10 February 2012. Sometimes what you don’t know can hurt you. In a small pilot study of people with dementia, those who had occasional small clots of solid material flowing through their cerebral arteries declined nearly twice as fast on several cognitive measures over a two-year period as people without such specks. This result is notable because these particles, called emboli, are a silent, asymptomatic marker of heart disease, and are potentially preventable with treatment. Researchers led by Nitin Purandare at the University of Manchester, U.K. (now at the Universities of Exeter and Plymouth), conducted the study, which is the first to look at the role of emboli in dementia progression. The data were published online December 2, 2011, in the American Journal of Psychiatry. Though preliminary, the findings help tighten the connection between cardiovascular health and dementia, and suggest that vascular disease might be a promising target for therapies. Meanwhile, in the February 1 Journal of Neuroscience, researchers led by Markus Rudin at the University of Zurich, Switzerland, describe the use of a high-resolution imaging technique to evaluate the health of small brain blood vessels in live AD mice. This technology may help researchers better monitor vascular pathology and evaluate the effects of drugs on blood vessels, the authors suggest.
Numerous epidemiological studies have tied cardiovascular risk factors (such as hypertension, diabetes, and obesity) to increased risk of dementia. Atherosclerosis is higher in AD brains than in healthy elderly brains (see Roher et al., 2011), and most cases of AD involve at least some vascular pathology. Yet not much is known about how vascular issues may contribute to the progression of dementia. To look at this issue, Purandare and colleagues recruited 144 dementia patients; 84 were diagnosed with AD and 60 with vascular dementia by geriatric psychiatrists using criteria from the National Institute of Neurological Disorders and Stroke.
The researchers used transcranial Doppler ultrasonography to monitor participants’ middle cerebral arteries in sessions lasting one hour, conducted every six months for two years. In about 40 percent of the participants, emboli would occasionally pass through the arteries. Emboli may represent pieces that break off from atherosclerotic plaques, or tiny blood clots, Purandare said. Emboli were equally common in people with AD and in those who had vascular dementia. Although the experiment did not include a control group, in previous work the authors found that emboli occur in only about 15 percent of age-matched, non-demented controls (see ARF related news story).
The researchers tested volunteers with several measures of cognitive and functional decline, including the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog), the Mini-Mental State Examination, the Interview for Deterioration in Daily Living Activities in Dementia, and the Neuropsychiatric Inventory. Over the two-year timeframe, people who had emboli deteriorated more than twice as fast on these scales as did participants without emboli, with the difference in neuropsychiatric scores being particularly dramatic. Again, participants with AD and vascular dementia were indistinguishable. One limitation of the study is that about one-third of the volunteers dropped out before the end, which could potentially have biased the results, the authors note. Also, in emboli-positive patients, the average number of emboli detected in one session was about two, a low number that did not allow the researchers to measure a dose effect.
Although the results need to be repeated in larger studies, Purandare suggested that emboli are “potentially a novel risk factor, or at least a risk marker, for progression of dementia.” It is not yet clear if emboli cause rapid cognitive decline, or merely correlate with it. It is possible that poor cardiovascular health leads to both. Purandare suggests that emboli might, however, directly affect brain health. For example, these tiny chunks of matter may get stuck in small blood vessels, leading to local ischemia that kicks up inflammation in the surrounding brain tissue. “What might be happening in dementia is that a small number of emboli don’t cause any symptoms immediately, but, over years, could lead to progressive damage,” Purandare speculated. In animal models, induced emboli have been shown to lead to β amyloid accumulation and increased hyperphosphorylated tau around brain blood vessels (see Han et al., 2008).
Purandare noted that several medications exist that may control emboli, such as the anti-platelet drug clopidogrel bisulfate (Plavix), anticoagulant drugs like warfarin, or even statins and other drugs that reduce atherosclerosis. Purandare is currently conducting a pilot study to see if clopidogrel plus a statin can reduce the number of emboli in people with dementia. If so, he would like to follow that up with a larger, longer-duration study to see if that combination slows dementia progression. Another important question to address is whether the presence of emboli in cognitively normal people increases the risk of getting dementia, he added.
Other scientists with whom ARF spoke found the paper intriguing. “This is a very clever study,” said Charlie DeCarli at the University of California, Davis. He pointed out that several studies have shown that microinfarcts in the brain increase the risk of dementia and the severity of symptoms (see Launer et al., 2011; Arvanitakis et al., 2011; Kövari et al., 2007). Microinfarcts are tiny regions of dead tissue that occur when blood supply is cut off by obstructed capillaries. “It may be that emboli and microinfarcts are related to each other. If we could prevent those microinfarcts, I think we could improve the course of the dementia,” DeCarli suggested.
Claudia Kawas at the University of California, Irvine, who runs the 90+ Study that looks for factors associated with longevity and health, noted that rates of decline in AD show incredible variability, and researchers still do not know why. “This [paper] suggests there are some things that are potentially modifiable that might make a difference,” she told ARF. Kawas pointed out that most cases of dementia are mixed, with vascular dementia quite common in AD, suggesting that cardiovascular issues should get more attention in AD research.
In the second paper, Rudin and colleagues describe a technique that may help researchers study the brain’s microvasculature. First author Jan Klohs wanted to examine vascular pathology in the arcAβ mouse, specifically to look for signs of cerebral amyloid angiopathy (CAA) in small blood vessels. This animal overexpresses APP containing the Arctic and Swedish mutations, and is known to develop numerous cerebrovascular problems (see Knobloch et al., 2007). The clinically established technique for visualizing cerebral vasculature is time-of-flight magnetic resonance angiography (TOF-MRA). However, because this technique requires high blood flow to get good contrast, it is only useful for imaging large blood vessels. The authors saw no abnormalities in blood flow in the arcAβ animals using this technique, Klohs told ARF.
Klohs and colleagues therefore turned to contrast-enhanced magnetic resonance microangiography (CE-μMRA). This technique records a high-resolution, three-dimensional image before and after administration of a contrast agent to the bloodstream; by subtracting the images, researchers get a detailed view of small blood vessels. With this method, the authors found that two-year-old arcAβ mice had a lower density of small brain blood vessels compared to controls. Histopathology studies revealed that the vessels were still there, but they were clogged with β amyloid deposits and fibrinogen that prevented blood from flowing.
In future work, CE-μMRA will be useful for revealing when vascular changes occur and how they relate to the progression of cognitive deficits, Klohs suggested. It could also monitor the effects of drugs on vasculature in mouse models. Rudin noted that such studies may help researchers disentangle the contribution of vascular and β amyloid pathologies to dementia.
Vincent Marchesi at Yale University, New Haven, Connecticut, wrote to ARF, “The advance in this paper is the technology [that allows researchers] to watch in real time the development of blood vessel damage in living animals, a very important and much needed technology.” He noted that diffuse vascular damage seen in the mouse brain looks remarkably similar to the distribution of vascular damage in elderly human AD brains (Buée et al., 1994). (See full comment below.)—Madolyn Bowman Rogers.
Purandare N, Burns A, Morris J, Perry EP, Wren J, McCollum C. Association of cerebral emboli with accelerated cognitive deterioration in Alzheimer’s disease and vascular dementia. Am J Psychiatry. 2011 Dec 2. Abstract
Klohs J, Baltes C, Princz-Kranz F, Ratering D, Nitsch RM, Knuesel I, Rudin M. Contrast-enhanced magnetic resonance microangiography reveals remodeling of the cerebral microvasculature in transgenic arcAβ mice. J Neurosci. 2012 Feb 1;32(5):1705-13. Abstract