Hypertension disrupts cerebrospinal fluid dynamics in association with lower cognitive function and blood pressure variability
S La Ferla, D Carnevale, G Lembo, L CarnevaleAbstract
Introduction
Hypertension is a major risk factor for dementia. Functional cerebral clearance of toxic byproducts, which relies on cerebrospinal fluid (CSF) circulation through the brain, is a key determinant for brain homeostasis and prevention of neurodegeneration. Although many studies demonstrated that cerebral hemodynamic modulates CSF movement, its relationship with hypertension is poorly understood.
Purpose
We hypothesized that arterial hypertension disrupts the physiological coupling between cerebral hemodynamic and CSF circulation, impairing brain clearance. Therefore, we leveraged functional Magnetic Resonance Imaging (fMRI) to compare this mechanism between hypertensive patients and normotensive controls, and examined short-term blood pressure variability (BPV), which may better relate to alterations in dynamic fluid regulation.
Methods
We conducted a case-control study of hypertensive patients and normotensive controls, and a prospective study of well-controlled hypertensive patients with one-year follow-up. From fMRI, we measured the temporal correlation between the cortical hemodynamic activity and the CSF inflow into the brain, as gBOLD-CSF coupling, an index positively associated with cerebral clearance. We evaluated group differences in the case-control cohort, while in the prospective cohort we assessed the longitudinal progression of gBOLD-CSF coupling and BPV, and their relationship at both time-points. At baseline, hypertensive patients were also profiled for circulating proteomics.
Results
The gBOLD-CSF coupling was significantly lower in hypertensive patients (N=48) than in normotensive controls (N=19) (p=0.023), and positively correlated with cognitive function assessed by MoCA score (r=0.33, p=0.018). In the longitudinal cohort of hypertensive patients (N=127), the gBOLD-CSF coupling at baseline was inversely associated with circulating IL-5 (r=-0.36, p=0.0046) and IL-13 (r=-0.34, p=0.0084), and directly associated with IL-10 (r=0.29, p=0.023). In one year, the coupling increased (p=0.028), while the pre/post-prandial systolic BPV decreased (p=0.031) and remained inversed associated with the gBOLD-CSF coupling at both baseline (r=-0.23, p=0.021) and follow-up (r=-0.25, p=0.039). Lastly, hypertensive patients enrolled with office SBP<130 mmHg showed higher gBOLD-CSF coupling at both time points (p=0.0014 and p=0.0007) than those enrolled with SBP≥130 mmHg.
Conclusions
Reduced hemodynamic-CSF coupling in hypertensives, associated with poorer cognitive performance, suggests that hypertension impairs cerebral clearance, potentially affecting cognitive function. Furthermore, well-controlled hypertensive patients showed one-year improvement in hemodynamic-CSF coupling, linked to decreased pre/post-prandial BPV and promoted by tighter BP control. The associations between coupling and circulating cytokines might indicate heightened inflammatory activity occurring alongside impaired brain clearance in hypertension.