available at year 30 in a subset of participants (n=144) who underwent magnetic resonance imaging. Multiple linear regression models were used to assess the association of cumulative BP exposure with gait and cognition. To test effect modification by WMH burden, participants were stratified at the median of WMH and tested for interaction. RESULTS: Higher cumulative systolic and diastolic BPs were associated with slower walking speed (both P=0.010), smaller step length (P=0.011 and 0.005, respectively), and higher gait variability (P=0.018 and 0.001, respectively). Higher cumulative systolic BP was associated with lower cognitive performance in the executive (P=0.021), memory (P=0.015), and global domains (P=0.010), and higher cumulative diastolic BP was associated with lower cognitive performance in the memory domain (P=0.012). All associations were independent of socio-demographics and vascular risk factors (body mass index, smoking, diabetes mellitus and total cholesterol). The association between cumulative BP and gait was moderated by WMH burden (interaction P<0.05). However, the relation between cumulative BP and cognitive function was not different based on the WMH burden (interaction P>0.05). CONCLUSIONS: Exposure to higher BP levels from young to midlife is associated with worse gait and cognitive performance in midlife. Furthermore, WMH moderates the association of cumulative BP exposure with gait, but not with cognitive function in midlife. The mechanisms underpinning the impact of BP exposure on brain structure and function must be investigated in longitudinal studies using a life course approach.