BY CHRISTINE LEHMANN
An analysis of blood pressure data from nearly 1,300 persons in late life found that both higher and declining systolic blood pressure increased the odds of having one or more brain infarcts. In addition, higher mean systolic blood pressure over time was associated with a higher number of Alzheimer's disease tangles in the brain, according to the paper published online July 11 in Neurology.
"While the relationship between high blood pressure and brain infarcts was expected based on previous research including a seminal study published in the July/August 1976 issue of Stroke, we were surprised that a faster decline in systolic blood pressure in late life also increased the odds of having one or more infarcts," lead investigator Zoe Arvanitakis, MD, MS, FAAN, medical director of Rush Alzheimer's Disease Center at Rush University Medical Center in Chicago, told Neurology Today. "The takeaway is that you can't ignore blood pressure even later in life because both increasing and decreasing levels appear to be unhealthy for the brain," said Dr. Arvanitakis.
Previous clinical and neuroimaging research, including a study published in the December 2012 Lancet Neurology, established that hypertension is a risk factor for stroke, but most of the studies involved subjects in mid-life. "Few studies have looked at people in late life to investigate the relationship between a range of blood pressure values and brain pathology," said Dr. Arvanitakis.
Although neuroimaging testing is now more sophisticated than ever, only postmortem assessments can definitively detect microscopic cerebrovascular disease such as infarcts and Alzheimer's pathologies including amyloid plaques and neurofibrillary tangles. "This study extends the knowledge from beyond what's available in the literature currently," said Dr. Arvanitakis.
This clinical pathologic study funded by the National Institutes of Health was derived from three ongoing prospective studies on aging involving community-based cohorts. In each, blood pressure data were collected at baseline and annually, and a self-reported history of hypertension and medications, including antihypertensives, was recorded annually. They also collected postmortem data on cerebrovascular disease, including different size infarcts and locations of infarcts, large and small vessel diseases (atherosclerosis and arteriolosclerosis), and neuropathological diseases (especially Alzheimer's disease).
The researchers analyzed postmortem data on 1,288 men and women whose mean age at death was 88.6 years; they were followed for a mean of eight years, and up to 24 years.
"Because late-life blood pressure varies over time, we investigated the role of both mean systolic and diastolic values and changes over time using the slope in late-life blood pressure. We also looked at how these blood pressure measures related to brain pathology," said Dr. Arvanitakis.
The researchers found that that the mean person-specific systolic blood pressure was 134 mmHG (SD=13) and the mean diastolic blood pressure was 71 mmHg (SD=8). Having a higher mean systolic blood pressure and a faster systolic decline over time increased the odds of having one or more brain infarcts. Specifically, a person with a blood pressure of one standard deviation above the mean (147 mmHg) would have a 46 percent increased odds of having one or more infarcts. A higher mean systolic blood pressure was also associated with a higher number of neurofibrillary tangles (p=0.038) but not with amyloid plaques, "both of which are defining pathologic measures of Alzheimer's disease," said Dr. Arvanitakis.
Diastolic blood pressure had a weaker association with infarcts (SD=8) with one standard deviation above the mean resulting in a 28 percent increased odds of having any infarct. The researchers found no relationship between mean and diastolic slope and Alzheimer's disease pathology.
The researchers adjusted for demographics and other factors to examine associations of both systolic and diastolic blood pressure with infarcts, cerebral vessel diseases, and overall and individual measures of Alzheimer's disease pathology, including plaques and tangles. Secondary analyses looked at effects of age, apolipoprotein E4, and variables related to blood pressure such as hypertension, antihypertensive medications, and vascular risk factors and diseases. There was no change in associations but there was an interaction of age with blood pressure, "such that the effect of mean systolic blood pressure on infarcts decreased with aging," said Dr. Arvanitakis.
The main strength of the study is that it looked at the full range of blood pressure values for both systolic and diastolic blood pressure "since these may have differential effects on the brain, as indeed shown by the results," said Dr. Arvanitakis.
The main limitations were a lack of access to midlife blood pressure measurements, and that most subjects were on hypertensive medications and their blood pressure was relatively well controlled. This limited the researchers' ability to observe effects of blood pressure on a wider distribution of values.
Rebecca F. Gottesman, MD, PhD, professor of neurology and epidemiology in the division of cerebrovascular neurology at Johns Hopkins University in Baltimore, who was not involved with the study, said, "This study confirms that blood pressure is still an important risk factor for silent stroke-like changes in the brain that can cause problems with thinking and memory."
Dr. Gottesman raised several questions about the finding that blood pressure can decline rapidly over time in people in late-life. Is this because this population is sick, on medications, or in preclinical states of Alzheimer's disease? Should clinicians be trying to lower blood pressure with antihypertensives as aggressively in older people or might this practice be harmful?
"The biggest strengths of the study were having both longitudinal and postmortem pathological data and the biggest weakness was the lack of mid-life data to compare with the late-life data in this population," Dr. Gottesman said.
"The results of this larger study add to the body of evidence in the literature reporting associations between late-life elevated and declining blood pressure in both mid and late-life and a risk of micro-infarcts, cortical atrophy and white matter disease burden, as well as clinical cognitive outcomes, including dementia and Alzheimer's disease," Emer McGrath, MBChB, PhD, associate neurologist at Brigham & Women's Hospital of Harvard Medical School in Boston, said in an email to Neurology Today.
Dr. McGrath suggested that reversal causality may explain the association between a rapid decline in blood pressure and increased infarct burden. "In the early stages of dementia/pre-clinical dementia, a decline in observed blood pressure was thought to be due to neurodegenerative effects on hypothalamic and brainstem nuclei that control blood pressure. Brainstem infarcts related to small vessel disease could also lead to a drop in blood pressure by involving brainstem nuclei controlling blood pressure. The development of cardiovascular disease in this older age group could also result in lower blood pressures, reducing systemic and cerebral perfusion."
Charles DeCarli, MD, FAAN, FAHA, director of the Alzheimer's Disease Center at University of California, Davis in Sacramento, said: "This is the first study to look specifically at the relationship between a decline in blood pressure and features of both cerebrovascular disease and Alzheimer's disease in late life. I was struck by the stronger relationship with cerebrovascular pathology than Alzheimer's pathology, which may indicate an association with dementia."
"The association between blood pressure and dementia is clear. Systolic blood pressure is a risk factor for dementia when it's high in mid-to-late life, and low in late-life," he said, citing a study published last December in Neurology.
Dr. DeCarli said a sensitivity analyses would have informed whether the findings, for example, are being driven by the number of people with hypertension.
Dr. Arvanitakis noted that the researchers conducted several sensitivity analyses, which due to space constraints, are only summarized in the paper. She added that there was no change in results when the researchers controlled for a history of stroke, Alzheimer's disease pathology, hypertension, antihypertensive medications, race, and age.
Finally, in response to comments by Drs. DeCarli and Gottesman about the lack of clinical information in the study, Dr. Arvanitakis said: "Our paper is a clinical pathologic study about the relation of annually measured blood pressure to postmortem neuropathology without any clinical diagnosis data and clinically actionable results." She noted that that another paper will address clinical outcomes such as dementia and cognition.
"This highlights the need for more research in this area because we know that pathologies are associated with clinical outcomes including cognitive impairment and dementia," said Dr. Arvanitakis.
LINK UP FOR MORE INFORMATION:
Arvanitakis Z, Capuano AW, Lamar M, et al. Late-life blood pressure association with cerebrovascular and Alzheimer's disease pathology. Neurology 2018; Epub 2018 Jul 11.
Bennett DA, Schneider JA, Arvanitakis Z, Wilson RS. Overview and findings from the religious orders study. Curr Alzheimer Res 2012;9(6):628-645.
Bennett DA, Schneider JA, Buchman AS, et al. Overview and findings from the Rush Memory and Aging Project. Curr Alzheimer Res 2012;9(6):646-663.
Kannel WB, Dawber TR, Sorlie P, Wolf PA. Components of blood pressure and risk of atherothrombotic brain infarction: The Framingham study. Stroke 1976;7(4):327-331.
Gottesman RF, Schneider ALC, Zhou Y, et al. Association between midlife vascular risk factors and estimated brain amyloid deposition. JAMA 2017: 317(14): 1443-1450.
Gottesman RF, Albert MS, Alonso A, et al. Associations between midlife vascular risk factors and 25-year incident dementia in the atherosclerosis risk in communities (ARIC) cohort. JAMA Neurol 2017;74(10):1246-1254.
McGrath ER, Beiser AS, DeCarli C, et al. Blood pressure from mid- to late life and risk of incident dementia. Neurology 2017; 89(24):2447-2454.