Pulse Pressure Impairs Cognition via White Matter Disruption

BACKGROUND In older adults, elevated pulse pressure predicts cognitive decline, irrespective of overall blood pressure. It is proposed to compromise cerebrovascular integrity, potentially leading to brain damage, though the underlying mechanisms remain unclear. We hypothesized that pulse pressure affects cognition by disrupting white matter microstructure, and that it does so independently of other cardiovascular risk factors. METHODS Indices of pulse pressure, overall blood pressure and heart rate variability were estimated in a cross-sectional population-based cohort (n=708, aged 18-88 years). An indicator of white matter microstructure was derived from diffusion-weighted imaging, termed the “peak width of skeletonised mean diffusivity” (PSMD). Cognitive function was assessed using measures of processing speed. RESULTS In robust multiple linear regressions, pulse pressure significantly predicted PSMD. We also found that PSMD significantly predicted processing speed. Thus higher pulse pressure was associated with greater white matter disruption, and greater white matter disruption was associated with slower processing abilities.This motivated testing whether PSMD mediates the effects of pulse pressure on processing speed. We tested this using a number of structural equation models. PSMD significantly and substantially mediated the effect of pulse pressure on processing speed, over and above age and other cardiovascular factors. We then expanded the model to show that vascular-related changes in processing speed in turn drive changes in higher cognitive functions. CONCLUSIONS High pulse pressure disrupts microstructural integrity of white matter in the brain, leading to slower processing speed. We propose that better manament of pulse pressure could help to preserve white matter integrity and reduce cognitive decline in later life.