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doi: 10.1097/01.NT.0000429373.24141.11
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The Potential Cumulative Effect of 1000 Small Lesions on the Brain

Fitzgerald, Susan

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ARTICLE IN BRIEF

Investigators used a unique mathematical model to estimate the cerebral microinfarct burden from autopsied brains, finding that even one or two microinfarcts may indicate the presence of hundreds to thousands of these lesions in the entire brain.

A mathematical model developed in concert with data from autopsies on the brains of more than 600 elderly participants in long-term dementia studies found that while only a couple of microinfarcts might be indentified under the microscope, there are likely hundreds or more of these tiny lesions throughout the brain.

The estimated numbers lend support to prior research that suggested that microinfarcts may play an important role in cognitive decline.

“The key conclusion from this analysis is that observing even 1 or 2 microinfarcts in routinely sampled sections of brain may indicate the presence of hundreds to thousands of these lesion in the entire brain,” according to the report in the Mar. 13 online edition of Neurology.

“If confirmed by further histopathological studies, the high estimated total infarct burden described here would support the hypothesis that these lesions are major contributors (rather than simply surrogate markers or bystanders) to small vessel disease-related cognitive impairment.”

Researchers studying the causes of dementia are becoming increasingly interested in the role of microinfarcts, tiny ischemic infarcts that aren't apparent on conventional MRI exams or during a visual inspection at autopsy.

Figure. DR. JULIE A....
Figure. DR. JULIE A....
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The study, by researchers at Harvard Medical School and Rush University Medical Center, involved creating a mathematical model based on microscopic analysis of brain tissue samples from 648 persons who had participated in either the Rush Religious Orders Study or the Memory and Aging Project, two community-based clinical-pathological cohort studies based at Rush that are examining factors of aging and dementia. The study volunteers, who were on average just over 88 years old at death, had agreed to donate their brains for study when they died.

In an e-mail, Dr. Schneider noted that that the research team had earlier done an analysis of microscopic infarcts — in a 2011 paper in Stroke — involving 425 participants in the Religious Orders Study — 192 had dementia and 233 did not. In the current study, though, she said they didn't account for how many participants had dementia.

According to background information on microinfarcts in the study, “these ‘invisible’ lesions are typically less than 1 to 2 mm in diameter, and therefore smaller than the 3 to 15 mm diameters characteristic of lacunar infarcts.” But the small lesions may have an overall burden that is detrimental to the brain. “Despite their small size, microinfarcts appear to be associated with dementia even after controlling for other neuropathologies (including macroscopic infarcts), suggesting that microinfarct burden may be an important link between small vessel disease and cognitive impairment,” the researchers hypothesized.

The 648 cases on which the mathematical model was based involved consecutive autopsies conducted between January 2002 and March 2011. Because it would be nearly impossible to examine the entire brain under the microscope, the researchers set up a protocol in which they analyzed tissue samples taken from nine predetermined sites — the midfrontal cortex, middle/superior temporal cortex, inferior parietal cortex, cingulate cortex, hippocampus, entorhinal cortex, anterior basal ganglia, anterior thalamus and midbrain — to look for microinfarcts. In each case, they counted anywhere from 0 microinfarcts (475 cases) to nine microinfarcts (one case). In 111 cases, one lesion was found.

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AN ESTIMATE OF TOTAL BURDEN

The researchers then applied their mathematical model to estimate the total number of infarcts throughout the brain based on those counts.

“Our results indicate that observing 1 or 2 microinfarcts in 9 routine neuropathological specimens implies a maximum-likelihood estimate of 552 or 1104 microinfarcts throughout the brain,” they reported. “We also note that failure to detect any microinfarcts in routine pathological specimens is still compatible with a >5 percent probability of up to 1653 microinfarcts hiding within the remaining unsampled brain.”

To test the validity of the mathematical model they used to project the total number of microinfarcts throughout the brain, the researchers did even more extensive sampling on two brains, analyzing specimens from 23 regions. In one of those cases, 88 tissue samples were examined under the microscope and in the other case 99 slides were analyzed. The number of microinfarcts identified was 21 and 13 respectively, which the researchers projected would translate into a total brain count of 1,350 and 652 lesions — a range in line with projections from the more limited sampling.

The bottom line: where there is one microinfarct there are likely many.

The researchers acknowledged there were potential problems with their statistical estimates. They assumed, for instance, that microinfarcts are uniformly distributed throughout the brain, though they may in fact be more prevalent in certain regions, such as the basal ganglia and cortex.

“Further, if microinfarcts tend to cluster together rather than occurring independently, this would also tend to undermine our analysis, since finding a single lesion might imply a few neighboring microinfarcts without necessarily implying a large number throughout the brain,” they said.

But the researchers noted that their estimate of hundreds or even thousands of microinfarcts throughout the brain is supported by studies using diffusion-weighted imaging (DWI-MRI), which found a “very high incidence of asymptomatic hyperintense lesions.”

Figure. DR. STEVEN M...
Figure. DR. STEVEN M...
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RISK FACTORS FOR MICROINFARCTS?

The study investigators told Neurology Today that more research is needed to understand the origin of microinfarcts, their relationship to large strokes and their risk factors. Steven M. Greenberg, MD, PhD — professor of neurology at Harvard — who directs hemorrhagic stroke research at the Massachusetts General Hospital Stroke Research Center — said it appears that microinfarcts are “not just innocent bystanders but actually contribute to a patient's level of impairment.” He said they could turn out to be “a bigger contributor to cognitive impairment than clinically recognized strokes.”

Another co-author, Julie A. Schneider, MD, associate professor of neuropathology and neurological sciences at Rush Medical Center, said previous research using brain autopsies has shown that about half of people with microinfarcts also have macroinfarcts, but half don't.

“The significance of micoinfarcts is much greater than previously recognized,” said Dr. Schneider, who is an investigator for the Rush Religious Orders Study and the Memory and Aging Project. “If you have a large stroke, you lose a significant portion of brain tissue. You can imagine that even with microinfarcts, if you have several hundred or a thousand of them, it adds up to something bigger.”

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EXPERTS COMMENT

Claudia Kawas, MD, professor of neurology and neurobiology & behavior at University of California, Irvine, who is not connected to the current study, agreed that microinfarcts warrant more scrutiny by scientists studying cognitive decline and dementia.

“We've been going down the amyloid road for a long time,” said Dr. Kawas, who is the principal investigator for another community-based aging study called The 90+ Study. “We may not be paying attention to other important things right under our nose.”

She said researchers need to look beyond the commonly-accepted risk factors for vascular disease and stroke, such as high blood pressure and diabetes, to determine what other factors might be involved with microinfarcts. She is interested in the possible role of low blood pressure and is writing a grant proposal to examine 24-hour ambulatory blood pressures in non-demented 90+ Study participants. The plan is to see whether low blood pressure during the day or night is related to the development of dementia and cognitive decline and whether it is associated with the prevalence of microinfarcts at autopsy.

“We need to first understand what is the relation of these microinfarcts to cognitive outcome and then we need to understand the risk factors and protective factors and to see if any of them are modifiable,” Dr. Kawas said. She said microinfarcts are probably “kind of like wrinkles. You accumulate them over a lifetime.”

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FOR FURTHER READING:

•. Westover MB, Bianchi MT, Greenberg SM, et al.Estimating cerebral microinfarct burden from autopsy samples. Neurology 2013: E-pub 2013 Mar. 13.
•. The Rush Religious Orders Study: http://bit.ly/127uCOn
•. The Rush Memory & Aging Project: http://bit.ly/MzYT4Q

©2013 American Academy of Neurology

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