Diabetes is an Independent Growth Factor of Ischemic Stroke During Reperfusion Phase Leading to Poor Clinical Outcome.

OBJECTIVES: Despite the success of recanalization by bridging therapy, about half of treated stroke patients remain disabled. While numerous reports propose clinical predictors of stroke clinical outcome in this context, we originally aimed to study pre-therapeutic factors influencing infarct growth (IG) and poor clinical outcome in strokes due to large vessel occlusion (LVO) successfully recanalized. MATERIALS AND METHODS: We enrolled 87 consecutive successfully recanalized patients (mTICI: 2b/2c/3) by mechanical thrombectomy (±rt-PA) after stroke due to middle cerebral artery (M1) occlusion within 6 h according to AHA guidelines. IG was defined by subtracting the initial DWI volume to the final 24 h-TDM volume. Statistical associations between poor clinical outcome (mRS≥2), IG and pertinent clinico-radiological variables, were measured using logistic and linear regression models. RESULTS: Among 87 enrolled patients (Age(y): 68.4 ± 17.5; NIHSS: 16.0 ± 5.4), 42/87 (48,28%) patients had a mRS ≥ 2 at 3 months. Diabetic history (OR: 3.70 CI95%[1.03;14.29] and initial NIHSS (/1 point: OR: 1.16 CI95%[1.05;1.27]) were independently associated with poor outcome. IG was significantly higher in stroke patients with poor outcome (+7.57 ± 4.52 vs -7.81 ± 1.67; p = 0.0024). Initial volumes were not significantly different (mRS≥2: 16.18 ± 2.67; mRS[0-1]: 14.70 ± 2.30; p = 0.6771). Explanatory variables of IG in linear regression were diabetic history (ß: 21.26 CI95%[5.43; 37.09]) and NIHSS (ß: 0.83 CI95%[0.02; 1.64]). IG was higher in diabetic stroke patients (23.54 ± 1.43 vs -6.20 ± 9.36; p = 0.0061). CONCLUSIONS: We conclude that diabetes leads to continued IG after complete recanalization, conditioning clinical outcome in LVO strokes successfully recanalized by bridging therapy. We suggest that poor tissular reperfusion by diabetic microangiopathy could explain this result.

Ingested Ketone Ester Leads to a Rapid Rise of Acetyl-CoA and Competes with Glucose Metabolism in the Brain of Non-Fasted Mice.

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 ß-hydroxybutyrate (ßHB) 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 ßHB uptake into the brain strongly correlated with the plasma ßHB 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.

Metabolome of Cerebral Thrombi Reveals an Association between High Glycemia at Stroke Onset and Good Clinical Outcome.

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.

Why Are Only Some Subcortical Ischemic Lesions on Diffusion Magnetic Resonance Imaging Associated With Stroke Symptoms in Small Vessel Disease?

Background and Purpose- In cerebral small vessel diseases, small subcortical ischemic lesions (SSIL) on diffusion imaging are responsible for stroke manifestations but can also be occasionally observed in the absence of overt neurological symptoms. We aimed to determine, in a large cohort of young patients with CADASIL (Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy), a severe monogenic condition leading to SSIL in young patients, the characteristics of SSIL and of surrounding cerebral tissue associated with the presence of stroke symptoms. Methods- Among a cohort of 323 genetically confirmed CADASIL patients who were systematically evaluated every 18 months clinically and with magnetic resonance imaging, we studied all visible SSIL and documented ischemic stroke events with available magnetic resonance imaging data. We used mixed-effect logistic regression models to determine whether the presence of stroke symptoms was associated with age, sex, the volume of SSIL, their location with respect to preexisting white matter hyperintensities and with the load of the different magnetic resonance imaging markers of small vessel disease. Results- We identified 73 SSIL (30 with stroke symptoms and 43 without) in 55 patients. In multivariable models, stroke symptoms were more frequent in male patients (estimate=1.94; SE=0.82; P=0.03) and less frequent when SSIL appeared in contact to preexisting white matter hyperintensities (estimate=-2.12; SE=0.83; P=0.01). Within pyramidal tracts, stroke symptoms were more frequent in patients with extensive white matter hyperintensities (estimate=3.8×10-5; SE=9.3×10-6; P<10-4). Conclusions- Altogether, our results suggest that when SSIL occur, the presence of stroke symptoms may depend on sex and alterations of the surrounding brain tissue rather than on the characteristics of the SSIL itself.