Damage to the walls of the smallest blood vessels of the brain correlates with future cognitive deterioration, report scientists in the June 6 JAMA Neurology online. Among thousands of volunteers who all started out cognitively normal, those who had cerebral microbleeds declined sooner on cognitive tests and were likelier to later receive a dementia diagnosis than people who didn’t have those lesions, according to researchers led by Meike Vernooij, Erasmus MC University Medical Center Rotterdam, The Netherlands. The results imply that people with microbleeds, an imaging marker of small vessel disease, are at higher risk for dementia, and strengthen the notion that cerebrovascular problems contribute to the pathogenesis of Alzheimer’s, said first author Saloua Akoudad.
“The large number of patients and long duration of follow-up make this a well-powered study,” said Wiesje van der Flier, VU University Medical Center, Amsterdam.
Cerebral microbleeds, visible in magnetic resonance imaging, mark the spots where tiny brain hemorrhages occurred. Clusters of hemosiderin-laden macrophages stick around after sopping up the blood and patch up ruptured vessel walls, appearing as small black dots (see image at left). Microbleeds occur in 11 to nearly 40 percent of older adults and signify that the walls of small blood vessels have weakened (Vernooij et al., 2008; Sveinbjornsdottir et al., 2008). It is generally thought that microbleeds in the frontal, temporal, parietal, and occipital lobes result from amyloid depositing in blood vessels there; bleeds in the deep white matter seem to stem from hypertension, diabetes, or smoking (for a review, see Martinez-Ramirez et al., 2014).
Previous studies suggest that microbleeds are associated with cognitive impairment, measured in lower MMSE scores and declining performance in particular cognitive domains (Meier et al., 2014; Poels et al., 2012; Qiu et al., 2010). However, in people who already have dementia, these lesions have no effect on how fast a patient’s cognition declines further (van der Vlies et al., 2012). Scientists have yet to examine whether cognitively healthy people who have microbleeds are at greater risk of dementia down the road, and whether that depends on how many of these lesions are there and where in the brain they appear.
To find out, Akoudad and colleagues did a prospective analysis within the Rotterdam Study, a large ongoing project in the Netherlands that examines risk factors for cardiovascular, endocrine, ophthalmological, and neurologic diseases. The researchers included data from 4,841 cognitively healthy middle-aged and elderly people, average age 64, who had an MRI scan at baseline. Every person was followed via cognitive assessments and/or medical records. A subset of 3,257 people took a neuropsychological test battery at baseline and about six years later. It assessed changes in information processing, motor speed, executive function, and memory.
For participants who took baseline and follow-up cognitive tests, having more than four microbleeds associated with decline. That suggests the number of microbleeds, which presumably correlates with the severity of small vessel disease, is important for cognitive decline, Akoudad told Alzforum. If these lesions were in lobar regions, the decline was in information processing, memory, and executive function. Deep microbleeds predicted slowing motor speed.
During the follow-up period, 72 people were diagnosed with dementia, 53 of whom had AD. Having microbleeds in any part of the brain doubled a person’s risk of dementia, though the association weakened, then lost significance, after adjusting for ApoE4 and cardiovascular risk factors. Nevertheless, the overall data suggest that for dementia, the location of microbleeds makes no difference, said Akoudad. This, in turn, implies that any cause of small vessel disease—be it cerebral amyloid angiopathy, hypertension, or diabetes—raises the dementia risk.
The finding of higher dementia risk regardless of where the microbleeds were intrigued van der Flier. Last year, she reported that among AD patients, lesions in lobar vs. non-lobar regions associated with different outcomes, i.e., increased risk for stroke or cardiovascular events, respectively (Mar 2015 news). Van der Flier noted that the risk elevation for dementia is small in this relatively healthy population, and not significant when adjusted for related risk factors.
The result needs to be replicated before it can be considered robust, conceded Akoudad, who would also like to repeat the baseline MRI scan to see how small vessel disease progressed relative to dementia.
“The association between microbleeds and Alzheimer's disease is unexpected,” wrote Joe Verghese, Albert Einstein College of Medicine, Bronx, New York, to Alzforum. “These findings lend support to vascular causes of Alzheimer's disease.” In a cross-sectional study based in India, Verghese saw no association between microbleeds and a pre-dementia state, though he did find a correlation with lacunar infarctions, another type of cerebral small vessel disease (Wang et al., 2016). Most of these studies have been conducted in Western populations, he said, and there may be regional or ethnic differences in the types of cerebral small vessel diseases and their association with cognition.
In an accompanying editorial, Philip Gorelick and Muhammad Farooq of Michigan State University, Grand Rapids, called the study well-executed. They noted that the new data raises questions about the safety of using drugs that reduce blood clots and can increase bleeding to prevent stroke in people who have cerebral microbleeds. The current study does not examine whether such treatment affects the rate of dementia.—Gwyneth Dickey Zakaib
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