More Evidence Links Arterial Stiffness and Brain Amyloid

Pauline Anderson

March 31, 2014

Evidence is mounting that arterial stiffness may be the driving force connecting hypertension with amyloid accumulation, and eventually cognitive impairment and dementia.

A previous study, published last year in Neurology, showed that arterial stiffness is related to the amount of β-amyloid (Aβ) present in the brain of nondemented elderly patients, independent of blood pressure and use of antihypertensive medications.

Now, another report by the same investigators has shown that arterial stiffness is also strongly associated with the accumulation of Aβ over almost 2 years in these adults.

"It's showing that there's a temporal relationship here in that measuring the arterial stiffness can tell you not just about how much amyloid is there, but also how much it progresses over time," said lead author Timothy M. Hughes, PhD, postdoctoral fellow Wake Forest School of Medicine, Winstom-Salem, North Carolina.

The new study is published online March 31 in JAMA Neurology.

GEMS Study

The study included participants from the Pittsburgh site of the Ginkgo Evaluation of Memory Study (GEMS), a multicenter, placebo-controlled, randomized trial of daily use of Gingko biloba in community-dwelling adults aged 72 to 96 years.

Dr. Timothy M. Hughes

In 2009, 190 nondemented participants underwent brain MRI and positron emission tomography (PET) using Aβ ligands. About 2 years later, researchers measured arterial stiffness in 91 of these participants.

To measure stiffness, researchers used pulse-wave velocity (PWV), or the speed at which pressure spreads through the arteries; when arteries stiffen, PWV increases. They calculated the PWV as the distance (in centimeters) between arterial sites over time (in seconds) that the pressure waveforms traveled from the heart to the respective arterial sites.

Investigators measured PWV in the following vascular beds: central (carotid-femoral [cfPWV], heart-femoral [hfPWV]), peripheral (femoral-ankle [faPWV]), and mixed (brachial-ankle [baPWV]).

Eighty-one participants remained nondemented and returned for a second neuroimaging assessment a mean of 1.8 years later. Whereas at baseline 48% of 91 participants were Aβ positive, 75% of these 81 participants were Aβ positive at this follow-up.

"A lot of things could be going on here," said Dr. Hughes. "Either their brains are handling the amount of amyloid and showing resilience, or they started off doing so cognitively well that we are not seeing them fall below these cutpoints for clinical impairment."

He noted that the cutoffs used in this study were "conservative" and that other studies using different points would find an even higher proportion of amyloid-positive persons.

The study showed that baPWV was significantly higher among Aβ-positive participants at baseline and at follow-up. With this measurement, after adjustments for age, body mass index, and antihypertensive medicine use, each standard deviation increase in stiffness was associated with a very significant increase in the odds of being Aβ positive at follow-up (odds ratio [OR], 4.06; 95% confidence interval [CI], 1.83 - 9.01; P < .001).

The analysis also found that faPWV was higher among Aβ-positive participants at follow-up (OR, 3.64; 95% CI, 1.46 - 9.08; P = .002).

Central arterial stiffness and blood pressure measures were not associated with Aβ status at baseline or follow-up. However, each standard deviation increase in central stiffness was associated with an increase in Aβ deposition over 2 years (cfPWV, P = .001; hfPWV, P = .004).

Better Marker

These results suggest that arterial stiffness, which can arise from the cumulative effect of hypertension and is a common feature of aging, is a better marker of Aβ deposition and accumulation than is blood pressure in elderly patients without dementia.

"From our research, this is more informative than blood pressure alone," said Dr. Hughes. "We feel that arterial stiffness provides something that just measuring blood pressure won't."

However, while blood pressure is checked regularly and hypertension treated with antihypertensive medications, no treatment reverses arterial stiffness, so regularly measuring arterial stiffness may not be useful.

It's thought that as arteries around the heart stiffen, vessels in the periphery lose resistance. "We don't yet know if arteries are stiffening in the periphery — in the heart and kidneys — but they do have to compensate when central stiffness is lost, so they may stiffen up as well," said Dr. Hughes.

Arterial stiffness, he added, is also linked to microvascular damage. His earlier study found that patients with cerebral vascular disease, as indicated by white matter hyperintensities (WMH), also had increased arterial stiffness. Patients with both amyloid deposits and WMH had the greatest arterial stiffness, supporting the idea that arterial stiffness is independently related to both of these risk factors.

Several hypotheses may explain how arterial stiffness causes cognitive decline, all of which should be tested, said Dr. Hughes. One of the top theories is that vascular stiffness changes the blood flow in the brain and may affect amyloid clearance from there.

One of the next items on his research agenda is to investigate whether arterial stiffness in younger people (in their fifties) will predict amyloid deposition over the following few years, said Dr. Hughes.

Important Insights

In an accompanying editorial, Kevin S. King, MD, Department of Radiology, University of Texas Southwestern Medical Center, Dallas, said the study provides "some important insights" into understanding the relationship between hypertensive insult and Aβ deposition.

"Of practical importance, measures of arterial stiffness in the study by Hughes et all show statistically significant associations with Aβ of a magnitude that also appears clinically relevant. Conversely, traditional blood pressure measurements show at best marginal statistical associations," Dr. King writes.

Given the new findings, "we can better appreciate potential contributions to Aβ positivity and progression as direct links between arterial stiffness from particular vascular trees and Alzheimer's dementia," he said.

Dr. King concluded that the study demonstrates that arterial stiffness is a useful marker of risk for predicting Aβ positivity and progression and that this risk predictor is an improvement over traditional risk factor models.

Research evaluating the processes underlying these associations "may improve our understanding of how arterial pulsatility damages the brain and perhaps lead to new therapeutic approaches," he writes.

The study was supported by grants from the National Institutes of Health. Dr. Hughes and Dr. King have disclosed no relevant financial relationships.

JAMA Neurol. Published online March 31, 2014.


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