High levels of D-serine occur in mammalian brain, where it appears to be an endogenous ligand of the glycine site of N-methyl-D-aspartate receptors. In glial cultures of rat cerebral cortex, D-serine is enriched in type II astrocytes and is released upon stimulation with agonists of non-N-methyl-D-aspartate glutamate receptors. The high levels of D-serine in discrete areas of rat brain imply the existence of a biosynthetic pathway. We have purified from rat brain a soluble enzyme that catalyzes the direct racemization of L-serine to D-serine. Purified serine racemase has a molecular mass of 37 kDa and requires pyridoxal 5-phosphate for its activity. The enzyme is highly selective toward L-serine, failing to racemize any other amino acid tested. Properties such as pH optimum, K m values, and the requirement for pyridoxal phosphate resemble those of bacterial racemases, suggesting that the biosynthetic pathway for D-amino acids is conserved from bacteria to mammalian brain.D-Amino acids are prominent in bacteria whereas in animal tissues L-amino acids occur exclusively, though there have been occasional reports of D-amino acids, usually in invertebrates (1, 2). Recently, D-serine (3-6) and D-aspartate (7,8) were reported in mammalian tissues, especially in the nervous system. Using highly selective antibodies, we localized D-aspartate to neuroendocrine tissues (9), whereas the immunohistochemical localizations of D-serine closely resemble N-methyl-D-aspartate (NMDA) receptors for the neurotransmitter glutamate, as the distribution of D-serine measured chemically (10, 11). Glutamate cannot activate the NMDA receptor in the absence of glycine, indicating a ''glycine site'' for the receptor (12, 13). D-Serine is up to three times more potent than glycine at this site (14), suggesting that D-serine is the endogenous ligand for this site. D-Serine is localized exclusively to type II astrocytes, a form of glia concentrated in gray matter in the same areas of the brain as NMDA receptors (10). Stimulation of the kainate subtype of glutamate receptors releases D-serine from type II astrocytes, implying that synaptic release of glutamate triggers release of D-serine from the astrocytes to activate NMDA receptors physiologically (10). Although in most parts of the brain the distribution of D-serine resembles NMDA receptors far better than glycine, in some areas glycine and NMDA receptors are colocalized, suggesting that D-serine is the predominant ligand for the receptor in most brain areas but that glycine serves this purpose in some sites (11).Understanding the neurobiology of D-serine requires delineation of its biosynthesis. D-Serine might be formed by direct racemization from L-serine. Dunlop and Neidle (15) reported the transformation of radiolabeled L-serine to D-serine in intact rats, but this might have involved multiple steps rather than any direct enzymatic racemization. In the present study we describe an enzyme activity that directly racemizes L-serine to D-serine and that is localized to the brain. We ...

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Background and Purpose In malignant infarction, brain edema leads to secondary neurological deterioration and poor outcome. We sought to determine whether swelling is associated with outcome in smaller volume strokes. Methods Two research cohorts of acute stroke subjects with serial brain magnetic resonance imaging (MRI) were analyzed. The categorical presence of swelling and/or infarct growth was assessed on diffusion weighted imaging (DWI) by comparing baseline and follow-up scans. The increase in stroke volume (ΔDWI) was then subdivided into swelling and infarct growth volumes using region-of-interest analysis. The relationship of these imaging markers with outcome was evaluated in univariable and multivariable regression. Results The presence of swelling independently predicted worse outcome after adjustment for age, NIH stroke scale, admission glucose, and baseline DWI volume(OR4.55, 95%CI1.21-18.9, p < 0.02). Volumetric analysis confirmed ΔDWI was associated with outcome (OR4.29, 95%CI 2.00-11.5, p < 0.001). After partitioning ΔDWI into swelling and infarct growth volumetrically, swelling remained an independent predictor of poor outcome (OR1.09, 95%CI 1.03-1.17, p < 0.005). Larger infarct growth was also associated with poor outcome (OR7.05, 95%CI 1.04-143, p < 0.045), although small infarct growth was not. The severity of cytotoxic injury measured on apparent diffusion coefficient maps was associated with swelling, whereas the perfusion deficit volume was associated with infarct growth. Conclusions Swelling and infarct growth each contribute to total stroke lesion growth in the days following stroke. Swelling is an independent predictor of poor outcome, with abrain swelling volume of ≥11mL identified as the threshold with greatest sensitivity and specificity for predicting poor outcome.

Background: Anecdotal reports suggest fewer patients with stroke symptoms are presenting to hospitals during the coronavirus disease 2019 (COVID-19) pandemic. We quantify trends in stroke code calls and treatments at 3 Connecticut hospitals during the local emergence of COVID-19 and examine patient characteristics and stroke process measures at a Comprehensive Stroke Center (CSC) before and during the pandemic. Methods: Stroke code activity was analyzed from January 1 to April 28, 2020, and corresponding dates in 2019. Piecewise linear regression and spline models identified when stroke codes in 2020 began to decline and when they fell below 2019 levels. Patient-level data were analyzed in February versus March and April 2020 at the CSC to identify differences in patient characteristics during the pandemic. Results: A total of 822 stroke codes were activated at 3 hospitals from January 1 to April 28, 2020. The number of stroke codes/wk decreased by 12.8/wk from February 18 to March 16 ( P =0.0360) with nadir of 39.6% of expected stroke codes called from March 10 to 16 (30% decrease in total stroke codes during the pandemic weeks in 2020 versus 2019). There was no commensurate increase in within-network telestroke utilization. Compared with before the pandemic (n=167), pandemic-epoch stroke code patients at the CSC (n=211) were more likely to have histories of hypertension, dyslipidemia, coronary artery disease, and substance abuse; no or public health insurance; lower median household income; and to live in the CSC city ( P <0.05). There was no difference in age, sex, race/ethnicity, stroke severity, time to presentation, door-to-needle/door-to-reperfusion times, or discharge modified Rankin Scale. Conclusions: Hospital presentation for stroke-like symptoms decreased during the COVID-19 pandemic, without differences in stroke severity or early outcomes. Individuals living outside of the CSC city were less likely to present for stroke codes at the CSC during the pandemic. Public health initiatives to increase awareness of presenting for non-COVID-19 medical emergencies such as stroke during the pandemic are critical.

Rationale Efficacy of mechanical thrombectomy for acute stroke due to large vessel occlusion initiated beyond 6 h of time last seen well has not been demonstrated in randomized trials. Aim To establish whether subjects considered to have substantial areas of salvageable brain based on age-adjusted clinical core mismatch who can undergo endovascular treatment within 6-24 h from time last seen well (TLSW) have better outcomes at three months compared to subjects treated with standard medical therapy alone. Age-adjusted clinical core mismatch is defined by age (≤80 or >80 years), baseline National Institutes of Health Stroke Scale (NIHSS) (10-20 or ≥21), and core size (0-20 cm in subjects older than 80 and, in subjects younger than 80, 0-30 cm with NIHSS 10-20 and 31-50 cm with NIHSS ≥21). Design Prospective, randomized, multicenter, Bayesian adaptive-enrichment, open label trial with blinded endpoint assessment. For the purpose of enrolment, ischemic core size will be evaluated by CT perfusion or magnetic resonance imaging-diffusion-weighted imaging measured by automated software (RAPID). Procedures Subjects with acute ischemic stroke due to computed tomography angiography- or magnetic resonance angiogram-proven arterial occlusion of the intracranial internal carotid and/or proximal middle cerebral artery (M1) with age-adjusted clinical core mismatch in whom treatment can be initiated between 6 and 24 h from TSLW are randomized in a 1:1 ratio to receive mechanical embolectomy with the Trevo device or medical management alone. Sequential interim analyses allowing adaptation of enrolment criteria or stopping new enrolment for futility or predicted success will occur in every 50 randomized patients starting at 150 to a maximum of 500 patients. Study outcomes The primary endpoint is the modified Rankin Scale score at 90 days. The primary safety outcome is stroke-related mortality at 90 days. Analysis The primary endpoint, expressed as a utility-weighted modified Rankin Scale score is analyzed using a Bayesian posterior probability with adjustment for ischemic core size. For regulatory reasons, a nested co-primary endpoint analysis was added consisting of the proportion of subjects with modified Rankin Scale 0-2 between the active and control groups also analyzed using a Bayesian model.

It is uncertain whether therapeutic reperfusion with endovascular treatment yields more or less brain edema. OBJECTIVE To elucidate the association between reperfusion and brain edema. The secondary objectives were to evaluate whether brain edema could partially be responsible for worse outcomes in patients with later reperfusion or lower Alberta Stroke Program Early Computed Tomography Score. DESIGN, SETTING, AND PARTICIPANTS This was a post hoc analysis of the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN), which was a prospective, randomized, multicenter clinical trial of endovascular treatment compared with conventional care of patients with acute anterior circulation ischemic stroke. Of 502 patients enrolled from December 2010 to June 2014, 2 patients declined to participate. Additionally, exclusion criteria were absence of follow-up imaging or presence of parenchymal hematoma, resulting in 462 patients included in this study. Brain edema was assessed retrospectively, from December 10, 2016, to July 24, 2017, by measuring midline shift (MLS) in all available follow-up scans. Observers were blinded to clinical data. MAIN OUTCOMES AND MEASURES Midline shift was assessed as present or absent and as a continuous variable. Reperfusion status was assessed by the modified thrombolysis in cerebral infarction score in the endovascular treatment arm. The modified arterial occlusive lesion score was used to evaluate the recanalization status in both arms. The modified Rankin scale score at 90 days was used for functional outcome. RESULTS Of 462 patients, the mean (SD) age was 65 (11) years, and 41.8% (n = 193) were women. Successful reperfusion and recanalization were associated with a reduced likelihood of having MLS (adjusted common odds ratio, 0.25; 95% CI, 0.12-0.53; P < .001 and adjusted common odds ratio, 0.34; 95% CI, 0.21-0.55; P < .001, respectively). Midline shift was partially responsible for worse modified Rankin scale scores in patients without reperfusion or recanalization (MLS changed the logistic regression coefficients by 30.3% and 12.6%, respectively). In patients with delayed reperfusion or lower Alberta Stroke Program Early Computed Tomography Score, MLS mediated part of the worse modified Rankin scale scores, corresponding to a change in the regression coefficient of 33.3% and 64.2%, respectively. CONCLUSIONS AND RELEVANCE Successful reperfusion was associated with reduced MLS. This study identifies an additional benefit of reperfusion in relation to edema, as well as rescuing ischemic brain tissue at risk for infarction.

Significant delays occur in treating patients with endovascular therapy in acute ischemic stroke, offering opportunities for improvements in systems of care. Ongoing prospective clinical trials can help to assess if HV centers are achieving better clinical outcomes and higher reperfusion rates.