The role of ketone bodies in the cerebral energy homeostasis of neurological diseases has begun to attract recent attention particularly in acute neurological diseases. In ketogenic therapies, ketosis is achieved by either a ketogenic diet or by the administration of exogenous ketone bodies. The oral ingestion of the ketone ester (KE), (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, is a new method to generate rapid and significant ketosis (i.e., above 6 mmol/L) in humans. KE is hydrolyzed into β-hydroxybutyrate (βHB) and its precursor 1,3-butanediol. Here, we investigate the effect of oral KE administration (3 mg KE/g of body weight) on brain metabolism of non-fasted mice using liquid chromatography in tandem with mass spectrometry. Ketosis (Cmax = 6.83 ± 0.19 mmol/L) was obtained at Tmax = 30 min after oral KE-gavage. We found that βHB uptake into the brain strongly correlated with the plasma βHB concentration and was preferentially distributed in the neocortex. We showed for the first time that oral KE led to an increase of acetyl-CoA and citric cycle intermediates in the brain of non-fasted mice. Furthermore, we found that the increased level of acetyl-CoA inhibited glycolysis by a feedback mechanism and thus competed with glucose under physiological conditions. The brain pharmacodynamics of this oral KE strongly suggest that this agent should be considered for acute neurological diseases.

BACKGROUND: The dramatic clinical improvement offered by mechanical thrombectomy raised questions about the relevance of prior intravenous thrombolysis in large-vessel occlusion strokes. Hence, studying intravenous thrombolysis susceptibility and its dependence on thrombus composition is crucial. We used an observational proteomic study of whole thrombi retrieved by mechanical thrombectomy to identify factors associated with fibrin content and fibrinolytic activity (FA). METHODS: In 104 stroke patients, the thrombi proteome was established by mass spectrometry coupled to liquid chromatography. FA was estimated in clots both outside (FA _out ) by measuring D-dimer levels at the blood-thrombus interface and inside (FA _in ) by evaluating the ratio of fibrinogen α to its plasmin-cleaved forms using proteomics coupled with protein electrophoresis. The factors associated with fibrin content, FA _in , and FA _out were determined by intravenous thrombolysis-adjusted linear regression. RESULTS: FA _out ( P <0.0001) and FA _in ( P =0.0147) were driven by recombinant tissue-type plasminogen activator (r-tPA) administration (47/104) and thrombus composition. Indeed, FA _out was greater with fibrin-rich than erythrocyte-rich thrombi, presumably because of more (r)tPA substrates. Thus, FA _out was increased with cardioembolic thrombi (72/104), which are rich in fibrin ( P =0.0300). Opposite results were found inside the thrombus, suggesting that (r)tPA penetrability was hampered by the density of the fibrinous cap. Moreover, blood cells had a strong impact on thrombus structure and susceptibility to (r)tPA. Indeed, fibrin content was negatively associated with erythrocyte-specific proteins in the thrombus, admission hematocrit ( P =0.0139), and hemoglobin level ( P =0.0080), which underlines the key role of erythrocytes in thrombus composition. Also, an increased number of neutrophils impaired FA _out ( P =0.0225), which suggests that their aggregation around the thrombus prevented the (r)tPA attack. Only FA _out was significantly associated with reduced thrombus weight ( P =0.0310), increased recanalization rate ( P =0.0150), good clinical outcome ( P =0.0480), and reduced mortality ( P =0.0080). CONCLUSIONS: Proteomics can offer new insights into the close relationship between thrombus composition and susceptibility to fibrinolysis, paving the way for new adjuvant therapies.

Despite the fact that glucose is the main fuel of the brain, hyperglycemia at hospital admission is generally associated with a poor functional outcome in stroke patients. This paradox may be explained by the lack of information about the blood glucose level at stroke onset. Here, we analyzed the metabolome of blood cells entrapped in cerebral thrombi to gain insight into their metabolism at stroke onset. Fourty-one consecutive stroke patients completely recanalized by mechanical thrombectomy within 6 h were included. The metabolome of retrieved thrombi was analyzed by liquid chromatography tandem with mass spectrometry. Discriminant Analysis (sparse Partial Least Squares Discriminant Analysis (sPLS-DA)) was performed to identify classification models and significant associated features of favorable clinical outcome at 3 months (modified Rankin Scale (mRS) < 2). sPLS-DA of the metabolomes of cerebral thrombi discriminated between stroke patients with a favorable or poor clinical outcome (Area Under the Curve (AUC) = 0.992 (0.931–1)). In addition, our results revealed that high sorbitol and glucose levels in the thrombi positively correlated with favorable clinical outcomes. Sorbitol, a short-term glycemic index reflecting a high blood glucose level at stroke onset, was found to be an independent predictor of good outcome (AUC = 0.908 (0.807–0.995)). This study demonstrates that a high blood glucose level at stroke onset is beneficial to the clinical outcome of the patient.

Background: Carotid free-floating thrombus (CFFT) is an uncommon disorder. The aim of this study was to describe a French cohort of CFFT patients. Methods: We conducted a retrospective monocentric study from a Stroke Center among patients admitted for stroke with CFFT. Results: Between January 2017 to December 2019, 2038 ischemic strokes were recorded. A total of 50 patients with CFFT were consecutively included (32 men/18 women). The mean age was 58.2 years (±11.7). Their etiologies were atheroma (46%), carotid dissection and web (20%), hypercoagulability disorders (16%) and arrhythmia (10%). Exclusive medical management was performed in 38 patients (76%): 29 (59.2%) were anticoagulated and 9 (18.4%) received antiplatelets alone in the first week. Surgical intervention was performed in the first 30 days for 11 patients (22%). The main surgical indication was a residual carotid stenosis over 70%. Only three patients had a recurrent stroke in the medical group with anticoagulants. No patients in the antiplatelet group or the surgical group had a recurrent stroke. Conclusions: Our study summarized a large cohort of 50 patients with CFFT. This diagnosis implies the need to search for a local arterial disease and to screen for hypercoagulability states. An initial medical strategy followed by a delayed carotid surgery if the follow-up imaging shows a residual stenosis appears to be safe.