Abstract
BackgroundStrokes are becoming less severe due to increased numbers of intensive care units and improved treatments. As patients survive longer, post-stroke cognitive impairment (PSCI) has become a major health public issue. Diabetes has been identified as an independent predictive factor for PSCI. Here, we characterized a clinically relevant mouse model of PSCI, induced by permanent cerebral artery occlusion in diabetic mice, and investigated whether a reliable biomarker of PSCI may emerge from the kynurenine pathway which has been linked to inflammatory processes.MethodsCortical infarct was induced by permanent middle cerebral artery occlusion in male diabetic mice (streptozotocin IP). Six weeks later, cognitive assessment was performed using the Barnes maze, hippocampi long-term potentiation using microelectrodes array recordings, and neuronal death, white matter rarefaction and microglia/macrophages density assessed in both hemispheres using imunohistochemistry. Brain and serum metabolites of the kynurenin pathway were measured using HPLC and mass fragmentography. At last, these same metabolites were measured in the patient’s serum, at the acute phase of stroke, to determine if they could predict PSCI 3 months later.ResultsWe found long-term spatial memory was impaired in diabetic mice 6 weeks after stroke induction. Synaptic plasticity was completely suppressed in both hippocampi along with increased neuronal death, white matter rarefaction in both striatum, and increased microglial/macrophage density in the ipsilateral hemisphere. Brain and serum quinolinic acid concentrations and quinolinic acid over kynurenic acid ratios were significantly increased compared to control, diabetic and non-diabetic ischemic mice, where PSCI was absent. These putative serum biomarkers were strongly correlated with degradation of long-term memory, neuronal death, microglia/macrophage infiltration and white matter rarefaction. Moreover, we identified these same serum biomarkers as potential predictors of PSCI in a pilot study of stroke patients.Conclusionswe have established and characterized a new model of PSCI, functionally and structurally, and we have shown that the QUIN/KYNA ratio could be used as a surrogate biomarker of PSCI, which may now be tested in large prospective studies of stroke patients.
Highlights
Strokes are becoming less severe due to increased numbers of intensive care units and improved treatments
Diabetic mice with or without stroke show increased anxiety features; no depression is evidenced in any group (Fig. 2b-d) Having shown that sensorimotor function had recovered at D21 after cerebral artery occlusion in permanent middle cerebral artery thermocoagulation (pMCAo)+D mice, we asked whether anxiety or depression could interfere with tests of spatial memory (n = 9–10)
As serum IDO did not discriminate between mice with or without post-stroke cognitive impairment, we studied metabolites produced by the kynurenine pathway, including quinolinic acid (QUIN) and kynurenic acid (KYNA) active in glutamatergic transmission
Summary
Strokes are becoming less severe due to increased numbers of intensive care units and improved treatments. Vascular cognitive impairment (VCI) encompasses all vascular contributions to cognitive impairment including stroke It is a heterogeneous syndrome, including lesions of large and/or small brain vessels that lead to large infarcts or haemorrhages, lacunar infarcts, microbleeds and/or white matter lesions [3], and to memory degradation and executive dysfunction [4]. A group of experts proposed a consensus updated conceptualization of VCI in order to facilitate standardization in research [7], supported by imaging (i.e. diffuse white matter hyperintensities, ischemic strokes and lacunes, microbleeds ...) [8] They defined post-stroke cognitive impairment (PSCI) as occurring when cognitive function is degraded immediately or within 6 months of a stroke and does not recover
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