Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 37, Issue 11, Pages 3599-3614Publisher
SAGE PUBLICATIONS INC
DOI: 10.1177/0271678X16685573
Keywords
Microinfarcts; microcirculation; neurovascular coupling; two-photon microscopy; vascular cognitive impairment
Categories
Funding
- NINDS [NS085402]
- Dana Foundation
- South Carolina Clinical and Translational Institute [UL1TR000062]
- Institutional Development Award (IDeA) from the NIGMS [P20GM12345]
- MUSC MSTP [NIH T32 GM08716]
- South Carolina Clinical & Translational Research (SCTR) Institute [NIH - NCATS UL1 TR001450, NIH - NCATS TL1 TR001451]
- F30 award [1F30NS096868]
- Office Of The Director
- Office of Integrative Activities [1539034] Funding Source: National Science Foundation
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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 invivo 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 invivo 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.
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