ARTICLE IN BRIEF
Investigators reported data from an observational study finding that a higher variability in visit-to-visit blood pressure measure was associated with worse performance on various cognitive and memory tests. The study authors — and independent commentators — agree that clinicians need to pay greater attention to monitoring blood pressure in their patients.
Over the past few decades, it has become increasingly clear that the human brain and heart are inextricably linked — and a growing body of research is elucidating just how an individual's cardiovascular health may affect their neurologic status. A new study, published in the July 30 online edition of the British Medical Journal, found that blood pressure variability between visits can signal faster cognitive decline in older patients.
The research, led by Simon P. Mooijaart, MD, PhD, an internist and clinical researcher at Leiden University Medical Center in the Netherlands, and colleagues, used participant data from the PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) study — a randomized, double-blind, placebo-controlled trial designed to investigate the effect of pravastatin in the prevention of vascular events in elderly people with pre-existing (or risk factors for) cardiovascular disease enrolled in centers in Ireland, Scotland, and the Netherlands.
“It has already been observed for a number of years now that not only high blood pressure, but also the variability of blood pressure is an independent risk for cardiovascular disease or stroke — and we know that cardiovascular risk factors are also involved in cognitive decline. So, we sought to associate blood pressure variability with cognitive decline,” Dr. Mooijaart told Neurology Today.
Most importantly, Dr. Mooijaart said, “we found that variability in blood pressure is an independent risk factor for cognitive decline, independent of the height of blood pressure. That highlights the intricate relationship between the brain and the cardiovascular system.”
STUDY PROTOCOLS, FINDINGS
There were almost 5500 participants included in this study, all of whom had risk factors for cardiovascular disease and were, on average, 75 years old. Individuals were enrolled in one of three collaborating centers in Cork, Ireland; Glasgow, Scotland; and Leiden, the Netherlands. Over the course of more than three years, blood pressure was measured every three months.
The researchers performed four different tests of cognitive function to obtain the study's main outcome measures: selective attention, processing speed, immediate and delayed memory. Dr. Mooijaart and colleagues also performed a substudy using magnetic resonance imaging (MRI) in 553 participants, where they measured structural brain volumes, cerebral microbleeds, infarcts, and white matter hyperintensities.
A higher variability in visit-to-visit blood pressure was associated with worse performance on the Stroop test for selective attention (both systolic and diastolic, p<0.001), letter-digit coding test for general cognitive speed (both p<0.001), immediate picture-word learning test for immediate memory (both systolic and diastolic, P<0.001), and delayed picture-word learning test for delayed memory (both systolic and diastolic, p=0.001). Dr. Mooijaart and colleagues adjusted for average blood pressure and cardiovascular diseases and risk factors.
They also found that those individuals with higher variability in blood pressure showed lower hippocampal volume (both systolic and diastolic, p=0.01) on MRI. Blood pressure variability was not significantly associated with any other volumetric changes in brain structure (all p>0.05), except for the association between higher variability in systolic blood pressure and lower amygdala and putamen volumes (both p=0.04).
Dr. Mooijaart noted that the study was observational, “so we cannot say anything about the direction of the cause — whether it is actually the variability that causes the cognitive decline or whether it might be the cognitive decline that causes the blood pressure to vary. We should do more studies to disentangle the mechanism.”
How can these findings be applied in clinical practice? “We now know that those patients who have high variability in blood pressure have a higher chance of cognitive decline, so if you observe a patient with very high blood pressure variability, you may be more cautious and suspicious of their cognitive performance.”
The interesting thing to study now, said Dr. Mooijaart, would be whether there are interventions to reduce blood pressure variability, and then whether those interventions also decrease rate of cognitive decline. “Ultimately, we hope to prevent cognitive decline and the incidence of dementia,” he said.
Dr. Mooijaart told Neurology Today that he and his colleagues are currently working on a second manuscript that examines different blood pressure medication use in this population and its effects on blood pressure variability and cognitive decline.
Charles DeCarli, MD, chair of the Geriatric Neurology Section of the AAN, said that this is probably the largest such study to date to look at variable blood pressure and cognition. “I think it's a reminder for us to think not just about the absolute value of the blood pressure, but also the impact of its treatment and its variability,” said Dr. DeCarli, the Victor and Genevieve Orsi chair in Alzheimer's research and director of the Alzheimer's Disease Center and Imaging of Dementia and Aging Laboratory at the University of California, Davis.
One limitation of this work, said Dr. DeCarli, is that, although they tried to control for contributing factors, “unless you know the duration of the diabetes, the duration of these other cofactors, it's harder to know exactly what impact they may have. For example, some of these people may have had diabetes for five years and some of these people may have had diabetes for 30 years.” He added that it would be important to also look at the cumulative effect of some of these cardiovascular risk factors: “Do you just have blood pressure that's variable; or do you have hypertension plus diabetes; or do you have hypertension, diabetes, and hypercholesterolemia? “
“You have to stratify the analysis,” said Dr. DeCarli, who has published extensively on vascular risk factors and neurology.
The study points to the need for neurologists to become better informed of vascular risk factors. Many general neurologists may not even measure blood pressure regularly, Dr. DeCarli said. “I think that we need to have better dissemination of the [American Heart Association] guidelines and speak to their entire impact on the body. It's not just the heart — it's also the brain and the kidneys. This heart-brain connection is really important; the health of the body and the brain are intimately intertwined.”
“This large study has the strengths of being carefully carried out, having an excellent neuroimaging facility and investigators, and the ability to control for many potentially confounding factors,” said Philip B. Gorelick, MD, medical director of the Mercy Health Hauenstein Neuroscience Center at Saint Mary's and professor in the department of translational science & molecular medicine at Michigan State University College of Human Medicine. However, he added that since the study data originate from a clinical trial setting, the generalizability of the findings to the community at-large may be questioned.
Both commentators agreed that it would be interesting to note the types of blood pressure- lowering drugs and drug classes that the participants were using. “This might lead to additional hypotheses and speculation about the value of certain blood pressure lowering drugs such as calcium channel blockers that have been recommended to reduce blood pressure variability,” explained Dr. Gorelick. Furthermore, looking at the precise times when blood pressure measurements were taken in relation to time when blood pressure lowering medications were given may also be of value, he said.
Overall, the many strengths of this study outweigh potential limitations, Dr. Gorelick said. Although the association of variable blood pressure to cognition and structural changes in the brain is not new, “this carefully done study adds important brain imaging information and emphasizes the importance of what clinicians do on a regular basis in the office — take patients' blood pressure.”
Should blood pressure variability by detected, said Dr. Gorelick, “the clinician should consider blood pressure lowering agents that reduce blood pressure variability (for example, calcium channel blockers, and to a lesser extent non-loop diuretics).” Often, he noted, patients are aware of changes in their own blood pressure because many take home measurements or have blood pressure measured at a local pharmacy or other facility.
“As practitioners, we may ignore intermittent high blood pressure measures in clinic or at home monitoring. Spikes in blood pressure should probably not be ignored — for example, escape of systolic blood pressure >/=160 mm Hg),” he told Neurology Today.
These findings provide a mandate for further study of blood pressure variability, Dr. Gorelick said. “Specifically, a clinical trial to test the efficacy and safety of blood pressure lowering agents that are thought to reduce blood pressure variability in relation to cognitive vitality and preservation of brain structure should be considered.”