Nilvadipine Increases Hippocampal Cerebral Blood Flow in Alzheimer Disease

Nilvadipine increased hippocampal cerebral blood flow while lowering blood pressure in adults with mild-to-moderate Alzheimer disease (AD), resulting in beneficial cerebrovascular effects, according to a study published in Hypertension.

Researchers examined how lowering blood pressure by using nilvadipine — an anti-hypertensive — would affect cerebral blood flow in adults with AD who were in a mild-to-moderate dementia stage in this randomized, double-blind, placebo-controlled study of 6-month duration.

In total, 58 participants were randomly assigned to nilvadipine (n=29) and placebo groups (n=29) in a substudy of the Nilvadipine in AD (NILVAD; trial identifier: NCT02017340) trial. In both groups, 22 participants had no magnetic resonance exclusion criteria and were medication compliant over 6 months. Mean mini-mental state examination was 20.4±3.4.

Cerebral blood flow was measured with magnetic resonance arterial spin labeling in whole-brain gray matter and in defined regions of interest including the hippocampus at baseline and after 6 months of treatment with nilvadipine or placebo. Nilvadipine treatment lowered systolic blood pressure at 6-month follow up visit (Δ=−11.5 mm Hg [95% CI, −19.7 to −3.2]; P <.01), while whole-brain gray-matter cerebral blood flow remained stable (Δ=5.4 mL/100 g per minute [95% CI, −6.4 to 17.2]; P =.36). Also, cerebral blood flow in the hippocampus increased (left: Δ=24.4 mL/100 g per minute [95% CI, 4.3-44.5]; P =.02; right: Δ=20.1 mL/100 g per minute [95% CI, −0.6 to 40.8]; P =.06).

There was no significant change in cerebral blood flow in the posterior cingulate cortex (Δ=5.2 mL/100 g per minute [95% CI, −16.5 to 27]; P =.63) or other regions of interest. Nilvadipine had no effect on whole-brain atrophy or hippocampal atrophy rates nor on change in white matter lesion volume. No new infarcts or microbleeds were observed.

Limitations of this study included that magnetic resonance arterial spin labeling has not been previously used in randomized trials and hence, the reliability and feasibility had not been established. There were approximately 10% missing data in the final results due to logistic reasons, which may have influenced the outcomes of the study. Only White Europeans were included in the study, limiting the racial diversity of the participants. No amyloid or τ biomarkers were used to confirm AD pathology. In those with vascular stiffness (diastolic pressure <60 mm Hg and a pulse pressure >60 mm Hg,), lowering blood pressure may cause lobar ischemia, and adults meeting these criteria were not included in the study.

The researchers concluded that that blood pressure reduction with nilvadipine resulted in an increase in hippocampal cerebral blood flow while global flow remained stable. However, it is unknown if these translate into clinical benefits. The main trial did not show any improvement in cognitive function, but the sample size was too small to reach a conclusion. The study conclusively showed that lowering blood pressure did not result in a reduction in cerebral blood flow resulting in hypoperfusion, thus showing preserved cerebral autoregulation.

Disclosure

One author declares a conflict of interest. Please see original reference for a full list of authors’ disclosures.

Reference

de Jong DLK, de Heus RAA, Rijpma A, et al. Effects of nilvadipine on cerebral blood flow in patients with Alzheimer disease: a randomized trial [published online June 17, 2019]. Hypertension. doi: 10.1161/HYPERTENSIONAHA.119.12892