Correlation of glymphatic system abnormalities with Parkinson's disease progression: a clinical study based on non-invasive fMRI.

BACKGROUND: The glymphatic system is reportedly involved in Parkinson's disease (PD). Based on previous studies, we aimed to confirm the correlation between the glymphatic system and PD progression by combining two imaging parameters, diffusion tensor image analysis along the perivascular space (DTI-ALPS), and enlarged perivascular spaces (EPVS). METHODS: Fifty-one PD patients and fifty healthy control (HC) were included. Based on the Hoehn-Yahr scale, the PD group was divided into early-stage and medium-to late-stage. All PD patients were scored using the Unified PD Rating Scale (UPDRS). We assessed the DTI-ALPS indices in the bilateral hemispheres and EPVS numbers in bilateral centrum semiovale (CSO), basal ganglia (BG), and midbrain. RESULTS: The DTI-ALPS indices were significantly lower bilaterally in PD patients than in the HC group, and EPVS numbers in any of the bilateral CSO, BG, and midbrain were significantly higher, especially for the medium- to late-stage group and the BG region. In PD patients, the DTI-ALPS index was significantly negatively correlated with age, while the BG-EPVS numbers were significantly positively correlated with age. Furthermore, the DTI-ALPS index was negatively correlated with UPDRS II and III scores, while the BG-EPVS numbers were positively correlated with UPDRS II and III scores. Similarly, the correlation was more pronounced in the medium- to late-stage group. CONCLUSION: The DTI-ALPS index and EPVS numbers (especially in the BG region) are closely related to age and PD progression and can serve as non-invasive assessments for glymphatic dysfunction and its interventions in clinical studies.

Effect of cognitive behavioral intervention on anxiety, depression, and quality of life in patients with epilepsy.

OBJECTIVE: This study aimed to investigate the effect of cognitive behavioral therapy (CBT) on quality of life, anxiety, and depression in patients with epilepsy. METHODS: Each study subject was randomly assigned to a CBT (n=46) or control (n=49) group (1:1 ratio), and the first group underwent an 8-week CBT treatment. Anxiety, depression, and quality of life (QOLIE-31) were assessed at both baseline and endpoint using the Self-Rating Anxiety Scale (SAS), Hamilton Depression Scale (HDMA) and quality of life in Epilepsy-31 (QOLIE-31) scales. The statistical analyses included between-and within-group comparisons of the effects of CBT on these measures and associations with demographic and clinical variables. RESULTS: No differences were found between variables at baseline (P>0.05). The repeated-measures analyses found that CBT group had greater improvement in depression score compared to the control group (P<0.05). The analysis of anxiety score showed that compared to the control group, CBT intervention had no statistical significance in the total anxiety population. However, the CBT intervention decreased anxiety in women and Combined-drug group (P<0.05). The CBT group had greater improvement in overall score, medication effect, and seizure worry score than the control group (P<0.05). Stratified analysis found total and medication effects score of CBT intervention group for the combined-drug group were higher than those of the single drug group (P<0.05). CONCLUSION: Increases in overall scores, seizure worry, cognitive functioning, and medication effect were better in the CBT group. CBT can improve anxiety, depression, and quality of life in patients with epilepsy. Women and combined-drug patients with epilepsy benefit most from CBT.

A tract-based spatial statistics study of white matter integrity in epilepsy.

OBJECTIVE: To explore the changes of cerebral white matter diffusion tensor in epilepsy. METHODS: This study was a retrospective study based on diffusion tensor imaging (DTI). Twenty-six epileptic patients and 42 normal controls matched for sex, age and handedness were enrolled in our research. Based on the method of tract-based spatial statistics (TBSS), we analyzed the changes of each relevant parameter index of DTI in white matter of the brain in all subjects, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). RESULTS: In comparison with the control group, epileptic patients had decreased FA and elevated MD, AD, and RD in the anterior thalamic radiation, corticospinal tract, forceps major, forceps minor, cingulum, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, superior longitudinal fasciculus and uncinate fasciculus (P < 0.05). CONCLUSION: Widespread white matter integrity was observed in epileptic patients, which may be the structural basis for the development of affective disorders, impaired cognition, and motor abnormalities.

Protective Effects of 28-O-Caffeoyl Betulin (B-CA) on the Cerebral Cortex of Ischemic Rats Revealed by a NMR-Based Metabolomics Analysis.

28-O-caffeoyl betulin (B-CA) has been demonstrated to reduce the cerebral infarct volume caused by transient middle cerebral artery occlusion (MCAO) injury. B-CA is a novel derivative of naturally occurring caffeoyl triterpene with little information associated with its pharmacological target(s). To date no data is available regarding the effect of B-CA on brain metabolism. In the present study, a 1H-NMR-based metabolomics approach was applied to investigate the therapeutic effects of B-CA on brain metabolism following MCAO in rats. Global metabolic profiles of the cortex in acute period (9 h after focal ischemia onset) after MCAO were compared between the groups (sham; MCAO + vehicle; MCAO + B-CA). MCAO induced several changes in the ipsilateral cortex of ischemic rats, which consequently led to the neuronal damage featured with the downregulation of NAA, including energy metabolism dysfunctions, oxidative stress, and neurotransmitter metabolism. Treatment with B-CA showed statistically significant rescue effects on the ischemic cortex of MCAO rats. Specifically, treatment with B-CA ameliorated the energy metabolism dysfunctions (back-regulating the levels of succinate, lactate, BCAAs, and carnitine), oxidative stress (upregulating the level of glutathione), and neurotransmitter metabolism disturbances (back-regulating the levels of γ-aminobutyric acid and acetylcholine) associated with the progression of ischemic stroke. With the administration of B-CA, the levels of three phospholipid related metabolites (O-phosphocholine, O-phosphoethanolamine, sn-glycero-3-phosphocholine) and NAA improved significantly. Overall, our findings suggest that treatment with B-CA may provide neuroprotection by augmenting the metabolic changes observed in the cortex following MCAO in rats.

A11, a novel diaryl acylhydrazone derivative, exerts neuroprotection against ischemic injury in vitro and in vivo.

There is an urgent need to develop effective therapies for ischemic stroke, but the complicated pathological processes after ischemia make doing so difficult. In the current study, we identified a novel diaryl acylhydrazone derivative, A11, which has multiple neuroprotective properties in ischemic stroke models. First, A11 was demonstrated to induce neuroprotection against ischemic injury in a dose-dependent manner (from 0.3 to 3 µM) in three in vitro experimental ischemic stroke models: oxygen glucose deprivation (OGD), hydrogen peroxide, and glutamate-stimulated neuronal cell injury models. Moreover, A11 was able to potently alleviate three critical pathological changes, apoptosis, oxidative stress, and mitochondrial dysfunction, following ischemic insult in neuronal cells. Further analysis revealed that A11 upregulated the phosphorylation levels of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) in OGD-exposed neuronal cells, suggesting joint activation of the phosphoinositide 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MEK)/ERK pathways. In rats with middle cerebral artery occlusion, single-dose administration of A11 (3 mg/kg per day, i.v.) at the onset of reperfusion significantly reduced the infarct volumes and ameliorated neurological deficits. Our study, for the first time, reports the anti-ischemic effect of diaryl acylhydrazone chemical entities, especially A11, which acts on multiple ischemia-associated pathological processes. Our results may provide new clues for the development of an effective therapeutic agent for ischemic stroke.

T-lymphocyte subsets as a predictive biomarker for stroke-associated pneumonia.

The aim of this study was to facilitate the clinical treatment and prognosis of stroke-associated pneumonia (SAP) by examining changes in T-lymphocyte subsets. Stroke patients admitted in Suzhou Hospital between 2014 and 2016 participated in the study. Patients were divided into a pneumonia group (50 patients) and a non-pneumonia group (254 patients) based on a diagnosis of pneumonia. Information regarding risk factors for ischemic stroke was collected from all patients using a questionnaire. Compared with non-SAP patients, SAP patients were older, dysphagic, smokers, had higher NIH stroke scale (NIHSS) scores and neutrophil: lymphocyte ratio, had higher leukocyte, neutrophil, and CD8 levels, had lower CD3, CD4, and lymphocyte levels, and had a lower CD4:CD8 ratio. Patients with a higher NIHSS score had higher CD8 levels, lower CD3 and CD4 levels, and a lower CD4:CD8 ratio. No significant differences in T-lymphocyte subsets were found between the left and right cerebral hemispheres. After adjusting for other variables, smoking, dysphagia, NIHSS score, and CD4:CD8 ratio were positively associated with SAP. The areas under the receiver operating characteristic curve for dysphagia, NIHSS score, CD4:CD8 ratio, CD4:CD8 ratio + NIHSS score, and Dysphagia+ CD4:CD8 ratio + NIHSS score were 0.583 (95% CI: 0.490-0.675), 0.791 (95% CI: 0.724-0.859), 0.676 (95% CI: 0.593-0.759), 0.846 (95% CI: 0.790-0.902), and 0.867 (95% CI: 0.815-0.918), respectively. A few T-lymphocyte subsets may increase susceptibility to pneumonia after acute ischemic stroke. Thus, the detection of T-lymphocyte subsets may predict the risk of SAP in such patients.

Influence of renal function on the association between homocysteine level and risk of ischemic stroke.

We examined whether the association between total homocysteine (tHCY) and risk of ischemic stroke (IS) varies depending on renal function to gain insight into why tHCY-lowering vitamins do not reduce the incidence of cardiovascular disease in clinical trials. We analyzed data from 542 IS patients with large artery atherosclerosis (LAA) or small artery occlusion (SAO) after stratification by estimated glomerular filtration rate (eGFR) to evaluate renal function. We found that tHCY level was positively associated with the occurrence of IS in both LAA (OR: 1.159, 95% CI: 1.074-1.252, P<0.001) and SAO (OR: 1.143, 95% CI: 1.064-1.228, P<0.001) patients and in LAA (OR: 1.135, 95% CI: 1.047-1.230, P=0.002) and SAO (OR: 1.159, 95% CI: 1.060-1.268, P=0.001) subgroups with normal renal function but not in LAA or SAO subgroups with renal insufficiency. eGFR level was positively associated with IS in LAA (OR: 1.022, 95% CI: 1.010-1.034, P<0.001) and SAO (OR: 1.024, 1.012-1.037, P<0.001) subgroups with normal renal function but was negatively associated with IS in LAA (OR: 0.875, 95% CI: 0.829-0.925, P<0.001) and SAO (OR: 0.890, 95% CI: 0.850-0.932, P<0.001) subgroups with renal insufficiency. Folic acid level was negatively associated with IS in LAA (OR: 0.734, 95% CI: 0.606-0.889, P=0.002) and SAO (OR: 0.861, 95% CI: 0.767-0.967, P=0.012) subgroups with renal insufficiency. Therefore, renal function as evaluated by eGFR exerts a significant influence on the association between tHCY and risk of IS.

Dual anti-ischemic effects of rosmarinic acid n-butyl ester via alleviation of DAPK-p53-mediated neuronal damage and microglial inflammation.

The discovery of efficacious anti-ischemic drugs remains a challenge. Recently we have found that rosmarinic acid n-butyl ester (RABE), a derivative of rosmarinic acid, significantly protects SH-SY5Y cells against oxygen glucose deprivation (OGD)-induced cell death. In the present study we simultaneously investigated the effects of RABE on the two key players in the pathophysiology of cerebral ischemia, ischemic neuronal damage and microglial inflammation. Pretreatment with RABE (1, 10 µmol/L) dose-dependently attenuated OGD- or H2O2-induced reduction of the viability of SH-SY5Y neuroblastoma cells. RABE pretreatment concurrently reduced the apoptotic cell rate, down-regulated the expression of the pro-apoptotic proteins Bax and p53, and up-regulated the expression of the anti-apoptotic protein phosphorylated death-associated protein kinase (DAPK). Furthermore, pretreatment with RABE (3 µmol/L) markedly inhibited lipopolysaccharide (LPS)-induced increases in the release of TNF-α, IL-1ß, NO and PGE2, and the expression levels of iNOS, and COX-2 in cultured rat microglial cells. In conclusion, these results reveal for the first time the potential anti-ischemic effects of RABE on neuronal and glial cells and elucidate the molecular mechanisms involved in its dual beneficial profiles in vitro. RABE may be a promising drug lead/candidate for the treatment of ischemic stroke.

Caffeoyl Triterpenoid Esters as Potential Anti-ischemic Stroke Agents from Celastrus orbiculatus.

Three new triterpenoids, celastrusins A-C (1-3), together with 3-O-caffeoyl-α-amyrin (4) were isolated from the root bark of Celastrus orbiculatus. Their structures were identified by spectroscopic analysis, X-ray crystallography using Cu Kα radiation, and the comparison of both observed and reported spectroscopic data. An in vitro bioassay revealed that the caffeoyl triterpenoid esters 1, 3, and 4 possess neuroprotective effects against oxygen-glucose deprivation (OGD) induced SH-SY5Y cell damage. Further animal studies indicated that compound 1 significantly reduced brain infarction after transient middle cerebral artery occlusion (MCAO) in rats using a 10 mg/kg (i.v.) dose.

Study on the correlation of vertebral artery dominance, basilar artery curvature and posterior circulation infarction.

Vertebral artery dominance (VAD), which is a common congenital variation of vertebral artery, may be associated with an increased risk of cerebral posterior circulation infarction (PCI). The aims of this study were to investigate the correlation of VAD with incidence and laterality of PCI, and oblige the correlation of VAD and basilar artery (BA) curvature. Incidence of separate territory infarction in posterior circulation and incidence of BA curvature were compared between 78 VAD patients and 68 controls. VA dominance, laterality of BA curvature and separate territory infarction, and their directional relationships were observed in VAD group. The incidence of BA curvature in VAD group was significantly higher than that in controls (P = 0.000). 89.7 % (35/39) of patients had an opposite directional relationship between dominant VA and BA curvature. The total incidence of PCI in VAD group was significantly higher than that in controls (P = 0.001). The incidences of posterior inferior cerebellar artery (PICA) and BA territory infarction were both significantly higher than those in controls [11.5 % (9/78) vs. 1.5 % (1/68), P = 0.016; 20.5 % (16/78) vs. 7.4 % (5/68), P = 0.024]. No differences were found in superior cerebellar artery and posterior cerebral artery territory infarction between two groups. 77.8 % (7/9) of PICA infarction were on the opposite side of dominant VA. 75.0 % (12/16) of BA infarction were on the side of dominant VA. The incidence of PCI in BA curvature patients was significantly higher than that in BA straight patients. The incidence of BA curvature is higher in VAD patients, and BA usually bends to the opposite side of dominant VA. The incidence of PCI is higher in VAD patients, especially in PICA infarction and BA infarction patients.