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Arterial Stiffness May Be an Indicator of Brain Amyloid Accumulation

Fitzgerald, Susan

doi: 10.1097/01.NT.0000449805.75263.61
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In a new study, researchers reported that arterial stiffness was strongly associated with the progression of amyloid-beta (Abeta) over a two-year period and may be a better indicator of Abeta deposition and accumulation than high blood pressure in older persons.

Arterial stiffness may be a good predictor of whether a person is experiencing a buildup of amyloid-beta (Abeta) in the brain, according to a new Alzheimer's disease study that involved nondemented elderly people.

The study found that arterial stiffness was strongly associated with the progression of Abeta over a two-year period and may be a better indicator of Abeta deposition and accumulation than high blood pressure in older persons.

The study, published March 31 in the online edition of JAMA Neurology, adds to the growing body of evidence that cardiovascular health and brain health are interconnected.

“Arterial stiffness is likely a driving factor connecting hypertension, cerebrovascular disease, and Abeta deposition in the brains of nondemented older adults,” the study authors concluded.

The study's lead author, Timothy Hughes, PhD, MPH, who is currently a post-doctoral scholar at Wake Forest School of Medicine's department of internal medicine but conducted the research when he was at the University of Pittsburgh, told Neurology Today that arterial stiffness seems to be “an especially strong predictor of Abeta deposition — stronger than age, blood pressure, and inflammatory markers.”

He said the latest findings may offer another reason for patients to follow a heart-healthy lifestyle by watching their weight, exercising, and keeping their blood sugar and blood pressure in line, especially in middle age when arterial stiffness begins to progress.

“If we can start to change that message to say, ‘This will help you not get dementia, this will protect your brain,’ maybe people will start to listen,” Dr. Hughes said.

Previous research has shown a link between hypertension and pathologic features of Alzheimer's disease (plaques and tangles), cerebrovascular disease, and white matter hyperintensities in the brain, according to background information in the study.

“Arterial stiffness appears to play a major role in the relationship between hypertension and its consequences in the brain,” the study authors, who included researchers from the University of Pittsburgh, wrote. “Mounting evidence implicates arterial stiffness in the pathogenesis of brain aging, cerebrovascular disease, impaired cognitive function, and dementia in the elderly.”

The same research team from the University of Pittsburgh reported last year in Neurology that greater arterial stiffness was associated with the amount of Abeta in the brain. In this study, the researchers analyzed the connection between arterial stiffness and Abeta accumulation over time.

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The current study drew on data collected from participants in the Ginkgo Evaluation of Memory Study, a multicenter study that tested the use of ginkgo biloba in people, ages 75 to 96, who lived in the community. (That study found that taking a gingko supplement did not prevent dementia or Alzheimer's disease.) As an extension to that study, the University of Pittsburgh, a participating center, conducted brain magnetic resonance imaging (MRI) and PET scans in 2009 on 190 participants. In 2011, 91 of the nondemented participants underwent testing to measure arterial stiffness and 81 of those who remained nondemented underwent a second round of brain imaging in 2010–2012.

Arterial stiffness was measured by pulse wave velocity (PWV) using a noninvasive and automated waveform analyzer, according to the published report. PWV is essentially a measure of the time it takes each pulse to travel from the heart to two measured points. The stiffer the arteries are, the faster the pulse waves travels. In this study, PWV was measured in the central (carotid-femoral and heart-femoral), peripheral (femoral-ankle), and mixed/systemic (brachial-ankle) vascular beds.

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Among the findings, the proportion of Abeta-positive individuals, by measure of PET scans, increased from 48 percent at baseline to 75 percent at the two-year follow-up; brachial-ankle PWV was significantly higher among Abeta-positive participants at baseline PET and follow-up. Each standard deviation increase in the PWV measure was associated with a several-fold increase in the odds of being Abeta positive at follow-up; and femoral-ankle PWV was only higher among participants who were Abeta-positive on follow-up PET scans.

Measures of central stiffness and blood pressure were not associated with Abeta status at baseline or follow-up PET scans, but central stiffness was only associated with a change in Abeta deposition over time.

“Each standard deviation increase in central stiffness…was linked with increases in Abeta deposition over 2 years,” the researchers reported.

“Taken all together, central stiffness may be the driving factor in Abeta deposition, or accumulation over time; whereas, systemic and peripheral arterial stiffness better represents the extent of Abeta deposition, now and before,” Dr. Hughes said. “Peripheral arteries must compensate for the increased central stiffness and pressure; therefore, peripheral measures may represent the ability to compensate for central stiffness. If that is true, those with stiffer arteries have less ability to compensate and protect the vital end organs, like the brain.”

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The researchers noted that in other studies of older adults, blood pressure tends to fall as people get older, making it less of a reliable predictor of dementia risk in late life.

“While systolic and diastolic measures of blood pressure may decline late in life, there is evidence that arterial stiffness increases without reversion across the age range,” the researchers noted.

The underlying mechanism that may connect arterial stiffness and amyloid buildup is not clear, the researchers noted, though they offered possible explanations. For one, “it is possible that increased arterial stiffness has a direct influence on penetrating arterioles of the brain, leading to altered structure and function, with subsequent effects on Abeta clearance from the brain.”

The study had limitations, as the researchers noted. It was a relatively small study, and measures of arterial stiffness were only in 2011, at the point of the follow-up brain scans.

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Philip B. Gorelick, MD, FAAN, a professor of translational science and molecular medicine at Michigan State University College of Human Medicine, told Neurology Today “the findings are of great interest but should be validated in other elderly patent populations.” He added that, “as the authors suggested, it would be useful to have baseline measures to determine changes in arterial stiffness.”

While the findings are bound to interest researchers, the clinical implications are not yet clear. Dr. Gorelick pointed out, for instance, that if it turns out to be proven that arterial stiffness causes microvascular damage well before old age, there might be a point in time along the lifespan when “blood pressure-lowering therapy may no longer be an effective treatment for preservation of cognitive vitality.”

Measuring arterial pressure is not done as part of routine medical care, though Anand Viswanathan, MD, PhD, assistant professor of neurology at Massachusetts General Hospital and Harvard Medical School, said he could envision a day when doctors would have at their disposal a quick and easy test to measure arterial stiffness.

If the results from this study are further validated, such a test might eventually serve to help identify people at increased risk for dementia or Alzheimer's disease.

“Further research is needed before we take these findings to the clinic,” Dr. Viswanathan said.

In the meantime, researchers are busy studying multiple connections between cardiovascular risk factors and Alzheimer's disease.

Sudha Seshadri, MD, FAAN, a professor of neurology at Boston University and a senior investigator for the Framingham Heart Study, said that keeping blood pressure under control, and in turn preventing arterial stiffness in people in their 40s, 50s, and 60s, is probably even more critical for maintaining good cognition than controlling blood pressure late in life.

She said limiting cumulative lifetime exposure to high blood pressure is also key. The Framingham team is now studying third-generation participants in the Framingham Heart Study to explore the mid-life connection between arterial stiffness and brain function. They reported last year in Neurology on data collected from second-generation participants who were, on average, 61 years old. That analysis found that persons with higher measures of arterial stiffness were more likely on MRI scans to show evidence of reduced cerebral brain volume, white matter hyperintensities, and silent infarctions; and tests also showed they had some memory deficits.

Lenore J. Launer, PhD, chief of the Neuroepidemiology Section of the Intramural Research Program at the National Institute on Aging, said the latest findings “are another indication that blood pressure, directly or indirectly, needs to be taken into consideration when we think about how we are going to mitigate the Alzheimer's problem, the dementia problem.”

She said her team's research suggests that 27 percent of cases of dementia could be prevented if persons with untreated blood pressure (systolic pressure of greater or equal to 120 mm Hg) in midlife brought it under control.

“High blood pressure in mid life is absolutely preventable,” Dr. Launer said. “When it comes to Alzheimer's prevention efforts, this is the first place to start.”

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•. Hughes TM, Kuller LH, Barinas-Mitchell EJM, et al. Arterial stiffness and beta-amyloid progression in nondemented elderly. JAMA Neurol 2014; E-pub 2014 March 31.
•. Tsao CW, Seshadri S, Beser AS, et al.. Relations of arterial stiffness and endothelial function to brain aging in the community. Neurology 2013; 81(11):984–991.
•. Hughes TM, Kuller LH, Barinas-Mitchell EJM, et al. Pulse wave velocity is associated with β-amyloid deposition in the brains of very elderly adults. Neurology 2013;81(19):1711–1718.
•. The Ginkgo Evaluation of Memory Study:
© 2014 American Academy of Neurology