Objective: To estimate whole-brain microinfarct burden from microinfarct counts in routine postmortem examination.Methods: We developed a simple mathematical method to estimate the total number of cerebral microinfarcts from counts obtained in the small amount of tissue routinely examined in brain autopsies. We derived estimates of total microinfarct burden from autopsy brain specimens from 648 older participants in 2 community-based clinical-pathologic cohort studies of aging and dementia.Results: Our results indicate that observing 1 or 2 microinfarcts in 9 routine neuropathologic specimens implies a maximum-likelihood estimate of 552 or 1,104 microinfarcts throughout the brain. Similar estimates were obtained when validating in larger sampled brain volumes.
Conclusions:The substantial whole-brain burden of cerebral microinfarcts suggested by even a few microinfarcts on routine pathologic sampling suggests a potential mechanism by which these lesions could cause neurologic dysfunction in individuals with small-vessel disease. The estimation framework developed here may generalize to clinicopathologic correlations of other imaging-negative micropathologies. Neurology Cerebral microinfarcts are defined as ischemic infarctions, located anywhere in the brain, identifiable by microscopic but not visual inspection.1-3 In practice, these "invisible" lesions are typically less than 1-2 mm in diameter, and therefore smaller than the 3-15 mm diameters characteristic of lacunar infarcts.4,5 As a result, microinfarcts cannot be seen by either conventional structural neuroimaging or gross evaluation of brain slices. They are instead most commonly detected by microscopic examination of routinely selected brain sections, 2,6 or possibly as small acute infarcts on diffusion-weighted imaging (DWI) MRI. 7,8 Despite their small size, microinfarcts appear to be associated with dementia even after controlling for other neuropathologies (including macroscopic infarcts), 2,6 suggesting that microinfarct burden may be an important link between small-vessel disease and cognitive impairment.A crucial step in assessing the mechanism by which microinfarcts impact neurologic function is to determine their total burden in the brain. Microscopic sampling of the entire brain is not feasible, however. As a step toward overcoming this limitation, we present a simple method for estimating the total number of microinfarcts in the brain based on lesion counts obtained from routinely selected autopsy sections. Our findings suggest that the presence of even 1 or 2 microinfarcts in limited samples of brain tissue indicates a likely overall burden of hundreds of these small lesions.METHODS Data for this study were obtained from brain samples of 648 deceased and autopsied participants of the Rush Religious Orders Study and Memory and Aging project, 2 community-based clinical-pathologic cohort studies of aging and dementia (mean age at death 5 88.3 years, SD 5 6.6; 222 men, 426 women).9 Details of recruitment, clinical evaluation, cognitive tes...