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Characterizing the metabolomes of microglia, astrocytes and neurons in ageing and Alzheimer’s brains
That author's affiliation: UT Southwestern First author institution: Unknown Last author institution: UT Southwestern
Yu, Li and colleagues explore the metabolome of neurons, microglia and astrocytes under normal, ageing and Alzheimer’s disease conditions. They find enrichment of glutathione and polyamine metabolism in microglia, which decreased with ageing and in Alzheimer’s disease.
The cognitive consequences of hypoglycemia in diabetes
Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
Hypoglycemia is a frequent and often serious complication of diabetes management. While its acute effects on cognition are well documented, growing evidence suggests that recurrent or severe hypoglycemia exposure may also contribute to long-term cognitive ...
Hypoglycemia is a frequent and often serious complication of diabetes management. While its acute effects on cognition are well documented, growing evidence suggests that recurrent or severe hypoglycemia exposure may also contribute to long-term cognitive ...
Early Inflammatory Biomarkers Associated With Functional Outcomes in Acute Cerebral Venous Thrombosis: CLOT-VENUS Substudy
Stroke, Ahead of Print.
BACKGROUND:Inflammatory serum biomarkers, including neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII), are associated with outcomes in acute cerebrovascular diseases. However, their prognostic role in cerebral venous thrombosis remains uncertain. We aimed to assess the prognostic value of these biomarkers in acute cerebral venous thrombosis by identifying optimal thresholds and internally validating their predictive performance.METHODS:This retrospective observational cohort study included adults diagnosed with acute cerebral venous thrombosis from the international CLOT-VENUS registry (Collaboration on Cerebral Venous Thrombosis Study; 2004–2024), including 2 comprehensive stroke centers in the United States and Mexico. Biomarkers of interest (neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, PLR, SII) were calculated from admission complete blood counts. The primary outcome was functional status at 6 months, measured by the modified Rankin Scale dichotomized as 0 to 2 versus 3 to 6. Secondary outcomes included modified Rankin Scale score at discharge and mortality. Associations were tested with multivariable logistic regression adjusted for clinically relevant covariates. Optimal biomarker cutoffs were identified using stratified bootstrap receiver operating characteristic analysis and internally validated with out-of-bag testing.RESULTS:Of 432 patients, 394 met the inclusion criteria, and complete data were available for 339 of those patients. Median age was 40 years [interquartile range, 27–45], and 65.2% were female. Elevated biomarkers at admission were associated with modified Rankin Scale score 3 to 6 at discharge and 6 months. At 6 months, optimal cutoff values for neutrophil-to-lymphocyte ratio >4.88 (adjusted odds ratio [aOR], 2.19;P=0.044), monocyte-to-lymphocyte ratio >0.54 (aOR, 2.32;P=0.027), PLR>161.04 (aOR, 3.33;P=0.003), and SII>1388.58 (aOR, 2.03;P=0.049). Similar associations occurred at discharge using the same thresholds. PLR and SII notably predicted mortality at discharge (PLR aOR, 6.33;P=0.008, and SII aOR, 3.93;P=0.031) and at 6 months (PLR aOR, 7.19;P=0.004, and SII aOR, 4.69;P=0.010).CONCLUSIONS:Elevated admission levels of neutrophil-to-lymphocyte ratio, PLR, monocyte-to-lymphocyte ratio, and SII are independently associated with poor discharge and 6-month outcomes in patients with acute cerebral venous thrombosis. These accessible biomarkers may aid early risk stratification. Further studies should validate and explore its usefulness in clinical models for personalized management.
BACKGROUND:Inflammatory serum biomarkers, including neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII), are associated with outcomes in acute cerebrovascular diseases. However, their prognostic role in cerebral venous thrombosis remains uncertain. We aimed to assess the prognostic value of these biomarkers in acute cerebral venous thrombosis by identifying optimal thresholds and internally validating their predictive performance.METHODS:This retrospective observational cohort study included adults diagnosed with acute cerebral venous thrombosis from the international CLOT-VENUS registry (Collaboration on Cerebral Venous Thrombosis Study; 2004–2024), including 2 comprehensive stroke centers in the United States and Mexico. Biomarkers of interest (neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, PLR, SII) were calculated from admission complete blood counts. The primary outcome was functional status at 6 months, measured by the modified Rankin Scale dichotomized as 0 to 2 versus 3 to 6. Secondary outcomes included modified Rankin Scale score at discharge and mortality. Associations were tested with multivariable logistic regression adjusted for clinically relevant covariates. Optimal biomarker cutoffs were identified using stratified bootstrap receiver operating characteristic analysis and internally validated with out-of-bag testing.RESULTS:Of 432 patients, 394 met the inclusion criteria, and complete data were available for 339 of those patients. Median age was 40 years [interquartile range, 27–45], and 65.2% were female. Elevated biomarkers at admission were associated with modified Rankin Scale score 3 to 6 at discharge and 6 months. At 6 months, optimal cutoff values for neutrophil-to-lymphocyte ratio >4.88 (adjusted odds ratio [aOR], 2.19;P=0.044), monocyte-to-lymphocyte ratio >0.54 (aOR, 2.32;P=0.027), PLR>161.04 (aOR, 3.33;P=0.003), and SII>1388.58 (aOR, 2.03;P=0.049). Similar associations occurred at discharge using the same thresholds. PLR and SII notably predicted mortality at discharge (PLR aOR, 6.33;P=0.008, and SII aOR, 3.93;P=0.031) and at 6 months (PLR aOR, 7.19;P=0.004, and SII aOR, 4.69;P=0.010).CONCLUSIONS:Elevated admission levels of neutrophil-to-lymphocyte ratio, PLR, monocyte-to-lymphocyte ratio, and SII are independently associated with poor discharge and 6-month outcomes in patients with acute cerebral venous thrombosis. These accessible biomarkers may aid early risk stratification. Further studies should validate and explore its usefulness in clinical models for personalized management.
Endovascular Thrombectomy Versus Standard Medical Management in Acute Anterior Cerebral Artery Occlusion Stroke: The ORIENTAL-MeVO Registry Study
Stroke, Ahead of Print.
BACKGROUND:The benefit of endovascular thrombectomy (EVT) in patients with stroke with proximal large vessel occlusion in the anterior circulation has been confirmed by several randomized controlled trials. However, evidence regarding EVT for anterior cerebral artery occlusion (ACAo) remains limited. This study aimed to compare clinical outcomes between EVT and standard medical management (SMM) in patients with ACAo.METHODS:This retrospective multicenter study examined data from patients with acute ischemic stroke caused by ACAo (A1/A2/A3 segments) within 24 hours of symptom onset across 25 Chinese centers between September 2019 and September 2024. Eligible patients had ACAo verified by computed tomography angiography, magnetic resonance angiography, and digital subtraction angiography, a prestroke modified Rankin Scale score of ≤2, and received either EVT or SMM exclusively. Patients were excluded due to clot migration from proximal major arteries to the anterior cerebral artery, multiterritory occlusion, or absence of 90-day modified Rankin Scale score data. The primary outcome was the 90-day modified Rankin Scale score distribution. Safety outcomes encompassed 24-hour symptomatic intracranial hemorrhage and 90-day mortality rates. Propensity score matching and inverse probability of treatment weighting analyses were conducted to equilibrate baseline confounders between the EVT and SMM groups.RESULTS:A total of 343 patients with ACAo met the inclusion criteria and were enrolled across all participating centers. Following adjustment for confounders using inverse probability of treatment weighting, the EVT group had statistically significant improvement in 90-day modified Rankin Scale score (adjusted odds ratio, 2.14 [95% CI, 1.59–2.89];P<0.001), excellent functional outcome (aRR, 1.77 [95% CI, 1.27–2.48];P<0.001) and functional independence (aRR, 2.35 [95% CI, 1.63–3.39];P<0.001) compared with the SMM group. Safety outcomes, including symptomatic intracranial hemorrhage and mortality, showed no significant differences between groups. Subgroup analysis revealed improved secondary outcomes in patients with baseline National Institutes of Health Stroke Scale score ≥6.CONCLUSIONS:EVT for ACAo is associated with better clinical outcomes compared with SMM, particularly in patients with moderate to severe stroke, without increased risk of symptomatic intracranial hemorrhage or 90-day mortality.REGISTRATION:URL:www.chictr.org.cn; Unique identifier: ChiCTR2500096954.
BACKGROUND:The benefit of endovascular thrombectomy (EVT) in patients with stroke with proximal large vessel occlusion in the anterior circulation has been confirmed by several randomized controlled trials. However, evidence regarding EVT for anterior cerebral artery occlusion (ACAo) remains limited. This study aimed to compare clinical outcomes between EVT and standard medical management (SMM) in patients with ACAo.METHODS:This retrospective multicenter study examined data from patients with acute ischemic stroke caused by ACAo (A1/A2/A3 segments) within 24 hours of symptom onset across 25 Chinese centers between September 2019 and September 2024. Eligible patients had ACAo verified by computed tomography angiography, magnetic resonance angiography, and digital subtraction angiography, a prestroke modified Rankin Scale score of ≤2, and received either EVT or SMM exclusively. Patients were excluded due to clot migration from proximal major arteries to the anterior cerebral artery, multiterritory occlusion, or absence of 90-day modified Rankin Scale score data. The primary outcome was the 90-day modified Rankin Scale score distribution. Safety outcomes encompassed 24-hour symptomatic intracranial hemorrhage and 90-day mortality rates. Propensity score matching and inverse probability of treatment weighting analyses were conducted to equilibrate baseline confounders between the EVT and SMM groups.RESULTS:A total of 343 patients with ACAo met the inclusion criteria and were enrolled across all participating centers. Following adjustment for confounders using inverse probability of treatment weighting, the EVT group had statistically significant improvement in 90-day modified Rankin Scale score (adjusted odds ratio, 2.14 [95% CI, 1.59–2.89];P<0.001), excellent functional outcome (aRR, 1.77 [95% CI, 1.27–2.48];P<0.001) and functional independence (aRR, 2.35 [95% CI, 1.63–3.39];P<0.001) compared with the SMM group. Safety outcomes, including symptomatic intracranial hemorrhage and mortality, showed no significant differences between groups. Subgroup analysis revealed improved secondary outcomes in patients with baseline National Institutes of Health Stroke Scale score ≥6.CONCLUSIONS:EVT for ACAo is associated with better clinical outcomes compared with SMM, particularly in patients with moderate to severe stroke, without increased risk of symptomatic intracranial hemorrhage or 90-day mortality.REGISTRATION:URL:www.chictr.org.cn; Unique identifier: ChiCTR2500096954.
Motor Impairment and Adaptation in a Novel Nonhuman Primate Model of Internal Capsule Infarct
Stroke, Ahead of Print.
BACKGROUND:Loss of hand control is a major source of poststroke disability, particularly when infarcts involve subcortical white matter. Yet, most preclinical models target the cortex and infer recovery from task performance without quantifying whether improvements reflect restoration or adaptation. To address this, we developed a novel nonhuman primate model of focal internal capsule infarct. This study is exploratory and hypothesis-testing, including prespecified hypotheses regarding motor impairment and adaptation.METHODS:Three adult male rhesus macaques (Macaca mulatta, 5–10 years) received stereotactically guided ET-1 (endothelin-1) injections (0.5 µg/µL; 9–10 µL total) into the left posterior limb of the internal capsule in a within-subject preinfarct versus postinfarct design. Infarcts were characterized by magnetic resonance imaging and postmortem histology. Motor function was tested with a center-out joystick task and a Klüver board task using standard behavioral metrics; hand posture was additionally scored by blinded raters to quantify adaptation. Preinfarct versus postinfarct comparisons used generalized linear mixed models with per-session random effects; adaptation covariates were evaluated using likelihood-ratio tests.RESULTS:Magnetic resonance imaging and histology confirmed focal posterior limb of the internal capsule–centered infarcts with variable volumes. All animals significantly reduced contralesional hand use postinfarct (Fisher exact test; allP<0.05). Generalized linear mixed models showed reduced center-out success rates in 2 animals (P<0.01) and increased path length in one (P=0.0015). Pooled generalized linear mixed models showed significant postinfarct increases in retrieval time (estimate=0.73 s;P<0.0001) and digit flexions (estimate=0.727;P<0.0001). Two animals developed a compensatory wrist-extended, digit-flexed posture by 4 weeks; augmenting generalized linear mixed models with these postural features significantly improved fit (likelihood-ratio tests;P<0.0001).CONCLUSIONS:This model recapitulates key features of human subcortical stroke, including persistent distal motor deficits, shifts in hand preference, systematic motor adaptation, and interindividual variability, establishing a translationally oriented platform for studying stroke mechanisms and evaluating recovery-promoting interventions.
BACKGROUND:Loss of hand control is a major source of poststroke disability, particularly when infarcts involve subcortical white matter. Yet, most preclinical models target the cortex and infer recovery from task performance without quantifying whether improvements reflect restoration or adaptation. To address this, we developed a novel nonhuman primate model of focal internal capsule infarct. This study is exploratory and hypothesis-testing, including prespecified hypotheses regarding motor impairment and adaptation.METHODS:Three adult male rhesus macaques (Macaca mulatta, 5–10 years) received stereotactically guided ET-1 (endothelin-1) injections (0.5 µg/µL; 9–10 µL total) into the left posterior limb of the internal capsule in a within-subject preinfarct versus postinfarct design. Infarcts were characterized by magnetic resonance imaging and postmortem histology. Motor function was tested with a center-out joystick task and a Klüver board task using standard behavioral metrics; hand posture was additionally scored by blinded raters to quantify adaptation. Preinfarct versus postinfarct comparisons used generalized linear mixed models with per-session random effects; adaptation covariates were evaluated using likelihood-ratio tests.RESULTS:Magnetic resonance imaging and histology confirmed focal posterior limb of the internal capsule–centered infarcts with variable volumes. All animals significantly reduced contralesional hand use postinfarct (Fisher exact test; allP<0.05). Generalized linear mixed models showed reduced center-out success rates in 2 animals (P<0.01) and increased path length in one (P=0.0015). Pooled generalized linear mixed models showed significant postinfarct increases in retrieval time (estimate=0.73 s;P<0.0001) and digit flexions (estimate=0.727;P<0.0001). Two animals developed a compensatory wrist-extended, digit-flexed posture by 4 weeks; augmenting generalized linear mixed models with these postural features significantly improved fit (likelihood-ratio tests;P<0.0001).CONCLUSIONS:This model recapitulates key features of human subcortical stroke, including persistent distal motor deficits, shifts in hand preference, systematic motor adaptation, and interindividual variability, establishing a translationally oriented platform for studying stroke mechanisms and evaluating recovery-promoting interventions.
How processing choices effect repeatability in BOLD–CVR imaging
Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
Cerebrovascular reactivity (CVR) is increasingly recognized as a valuable clinical biomarker, making accurate, and reliable quantification essential, particularly in the absence of a gold-standard reference. However, both the acquisition and processing of ...
Cerebrovascular reactivity (CVR) is increasingly recognized as a valuable clinical biomarker, making accurate, and reliable quantification essential, particularly in the absence of a gold-standard reference. However, both the acquisition and processing of ...