Impact of Late-Life Blood Pressure on the Brain Revealed

Higher late-life systolic blood pressure (SBP) has been tied to more brain infarcts and more markers of Alzheimer's disease, specifically neurofibrillary tangles, results of a novel autopsy study show.

The association between blood pressure and tangles is "very intriguing" and "a novel finding," lead author Zoe Arvanitakis, MD, medical director, Memory Clinic, Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, told Medscape Medical News.

"Although we expected to see a relationship between blood pressure and infarcts given that blood pressure is related to stroke, the relationship with Alzheimer's disease pathology has not been studied much at all, and what we found was somewhat surprising."

The study, which was published online July 11 in Neurology, is one of only a few to examine how changes in blood pressure over time affect the brain.

Under the Microscope

The overall hypothesis of the study was that late-life blood pressure is associated with common brain pathology of aging, specifically cerebrovascular disease and neurodegeneration, the investigators note.

To test this hypothesis, investigators analyzed data from 1288 participants from prospective cohort studies of aging. These included the Religious Order Study, Rush Memory and Aging Project, and Minority Aging Research Study.

Study participants underwent annual clinical evaluations that included medical history, physical examination, and neuropsychological testing.

Researchers separately computed the standardized person-specific SBP and diastolic blood pressure (DBP) over time to represent the mean level and slope of change.

Using "measured blood pressure" that revealed "the full range of blood pressure, from normal, to lower to high" was a different approach than that of other research that "simply looked at hypertension," said Arvanitakis.

On average, participants were followed for 8 years. During the study, two thirds had hypertension and 87% took an antihypertensive medication. Two thirds had at least one vascular risk factor at baseline, and nearly a third had a vascular disease.

The mean SBP was 136 mm Hg at baseline and 134 mm Hg when averaged across the years of the study. On average, SBP declined 0.8 mm Hg per year.

DBP was 72 mm Hg at baseline and 71 mm Hg when averaged across the years. On average, DBP declined 0.1 mm Hg per year.

Study participants died at an average age of 88.6 years. Postmortem neuropathologic evaluations were conducted at autopsy.

This, said Arvanitakis, was another key difference from previous studies.

"Rather than using a brain scan like an MRI or a CT scan, and trying to look for infarcts, we actually studied the brains after death under the microscope."

She added that this allowed the investigators to "really define the pathology that was present in a much more conclusive way."

Aging Effect

Researchers classified the number, volume, and location of each infarct. They also collected data on neurodegenerative pathology, including neuritic plaques, diffuse plaques, and neuronal neurofibrillary tangles.

About half (48%) of the patients had one or more chronic infarct of any size or location. One third had gross infarcts, one third had micro-infarcts, and 15% had both gross infarcts and micro-infarcts.

Most also had some Alzheimer's disease (AD) pathology, which wasn't surprising.

"Most people have mild levels of amyloid or tangles by the time they get into their 80s," said Arvanitakis.

After adjusting for age at death, sex, education, and years in the study, the analysis showed that for an increase of 1 standard deviation (SD) in mean SBP, there was a 46% increased odds of having at least one infarct of any size or location (odds ratio [OR], 146; 95% confidence interval [CI], 1.24 - 1.72).

This "is quite substantial" and, according to the statistical models used in the study, equivalent to 9 years of aging, said Arvanitakis.

"We know that years of aging is a recognized risk factor for brain infarcts. In other words, the older you get, the more likely you are to have infarcts in your brain. In this study, we wanted to use something that is well recognized and tangible so people could really understand the effect of blood pressure on the brain, so we used aging."

A 1-unit-faster decline in the slope of SBP increased the odds of having at least one infarct by 20% (OR, 1.20; 95% CI, 1.03 - 1.39).

Other analytic models showed that the mean and slope of SBP were associated with increasing odds of having more gross infarcts and more micro-infarcts.

The slope of SBP was associated with cortical infarcts, and the mean SBP with subcortical infarcts.

Weaker Relationship to DBP

As for DBP, the relationship to infarcts was weaker and less consistent compared than that seen with SBP. A 1-SD increase from the mean DBP value was associated with a 28% increased odds of any infarct (OR, 1.28; 95% CI, 1.09 - 1.50), but the slope in DBP was not associated with infarcts.

The mean DBP was associated with gross infarcts, and both the mean DBP and slope were associated with micro-infarcts.

Regional outcomes showed only an association of mean DBP with subcortical pathology.

The investigators also found that the mean SBP was associated with higher severity of atherosclerosis (OR, 1.95; 95% CI, 1.66 - 2.29). There was a borderline relation with the declining slope of SBP with higher severity grades (P = .0507).

For arteriosclerosis, the mean SBP was associated with higher severity (OR, 1.23; 95% CI, 1.05 - 1.43), but there was no association with the slope of SBP.

Again, results with DBP were less consistent. The mean and slope of DBP were associated with atherosclerosis but not arteriolosclerosis.

The researchers uncovered an association between higher mean SBP and more neurofibrillary tangles (P = .038) but no relationship between SBP slope of change and tangles.

There was also no relationship between mean or slope of SBP and other AD pathology, including amyloid plaques, or between mean and slope of DBP and AD neuropathology.

"We found more relationships with systolic blood pressure than with diastolic blood pressure, not only on different infarcts but also on the Alzheimer's disease pathology," said Arvanitakis.

BP Important Across the Lifespan

The finding that blood pressure is related to neurofibrillary tangles "opens the door" for more research, she said.

"It certainly speaks to the fact that there might be differential relationships of blood pressure on pathology because we didn't find it with all types of pathology, only with tangles."

Researchers conducted additional analyses controlling for APOE ε4, history of hypertension, use of antihypertensive medication, vascular risk factors, and vascular diseases. The associations of SBP and DBP with any infarct and with neurofibrillary tangles were essentially unchanged.

While researchers have long known that blood pressure is important for cardiovascular and brain health, this new study emphasizes the importance of blood pressure "across the life course and not just at mid-life," said Arvanitakis.

And it's not just mean blood pressure but also changes in blood pressure that affect the brain, she added.

"Even if the number is in the normal range, but it's declining over time, so say you have systolic blood pressure that's in the 120s, but it's declining over the years little by little, that's not good for your brain either."

It could be that the body becomes used to a slightly elevated blood pressure and has difficulty coping with even a small change.

"If you go for many, many years with a certain level of blood pressure and then it starts declining, your brain might not have the same tools as when you were younger to compensate for that, and make sure you're getting an adequate amount of oxygen or other things that are important for brain health," said Arvanitakis.

The findings need to be replicated, so it's "premature" to change blood pressure cutoffs for the elderly, she said.

"We need to stick with the published blood pressure guidelines for now. We will have to discover more before we can make tweaks to those recommendations."

Arvanitakis and colleagues are already working on follow-up research looking at the effects of blood pressure on cognitive function in the same cohort.

"We know that both infarcts and Alzheimer's disease are associated with cognitive impairment and dementia, and so we need to figure out the effects of the level of blood pressure, as well as changes in blood pressure, later in life on cognitive function."

Researchers did not have access to information on participants' blood pressure in middle age. Another study limitation was that blood pressure information was recorded only once a year.

Filling a Research Gap

Commenting on the study for Medscape Medical News, Eliezer Masliah, MD, a neuropathologist and the director, Division of Neuroscience, National Institute on Aging, Bethesda, Maryland, said it "fills a gap" in the field.

"This is important information that people have been talking about for a while, but we really didn't have these kind of data."

He described the size of the new series as "remarkable" and "by far" the largest to date. What's also "extraordinary," said Masliah, is that all the cases had postmortem confirmation of pathology.

In addition to diffuse and neuritic plaques and neurofibrillary tangles, Masliah said it would be interesting to see how other neurobiological markers are related to blood pressure.

Among the markers he's interested include α-synuclein protein and TAR DNA-binding protein 43 (TDP-43), which have been linked to the pathology of various neuropsychiatric disorders.

In future studies, it would be interesting to see whether there is any relationship with these other pathologies. It's also important to determine whether there's a relationship with cerebrovascular amyloid, said Masliah.

"I would like to know the relationship between blood pressure and amyloid, not only outside of the cells but around the vessels," he said.

Highly Generalizable

Also commenting for Medscape Medical News, Pinky Agarwal, MD, a neurologist in Kirkland, Washington, and fellow of the American Academy of Neurology, noted that this large prospective study has "high internal validity" because it used autopsy data.

In addition, the study has "high generalizability" because it was community-based.

However, she added that information on subgroup analysis, such as by race and occupation, would have improved the study's generalizability.

"Clinically, this study has implications for optimizing both systolic and diastolic blood pressure and for avoiding aggressive lowering of systolic blood pressure in hypertensive patients," said Agarwal.

A limitation of the study is that it's unclear how many patients with neurofibrillary tangles on autopsy had clinical features of mild cognitive impairment or AD, she added.

Furthermore, in addition to hypertension and medications, the role of other vascular factors on autopsy findings needs to be evaluated, she said.

The study was funded by the National Institutes of Health. Arvanitakis, Masliah, and Agarwal have disclosed no relevant financial relationships.

Neurology. Published online July 11, 2018. Abstract

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