Ticking Brain: Circadian Rhythm as a New Target for Cerebroprotection.

Circadian rhythm is a master process observed in nearly every type of cell throughout the body, and it macroscopically regulates daily physiology. Recent clinical trials have revealed the effects of circadian variation on the incidence, pathophysiological processes, and prognosis of acute ischemic stroke. Furthermore, core clock genes, the cell-autonomous pacemakers of the circadian rhythm, affect the neurovascular unit-composing cells in a nonparallel manner after the same pathophysiological processes of ischemia/reperfusion. In this review, we discuss the influence of circadian rhythms and clock genes on each type of neurovascular unit cell in the pathophysiological processes of acute ischemic stroke.

Clinical, genetic, and neuroimaging profiles of autosomal recessive spinocerebellar ataxia type 4 caused by novel VPS13D variants in Chinese.

Autosomal recessive spinocerebellar ataxias (SCARs) are a heterogeneous group of neurodegenerative disorders. VPS13D gene is currently the only gene associated with autosomal recessive spinocerebellar ataxia type 4 (SCAR4), also known as VPS13D dyskinesia. SCAR4 is a rare inherited disease, with only 34 reported cases reported worldwide. In this study, we reported three independent SCAR4 cases with adolescent onsets caused by five novel variants of the VPS13D gene. Each patient carried one frameshift and one missense variant: Patient 1 with c.10474del and c.9734C > A (p.Leu3492Tyrfs*43 and p.Thr3245Asn), Patient 2 with c.6094_6107delGTTCTCTTGATCCC and c.9734C > A (p.Val2032Argfs*7 and p.Thr3245Asn), and Patient 3 with c.11954_11963del and c.9833 T > G (p.Phe3985Serfs*10 and p.Ile3278Ser). Two of the three patients shared nystagmus with an identical variant c.9734C > A. Magnetic resonance imaging indicated thoracic spinal atrophy in all three patients and corpus callosum atrophy in one patient, along with other typical manifestations of white matter degradation, cerebral atrophy, and cerebellar atrophy. These findings expanded the genetic, clinical, and neuroimaging spectrum of SCAR4, and provided new insights into the genetic counseling, molecular mechanisms, and differential diagnosis of the disease.

Risk Factors for Severe Residual Headache in Cerebral Venous Thrombosis.

BACKGROUND AND PURPOSE: Which factors will influence the presence of severe residual headache after cerebral venous thrombosis (CVT) is unclear. The purpose of this study was to identify risk factors for severe residual headache in a large single-center cohort of patients with CVT. METHODS: We consecutively included eligible patients with CVT from a prospective stroke registry. Severe residual headache was defined as a residual headache attack requiring bed rest or hospital admission within 1 month before the last follow-up visit. We identified the risk factors of severe residual headache in all survivors and in those with favorable functional outcome (a modified Rankin Scale score, 0-2). RESULTS: A total of 325 patients' data were analyzed. At the last follow-up (median 13 months), 43 patients (13.2%) reported severe headache. In the multivariable analysis, isolated intracranial hypertension (odds ratio [OR], 3.309 [95% CI, 1.434-7.634]; P=0.005), CVT recurrence (OR, 4.722 [95% CI, 1.639-13.602]; P=0.004), and no recanalization (OR, 10.158 [95% CI, 4.194-24.600]; P<0.001) were independently associated with severe headache. Severe headache was more frequent in patients with unfavorable outcome (11/25 [44.0%] versus 32/300 [10.7%]; P<0.001). In patients with favorable outcome, the risk factors for severe headache were isolated intracranial hypertension (OR, 3.236 [95% CI, 1.268-8.256]; P=0.014) and no recanalization (OR, 7.863 [95% CI, 3.120-19.812]; P<0.001). CONCLUSIONS: Isolated intracranial hypertension, CVT recurrence, and no recanalization increased the risk for severe residual headache after CVT.

No-reflow after stroke reperfusion therapy: An emerging phenomenon to be explored.

In the field of stroke thrombectomy, ineffective clinical and angiographic reperfusion after successful recanalization has drawn attention. Partial or complete microcirculatory reperfusion failure after the achievement of full patency of a former obstructed large vessel, known as the "no-reflow phenomenon" or "microvascular obstruction," was first reported in the 1960s and was later detected in both experimental models and patients with stroke. The no-reflow phenomenon (NRP) was reported to result from intraluminal occlusions formed by blood components and extraluminal constriction exerted by the surrounding structures of the vessel wall. More recently, an emerging number of clinical studies have estimated the prevalence of the NRP in stroke patients following reperfusion therapy, ranging from 3.3% to 63% depending on its evaluation methods or study population. Studies also demonstrated its detrimental effects on infarction progress and neurological outcomes. In this review, we discuss the research advances, underlying pathogenesis, diagnostic techniques, and management approaches concerning the no-reflow phenomenon in the stroke population to provide a comprehensive understanding of this phenomenon and offer references for future investigations.

Long term for patients with futile endovascular reperfusion after stroke.

AIMS: With the progress of thrombectomy technology, the vascular recanalization rate of patients with stroke has been continuously improved, but the proportion of futile recanalization (FR) is still quite a few. The long-term prognosis and survival of patients with FR and its influencing factors remain unclear. METHODS: Consecutive patients who received endovascular treatment (EVT) for ischemic stroke were enrolled between 2013 and 2021 from a single-center prospectively registry study. We evaluated the long-term outcome of these patients by Kaplan-Meier survival analysis, and the multivariable logistic regression curve was performed to analyze influencing factors. RESULTS: Among 458 patients with FR, 56.4% of patients survived at 1 year, and 50.4% at 2 years. In the multivariate regression analysis, age, premorbid modified Rankin Scale (mRS), National Institutes of Health Stroke Scale (NIHSS), posterior circulation infarct, general anesthesia, symptomatic intracerebral hemorrhage (sICH), and decompressive craniectomy were found to be related to unfavorable outcomes in long-term. Age, premorbid mRS, NIHSS, general anesthesia, and sICH were predictors of long-term mortality. CONCLUSIONS: Futile recanalization accounts for a large proportion of stroke patients after thrombectomy. This study on the long-term prognosis of such patients is beneficial to the formulation of treatment plans and the prediction of therapeutic effects.

Predicting Futile Recanalization in Acute Ischemic Stroke Patients Undergoing Endovascular Thrombectomy: The Role of White Blood Cell Count to Mean Platelet Volume Ratio.

BACKGROUND: Approximately half of AIS patients have an unfavorable outcome even after complete reperfusion. White blood cell (WBC) count to mean platelet volume (MPV) ratio (WMR) may be a promising predictive factor for futile recanalization. This study aimed to determine the predictive value of WMR in identifying individuals at higher risk of futile recanalization. METHODS: In this retrospective cohort study, 296 patients who achieved complete reperfusion after endovascular treatment (EVT) were included in the analysis. WBC count and MPV were collected at admission. Multivariable logistic regression was used to examine the independent association of the WMR with functional outcomes at three months. Net reclassification improvement (NRI) and integrated discrimination improvement (IDI) analyses were used to compare the accuracy of WMR for predicting futile recanalization. RESULTS: The adjusted odds ratios for the fourth quartile of WMR were 3.142 (95% CI 1.405- 7.027, P = 0.005) for unfavorable outcomes at 3 months in comparison with the first quartile. The inclusion of WMR in the traditional model enabled a more accurate prediction of unfavorable outcomes (NRI 0.250, P = 0.031; IDI 0.022, P = 0.017). CONCLUSION: Elevated WMR at admission was independently associated with futile recanalization among AIS patients who received EVT and might be useful in identifying futile recanalization.

Mild hypothermia therapy attenuates early BBB leakage in acute ischaemic stroke.

Reperfusion therapy inevitably leads to brain-blood barrier (BBB) disruption and promotes damage despite its benefits for acute ischaemic stroke (AIS). An effective brain cytoprotective treatment is still needed as an adjunct to reperfusion therapy. Here, we explore the potential benefits of therapeutic hypothermia (HT) in attenuating early BBB leakage and improving neurological outcomes. Mild HT was induced during the early and peri-recanalization stages in a mouse model of transient middle cerebral artery occlusion and reperfusion (tMCAO/R). The results showed that mild HT attenuated early BBB leakage in AIS, decreased the infarction volume, and improved functional outcomes. RNA sequencing data of the microvessels indicated that HT decreased the transcription of the actin polymerization-related pathway. We further discovered that HT attenuated the ROCK1/MLC pathway, leading to a decrease in the polymerization of G-actin to F-actin. Arachidonic acid (AA), a known structural ROCK agonist, partially counteracted the protective effects of HT in the tMCAO/R model. Our study highlights the importance of early vascular protection during reperfusion and provides a new strategy for attenuating early BBB leakage by HT treatment for ischaemic stroke.

Normobaric Hyperoxia (NBHO): An Adjunctive Therapy to Cerebrovascular Recanalization in Ischemic Stroke.

Acute ischemic stroke (AIS) is a serious neurological disease. Normobaric hyperoxia (NBHO) is both a non-invasive and easy method that seems to be able to improve outcomes after cerebral ischemia/reperfusion. In clinical trials, normal low-flow oxygen has been shown to be ineffective, but NBHO has been shown to have a transient brain-protective effect. Today, NBHO combined with recanalization is the best treatment available. NBHO combined with thrombolysis is considered to improve neurological scores and long-term outcomes. Large randomized controlled trials (RCTs), however, are still needed to determine the role they will have in stroke treatment. RCTs of NBHO combined with thrombectomy have both improved infarct volume at 24 hours and the long-term prognosis. These two mechanisms most likely play key roles in the neuroprotective actions of NBHO after recanalization, including the increase in penumbra oxygen supply and the integrity of the blood-brain barrier (BBB). Considering the mechanism of action of NBHO, oxygen should be given as early as possible to increase the duration of oxygen therapy before recanalization is initiated. NBHO can further prolong the existence time of penumbra, so that more patients may benefit from it. Overall, however, recanalization therapy is still essential.

Neuroimaging biomarkers of small vessel disease in cerebral amyloid angiopathy-related intracerebral hemorrhage.

AIMS: The significance of the correlation of computed tomography (CT)-based cerebral small vessel disease (SVD) markers with the clinical outcomes in patients with cerebral amyloid angiopathy (CAA)-related intracerebral hemorrhage (ICH) remains uncertain. Thus, this study aimed to explore the relationship between SVD markers and short-term outcomes of CAA-ICH. METHODS: A total of 183 patients with CAA-ICH admitted to the Xuanwu Hospital, and Beijing Fengtai You'anmen Hospital, from 2014 to 2021 were included. The multivariate logistic regression analysis was performed to identify the correlation between SVD markers based on CT and clinical outcomes at 7-day and 90-day. RESULTS: Of the 183 included patients, 66 (36%) were identified with severe SVD burden. The multivariate analysis showed that the total SVD burden, white matter lesion (WML) grade, and brain atrophy indicator were independent risk factors for unfavorable outcomes at 90-day. The brain atrophy indicator was independently associated with mortality at 90-day. Severe cortical atrophy was significantly associated with early neurological deterioration. CONCLUSIONS: The neuroimaging profiles of SVD based on CT in patients with CAA-ICH might predict the short-term outcome more effectively. Further studies are required to validate these findings and identify modifiable factors for preventing CAA-ICH development.

Cerebral Venous-Associated Brain Damage May Lead to Anxiety and Depression.

Background and purpose: Anxiety and depression are common in patients with Cerebral venous outflow disturbance (CVOD). Here, we aimed to explore possible mechanisms underlying this phenomenon. Methods: We enrolled patients diagnosed with imaging-confirmed CVOD, including internal jugular venous stenosis (IJVS) and cerebral venous sinus stenosis (CVSS) between 2017 and 2020. All of them had MRI/PWI scans. The Hamilton Anxiety Scale (HAMA) and 24-item Hamilton Depression Scale (HAMD) were used to evaluate the degree of anxiety and depression at the baseline and three months post-stenting. In addition, the relationships between the HAMA and HAMD scores, white matter lesions, and cerebral perfusion were analyzed using multiple logistic regressions. Results: A total of 61 CVOD patients (mean age 47.95 ± 15.26 years, 59.0% females) were enrolled in this study. Over 70% of them reported symptoms of anxiety and/or depression. Severe CVOD-related anxiety correlated with older age (p = 0.046) and comorbid hyperlipidemia (p = 0.005). Additionally, head noise, sleep disturbances, and white matter lesions (WMLs) were common risk factors for anxiety and depression (p < 0.05). WMLs were considered an independent risk factor for anxiety based on multiple regression analysis (p = 0.029). Self-contrast displayed that CVOD-related anxiety (p = 0.027) and depression (p = 0.017) scores could be corrected by stenting, as the hypoperfusion scores in the limbic lobes of patients with anxiety and depression were significantly higher than those in patients without. Conclusions: CVOD-induced hypoperfusion-mediated changes in the white matter microstructure may represent an underlying mechanism of anxiety and depression in patients with chronic CVOD.

Association between the time of day at stroke onset and functional outcome of acute ischemic stroke patients treated with endovascular therapy.

To investigate the association between time-of-day of stroke onset and functional outcome in patients with acute ischemic stroke(AIS) treated with endovascular thrombectomy(EVT). AIS patients treated with EVT between January 2013 and December 2018 were recruited and divided them into four 6-h interval groups according to the time-of-day of stroke onset. A total of 438 patients were enrolled, 3-month favorable outcome were achieved in 58.6%, 43.7%, 36.6%, and 30.5% of patients in the 00:00-06:00, 06:00-12:00, 12:00-18:00, and 18:00-24:00 groups, respectively (adjusted OR 0.61, 95% CI 0.40-0.93; p = 0.020). Compared with the 18:00-24:00 interval, patients in the 00:00-06:00 interval (adjusted OR 4.01, 95%CI 1.02-15.80, p = 0.047) and the 06:00-12:00 interval (adjusted OR 3.24, 95% CI 1.09-9.64, p = 0.034) were more likely to achieve favorable outcome. The time-of-day of stroke onset was not associated with 3-month mortality (adjusted p = 0.829), symptomatic intracerebral hemorrhage (sICH, adjusted p = 0.296), or early successful recanalization (adjusted p = 0.074). In conclusion, in AIS patients treated with EVT, those onsets either between 00:00 and 06:00 or between 06:00 and 12:00 appeared to be associated with a higher proportion of favorable outcomes at 3 months, but the time-of-day at stroke onset was not associated with the incidence of sICH, rate of early successful recanalization, or 3-month mortality.