Comprehensive analysis of the impact of procedure time and the 'golden hour' in subpopulations of stroke thrombectomy patients.

OBJECTIVE: To evaluate the effect of procedure time on thrombectomy outcomes in different subpopulations of patients undergoing endovascular thrombectomy (EVT), given the recently expanded indications for EVT. METHODS: This multicenter study included patients undergoing EVT for acute ischemic stroke at 35 centers globally. Procedure time was defined as time from groin puncture to successful recanalization (Thrombolysis in Cerebral Infarction score ≥2b) or abortion of procedure. Patients were stratified based on stroke location, use of IV tissue plasminogen activator (tPA), Alberta Stroke Program Early CT score, age group, and onset-to-groin time. Primary outcome was the 90-day modified Rankin Scale (mRS) score, with scores 0-2 designating good outcome. Secondary outcome was postprocedural symptomatic intracranial hemorrhage (sICH). Multivariate analyses were performed using generalized linear models to study the impact of procedure time on outcomes in each subpopulation. RESULTS: Among 8961 patients included in the study, a longer procedure time was associated with higher odds of poor outcome (mRS score 3-6), with 10% increase in odds for each 10 min increment. When procedure time exceeded the 'golden hour', poor outcome was twice as likely. The golden hour effect was consistent in patients with anterior and posterior circulation strokes, proximal or distal occlusions, in patients with large core infarcts, with or without IV tPA treatment, and across age groups. Procedures exceeding 1 hour were associated with a 40% higher sICH rate. Posterior circulation strokes, delayed presentation, and old age were the variables most sensitive to procedure time. CONCLUSIONS: In this work we demonstrate the universality of the golden hour effect, in which procedures lasting more than 1 hour are associated with worse clinical outcomes and higher rates of sICH across different subpopulations of patients undergoing EVT.

The effect of occlusion location and technique in mechanical thrombectomy for minor stroke.

INTRODUCTION: Endovascular mechanical thrombectomy (MT) is an established treatment for large vessel occlusion strokes with a National Institutes of Health Stroke Scale (NIHSS) score of 6 or higher. Data pertaining to minor strokes, medium, or distal vessel occlusions, and most effective MT technique is limited and controversial. METHODS: A multicenter retrospective study of all patients treated with MT presenting with NIHSS score of 5 or less at 29 comprehensive stroke centers. The cohort was dichotomized based on location of occlusion (proximal vs. distal) and divided based on MT technique (direct aspiration first-pass technique [ADAPT], stent retriever [SR], and primary combined [PC]). Outcomes at discharge and 90 days were compared between proximal and distal occlusion groups, and across MT techniques. RESULTS: The cohort included 759 patients, 34% presented with distal occlusion. Distal occlusions were more likely to present with atrial fibrillation (p = 0.008) and receive IV tPA (p = 0.001). Clinical outcomes at discharge and 90 days were comparable between proximal and distal groups. Compared to SR, patients managed with ADAPT were more likely to have a modified Rankin Scale of 0-2 at discharge and at 90 days (p = 0.024 and p = 0.013). Primary combined compared to ADAPT, prior stroke, multiple passes, older age, and longer procedure time were independently associated with worse clinical outcome, while successful recanalization was positively associated with good clinical outcomes. CONCLUSIONS: Proximal and distal occlusions with low NIHSS have comparable outcomes and safety profiles. While all MT techniques have a similar safety profile, ADAPT was associated with better clinical outcomes at discharge and 90 days.

Risk factors and predictors of intracranial hemorrhage after mechanical thrombectomy in acute ischemic stroke: insights from the Stroke Thrombectomy and Aneurysm Registry (STAR).

BACKGROUND: Reducing intracranial hemorrhage (ICH) can improve patient outcome in acute ischemic stroke (AIS) intervention. We sought to identify ICH risk factors after AIS thrombectomy. METHODS: This is a retrospective review of the Stroke Thrombectomy and Aneurysm Registry (STAR) database. All patients who underwent AIS thrombectomy with available ICH data were included. Multivariable regression models were developed to identify predictors of ICH after thrombectomy. Subgroup analyses were performed stratified by symptom status and European Cooperative Acute Stroke Study (ECASS) grade. RESULTS: The study cohort comprised 6860 patients. Any ICH and symptomatic ICH (sICH) occurred in 25% and 7% of patients, respectively. Hemorrhagic infarction 1 (HI1) occurred in 36%, HI2 in 24%, parenchymal hemorrhage 1 (PH1) in 22%, and PH2 in 17% of patients classified by ECASS grade. Intraprocedural complications independently predicted any ICH (OR 3.8083, P<0.0001), PH1 (OR 1.9053, P=0.0195), and PH2 (OR 2.7347, P=0.0004). Race also independently predicted any ICH (black: OR 0.5180, P=0.0017; Hispanic: OR 0.4615, P=0.0148), sICH (non-white: OR 0.4349, P=0.0107), PH1 (non-white: OR 3.1668, P<0.0001), and PH2 (non-white: OR 1.8689, P=0.0176), with white as the reference. Primary mechanical thrombectomy technique also independently predicted ICH. ADAPT (A Direct Aspiration First Pass Technique) was a negative predictor of sICH (OR 0.2501, P<0.0001), with stent retriever as the reference. CONCLUSIONS: This study identified ICH risk factors after AIS thrombectomy using real-world data. There was a propensity towards a reduced sICH risk with direct aspiration. Procedural complications and ethnicity were predictors congruent between categories of any ICH, sICH, PH1, and PH2. Further investigation of technique and ethnicity effects on ICH and outcomes after AIS thrombectomy is warranted.

Mechanical thrombectomy for large vessel occlusion strokes beyond 24 hours.

BACKGROUND: Recent clinical trials have shown that mechanical thrombectomy is superior to medical management for large vessel occlusion for up to 24 hours from onset. Our objective is to examine the safety and efficacy of thrombectomy beyond the standard of care window. METHODS: A retrospective review was undertaken of the multicenter Stroke Thrombectomy and Aneurysm Registry (STAR). We identified patients who underwent mechanical thrombectomy for large vessel occlusion beyond 24 hours. We selected a matched control group from patients who underwent thrombectomy in the 6-24-hour window. We used functional independence at 3 months as our primary outcome measure. RESULTS: We identified 121 patients who underwent thrombectomy beyond 24 hours and 1824 in the 6-24-hour window. We selected a 2:1 matched group of patients with thrombectomy 6-24 hours as a comparison group. Patients undergoing thrombectomy beyond 24 hours were less likely to be independent at 90 days (18 (18.8%) vs 73 (34.9%), P=0.005). They had higher odds of mortality at 90 days in the adjusted analysis (OR 2.34, P=0.023). Symptomatic intracerebral hemorrhage and other complications were similar in the two groups. In a multivariate analysis only lower number of attempts was associated with good outcomes (OR 0.27, P=0.022). CONCLUSIONS: Mechanical thrombectomy beyond 24 hours appears to be safe and tolerable with no more hemorrhages or complications compared with standard of care thrombectomy. Outcomes and mortality in this time window are worse compared with an earlier time window, but the rates of good outcomes may justify this therapy in selected patients.

Failed mechanical thrombectomy: prevalence, etiology, and predictors.

OBJECTIVE: Despite advances in endovascular techniques, mechanical thrombectomy (MT) fails to achieve successful reperfusion in approximately 20% of patients. This study aimed to identify common etiologies and predictors of failed thrombectomy in a contemporary series. METHODS: A prospectively maintained database of MT patients between January 2013 and August 2021 was interrogated. Failed MT was defined as a final modified Thrombolysis in Cerebral Infarction score < 2b. Demographic data, procedural details, stroke etiology, and anatomical data in patients who underwent MT with subsequent failed reperfusion were collected. RESULTS: Of a total 1010 MT procedures, 120 (11.9%) were unsuccessful. The mean patient age was 66.8 years; 51.5% of patients were male, and 61.1% were White. The most common failure location was intracranial (93.3%) followed by failure at the arch (3.3%) and neck (3.3%). Among patients with intracranial failure, underlying intracranial atherosclerosis (ICAS) was the cause of failure in 84 patients (70%). Compared with patients with successful MT, patients with failed MT had a longer onset to puncture time (p = 0.012) and onset to groin time (p = 0.04). Rescue stenting was performed in 45 cases: 39 patients (4.4%) with successful MT and 6 (5.0%) with MT failure (p = 0.765). Multivariate analysis demonstrated that diabetes mellitus (p = 0.009) was independently associated with unsuccessful reperfusion. CONCLUSIONS: Failed MT was encountered in approximately 12% of MT procedures. The most common cause of failed MT was underlying ICAS. Further studies to evaluate better ways of early identification and treatment of ICAS-related large-vessel occlusion are warranted.

Outcomes after endovascular mechanical thrombectomy for low compared to high National Institutes of Health Stroke Scale (NIHSS): A multicenter study.

OBJECTIVE: The role of endovascular mechanical thrombectomy (MT) in patients presenting with "minor" stroke is uncertain. We aimed to compare outcomes after MT for ischemic stroke patients presenting with National Institutes of Health Stroke Scale (NIHSS) 5 and - within the low NIHSS cohort - identify predictors of a favorable outcome, mortality, and symptomatic intracranial hemorrhage (ICH). METHODS: We retrospectively analyzed a prospectively maintained, international, multicenter database. RESULTS: The study cohort comprised a total of 7568 patients from 29 centers. NIHSS was low (<5) in 604 patients (8%), and > 5 in 6964 (92%). Patients with low NIHSS were younger (67 + 14.8 versus 69.6 + 14.7 years, p < 0.001), more likely to have diabetes (31.5% versus 26.9%, p = 0.016), and less likely to have atrial fibrillation (26.6% versus 37.6%, p < 0.001) compared to those with higher NIHSS. Radiographic outcomes (TICI > 2B 84.6% and 84.3%, p = 0.412) and complication rates (8.1% and 7.2%, p = 0.463) were similar between the low and high NIHSS groups, respectively. Clinical outcomes at every follow up interval, including NIHSS at 24 h and discharge, and mRS at discharge and 90 days, were better in the low NIHSS group, however patients in the low NIHSS group experienced a relative decline in NIHSS from admit to discharge. Mortality was lower in the low NIHSS group (10.4% versus 24.5%, p < 0.001). CONCLUSIONS: Relative to patients with high NIHSS, MT is safe and effective for stroke patients with low NIHSS, and it is reasonable to offer it to appropriately selected patients presenting with minor stroke symptoms. Our findings justify efforts towards a randomized trial comparing MT versus medical management for patients with low NIHSS.

Multicenter investigation of technical and clinical outcomes after thrombectomy for distal vessel occlusion by frontline technique.

BACKGROUND: Endovascular thrombectomy (EVT) is the standard-of-care for proximal large vessel occlusion (LVO) stroke. Data on technical and clinical outcomes in distal vessel occlusions (DVOs) remain limited. METHODS: This was a retrospective study of patients undergoing EVT for stroke at 32 international centers. Patients were divided into LVOs (internal carotid artery/M1/vertebrobasilar), medium vessel occlusions (M2/A1/P1) and isolated DVOs (M3/M4/A2/A3/P2/P3) and categorized by thrombectomy technique. Primary outcome was a good functional outcome (modified Rankin Scale ≤2) at 90 days. Secondary outcomes included recanalization, procedure-time, thrombectomy attempts, hemorrhage, and mortality. Multivariate logistic regressions were used to evaluate the impact of technical variables. Propensity score matching was used to compare outcome in patients with DVO treated with aspiration versus stent retriever RESULTS: We included 7477 patients including 213 DVOs. Distal location did not independently predict good functional outcome at 90 days compared with proximal (p=0.467). In distal occlusions, successful recanalization was an independent predictor of good outcome (adjusted odds ratio (aOR) 5.11, p<0.05) irrespective of technique. Younger age, bridging therapy, and lower admission National Institutes of Health Stroke Scale (NIHSS) were also predictors of good outcome. Procedure time ≤1 hour or ≤3 thrombectomy attempts were independent predictors of good outcomes in DVOs irrespective of technique (aOR 4.5 and 2.3, respectively, p<0.05). There were no differences in outcomes in a DVO matched cohort of aspiration versus stent retriever. Rates of hemorrhage and good outcome showed an exponential relationship to procedural metrics, and were more dependent on time in the aspiration group and attempts in the stent retriever group. CONCLUSIONS: Outcomes following EVT for DVO are comparable to LVO with similar results between techniques. Techniques may exhibit different futility metrics; stent retriever thrombectomy was influenced by attempts whereas aspiration was more dependent on procedure time.

Association of Noncontrast Computed Tomography and Perfusion Modalities With Outcomes in Patients Undergoing Late-Window Stroke Thrombectomy.

Importance: There is substantial controversy with regards to the adequacy and use of noncontrast head computed tomography (NCCT) for late-window acute ischemic stroke in selecting candidates for mechanical thrombectomy. Objective: To assess clinical outcomes of patients with acute ischemic stroke presenting in the late window who underwent mechanical thrombectomy stratified by NCCT admission in comparison with selection by CT perfusion (CTP) and diffusion-weighted imaging (DWI). Design, Setting, and Participants: In this multicenter retrospective cohort study, prospectively maintained Stroke Thrombectomy and Aneurysm (STAR) database was used by selecting patients within the late window of acute ischemic stroke and emergent large vessel occlusion from 2013 to 2021. Patients were selected by NCCT, CTP, and DWI. Admission Alberta Stroke Program Early CT Score (ASPECTS) as well as confounding variables were adjusted. Follow-up duration was 90 days. Data were analyzed from November 2021 to March 2022. Exposures: Selection by NCCT, CTP, or DWI. Main Outcomes and Measures: Primary outcome was functional independence (modified Rankin scale 0-2) at 90 days. Results: Among 3356 patients, 733 underwent late-window mechanical thrombectomy. The median (IQR) age was 69 (58-80) years, 392 (53.5%) were female, and 449 (65.1%) were White. A total of 419 were selected with NCCT, 280 with CTP, and 34 with DWI. Mean (IQR) admission ASPECTS were comparable among groups (NCCT, 8 [7-9]; CTP, 8 [7-9]; DWI 8, [7-9]; P = .37). There was no difference in the 90-day rate of functional independence (aOR, 1.00; 95% CI, 0.59-1.71; P = .99) after adjusting for confounders. Symptomatic intracerebral hemorrhage (NCCT, 34 [8.6%]; CTP, 37 [13.5%]; DWI, 3 [9.1%]; P = .12) and mortality (NCCT, 78 [27.4%]; CTP, 38 [21.1%]; DWI, 7 [29.2%]; P = .29) were similar among groups. Conclusions and Relevance: In this cohort study, comparable outcomes were observed in patients in the late window irrespective of neuroimaging selection criteria. Admission NCCT scan may triage emergent large vessel occlusion in the late window.

Multicenter investigation of technical and clinical outcomes after thrombectomy for Proximal Medium Vessel Occlusion (pMeVO) by frontline technique.

BACKGROUND: Endovascular thrombectomy(EVT) is the standard of care for large vessel occlusion(LVO) stroke. Data on technical and clinical outcome in proximal medium vessel occlusions(pMeVOs) comparing frontline techniques remain limited. METHODS: We report an international multicenter retrospective study of patients undergoing EVT for stroke at 32 centers between 2015-2021. Patients were divided into LVOs(ICA/M1/Vertebrobasilar) or pMeVOs(M2/A1/P1) and categorized by thrombectomy technique. Primary outcome was 90-day good functional outcome(mRS ≤ 2). Multivariate logistic regressions were used to evaluate the impact of technical variables on clinical outcomes. Propensity score matching was used to compare outcome in patients with pMeVO treated with aspiration versus stent-retriever. RESULTS: In the cohort of 5977 LVO and 1287 pMeVO patients, pMeVO did not independently predict good-outcome(p = 0.55). In pMeVO patients, successful recanalization irrespective of frontline technique(aOR = 3.2,p < 0.05), procedure time ≤ 1-h(aOR = 2.2,p < 0.05), and thrombectomy attempts ≤ 4(aOR = 2.8,p < 0.05) were independent predictors of good-outcomes.In a propensity-matched cohort of aspiration versus stent-retriever pMeVO patients, there was no difference in good-outcomes. The rates of hemorrhage were higher(9%vs.4%,p < 0.01) and procedure time longer(51-min vs. 33-min,p < 0.01) with stent-retriever, while the number of attempts was higher with aspiration(2.5vs.2,p < 0.01). Rates of hemorrhage and good-outcome showed an exponential relationship to procedural metrics, and were more dependent on time in the aspiration group compared to attempts in the stent-retriever group. CONCLUSIONS: Clinical outcomes following EVT for pMeVO are comparable to those in LVOs. The golden hour or 3-pass rules in LVO thrombectomy still apply to pMeVO thrombectomy. Different techniques may exhibit different futility metrics; SR thrombectomy was more influenced by attempts whereas aspiration was more dependent on procedure time.

Impact of Increasing Aspiration Catheter Size and Refinement of Technique: Experience of Over 1000 Strokes Treated With ADAPT.

BACKGROUND: We present longitudinal data regarding the outcomes and evolution of mechanical thrombectomy (MT) using a direct aspiration first pass technique. OBJECTIVE: To evaluate the impact of increasing aspiration catheter size. METHODS: This is a planned analysis of a prospective cohort study that enrolled all patients who underwent a direct aspiration first pass technique MT in a comprehensive stroke center from January 2013 to December 2020. We did exploratory analysis of the characteristics and outcomes of patients who had intracranial internal carotid artery or M1 segment of middle cerebral artery occlusion based on the aspiration catheter bore size (small [041, 054, 058, and 060 inch] vs medium [0.064 and 0.068 inch] and medium vs large [0.071, 0.072, and 0.074 inch]). RESULTS: During the 8-year study period, a total of 1004 patients were included. Median age was 69 years, 49% were female patients, and 60.6% were White. Symptomatic hemorrhagic transformation was observed in 47 patients (4.7%), and 366 patients (36.5%) achieved the modified Rankin scale of 0 to 2 at 90 days after the stroke. For patients with intracranial internal carotid artery or M1 occlusion, medium-bore aspiration catheters were more likely to achieve successful recanalization after first aspiration attempt (63.9% vs 51.4%, P = .015) and had a faster groin-to-reperfusion time (16 vs 20 minutes, P = .001) when compared with small-bore catheters. However, these differences were not significant when comparing medium-bore with large-bore catheters. CONCLUSION: Medium-bore catheters had better performance measures compared with small-bore catheters. However, large-bore catheters did not show significantly better performance results that suggest a plateau effect.

Drug versus non-drug behaviors: A dual-reward model of sex differences and neurobiological mechanisms in rats.

Substance Use Disorders (SUDs) are an impactful problem characterized by chronic relapse and engagement in drug-related behaviors at the expense of non-drug behaviors. Brain regions implicated in drug and non-drug-related behaviors often overlap, complicating investigations of neurobiological mechanisms underlying SUDs. Here we presented a within-subject model for studying self-administration, reinforcer competition, extinction, and cued reinstatement of cocaine- and food-seeking in rats. Due to differences in cocaine- and food-reinforced behavior, we transformed data to proportions of baseline, revealing increased resistance to extinction and disproportionately greater cued reinstatement of cocaine seeking relative to food seeking. Consistent with previous reports, females showed greater preference for cocaine reinforcement than males, though these findings failed to reach statistical significance. To demonstrate the model's utility for investigating neurobiological mechanisms, we included proof-of-concept calcium imaging data demonstrating the utility of the behavioral model for detecting cellular activity patterns associated with cocaine- and food-seeking behaviors. Future studies utilizing this model should improve understanding of the development and expression of pathological behaviors characteristic of SUDs in humans, sex differences in these behaviors, and their neurobiological correlates. Thus, the model has utility for improving understanding of SUDs, leading to novel treatments to reduce the pathological behaviors associated with SUDs.

Is a picture-perfect thrombectomy necessary in acute ischemic stroke?

BACKGROUND: The benefit of complete reperfusion (modified Thrombolysis in Cerebral Infarction (mTICI) 3) over near-complete reperfusion (≥90%, mTICI 2c) remains unclear. The goal of this study is to compare clinical outcomes between mechanical thrombectomy (MT)-treated stroke patients with mTICI 2c versus 3. METHODS: This is a retrospective study from the Stroke Thrombectomy and Aneurysm Registry (STAR) comprising 33 centers. Adults with anterior circulation arterial vessel occlusion who underwent MT yielding mTICI 2c or mTICI 3 reperfusion were included. Patients were categorized based on reperfusion grade achieved. Primary outcome was modified Rankin Scale (mRS) 0-2 at 90 days. Secondary outcomes were mRS scores at discharge and 90 days, National Institutes of Health Stroke Scale score at discharge, procedure-related complications, and symptomatic intracerebral hemorrhage. RESULTS: The unmatched mTICI 2c and mTICI 3 cohorts comprised 519 and 1923 patients, respectively. There was no difference in primary (42.4% vs 45.1%; p=0.264) or secondary outcomes between the unmatched cohorts. Reperfusion status (mTICI 2c vs 3) was also not predictive of the primary outcome in non-imputed and imputed multivariable models. The matched cohorts each comprised 191 patients. Primary (39.8% vs 47.6%; p=0.122) and secondary outcomes were also similar between the matched cohorts, except the 90-day mRS which was lower in the matched mTICI 3 cohort (p=0.049). There were increased odds of the primary outcome with mTICI 3 in patients with baseline mRS ≥2 (36% vs 7.7%; p=0.011; pinteraction=0.014) and a history of stroke (42.3% vs 15.4%; p=0.027; pinteraction=0.041). CONCLUSIONS: Complete and near-complete reperfusion after MT appear to confer comparable outcomes in patients with acute stroke.

Outcomes of Mechanical Thrombectomy for Patients With Stroke Presenting With Low Alberta Stroke Program Early Computed Tomography Score in the Early and Extended Window.

Importance: Limited data are available about the outcomes of mechanical thrombectomy (MT) for real-world patients with stroke presenting with a large core infarct. Objective: To investigate the safety and effectiveness of MT for patients with large vessel occlusion and an Alberta Stroke Program Early Computed Tomography Score (ASPECTS) of 2 to 5. Design, Setting, and Participants: This retrospective cohort study used data from the Stroke Thrombectomy and Aneurysm Registry (STAR), which combines the prospectively maintained databases of 28 thrombectomy-capable stroke centers in the US, Europe, and Asia. The study included 2345 patients presenting with an occlusion in the internal carotid artery or M1 segment of the middle cerebral artery from January 1, 2016, to December 31, 2020. Patients were followed up for 90 days after intervention. The ASPECTS is a 10-point scoring system based on the extent of early ischemic changes on the baseline noncontrasted computed tomography scan, with a score of 10 indicating normal and a score of 0 indicating ischemic changes in all of the regions included in the score. Exposure: All patients underwent MT in one of the included centers. Main Outcomes and Measures: A multivariable regression model was used to assess factors associated with a favorable 90-day outcome (modified Rankin Scale score of 0-2), including interaction terms between an ASPECTS of 2 to 5 and receiving MT in the extended window (6-24 hours from symptom onset). Results: A total of 2345 patients who underwent MT were included (1175 women [50.1%]; median age, 72 years [IQR, 60-80 years]; 2132 patients [90.9%] had an ASPECTS of ≥6, and 213 patients [9.1%] had an ASPECTS of 2-5). At 90 days, 47 of the 213 patients (22.1%) with an ASPECTS of 2 to 5 had a modified Rankin Scale score of 0 to 2 (25.6% [45 of 176] of patients who underwent successful recanalization [modified Thrombolysis in Cerebral Ischemia score ≥2B] vs 5.4% [2 of 37] of patients who underwent unsuccessful recanalization; P = .007). Having a low ASPECTS (odds ratio, 0.60; 95% CI, 0.38-0.85; P = .002) and presenting in the extended window (odds ratio, 0.69; 95% CI, 0.55-0.88; P = .001) were associated with worse 90-day outcome after controlling for potential confounders, without significant interaction between these 2 factors (P = .64). Conclusions and Relevance: In this cohort study, more than 1 in 5 patients presenting with an ASPECTS of 2 to 5 achieved 90-day functional independence after MT. A favorable outcome was nearly 5 times more likely for patients with low ASPECTS who had successful recanalization. The association of a low ASPECTS with 90-day outcomes did not differ for patients presenting in the early vs extended MT window.

Accumbens D2-MSN hyperactivity drives antipsychotic-induced behavioral supersensitivity.

Antipsychotic-induced dopamine supersensitivity, or behavioral supersensitivity, is a problematic consequence of long-term antipsychotic treatment characterized by the emergence of motor abnormalities, refractory symptoms, and rebound psychosis. The underlying mechanisms are unclear and no approaches exist to prevent or reverse these unwanted effects of antipsychotic treatment. Here we demonstrate that behavioral supersensitivity stems from long-lasting pre, post and perisynaptic plasticity, including insertion of Ca2+-permeable AMPA receptors and loss of D2 receptor-dependent inhibitory postsynaptic currents (IPSCs) in D2 receptor-expressing medium spiny neurons (D2-MSNs) in the nucleus accumbens core (NAcore). The resulting hyperexcitability, prominent in a subpopulation of D2-MSNs (21%), caused locomotor sensitization to cocaine and was associated with behavioral endophenotypes of antipsychotic treatment resistance and substance use disorder, including disrupted extinction learning and augmented cue-induced cocaine-seeking behavior. Chemogenetic restoration of IPSCs in D2-MSNs in the NAcore was sufficient to prevent antipsychotic-induced supersensitivity, pointing to an entirely novel therapeutic direction for overcoming this condition.

Mechanical Thrombectomy for Distal Occlusions: Efficacy, Functional and Safety Outcomes: Insight from the STAR Collaboration.

BACKGROUND: Mechanical thrombectomy (MT) is the standard of care for the treatment of proximal anterior circulation large vessel occlusions. However, little is known about its efficacy and safety in the treatment of distal intracranial occlusions. METHODS: This is a multicenter retrospective study of patients treated with MT at 15 comprehensive centers between January 2015 and December 2018. The study cohort was divided into 2 groups based on the location of occlusion (proximal vs. distal). Distal occlusion was defined as occlusion of M3 segment of the middle cerebral artery, any segment of the anterior cerebral artery, or any segment of the posterior cerebral artery. Only isolated distal occlusion was included. Good outcome was defined as 90-day modified Rankin scale score 0-2. RESULTS: A total of 4710 patients were included in this study, of whom 189 (4%) had MT for distal occlusions. Compared with the proximal occlusion group, distal occlusion group had a higher rate of good outcome (45% vs. 36%; P = 0.03) and a lower rate of successful reperfusion (78% vs. 84%; P = 0.04). However, the differences did not retain significance in adjusted models. Otherwise there was no difference in the rate of hemorrhagic complications, mortality, or procedure-related complications between the 2 groups. Successful reperfusion, age, and admission stroke severity emerged as predictors of good functional outcome in the distal occlusion group. CONCLUSIONS: Thrombectomies of distal vessels achieve high rate of successful reperfusion with similar safety profile to those in more proximal locations.

Complement Drives Synaptic Degeneration and Progressive Cognitive Decline in the Chronic Phase after Traumatic Brain Injury.

Cognitive deficits following traumatic brain injury (TBI) remain a major cause of disability and early-onset dementia, and there is increasing evidence that chronic neuroinflammation occurring after TBI plays an important role in this process. However, little is known about the molecular mechanisms responsible for triggering and maintaining chronic inflammation after TBI. Here, we identify complement, and specifically complement-mediated microglial phagocytosis of synapses, as a pathophysiological link between acute insult and a chronic neurodegenerative response that is associated with cognitive decline. Three months after an initial insult, there is ongoing complement activation in the injured brain of male C57BL/6 mice, which drives a robust chronic neuroinflammatory response extending to both hemispheres. This chronic neuroinflammatory response promotes synaptic degeneration and predicts progressive cognitive decline. Synaptic degeneration was driven by microglial phagocytosis of complement-opsonized synapses in both the ipsilateral and contralateral brain, and complement inhibition interrupted the degenerative neuroinflammatory response and reversed cognitive decline, even when therapy was delayed until 2 months after TBI. These findings provide new insight into our understanding of TBI pathology and its management; and whereas previous therapeutic investigations have focused almost exclusively on acute treatments, we show that all phases of TBI, including at chronic time points after TBI, may be amenable to therapeutic interventions, and specifically to complement inhibition.SIGNIFICANCE STATEMENT There is increasing evidence of a chronic neuroinflammatory response after traumatic brain injury (TBI), but little is known about the molecular mechanisms responsible for triggering and maintaining chronic inflammation. We identify complement, and specifically complement-mediated microglial phagocytosis of synapses, as a pathophysiological link between acute insult and a chronic neurodegenerative response, and further that this response is associated with cognitive decline. Complement inhibition interrupted this response and reversed cognitive decline, even when therapy was delayed until 2 months after injury. The data further support the concept that TBI should be considered a chronic rather than an acute disease condition, and have implications for the management of TBI in the chronic phase of injury, specifically with regard to the therapeutic application of complement inhibition.

Stem Cells: In Sickness and in Health.

Stem cells are undifferentiated cells with the ability to proliferate and convert to different types of differentiated cells that make up the various tissues and organs in the body. They exist both in embryos as pluripotent stem cells that can differentiate into the three germ layers and as multipotent or unipotent stem cells in adult tissues to aid in repair and homeostasis. Perturbations in these cells' normal functions can give rise to a wide variety of diseases. In this review, we discuss the origin of different stem cell types, their properties and characteristics, their role in tissue homeostasis, current research, and their potential applications in various life-threatening diseases. We focus on neural stem cells, their role in neurogenesis and how they can be exploited to treat diseases of the brain including neurodegenerative diseases and cancer. Next, we explore current research in Induced Pluripotent Stem Cells (iPSC) techniques and their clinical applications in regenerative and personalized medicine. Lastly, we tackle a special type of stem cells called Cancer Stem Cells (CSCs) and how they can be responsible for therapy resistance and tumor recurrence and explore ways to target them.

Tideglusib attenuates growth of neuroblastoma cancer stem/progenitor cells in vitro and in vivo by specifically targeting GSK-3ß.

BACKGROUND: Neuroblastoma (NB) is the most frequently diagnosed extracranial solid tumor among the pediatric population. It is an embryonic tumor with high relapse rates pertaining to the presence of dormant slowly dividing cancer stem cells (CSC) within the tumor bulk that are responsible for therapy resistance. Therefore, there is a dire need to develop new therapeutic approaches that specifically target NB CSCs. Glycogen synthase kinase (GSK)-3ß is a serine/threonine kinase that represents a common signaling node at the intersection of many pathways implicated in NB CSCs. GSK-3ß sustains the survival and maintenance of CSCs and renders them insensitive to chemotherapeutic agents and radiation. METHODS: In our study, we aimed at evaluating the potential anti-tumor effect of Tideglusib (TDG), an irreversible GSK-3ß inhibitor drug, on three human NB cell lines, SK-N-SH, SH-SY5Y, and IMR-32. RESULTS: Our results showed that TDG significantly reduced cell proliferation, viability, and migration of the NB cells, in a dose- and time-dependent manner, and also significantly hindered the neurospheres formation eradicating the self-renewal ability of highly resistant CSCs. Besides, TDG potently reduced CD133 cancer stem cell marker expression in both SH-SY5Y cells and G1 spheres. Lastly, TDG inhibited NB tumor growth and progression in vivo. CONCLUSION: Collectively, we concluded that TDG could serve as an effective treatment capable of targeting the NB CSCs and hence overcoming therapy resistance. Yet, future studies are warranted to further investigate its potential role in NB and decipher the subcellular and molecular mechanisms underlying this role.

The potential use of tideglusib as an adjuvant radio-therapeutic treatment for glioblastoma multiforme cancer stem-like cells.

BACKGROUND: Glioblastoma multiforme (GBM), a stage IV astrocytoma, is the most common brain malignancy among adults. Conventional treatments of surgical resection followed by radio and/or chemotherapy fail to completely eradicate the tumor. Resistance to the currently available therapies is mainly attributed to a subpopulation of cancer stem cells (CSCs) present within the tumor bulk that self-renew leading to tumor relapse with time. Therefore, identification of characteristic markers specific to these cells is crucial for the development of targeted therapies. Glycogen synthase kinase 3 (GSK-3), a serine-threonine kinase, is deregulated in a wide range of diseases, including cancer. In GBM, GSK-3ß is overexpressed and its suppression in vitro has been shown to induce apoptosis of cancer cells. METHODS: In our study, we assessed the effect of GSK-3ß inhibition with Tideglusib (TDG), an irreversible non-ATP competitive inhibitor, using two human GBM cell lines, U-251 MG and U-118 MG. In addition, we combined TDG with radiotherapy to assess whether this inhibition enhances the effect of standard treatment. RESULTS: Our results showed that TDG significantly reduced cell proliferation, cell viability, and migration of both GBM cell lines in a dose- and time-dependent manner in vitro. Treatment with TDG alone and in combination with radiation significantly decreased the colony formation of U-251 MG cells and the sphere formation of both cell lines, by targeting and reducing their glioblastoma cancer stem-like cells (GSCs) population. Finally, cells treated with TDG showed an increased level of unrepaired radio-induced DNA damage and, thus, became sensitized toward radiation. CONCLUSIONS: In conclusion, TDG has proven its effectiveness in targeting the cancerous properties of GBM in vitro and may, hence, serve as a potential adjuvant radio-therapeutic agent to better target this deadly tumor.