Jining First People's Hospital

D-serine is an endogenous D-amino acid and a crucial co-agonist for the N-methyl-D-aspartate (NMDA) receptor, well known as a key regulator of synaptic plasticity, learning, and memory. This review summarizes recent advances that extend beyond this canonical role, positioning D-serine as a dynamic nexus linking brain function to systemic homeostasis. We explore its spatiotemporal dynamics in synaptic microdomains, sophisticated epigenetic and transcriptional regulation, and emerging role as a metabolic sensor linking cellular energetics to neuronal signaling. Furthermore, we highlight novel non-canonical signaling pathways, including its function as a ligand for the glutamate delta-1 receptor (GluD1) and its direct role in peripheral organs like the gut and kidney. The pathophysiological implications of disrupted D-serine homeostasis are detailed across a spectrum of CNS disorders—from schizophrenia and Alzheimer’s disease (AD) to addiction and neuropathic pain—as well as in peripheral conditions including diabetic complications and osteoporosis. Finally, we discuss the translational potential of targeting D-serine pathways through innovative therapeutic strategies—such as serine racemase (SR) modulators, D-amino acid oxidase (DAAO) inhibitors, and gene therapy—and its promise as a biomarker for personalized medicine in neurology and psychiatry.

To investigate the multivariate associations among focal hemodynamic impairment, cerebral interstitial fluid accumulation (measured as free water in white matter, FW-WM), diffuse white matter injury, and cognitive decline in patients with asymptomatic unilateral severe extracranial internal carotid artery stenosis (ICAS). This study included 40 patients with asymptomatic unilateral severe extracranial ICAS and 40 matched healthy controls (HCs). All participants underwent multimodal MRI, including diffusion tensor imaging for FW-WM and FW-corrected fractional anisotropy (fwcFA), 3D-T2 FLAIR for white matter hyperintensities (WMH) volume, and arterial spin labeling for cerebral blood flow (CBF). CBF was quantified at two post-labeling delays (PLDs: 1500 ms and 2500 ms) in grey matter (GM) and, at 2500 ms, additionally in white matter (WM) of the anterior, middle, and posterior cerebral artery (ACA, MCA, PCA) territories. Cognitive function was evaluated using the Montreal Cognitive Assessment (MoCA) within the patient group. Compared to HCs, patients exhibited significantly elevated global FW-WM (0.20 ± 0.03 vs. 0.18 ± 0.02, p < 0.001), reduced fwcFA (0.45 ± 0.014 vs. 0.46 ± 0.013, p = 0.017), greater WMH volume (median: 4.41 vs. 2.43 cm³, p = 0.003), and more pronounced lateralized CBF reductions in the ACA and MCA territories (all p < 0.05), indicating hemodynamic impairment. Within-patient analyses revealed a dual pathology: focal ipsilateral changes (elevated FW-WM and reduced CBF) and diffuse bilateral changes (symmetric WMH and FA reduction). After controlling for covariates, ipsilateral FW-WM correlated negatively with the lateralization index of CBF in the ACA GM (LI-CBF-ACA-GM) at PLD 1500ms and 2500ms (r = -0.464, p = 0.005 and r = -0.416, p = 0.013, respectively). Global FW-WM correlated positively with total WMH volume (r = 0.344, p = 0.043) and strongly negatively with fwcFA (r = -0.599, p < 0.001). Multivariable linear regression confirmed that FW-WM was independently associated with both ipsilateral hemodynamic impairment and global white matter injury, adjusting for age, sex, hypertension, diabetes, and homocysteine. Crucially, higher global FW-WM was associated with worse MoCA scores (r = -0.435, p = 0.007), and this association remained significant after separately adjusting for either WMH volume (partial r = -0.361, p = 0.030) or LI-CBF-ACA-GM (partial r = -0.363, p = 0.029). In asymptomatic extracranial ICAS, elevated FW‑WM integrates dual pathologies of focal hemodynamic impairment and diffuse white matter injury. Its independent association with cognitive decline positions FW-WM not only as a pivotal mechanistic link between hemodynamic compromise and clinical impairment, but also as a promising imaging biomarker. Prospective studies are warranted to validate its utility in stratifying the risk of progressive white matter injury and cognitive decline in this population.

To evaluate the efficacy and safety of mechanical thrombectomy performed beyond 24 hours from symptom onset in patients with acute ischemic stroke (AIS) and large vessel occlusion (LVO). In this retrospective cohort study, patients with LVO-related AIS who underwent mechanical thrombectomy within 72 hours of onset were enrolled from the Acute Stroke Patients for Stroke Management Quality Evaluation online database (CASE-Ⅱ, NCT04487340) between January 2017 and December 2024. Patients were stratified into beyond 24-hour thrombectomy group and within 24-hour thrombectomy group based on the time from onset to mechanical thrombectomy. Propensity score matching (PSM) was used to balance baseline characteristics between the two groups. Binary logistic regression and generalized linear models were employed to compare 3-month functional and safety outcomes between the groups. Sensitivity analyses were conducted separately in patients undergoing mechanical thrombectomy within the extended time window (6-24 hours) and in those receiving mechanical thrombectomy alone (without prior intravenous thrombolysis). Subgroup analyses were performed based on age, presence of atrial fibrillation, use of oral anticoagulants, pre-stroke modified Rankin Scale (mRS) score, baseline National Institutes of Health Stroke Scale (NIHSS) score, and occlusion site. Of the 9121 patients included, 277 underwent mechanical thrombectomy beyond 24 hours and 8844 within 24 hours. After PSM, 534 patients were analyzed (267 per group). No significant difference was found in the rate of 3-month functional independence (mRS score 0-2) between the beyond 24-hour and within 24-hour thrombectomy groups, both before and after matching (OR=0.977, 95%CI: 0.753-1.268, P=0.861; OR=1.151, 95%CI: 0.712-1.549, P=0.804, respectively). The rates of 24-hour symptomatic intracranial hemorrhage, 24-hour parenchymal hemorrhage, and 3-month all-cause mortality also showed no significant differences between the two groups (all P>0.05). Sensitivity analyses among patients in the extended time window (6-24 hours) and those receiving mechanical thrombectomy alone yielded similar results, with no significant differences in functional or safety outcomes (all P>0.05). Subgroup analyses revealed no significant heterogeneity in the 3-month functional independence across various baseline characteristics (all P>0.05). For AIS patients with LVO, the efficacy and safety of mechanical thrombectomy performed beyond 24 hours appear comparable to those of mechanical thrombectomy performed within 24 hours.