Functional deficits induced by cortical microinfarcts

Abstract

Clinical studies have revealed a strong link between increased burden of cerebral microinfarcts and risk for cognitive impairment. Since the sum of tissue damage incurred by microinfarcts is a miniscule percentage of total brain volume, we hypothesized that microinfarcts disrupt brain function beyond the injury site visible to histological or radiological examination. We tested this idea using a mouse model of microinfarcts, where single penetrating vessels that supply mouse cortex were occluded by targeted photothrombosis. We found that in vivo structural and diffusion MRI reliably reported the acute microinfarct core, based on spatial co-registrations with post-mortem stains of neuronal viability. Consistent with our hypothesis, c-Fos assays for neuronal activity and in vivo imaging of single vessel hemodynamics both reported functional deficits in viable peri-lesional tissues beyond the microinfarct core. We estimated that the volume of tissue with functional deficit in cortex was at least 12-fold greater than the volume of the microinfarct core. Impaired hemodynamic responses in peri-lesional tissues persisted at least 14 days, and were attributed to lasting deficits in neuronal circuitry or neurovascular coupling. These data show how individually miniscule microinfarcts could contribute to broader brain dysfunction during vascular cognitive impairment and dementia.

Detection, risk factors, and functional consequences of cerebral microinfarcts

“…56–62 Penetrating arterioles have emerged as a key locus for occlusion, because unlike the interconnected pial and capillary systems, blood flow through a penetrating arteriole cannot be efficiently re-routed around a localised clot. 63 Cerebral microinfarcts induced in rodents show remarkable similarity to human cerebral microinfarcts, with respect to their range of shapes, size, and location, and their temporal evolution (figure 4).…”

“…For example, the core of a cerebral microinfarct in an animal model becomes packed with microglia and is surrounded by reactive astrocytes, which is also observed in cerebral microinfarcts in human beings. 56 …”

“…These deficits involved persistent alterations in neuronal circuitry, observed by displacement and disorganisation of sensorimotor maps. 72 A study published in 2017 56 estimated that a single cerebral microinfarct, with a mean lesion core of 0·2 mm 3 in volume (approximately 0·5 mm in diameter), could impair neuronal function over cortical regions at least 12 times larger in size than the lesion core. However, this calculation is likely to be an underestimate because cerebral microinfarcts in both grey and white matter can also disrupt neighbouring fibres of passage, with demyelination and damage of axonal structure.…”

“…Evidence supports delayed, selective neuronal loss (5–10% decrease), 58 thinning of dendritic processes, and reduced dendritic spine density. 56,59 Non-neuronal changes include widespread astrogliosis, reduced expression of aquaporin 4, and myelin loss. 56,58,59,61,75 Blood–brain barrier disruption is also evident on the basis of extravasation of plasma proteins and nitrosative stress at the capillary walls.…”

“…56,59 Non-neuronal changes include widespread astrogliosis, reduced expression of aquaporin 4, and myelin loss. 56,58,59,61,75 Blood–brain barrier disruption is also evident on the basis of extravasation of plasma proteins and nitrosative stress at the capillary walls. 61,73 One striking manifestation of this pathology is the coalescence of isolated cerebral microinfarcts into larger contiguous infarcts when their perilesional zones begin to overlap.…”