Treatment with an Angiopoietin-1 mimetic peptide promotes neurological recovery after stroke in diabetic rats

AimVasculotide (VT), an angiopoietin‐1 mimetic peptide, exerts neuroprotective effects in type one diabetic (T1DM) rats subjected to ischemic stroke. In this study, we investigated whether delayed VT treatment improves long‐term neurological outcome after stroke in T1DM rats.MethodsMale Wistar rats were induced with T1DM, subjected to middle cerebral artery occlusion (MCAo) model of stroke, and treated with PBS (control), 2 µg/kg VT, 3 µg/kg VT, or 5.5 µg/kg VT. VT treatment was initiated at 24 h after stroke and administered daily (i.p) for 14 days. We evaluated neurological function, lesion volume, vascular and white matter remodeling, and inflammation in the ischemic brain. In vitro, we evaluated the effects of VT on endothelial cell capillary tube formation and inflammatory responses of primary cortical neurons (PCN) and macrophages.ResultsTreatment of T1DM‐stroke with 3 µg/kg VT but not 2 µg/kg or 5.5 µg/kg significantly improves neurological function and decreases infarct volume and cell death compared to control T1DM‐stroke rats. Thus, 3 µg/kg VT dose was employed in all subsequent in vivo analysis. VT treatment significantly increases axon and myelin density, decreases demyelination, decreases white matter injury, increases number of oligodendrocytes, and increases vascular density in the ischemic border zone of T1DM stroke rats. VT treatment significantly decreases MMP9 expression and decreases the number of M1 macrophages in the ischemic brain of T1DM‐stroke rats. In vitro, VT treatment significantly decreases endothelial cell death and decreases MCP‐1, endothelin‐1, and VEGF expression under high glucose (HG) and ischemic conditions and significantly increases capillary tube formation under HG conditions when compared to non‐treated control group. VT treatment significantly decreases inflammatory factor expression such as MMP9 and MCP‐1 in macrophages subjected to LPS activation and significantly decreases IL‐1β and MMP9 expression in PCN subjected to ischemia under HG conditions.ConclusionDelayed VT treatment (24 h after stroke) significantly improves neurological function, promotes vascular and white matter remodeling, and decreases inflammation in the ischemic brain after stroke in T1DM rats.     

Spinal microglial β‐endorphin signaling mediates IL‐10 and exenatide‐induced inhibition of synaptic plasticity in neuropathic pain

AimThis study aimed to investigate the regulation of pain hypersensitivity induced by the spinal synaptic transmission mechanisms underlying interleukin (IL)‐10 and glucagon‐like peptide 1 receptor (GLP‐1R) agonist exenatide‐induced pain anti‐hypersensitivity in neuropathic rats through spinal nerve ligations.MethodsNeuropathic pain model was established by spinal nerve ligation of L5/L6 and verified by electrophysiological recording and immunofluorescence staining. Microglial expression of β‐endorphin through autocrine IL‐10‐ and exenatide‐induced inhibition of glutamatergic transmission were performed by behavioral tests coupled with whole‐cell recording of miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) through application of endogenous and exogenous IL‐10 and β‐endorphin.ResultsIntrathecal injections of IL‐10, exenatide, and the μ‐opioid receptor (MOR) agonists β‐endorphin and DAMGO inhibited thermal hyperalgesia and mechanical allodynia in neuropathic rats. Whole‐cell recordings of bath application of exenatide, IL‐10, and β‐endorphin showed similarly suppressed enhanced frequency and amplitude of the mEPSCs in the spinal dorsal horn neurons of laminae II, but did not reduce the frequency and amplitude of mIPSCs in neuropathic rats. The inhibitory effects of IL‐10 and exenatide on pain hypersensitive behaviors and spinal synaptic plasticity were totally blocked by pretreatment of IL‐10 antibody, β‐endorphin antiserum, and MOR antagonist CTAP. In addition, the microglial metabolic inhibitor minocycline blocked the inhibitory effects of IL‐10 and exenatide but not β‐endorphin on spinal synaptic plasticity.ConclusionThis suggests that spinal microglial expression of β‐endorphin mediates IL‐10‐ and exenatide‐induced inhibition of glutamatergic transmission and pain hypersensitivity via presynaptic and postsynaptic MORs in spinal dorsal horn.     

White matter degeneration revealed by fiber‐specific analysis relates to recovery of hand function after stroke

Recent developments of higher‐order diffusion‐weighted imaging models have enabled the estimation of specific white matter fiber populations within a voxel, addressing limitations of traditional imaging markers of white matter integrity. We applied fixel based analysis (FBA) to investigate the evolution of fiber‐specific white matter changes in a prospective study of stroke patients and upper limb motor deficit over 1 year after stroke. We studied differences in fiber density and macrostructural changes in fiber cross‐section. Motor function was assessed by grip strength. We conducted a whole‐brain analysis of fixel metrics and predefined corticospinal tract (CST) region of interest in relation to changes in motor functions. In 30 stroke patients (mean age 62.3 years, SD ±16.9; median NIHSS 4, IQR 2–5), whole‐brain FBA revealed progressing loss of fiber density and cross‐section in the ipsilesional corticospinal tract and long‐range fiber tracts such as the superior longitudinal fascicle and trans‐callosal tracts extending towards contralesional white matter tracts. Lower FBA metrics measured at the brainstem section of the CST 1 month after stroke were significantly associated with lower grip strength 3 months (p = .009, adjusted R ² = 0.259) and 1 year (T4: p < .001, adj. R ² = 0.515) after stroke. Compared to FA, FBA metrics showed a comparably strong association with grip strength at later time points. Using FBA, we demonstrate progressive fiber‐specific white matter loss after stroke and association with functional motor outcome. Our results promote the application of fiber‐specific analysis to detect secondary neurodegeneration after stroke in relation to clinical recovery.     

DNA methylation analysis with methylation‐sensitive high‐resolution melting (MS‐HRM) reveals gene panel for glioma characteristics

IntroductionLocal DNA hypermethylation is a potential source of cancer biomarkers. While the evaluation of single gene methylation has limited value, their selected panel may provide better information.AimsThis study aimed to analyze the promoter methylation level in a 7‐gene panel in brain tumors and verifies the usefulness of methylation‐sensitive high‐resolution melting (MS‐HRM) for this purpose.MethodsForty‐six glioma samples and one non‐neoplastic brain sample were analyzed by MS‐HRM in terms of SFRP1, SFRP2, RUNX3, CBLN4, INA, MGMT, and RASSF1A promoter methylation. The results were correlated with patients’ clinicopathological features.ResultsDNA methylation level of all analyzed genes was significantly higher in brain tumor samples as compared to non‐neoplastic brain and commercial, unmethylated DNA control. RASSF1A was the most frequently methylated gene, with statistically significant differences depending on the tumor WHO grade. Higher MGMT methylation levels were observed in females, whereas the levels of SFRP1 and INA promoter methylation significantly increased with patients’ age. A positive correlation of promoter methylation levels was observed between pairs of genes, for example, CBLN4 and INA or MGMT and RASSF1A.ConclusionsOur 7‐gene panel of promoter methylation can be helpful in brain tumor diagnosis or characterization, and MS‐HRM is a suitable method for its analysis.     

Cerebral perfusion imaging predicts final infarct volume after basilar artery thrombectomy

ObjectivesCerebral perfusion imaging may be used to identify the ischemic core in acute ischemic stroke (AIS) patients with a large vessel occlusion of the anterior circulation; however, perfusion parameters that predict the ischemic core in AIS patients with a basilar artery occlusion (BAO) are poorly described. We determined which cerebral perfusion parameters best predict the ischemic core after successful endovascular thrombectomy (EVT) in BAO patients.Materials and methodsWe performed multicenter retrospective study of BAO patients with perfusion imaging before EVT and a DWI after successful EVT. The ischemic core was defined as regions on CTP, which were co-registered to the final DWI infarct. Various time-to-maximum (Tmax) and cerebral blood flow (CBF) thresholds were compared to final infarct volume to determine the best predictor of the final infarct.Results28 patients were included in the analysis for this study. Tmax >8s (r²: 0.56; median absolute error, 16.0 mL) and Tmax >10s (r²: 0.73; median absolute error, 11.3 mL) showed the strongest agreement between the pre-EVT CTP study and the final DWI. CBF <38% (r²: 0.76; median absolute error, 8.2 mL) and CBF <34% (r²: 0.76; median absolute error, 9.1 mL) also correlated well with final infarct volume on DWI.ConclusionsPre-EVT CT perfusion imaging is useful to predict the final ischemic infarct volume in BAO patients. Tmax >8s and Tmax >10s were the strongest predictors of the post-EVT final infarct volume.     

Poldip2 mediates blood‐brain barrier disruption and cerebral edema by inducing AQP4 polarity loss in mouse bacterial meningitis model

BackgroundSpecific highly polarized aquaporin‐4 (AQP4) expression is reported to play a crucial role in blood‐brain barrier (BBB) integrity and brain water transport balance. The upregulation of polymerase δ‐interacting protein 2 (Poldip2) was involved in aggravating BBB disruption following ischemic stroke. This study aimed to investigate whether Poldip2‐mediated BBB disruption and cerebral edema formation in mouse bacterial meningitis (BM) model occur via induction of AQP4 polarity loss.Methods and ResultsMouse BM model was induced by injecting mice with group B hemolytic streptococci via posterior cistern. Recombinant human Poldip2 (rh‐Poldip2) was administered intranasally at 1 hour after BM induction. Small interfering ribonucleic acid (siRNA) targeting Poldip2 was administered by intracerebroventricular (i.c.v) injection at 48 hours before BM induction. A specific inhibitor of matrix metalloproteinases (MMPs), UK383367, was administered intravenously at 0.5 hour before BM induction. Western blotting, immunofluorescence staining, quantitative real‐time PCR, neurobehavioral test, brain water content test, Evans blue (EB) permeability assay, transmission electron microscopy (TEM), and gelatin zymography were carried out. The results showed that Poldip2 was upregulated and AQP4 polarity was lost in mouse BM model. Both Poldip2 siRNA and UK383367 improved neurobehavioral outcomes, alleviated brain edema, preserved the integrity of BBB, and relieved the loss of AQP4 polarity in BM model. Rh‐Poldip2 upregulated the expression of MMPs and glial fibrillary acidic protein (GFAP) and downregulated the expression of β‐dystroglycan (β‐DG), zonula occludens‐1 (ZO‐1), occludin, and claudin‐5; whereas Poldip2 siRNA downregulated the expression of MMPs and GFAP, and upregulated β‐DG, ZO‐1, occludin, and claudin‐5. Similarly, UK383367 downregulated the expression of GFAP and upregulated the expression of β‐DG, ZO‐1, occludin, and claudin‐5.ConclusionPoldip2 inhibition alleviated brain edema and preserved the integrity of BBB partially by relieving the loss of AQP4 polarity via MMPs/β‐DG pathway.     

Exercise pre-conditioning reduces brain inflammation in stroke via tumor necrosis factor-α, extracellular signal-regulated kinase 1/2 and matrix metalloproteinase-9 activity

Abstract

Objective: We sought to determine whether cerebral inflammation in ischemic rats was reduced by a neuroprotective action of pre-ischemic tumor necrosis factor-α up-regulation, which down-regulated matrix metalloproteinase-9 activity via extracellular signal-regulated kinase 1/2 phosphorylation.

Material and methods: Adult male Sprague–Dawley rats were subjected to 30 minutes of exercise on a treadmill for 3 weeks. Stroke was induced by a 2 hour middle cerebral artery occlusion using an intraluminal filament. The exercised animals were treated with tumor necrosis factor-α antibody, UO126 (extracellular signal-regulated kinase 1/2 inhibitor), or both UO126 and doxycycline (matrix metalloproteinase-9 inhibitor). Brain infarct volume was assessed using Nissl staining. Leukocyte infiltration was evaluated using myeloperoxidase immunostaining. Intercellular adhesion molecule-1 and matrix metalloproteinase protein levels were determined by Western blot, and enzyme activity was evaluated using zymography.

Results: There was a significant decrease in neurological deficits, brain infarct volume and leukocyte infiltration, in association with reduction in matrix metalloproteinase-9 and intercellular adhesion molecule-1 expression in exercised animals. Exercised animals treated with either tumor necrosis factor-α antibody or with UO126 showed a reversal of neurological outcome, infarct volume and leukocyte infiltration. Matrix metalloproteinase-9 activity was reversed, at least partially, but the intercellular adhesion molecule-1expression was not. Neuroprotection remained when the exercised ischemic rats were treated with both UO126 and doxycycline.

Conclusion: These results suggest that exercise-induced up-regulation of tumor necrosis factor-α before stroke and extracellular signal-regulated kinase 1/2 phosphorylation play a role in decreasing brain inflammation by regulating matrix metalloproteinase-9 activity.     

MicroRNA-30a regulates acute cerebral ischemia-induced blood–brain barrier damage through ZnT4/zinc pathway

The mechanism of early blood–brain barrier (BBB) disruption after stroke has been intensively studied but still not fully understood. Here, we report that microRNA-30a (miR-30a) could mediate BBB damage using both cellular and animal models of ischemic stroke. In the experiments in vitro, inhibition of miR-30a decreased BBB permeability, prevented the degradation of tight junction proteins, and reduced intracellular free zinc in endothelial cells. We found that the zinc transporter ZnT4 was a direct target of negative regulation by miR-30a, and ZnT4/zinc signaling pathway contributed significantly to miR-30a-mediated BBB damage. Consistent with these in vitro findings, treatment with miR-30a inhibitor reduced zinc accumulation, increased the expression of ZnT4, and prevented the loss of tight junction proteins in microvessels of ischemic animals. Furthermore, inhibition of miR-30a, even at 90 min post onset of middle cerebral artery occlusion, prevented BBB damage, reduced infarct volume, and ameliorated neurological deficits. Together, our findings provide novel insights into the mechanisms of cerebral ischemia-induced BBB disruption and indicate miR-30a as a regulator of BBB function that can be an effective therapeutic target for ischemic stroke.     

Machine learning‐based multimodal prediction of language outcomes in chronic aphasia

Recent studies have combined multiple neuroimaging modalities to gain further understanding of the neurobiological substrates of aphasia. Following this line of work, the current study uses machine learning approaches to predict aphasia severity and specific language measures based on a multimodal neuroimaging dataset. A total of 116 individuals with chronic left‐hemisphere stroke were included in the study. Neuroimaging data included task‐based functional magnetic resonance imaging (fMRI), diffusion‐based fractional anisotropy (FA)‐values, cerebral blood flow (CBF), and lesion‐load data. The Western Aphasia Battery was used to measure aphasia severity and specific language functions. As a primary analysis, we constructed support vector regression (SVR) models predicting language measures based on (i) each neuroimaging modality separately, (ii) lesion volume alone, and (iii) a combination of all modalities. Prediction accuracy across models was subsequently statistically compared. Prediction accuracy across modalities and language measures varied substantially (predicted vs. empirical correlation range: r = .00–.67). The multimodal prediction model yielded the most accurate prediction in all cases (r = .53–.67). Statistical superiority in favor of the multimodal model was achieved in 28/30 model comparisons (p‐value range: <.001–.046). Our results indicate that different neuroimaging modalities carry complementary information that can be integrated to more accurately depict how brain damage and remaining functionality of intact brain tissue translate into language function in aphasia.     

Ultrastructural studies of the neurovascular unit reveal enhanced endothelial transcytosis in hyperglycemia-enhanced hemorrhagic transformation after stroke

AimsPre‐existing hyperglycemia (HG) aggravates the breakdown of blood–brain barrier (BBB) and increases the risk of hemorrhagic transformation (HT) after acute ischemic stroke in both animal models and patients. To date, HG‐induced ultrastructural changes of brain microvascular endothelial cells (BMECs) and the mechanisms underlying HG‐enhanced HT after ischemic stroke are poorly understood.MethodsWe used a mouse model of mild brain ischemia/reperfusion to investigate HG‐induced ultrastructural changes of BMECs that contribute to the impairment of BBB integrity after stroke. Adult male mice received systemic glucose administration 15 min before middle cerebral artery occlusion (MCAO) for 20 min. Ultrastructural characteristics of BMECs were evaluated using two‐dimensional and three‐dimensional electron microscopy and quantitatively analyzed.ResultsMice with acute HG had exacerbated BBB disruption and larger brain infarcts compared to mice with normoglycemia (NG) after MCAO and 4 h of reperfusion, as assessed by brain extravasation of the Evans blue dye and microtubule‐associated protein 2 immunostaining. Electron microscopy further revealed that HG mice had more endothelial vesicles in the striatal neurovascular unit than NG mice, which may account for their deterioration of BBB impairment. In contrast with enhanced endothelial transcytosis, paracellular tight junction ultrastructure was not disrupted after this mild ischemia/reperfusion insult or altered upon HG. Consistent with the observed increase of endothelial vesicles, transcytosis‐related proteins caveolin‐1, clathrin, and hypoxia‐inducible factor (HIF)‐1α were upregulated by HG after MCAO and reperfusion.ConclusionOur study provides solid structural evidence to understand the role of endothelial transcytosis in HG‐elicited BBB hyperpermeability. Enhanced transcytosis occurs prior to the physical breakdown of BMECs and is a promising therapeutic target to preserve BBB integrity.     

Intranasal salvinorin A improves neurological outcome in rhesus monkey ischemic stroke model using autologous blood clot

Salvinorin A (SA) exerts neuroprotection and improves neurological outcomes in ischemic stroke models in rodents. In this study, we investigated whether intranasal SA administration could improve neurological outcomes in a monkey ischemic stroke model. The stroke model was induced in adult male rhesus monkeys by occluding the middle cerebral artery M2 segment with an autologous blood clot. Eight adult rhesus monkeys were randomly administered SA or 10% dimethyl sulfoxide as control 20 min after ischemia. Magnetic resonance imaging was used to confirm the ischemia and extent of injury. Neurological function was evaluated using the Non-Human Primate Stroke Scale (NHPSS) over a 28-day observation period. SA significantly reduced infarct volume (3.9 ± 0.7 cm³ vs. 7.2 ± 1.0 cm³; P = 0.002), occupying effect (0.3 ± 0.2% vs. 1.4 ± 0.3%; P = 0.002), and diffusion limitation in the lesion (−28.2 ± 11.0% vs. −51.5 ± 7.1%; P = 0.012) when compared to the control group. SA significantly reduced the NHPSS scores to almost normal in a 28-day observation period as compared to the control group (P = 0.005). Intranasal SA reduces infarct volume and improves neurological outcomes in a rhesus monkey ischemic stroke model using autologous blood clot.     

More severe type 2 diabetes‐associated ischemic stroke injury is alleviated in aldose reductase‐deficient mice

Aldose reductase (AR), the first enzyme in the polyol pathway, has been implicated in a wide variety of physiological and pathological functions, such as diabetic vascular and neural complications. It is known that diabetes mellitus can exacerbate brain and retina damage after ischemic injuries. However, the underlying mechanisms are not clear. In the present study, we made use of db/db mice with an AR null mutation (AR^?/?db/db) to understand better the role of AR in the pathogenesis of brain and retina ischemic injuries under diabetic conditions. Cerebral and retinal ischemia was induced by transient middle cerebral artery occlusion in control and diabetic mice either with or without an AR null mutation. Mice were evaluated for neurological deficits after 30 min of ischemia and 23.5 hr of reperfusion. Our results showed that the diabetic db/db mice had significantly more severe neurological deficit and larger brain infarct size than the nondiabetic mice. Compared with wild‐type db/db mice, the AR^?/?db/db mice had significantly lower neurological scores, smaller brain infarct areas, and less hemispheric brain swelling. Retinal swelling was also significantly decreased in the AR^?/?db/db mice. Less swelling in the brain and retina of the AR^?/?db/db mice correlated with less expression of the water channel aquaporin 4. Taken together, these data clearly show that deletion of AR leads to less severe brain and retinal ischemic injuries in the diabetic db/db mouse. The present study indicates that inhibition of AR in diabetics may protect against damage in the brain and retina following ischemic reperfusion injury. © 2010 Wiley‐Liss, Inc.     

Transcriptome profiling of five brain regions in a 6‐hydroxydopamine rat model of Parkinson’s disease

BackgroundParkinson''s disease (PD) is a neurodegenerative disease, and its pathogenesis is unclear. Previous studies mainly focus on the lesions of substantia nigra (SN) and striatum (Str) in PD. However, lesions are not limited. The olfactory bulb (OB), subventricular zone (SVZ), and hippocampus (Hippo) are also affected in PD.AimTo reveal gene expression changes in the five brain regions (OB, SVZ, Str, SN, and Hippo), and to look for potential candidate genes and pathways that may be correlated with the pathogenesis of PD.Materials and methodsWe established control group and 6‐hydroxydopamine (6‐OHDA) PD model group, and detected gene expressions in the five brain regions using RNA‐seq and real‐time quantitative polymerase chain reaction (RT‐qPCR). We further analyzed the RNA‐seq data by bioinformatics.ResultsWe identified differentially expressed genes (DEGs) in all five brain regions. The DEGs were significantly enriched in the “dopaminergic synapse” and “retrograde endocannabinoid signaling,” and Gi/o‐GIRK is the shared cascade in the two pathways. We further identified Ephx2, Fam111a, and Gng2 as the potential candidate genes in the pathogenesis of PD for further studies.ConclusionOur study suggested that gene expressions change in the five brain regions following exposure to 6‐OHDA. The “dopaminergic synapse,” “retrograde endocannabinoid signaling,” and Gi/o‐GIRK may be the key pathways and cascade of the synaptic damage in 6‐OHDA PD rats. Ephx2, Fam111a, and Gng2 may play critical roles in the pathogenesis of PD.     

Endothelial progenitor cell transplantation alleviated ischemic brain injury via inhibiting C3/C3aR pathway in mice

Endothelial progenitor cell transplantation is a potential therapeutic approach in brain ischemia. However, whether the therapeutic effect of endothelial progenitor cells is via affecting complement activation is unknown. We established a mouse focal ischemia model (n = 111) and transplanted endothelial progenitor cells into the peri-infarct region immediately after brain ischemia. Neurological outcomes and brain infarct/atrophy volume were examined after ischemia. Expression of C3, C3aR and pro-inflammatory factors were further examined to explore the role of endothelial progenitor cells in ischemic brain. We found that endothelial progenitor cells improved neurological outcomes and reduced brain infarct/atrophy volume after 1 to 14 days of ischemia compared to the control (p < 0.05). C3 and C3aR expression in the brain was up-regulated at 1 day up to 14 days (p < 0.05). Endothelial progenitor cells reduced astrocyte-derived C3 (p < 0.05) and C3aR expression (p < 0.05) after ischemia. Endothelial progenitor cells also reduced inflammatory response after ischemia (p < 0.05). Endothelial progenitor cell transplantation reduced astrocyte-derived C3 expression in the brain after ischemic stroke, together with decreased C3aR and inflammatory response contributing to neurological function recovery. Our results indicate that modulating complement C3/C3aR pathway is a novel therapeutic target for the ischemic stroke.     

Benzodiazepine high‐doses: The need for an accurate definition

ObjectivesA clear definition of what we understand of high‐dose misuse or of a ‘markedly increased dose’ (as stated by the DSM‐5) is important and past definitions may be inadequate. The aim of this review is to describe the different definitions used and to test these definitions for their accuracy.MethodsA narrative PubMed literature review was conducted based on articles published between 1 January 1990 and 31 December 2020 describing benzodiazepines (in MeSH Terms or MeSH Major Topic) and high‐dose (or high‐dosage). Specific definitions were applied to a population sample to show how definitions affect high‐dose benzodiazepine prevalence.ResultsMultiples of an equivalent‐diazepam dose or of the World Health Organization ‘defined daily dosage’ were used more frequently than the overstep of the recommended maximum therapeutic dosage as a cut‐off point.ConclusionHigh‐dose use is rare but the prevalence in the general population varies among studies, mainly due to different definitions, making both clinical and epidemiological comparisons between studies difficult. Defining a high‐dose user as a person who takes at least a higher dose than the maximum usual therapeutic dose over a defined period of time therefore appears to be clinically more consistent.     

Do self‐reports of procrastination predict actual behavior?

ObjectivesProcrastination is typically assessed via self‐report questionnaires. So far, only very few studies have examined actual procrastination behavior, providing inconclusive results regarding the real‐life validity of self‐reports in this domain. The present study aimed to examine for the first time whether participants'' self‐reported procrastination can predict their actual behavior on a real‐life task.MethodsFor that purpose, we assessed self‐reported levels of procrastination [via the Pure Procrastination Scale, PPS] and actual procrastination behavior on a naturalistic task [i.e., having to send in an attendance sheet before a deadline] in 93 participants.ResultsResults show that self‐reports significantly predicted procrastination behavior. Analyses of underlying dimensions suggest that real‐life procrastination can be the result of “voluntarily delaying planned actions,” but can also have more passive causes such as “running out of time.”ConclusionsComparing our results with the available literature suggests that PPS self‐reports reflect a particularly valid tool to assess real‐life procrastination behavior. Findings are discussed in the context of strategies and mechanisms that potential interventions may target in order to reduce procrastination.     

The stage‐specifically accelerated brain aging in never‐treated first‐episode patients with depression

Depression associated with structural brain abnormalities is hypothesized to be related with accelerated brain aging. However, there is far from a unified conclusion because of clinical variations such as medication status, cumulative illness burden. To explore whether brain age is accelerated in never‐treated first‐episode patients with depression and its association with clinical characteristics, we constructed a prediction model where gray matter volumes measured by voxel‐based morphometry derived from T1‐weighted MRI scans were treated as features. The prediction model was first validated using healthy controls (HCs) in two Chinese Han datasets (Dataset 1, N = 130 for HCs and N = 195 for patients with depression; Dataset 2, N = 270 for HCs) separately or jointly, then the trained prediction model using HCs (N = 400) was applied to never‐treated first‐episode patients with depression (N = 195). The brain‐predicted age difference (brain‐PAD) scores defined as the difference between predicted brain age and chronological age, were calculated for all participants and compared between patients with age‐, gender‐, educational level‐matched HCs in Dataset 1. Overall, patients presented higher brain‐PAD scores suggesting patients with depression having an “older” brain than expected. More specially, this difference occurred at illness onset (illness duration <3 months) and following 2 years then disappeared as the illness further advanced (>2 years) in patients. This phenomenon was verified by another data‐driven method and significant correlation between brain‐PAD scores and illness duration in patients. Our results reveal that accelerated brain aging occurs at illness onset and suggest it is a stage‐dependent phenomenon in depression.     

Cerebral dopamine neurotrophic factor increases proliferation,Migration and differentiation of subventricular zone neuroblasts in photothrombotic stroke model of mouse

BackgroundCerebral ischemic stroke can induce the proliferation of subventricular zone (SVZ) neural stem cells (NSCs) in the adult brain. However, this reparative process is restricted because of NSCs’ death shortly after injury or disability of them to reach the infarct boundary. In the present study, we investigated the ability of cerebral dopamine neurotrophic factor (CDNF) on the attraction of SVZ-resident NSCs toward the lesioned area and neurological recovery in a photothrombotic (PT) stroke model of miceMethodsThe mice were assigned to three groups stroke, stroke+phosphate buffered saline (PBS), and stroke+CDNF. Migration of SVZ NSCs were evaluated by BrdU/doublecortin (DCX) double immunofluorescence method on days 7 and 14 and their differentiation were evaluated by BrdU/ Neuronal Nuclei (NeuN) double immunofluorescence method 28 days after intra-SVZ CDNF injection. Serial coronal sections were stained with cresyl violet to detect the infarct volume and a modified neurological severity score (mNSS) was performed to assess the neurological performanceResultsInjection of CDNF increased the proliferation of SVZ NSCs and the number of DCX-expressing neuroblasts migrated from the SVZ toward the ischemic site. It also enhanced the differentiation of migrated neuroblasts into the mature neurons in the lesioned site. Along with this, the infarct volume was significantly decreased and the neurological performance was improved as compared to other groupsConclusionThese results demonstrate that CDNF is capable of enhancing the proliferation of NSCs residing in the SVZ and their migration toward the ischemia region and finally, differentiation of them in stroke mice, concomitantly decreased infarct volume and improved neurological abilities were revealed.     

Change and predictive ability of circulating immunoregulatory lymphocytes in long-term outcomes of acute ischemic stroke

Lymphocytes play an important role in the immune response after stroke. However, our knowledge of the circulating lymphocytes in ischemic stroke is limited. Herein, we collected the blood samples of clinical ischemic stroke patients to detect the change of lymphocytes from admission to 3 months after ischemic stroke by flow cytometry. A total of 87 healthy controls and 210 patients were enrolled, and the percentages of circulating T cells, CD4⁺ T cells, CD8⁺ T cells, double negative T cells (DNTs), CD4⁺ regulatory T cells (Tregs), CD8⁺ Tregs, B cells and regulatory B cells (Bregs) were measured. Among patients, B cells, Bregs and CD8⁺ Tregs increased significantly, while CD4⁺ Tregs dropped and soon reversed after ischemic stroke. CD4⁺ Tregs, CD8⁺ Tregs, and DNTs also showed high correlations with the infarct volume and neurological scores of patients. Moreover, these lymphocytes enhanced the predictive ability of long-term prognosis of neurological scores when added to basic clinical information. The percentage of CD4⁺ Tregs within lymphocytes showed high correlations with both acute and long-term neurological outcomes, which exhibited a great independent predictive ability. These findings suggest that CD4⁺ Tregs can be a biomarker to predict stroke outcomes and improve existing therapeutic strategies of immunoregulatory lymphocytes.