Abstract
Cortical microinfarcts (CMIs) are microscopically identified wedge-shaped ischemic lesions that occur at or near the cortical surface and result from occlusion of penetrating arterioles. These microscopic lesions can be observed with high-resolution magnetic resonance imaging in aging brains and in patients with cerebrovascular disease. Recent studies have suggested that strategically located microinfarcts strongly correlate with cognitive deficits, which can contribute to Alzheimer’s disease as well as other forms of dementia. We have recently shown that the molecular organization of axons into functional microdomains is altered in areas adjacent to white matter lacunar and microinfarcts, creating a peri-infarct penumbral injury in surviving axons. Whether similar changes in nodal, adjacent paranodal, and proximal axon initial segment molecular organization occur in the cortex adjacent to human CMIs is not known. Paraffin-embedded sections of autopsy brain tissue from five patients with CMIs were immunofluorescently labeled for nodal and paranodal markers including beta-IV spectrin, ankyrin-G, and contactin-associated protein. High magnification images from the peri-infarct cortical tissue were generated using confocal microscopy. In surviving cortical tissue adjacent to microinfarcts, we observed a dramatic loss of axon initial segments, suggesting that neuronal firing capacity in adjacent cortical tissue is likely compromised. The number of identifiable nodal/paranodal complexes in surviving cortical tissue is reduced adjacent to microinfarcts, while the average paranodal length is increased indicating a breakdown of axoglial contact. This axonal microdomain disorganization occurs in the relative absence of changes in the structural integrity of myelinated axons as measured by myelin basic protein and neurofilament staining. These findings indicate that the molecular organization of surviving axons adjacent to human CMIs is abnormal, reflecting lost axoglial contact and the functional elements necessary for neural transmission. This study provides support for the concept of a microinfarct penumbral injury that may account for the cumulative cognitive effect of these tiny strokes.
Highlights
The pathophysiologic cause(s) of cognitive impairment leading to dementia remains unclear
Age-matched control subjects were identified from the neuropathology database available at our institution
Hematoxylin and eosin staining of each of the Cortical microinfarcts (CMIs) studied is presented in Figure S1 in Supplementary Material, and each demonstrate the classic hallmarks of infarction with a necrotic core, tissue pallor, and an elliptical or wedge-shaped pattern consistent with infarction secondary to occlusion of a penetrating arteriole from the cortical surface
Summary
The pathophysiologic cause(s) of cognitive impairment leading to dementia remains unclear. Accumulations of amyloid-beta, neurofibrillary tangles with hyperphosphorylated tau, selective neuronal loss, as well as poorly classified ischemic brain lesions are all implicated, yet appear to incompletely explain the pathophysiology. In part because of their small size, comparatively little is known about how these lesions might contribute to cognitive decline and dementia. The size of a microinfarct is generally defined as “not visible with the naked eye” or “only visible upon light microscopy,” but the size of a microinfarct is generally accepted as being 50–400 μm and described as gliotic or cystic lesions with neuronal loss and tissue pallor that may occur in all brain regions, the cerebral cortex may be a preferential location [3]. Detailed pathologic analysis of these lesions is critical to understanding how they contribute to cognitive decline
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