Systolic Orthostatic Hypotension Tied to Dementia Risk

Erik Greb

August 20, 2020

Systolic, but not diastolic, orthostatic hypotension is associated with a 40% increase in risk for incident dementia ― and the risk is not affected by demographic variables or medical comorbidities, new research suggests.

Data from the prospective Health, Aging, and Body Composition (Health ABC) study also showed that variability over time in postural changes in systolic blood pressure (BP) was associated with an increased risk for dementia. It may be the first time this association has been demonstrated, the investigators note.

However, variability in postural changes in diastolic BP was not associated with increased dementia risk.

Dr Laure Rouch

In previous studies of orthostatic hypotension and risk for dementia, follow-up time was limited, whereas in the current study, the investigators "measured orthostatic hypotension repeatedly and assessed incident dementia over a total period of 17 years, making potential reverse causality much less likely," Laure Rouch, PharmD, PhD, visiting scholar at the University of California, San Francisco, told Medscape Medical News.

"More importantly, what is totally new here is that no one has looked at the effect of long-term variability of postural changes in blood pressure over time on dementia risk," Rouche added.

The findings were published online July 20 in Neurology.

Conflicting Results

Up to 30% of elderly individuals experience postural changes in BP. Past research has shown an association between orthostatic hypotension and increased risk for cardiovascular events, but whether the condition influences cognitive outcomes has been uncertain. The few investigations into this possible relationship have yielded conflicting results.

In addition, BP variability has been identified as a predictor of cardiovascular outcomes, such as myocardial infarction, but its potential relationship with incident dementia has not been studied.

To examine these issues, the current investigators assessed data from the prospective Health ABC cohort. The study enrolled community-dwelling Medicare members between the ages of 70 and 79 years who were cognitively normal and had no mobility limitations at baseline. Participants lived in Memphis, Tennessee, or Pittsburgh, Pennsylvania. The investigators followed them for as long as 17 years.

Orthostatic BP changes were measured at baseline and at 1, 3, and 5 years. Two measurements were taken while participants were seated and had been resting for 5 minutes. One measurement was taken after 1 minute of standing. These measurements were used as a 5-year baseline period.

Following proposed diagnostic criteria, the researchers defined orthostatic hypotension as a decrease in systolic BP of at least 15 mmHg or a decrease in diastolic BP of at least 7 mmHg after postural change at any of the two measurements. They defined orthostatic hypotension during the baseline period as having orthostatic hypotension for at least one third of visits.

To gauge the variability of postural changes in systolic BP between visits during the baseline period, the ratio of seated systolic BP to standing systolic BP was measured at each visit. The researchers also analyzed visit-to-visit variability of postural changes in systolic BP using various indicators, such as standard deviation, coefficient of variation, and variation of independent mean.

After the baseline period, the Modified Mini–Mental Status Examination (3MS) was used to assess cognition during a period of 12 years. Dementia was determined on the basis of the following: a hospitalization in which dementia was listed as a primary or secondary diagnosis; a documented prescription for dementia medication, including galantamine, rivastigmine, donepezil, or memantine; or a race-stratified decline of 1.5 standard deviations or more on repeated 3MS measures from baseline through last visit.

The investigators controlled for the potential confounders of demographic characteristics and of comorbidities, such as hypertension, diabetes, cerebrovascular disease, depression, and smoking.

Significant Association

The researchers analyzed 2131 participants in Health ABC, of whom 53.3% were women and 38.7% were Black persons. Mean age at baseline was 73.4 years.

During the baseline period, 192 participants (9.0%) had systolic orthostatic hypotension, 132 (6.2%) had diastolic orthostatic hypotension, and 309 (14.5%) had orthostatic hypotension. Participants with orthostatic hypotension were more likely to have higher seated systolic BP, hypertension, and depressive symptoms.

In all, 462 participants (21.7%) developed incident dementia during follow-up.

A significant association was found between systolic orthostatic hypotension and increased risk for dementia (unadjusted hazard ratio [HR], 1.35). After the data were adjusted for potential confounders, the association remained statistically significant (adjusted HR, 1.37).

Age, race, and seated systolic BP did not interact with orthostatic hypotension so as to influence the risk for incident dementia.

Compared with participants in the lowest tertile of variability of postural changes in systolic BP, those in the highest tertile had a greater risk of developing dementia (unadjusted HR, 1.33).

The results remained significant after adjusting for potential confounders (HR, 1.35). Similar findings were shown when the other indicators of variability were analyzed.

However, visit-to-visit variability of postural changes in systolic BP was not significantly associated with risk for dementia.

Mechanism Uncertain

Systolic orthostatic hypotension and visit-to-visit variability in postural changes in systolic BP may be associated with risk for dementia through various mechanisms, the investigators note.

The most common theory is that orthostatic hypotension promotes recurrent, transient cerebral hypoperfusion. Repeated episodes of hypoperfusion may cause hypoxia, neuroinflammation, and oxidative stress.

In addition, increased fluctuations in BP induce shear stress on the vessel wall that can cause microvascular damage by promoting endothelial injury and disturbing vascular smooth muscle functioning.

"This cerebral microcirculatory dysfunction could, in turn, influence the integrity of the blood-brain barrier, which is the major system to remove potentially vasculotoxic and neurotoxic molecules from the central nervous system," Rouch noted.

"Previous research has shown that a dysfunctional blood-brain barrier could promote amyloid beta accumulation, for instance, as a result of altered clearance and permeability," she said.

Overall, the new findings increase the evidence of the close relationship between vascular disease and brain health, she added.

"While we don't know the exact mechanism underlying the association between orthostatic blood pressure changes and dementia, we hope this research will raise awareness among clinicians about the importance of monitoring as accurately as possible orthostatic blood pressure and its long-term variability in older adults," said Rouch.

This monitoring is "critically important to promote healthy brain aging, given that orthostatic hypotension affects approximately 30% of older adults and that multiple pharmacologic and nonpharmacologic interventions may improve its symptoms," Rouch said.

In future research, the investigators intend to identify the mechanisms by which orthostatic hypotension and variability in BP postural changes increase dementia risk. They also plan to investigate whether controlling orthostatic BP and its variability, such as by optimizing antihypertensive treatment, prevents or slows dementia.

Optimal BP Measures Needed

Dr Vladimir Hachinski

Commenting on the findings for Medscape Medical News, Vladimir Hachinski, MD, DSc, distinguished university professor of clinical neurologic sciences at London Health Sciences Center in Ontario, Canada, said strengths of the study include its large numbers, long follow-up, and extensive standardized assessments.

However, the study's observational design is a weakness, said Hachinski, who was not involved with the research.

Cerebral blood flow studies would be required to establish a causal relationship between systolic orthostatic hypotension and dementia, he noted. These studies ideally would use techniques that measure capillary failure while sitting and standing, such as those described by Ostergaard and colleagues, he added.

Establishing causation also would require 24-hour blood pressure monitoring with continuous EEG monitoring.

"Typically, blood pressure dips at night, and this could be exaggerated in orthostatic hypotension," Hachinski said. "A quantitative EEG sitting and standing would give a rough indication of whether the change in posture produces major physiological changes, such as hypoperfusion."

The current study also raises questions for future research.

"The real need is to develop a practical method of evaluating the cerebral blood flow autoregulation in individual patients and to answer the question, 'What is the optimal blood pressure for my brain?,' " Hachinski said.

He added that clinical trials can only report what is best on average, not what is best for the individual.

"Blood pressure ― high, low, and fluctuations ― is the most powerful, treatable risk factor for stroke and dementia. It is imperative to develop a method of assessing the optimal blood pressure for our individual brains. This could be the single most important measurement in personalized medicine," Hachinski said.

Health ABC was funded by the National Institute on Aging (NIA). The current study was funded by the Intramural Research Program of the National Institutes of Health, NIA. Rouch and Hachinski have reported no relevant financial relationships.

Neurology. Published online July 20, 2020. Abstract

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