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Intensive lowering of blood pressure (BP) in older patients with hypertension does not appear to reduce the risk for the occurrence of brain biomarkers that have been linked to mild cognitive impairment (MCI) or Alzheimer’s disease (AD) and may even increase the risk, a new imaging study suggests.

Using brain MRI, investigators found a small but statistically significant decrease in hippocampal volume in patients who underwent intensive treatment to lower BP in comparison with patients who underwent standard treatment to lower BP. There were no significant differences in other AD brain biomarkers.

“We investigated imaging biomarkers of AD and vascular disease in the brain using MRI. In brief, while various individual measures appeared more favorable in one group or another, we did not see a consistent effect or any group difference that is likely to be significant in the 4-year time frame,” study investigator Ilya Nasrallah, MD, medication metformin hcl 500mg PhD, assistant professor of radiology at the Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, told Medscape Medical News.

The study was published online March 8 in JAMA Neurology.

Hallmark Biomarker

The current study was a secondary analysis of findings from the SPRINT MIND trial, a large randomized trial that had found less progression of white matter lesions in those who had received more intensive BP control, compared to those who had received standard treatment, Nasrallah said.

White matter lesions are a biomarker for cerebrovascular injury. Other studies have had similar findings, but “other mechanistic markers of cognitive impairment and dementia have yet to be explored,” the authors note.

Although previous research had found that treating hypertension may reduce the incidence of AD, it is “unclear whether this could be a direct effect on AD-related neurodegeneration or comorbid vascular pathology,” the investigators write. The neurodegeneration of AD results in brain atrophy in particular brain regions, they note.

“Biomarkers measuring these changes may be more sensitive to early AD-related change than downstream cognitive or clinical variables, such as incident dementia,” they write.

The most widely studied MRI biomarker for AD-related brain change is hippocampal atrophy, a “hallmark of typical mild cognitive impairment and AD,” although regions other than the hippocampus may be implicated as well, the authors note.

In addition to hippocampal atrophy, new research has identified “patterns of AD-like atrophy that often have reported higher sensitivity and specificity than hippocampal atrophy,” the authors note. The Spatial Pattern of Abnormality for Recognition of Early Alzheimer’s Disease (SPARE-AD) assigns a single global score that is based on overall similarity of the brain to an AD pattern in comparison with the normal brain and includes other regions as well.

Moreover, “prior to SPRINT, there was consensus that treating hypertension was beneficial; however, there was no consensus on whether intensive therapy would add further benefit or might itself cause harm,” Nasrallah added.

Short Time Frame

Participants with hypertension, no history of diabetes, but increased cardiovascular risk (n = 673; mean [SD] age, 67.3 [8.2] years; 40.3% women; 32.4% Black) underwent baseline MRI; 454 participants completed the follow-up MRI roughly 4 years after randomization.

In the total sample, the mean systolic BP was 138.1 [16.7] mm Hg; the mean diastolic BP was 77.9 [11.5] mm Hg.

At baseline, 6.4% of participants had positive SPARE-AD scores, indicating a “pattern more AD-like than normal.” The remaining participants had negative SPARE-AD scores. Among older participants (≥75 years), baseline hippocampal volumes were lower and SPARE-AD scores were worse in comparison with younger participants. Lower hippocampal volume was associated with higher SPARE-AD score.

Participants in the intensive treatment group experienced larger declines in mean hippocampal volume during the follow-up period, compared with those in the standard treatment group.

Treatment GroupDeclineDifference (95% CI)
IntensiveFrom 7.45 cm3 to 7.39 cm3−0.06 cm3 (−0.08 to −0.04)
StandardFrom 7.48 cm3 to 7.46 cm3−0.02 cm3 (−0.05 to −0.003)

 

The between-group difference in change was -.033 cm3 (−0.062 to −0.003; P = .03).

There were no significant differences in the treatment group with regard to measures of AD regional atrophy, cerebral blood flow, or mean fractional anisotropy, and there were no differences in SPARE-AD score.

Changes in most AD-related biomarkers were greater in older adults in comparison with patients aged <75 years — in particular, hippocampal volumes were smaller and SPARE-AD scores were higher.

Nasrallah noted that finding a clinically significant, consistent effect or group difference is “unlikely” in the 4-year time frame of the SPRINT-MIND study.

“Unfortunately, it’s hard to make a study long enough to match the time scale of AD and vascular disease, which progress over decades, but, in short, we don’t see that differential effects on either pathology point to a clear benefit for brain health or for any clear adverse risk for the intensive therapy,” he said.

He explained that the SPRINT-MIND trial did not show an association between lower risk for MCI/dementia and more intensive antihypertensive therapy in comparison with standard antihypertensive therapy.

However, the trial did show benefit in reducing rates of fatal and nonfatal major cardiovascular events and death from any cause, and it was stopped early.

“SPRINT showed a clear reduction in cardiovascular morbidity in the intensive group, which is the reason the trial was stopped early. So it may be that intensive therapy reduces the incidence of MCI/dementia by removing systemic disease barriers that otherwise might interfere with patient functional abilities,” Nasrallah suggested.

“Elusive” Link

Commenting on the study for Medscape Medical News, Susan Landau, PhD, a research scientist at the Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, California, described the link between cardiovascular risk management and AD as “elusive.”

Landau, who is the coauthor of an accompanying editorial and was not involved with the study, said, “Reducing cardiovascular events appears to be the key benefit of intensive hypertension control.”

The SPRINT-MIND study “does not point to a further additional benefit of intensive hypertension control in maintaining cognitive function or in reducing the risk of Alzheimer’s disease,” said Landau.

The Systolic Blood Pressure Intervention Trial was funded by the National Institutes of Health (including the National Heart, Lung, and Blood Institute; the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute on Aging; and the National Institute of Neurological Disorders and Stroke. It was also supported in part with resources and use of facilities through the US Department of Veterans Affairs and the Alzheimer’s Association. Additional sources of funding are listed on the original article. Nasrallah received grants from the National Institutes of Health during the conduct of the study and personal fees from Biogen outside the current study. The other authors’ disclosures are listed on the original article. Landau has received grants from the National Institutes of Health and the US Department of Defense. Theresa M. Harrison, PhD, coauthor of the editorial, has disclosed no relevant financial relationships.

JAMA Neurology. Published online March 8, 2021. Abstract, Editorial

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