Adrien Cogo1,2, Gabrielle Mangin1,2, Benjamin Maïer2, Jacques Callebert3, Mikael Mazighi1,4, Hughes Chabriat4, Jean-Marie Launay3, Gilles Huberfeld5,6, Nathalie Kubis7,8,9. 1. Université de Paris, INSERM U1148, Laboratory for Vascular Translational Science, F-75018, Paris, France. 2. Université de Paris, INSERM U965, CART, F-75010, Paris, France. 3. Université de Paris, Inserm UMR-S 942; Département de Biochimie et de Biologie Moléculaire, APHP, Hôpital Lariboisière, F-75010, Paris, France. 4. Service de Neurologie, APHP, Hôpital Lariboisière, F-75010, Paris, France. 5. Neuroglial Interactions in Cerebral Physiopathology, Center for Interdisciplinary Research in Biology, Collège de France, CNRS UMR 7241, INSERM U1050, Labex Memolife, PSL Research University, F-75005, Paris, France. 6. Clinical Neurophysiology department, APHP, Pitie-Salpetriere Hospital, Sorbonne Université, APHP, F-75013, Paris, France. 7. Université de Paris, INSERM U1148, Laboratory for Vascular Translational Science, F-75018, Paris, France. nathalie.kubis@aphp.fr. 8. Université de Paris, INSERM U965, CART, F-75010, Paris, France. nathalie.kubis@aphp.fr. 9. Service de Physiologie Clinique-Explorations Fonctionnelles, DMU DREAM, APHP, Hôpital Lariboisière, F-75010, Paris, France. nathalie.kubis@aphp.fr.
Abstract
BACKGROUND: Strokes 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. METHODS: Cortical 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. RESULTS: We 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. CONCLUSIONS: we 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.
BACKGROUND:Strokes 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 diabeticmice, and investigated whether a reliable biomarker of PSCI may emerge from the kynurenine pathway which has been linked to inflammatory processes. METHODS: Cortical infarct was induced by permanent middle cerebral artery occlusion in male diabeticmice (streptozotocinIP). 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. RESULTS: We found long-term spatial memory was impaired in diabeticmice 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 ischemicmice, 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 strokepatients. CONCLUSIONS: we 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 strokepatients.
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