Researchers in the Netherlands have found that a common blood pressure drug can boost blood flow to the learning and memory center of the brain in patients with Alzheimer’s disease (AD).

Previous studies have suggested that reduced cerebral blood flow (CBF) is a manifestation of cerebrovascular dysfunction that is causally linked to AD. Using an advanced magnetic resonance imaging (MRI) technique to look at blood flow in the brains of patients with mild-to-moderate AD, a Radboud University Medical Center-led team of scientists demonstrated that compared patients given placebo, six months of treatment using the calcium antagonist nilvadipine was associated with a 20% increase in CBF to the hippocampus, without affecting CBF to other areas of the brain.

“This high blood pressure treatment holds promise as it doesn’t appear to decrease blood flow to the brain, which could cause more harm than benefit,” said associate professor Jurgen Claassen, MD, PhD, who is lead author of the researchers’ published paper in Hypertension. “Even though no medical treatment is without risk, getting treatment for high blood pressure could be important to maintain brain health in patients with Alzheimer’s disease.” Claassen’s team, together with colleagues in the Netherlands, Germany, and Ireland, reported their findings in a paper titled, “Effects of Nilvadipine on Cerebral Blood Flow in Patients with Alzheimer Disease: A Randomized Trial.”

Cerebrovascular changes, including reduced CBF, occur early in AD development and may accelerate worsening disease, the authors commented. “A reduction in CBF has been established as an early marker of AD, predicting disease progression and correlating with cognitive impairment.”  It is thus feasible that, cerebrovascular pathology could represent a “plausible mechanism” to explain how hypertension—which is a major risk factor for cerebrovascular disease—might increase the risk of sporadic, late-onset AD. “Restoring CBF through vascular (e.g., antihypertensive) treatment could, therefore, become a new and feasible therapeutic target aimed at slowing down the progressive cognitive and functional decline in AD,” the researchers continued.

Jurgen Claassen, MD, PhD, associate professor, Radboud University Medical Center, Nijmegen, The Netherlands. [Radboud University Medical Center]
The team’s prior research had found that treating middle-aged hypertensive mice using an angiotensin receptor blocker boosted CBF in the hippocampus, but little has been known about how blood pressure (BP)-lowering drugs might affect blood flow in older people with AD. “…we asked how BP lowering with antihypertensive medication would affect CBF in patients with Alzheimer clinical syndrome in a mild-to-moderate dementia stage.”

The scientists carried out a prospective, randomized, double-blind placebo-controlled study involving 44 patients with clinical symptoms of mild-to-moderate AD, through which they used a technology known as magnetic resonance arterial spin labeling (ASL-MRI) to evaluate the effects of nilvadipine on CBF. The trial was designed as a preplanned substudy within the larger randomized controlled NILVAD trial that was comparing the effects of nilvadipine and placebo in more than 500 people with mild-to-moderate Alzheimer’s disease. The larger, parent study didn’t include measuring the effects of nilvadipine on CBF.

Source: American Heart Association

Results from the 44-patient substudy confirmed that nilvadipine treatment reduced the patients’ blood pressure, without reducing either overall CBF, or reducing blood flow in any specific regions of the brain. This indicates that cerebral autoregulation, which is the mechanism that aims to stabilize CBF, functioned well enough to counteract the drug-related reduction in perfusion pressure.

The ASL-MRI results data showed that the drug therapy was actually associated with increased blood flow in the hippocampus—although not in other areas of the brain—a finding that supported the team’s previous research in mice. “The increase in hippocampal CBF provides translational evidence for our earlier observations of increased hippocampal CBF after antihypertensive treatment in an AD animal model,” they wrote. The fact that the previous mouse studies had used a different type of antihypertensive drug suggested that it’s the fact of blood pressure lowering, rather than the effects of a specific class of drug, that was driving the increased hippocampal CBF.

The reported study has been one of relatively few to use ASL-MRI to evaluate the effects of drug treatment on CBF. “… this study demonstrates that ASL-MRI is a feasible and valid method to evaluate physiological changes in a relatively small sample of AD patients,” the authors wrote. They do acknowledge that their trial involved primarily Caucasian, European individuals, and so the results can’t be directly extrapolated to other populations. The study similarly wasn’t powered to evaluate whether lowering blood pressure and increasing hippocampal CBF would lead to cognitive improvements, or help to maintain brain structure. “Unfortunately, sample sizes were too small and follow-up time too short to reliably study the effects of this CBF increase on structural brain measures and cognitive measures.”

The main NILVAD trial didn’t find any overall clinical benefits associated with nilvadipine therapy among the cohort of 500 AD patients, although a subgroup of individuals with mild AD did demonstrate a slower decline in memory. “It would, therefore, be important to investigate, in a larger study with longer follow-up, whether the improvement in hippocampal CBF leads to cognitive benefits in earlier stages of disease (mild cognitive impairment or earlier), where the potential for prevention of cognitive decline may be much higher,” the researchers wrote.

“In the future, we need to find out whether the improvement in blood flow, especially in the hippocampus, can be used as a supportive treatment to slow down progression of Alzheimer’s disease, especially in earlier stages of disease,” Claassen said. As the researchers concluded in their paper, “These findings not only indicate preserved cerebral autoregulation in Alzheimer’s disease but also point toward beneficial cerebrovascular effects of antihypertensive treatment.”

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