Estimating cerebral microinfarct burden from autopsy samples

Abstract

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...

The Spectrum of MR Detectable Cortical Microinfarcts: A Classification Study with 7-Tesla Postmortem MRI and Histopathology

“…A recent study showed that observing one or a few CMIs on standard histopathologic examination is indicative for hundreds or even thousands of CMIs throughout the whole postmortem brain. 25 Probably, the observation of one or a few CMIs on in vivo MRI could indicate the presence of more smaller CMIs.…”

Ischemic brain injury in cerebral amyloid angiopathy

“…59,60 Furthermore, DWI lesions in the white matter have found to cause chronic local microstructural injury. 62 The fact that these DWI lesions are a frequent finding in CAA despite the short time window in which they remain visible has led to the belief that they are the most prevalent of all infarct types 10,61,63 and therefore may have a substantial impact on cognitive functioning. 12,[64][65][66] The hypothesis that microinfarcts occur in large numbers in patients with CAA is supported by a recently developed mathematical model used to estimate the total microinfarct burden based on the number of microinfarcts found on routine postmortem examination.…”

“…12,[64][65][66] The hypothesis that microinfarcts occur in large numbers in patients with CAA is supported by a recently developed mathematical model used to estimate the total microinfarct burden based on the number of microinfarcts found on routine postmortem examination. 63 The model predicted that one or two microinfarcts on routine postmortem examination of an autopsied brain indicate hundreds to thousands of microinfarcts throughout the whole brain. The cumulative effect of these microinfarcts on the brain forms therefore a potential mechanism through which CAA can contribute to vascular cognitive impairment.…”

“…Recent radiologic-pathologic studies have shown that microinfarcts of approximately 1 to 2 mm can be detected on 3-and 7-Tesla in vivo MRI scans ( Figure 1C). 67,68 However, microinfarcts can be as small as 100 microns, 54,63 thus a large proportion of these lesions remain invisible on brain imaging. 10 The rapid development of imaging techniques and optimization of T1-and T2*-weighted MRI sequences, both on 7 Tesla and on lower field strength MRI, makes it likely that we will be able to quantify smaller lesions in vivo in the near future.…”

Microinfarct disruption of white matter structure

“…2 These numbers suggest that CMIs may substantially affect neurologic function, a possibility supported by clinical-pathologic studies. [3][4][5][6] It remains unclear, however, whether such tiny lesions (typically ,1-mm diameter 1 ) are capable of disrupting brain structure.…”