Shao-Hua Su

Elevated C-reactive protein levels may be a predictor of persistent unfavourable symptoms in patients with mild traumatic brain injury: A preliminary study

The pathogenesis of persistent unfavourable outcomes following mild traumatic brain injury (mTBI) are not fully understood. Low-grade systemic inflammation might contribute to the development of persistent unfavourable outcomes in patients with mTBI. We used plasma high-sensitivity C-reactive protein (CRP) levels as the biomarker of systemic inflammation to investigate whether elevated CRP levels were associated with persistent adverse outcomes in these patients. A total of 213 consecutive patients with mTBI were identified in our study. Plasma high-sensitivity CRP levels were measured at baseline, 1month, 2months and 3months after initial traumatic brain injury. The study endpoints included persistent postconcussion syndrome (PCS), persistent psychological problems (depression and anxiety), persistent physiological problems (frequent headache, nausea, insomnia, dizziness and fatigue) and persistent cognitive impairment, which were screened by International Classification of Diseases (ICD-10), diagnostic and statistical manual of mental disorders (DSM-IV), Beck anxiety inventory (BAI), Beck depression inventory (BDI) and montreal cognitive assessment (MoCA) 3months post-injury. The associations between baseline CRP levels and persistent unfavourable outcomes were estimated from multiple regression models adjusting for various confounding covariates. Elevated baseline CRP levels were associated with a significant increase in the incidence of persistent PCS (odds ratio [OR], 2.719; 95% confidence interval [CI], 1.609-4.594; p=0.000), persistent psychological problems (OR, 1.535; 95% CI, 1.063-2.216; p=0.022), and persistent cognitive impairment (OR, 1.687; 95% CI, 1.135-2.507; p=0.010). However, elevated CRP levels were not associated with persistent physiological problems (OR, 1.330; 95% CI, 0.905-1.956; p=0.146). Furthermore, three adjusted models did not essentially affect the OR of elevated CRP levels for these persistent unfavourable outcomes. Among patients with mTBI, baseline elevated CRP levels may be an independent predictor of persistent persistent PCS, psychological problems and cognitive impairment.

The Effects of Intracranial Pressure Monitoring in Patients with Traumatic Brain Injury

Background Although international guideline recommended routine intracranial pressure (ICP) monitoring for patients with severe traumatic brain injury(TBI), there were conflicting outcomes attributable to ICP monitoring according to the published studies. Hence, we conducted a meta-analysis to evaluate the efficacy and safety of ICP monitoring in patients with TBI. Methods Based on previous reviews, PubMed and two Chinese databases (Wangfang and VIP) were further searched to identify eligible studies. The primary outcome was mortality. Secondary outcomes included unfavourable outcome, adverse events, length of ICU stay and length of hospital stay. Weighted mean difference (WMD), odds ratio (OR) and 95% confidence intervals (CIs) were calculated and pooled using fixed-effects or random-effects model. Results two randomized controlled trials (RCTs) and seven cohort studies involving 11,038 patients met the inclusion criteria. ICP monitoring was not associated with a significant reduction in mortality (OR, 1.16; 95% CI, 0.87–1.54), with substantial heterogeneity (I2 = 80%, P<0.00001), which was verified by the sensitivity analyses. No significant difference was found in the occurrence of unfavourable outcome (OR, 1.40; 95% CI, 0.99–1.98; I2 = 4%, P = 0.35) and advese events (OR, 1.04; 95% CI, 0.64–1.70; I2 = 78%, P = 0.03). However, we should be cautious to the result of adverse events because of the substantial heterogeneity in the comparison. Furthermore, longer ICU and hospital stay were the consistent tendency according to the pooled studies. Conclusions No benefit was found in patients with TBI who underwent ICP monitoring. Considering substantial clinical heterogeneity, further large sample size RCTs are needed to confirm the current findings.

Cannabinoid receptor agonist WIN55,212-2 and fatty acid amide hydrolase inhibitor URB597 may protect against cognitive impairment in rats of chronic cerebral hypoperfusion via PI3K/AKT signaling

The present study further investigated the protective effects of cannabinoid receptor agonist WIN55,212-2 (WIN) and fatty acid amide hydrolase (FAAH) inhibitor URB597 (URB) on chronic cerebral hypoperfusion (CCH)-induced cognitive impairment in rats. Spatial learning and memory were assessed with the Morris water maze and by measuring Long-term potentiation. The expression of microtubule-associated protein-2 (MAP)-2, growth-associated protein-43 (GAP)-43, synaptophysin, cannabinoid receptor 1 (CB1), brain-derived neurotrophic factor (BDNF), FAAH, N-acylphosphatidylethanolamine phospholipase D(NAPE-PLD) and monoacyl glycerol lipase (MGL) as well as phosphoinositide 3-kinase (PI3K)/AKT signaling pathway molecules and downstream targets including AKT, phosphorylated (p-)AKT, cyclic AMP response element- binding protein (CREB), p-CREB, Bcl-2-associated death protein (BAD), p-BAD, glycogen synthase kinase (GSK)-3β, p-GSK-3β, forkhead box protein (FOXO) 3A and p-FOXO3A was determined by western blotting. WIN and URB treatment improved learning and memory performance, effects that were abolished by co-administration of the PI3K/AKT inhibitor LY294002. Moreover, WIN and URB reversed the decreases in MAP-2 and synaptophysin expression resulting from CCH, and stimulated BDNF and CB1 expression as well as CREB, FOXO3A, GSK-3β, and BAD phosphorylation, confirming that WIN and URB mediate neuroprotection by preventing neuronal apoptosis and improving cognition via PI3K/AKT signaling. These findings suggest that WIN and URB are promising agents for therapeutic management of CCH.

Assessment of cognitive function in adult patients with hemorrhagic moyamoya disease who received no surgical revascularization

Due to controversial surgical treatment for hemorrhagic moyamoya disease (MMD), a large proportion of these patients chose conservative treatment. The aim of this study was to assess cognitive function in adult patients with hemorrhagic MMD who received no surgical revascularization.

Effects of statins-use for patients with aneurysmal subarachnoid hemorrhage: a meta-analysis of randomized controlled trials

Aneurysmal subarachnoid hemorrhage (aSAH)-induced cerebral vasospasm and delayed ischemic neurological deficit (DIND) are the major causes of morbidity and mortality in patients with aSAH. The effects of statins-use for patients with aSAH remain controversial. Here,a total of 249 patients from six randomized controlled trials(RCTs) were subjected to meta-analysis. No significant decrease was found in the incidence of vasospasm(RR, 0.80; 95% CI, 0.54–1.17), with substantial heterogeneity (I2 = 49%, P = 0.08), which was verified by the further sensitivity analysis and subgroup meta-analysis. Furthermore, no significant difference was presented in the incidence of poor neurological outcome(RR, 0.94; 95% CI, 0.77–1.16), and potential side effects(RR, 2.49; 95% CI, 0.75–8.33). Nevertheless, significant difference was reported in the occurrence of DIND(RR, 0.58; 95% CI, 0.37–0.92) and mortality(RR, 0.30; 95% CI, 0.14–0.64). At present, although statins-use in the patients with aSAH should not be considered standard care at present, statins-use may have the potential effects in the prevention of mortality in patients with aSAH.

Chronic cerebral hypoperfusion in rats causes proteasome dysfunction and aggregation of ubiquitinated proteins

The deposition of abnormal protein aggregates is a feature of several neurodegenerative diseases. We have employed a rat model to investigate whether chronic cerebral hypoperfusion (CCH) induces proteasome dysfunction and the accumulation of ubiquitinated proteins and aggregates in the CNS. Protein aggregation was analyzed by ethanolic phosphotungstic acid (EPTA) electron microscopy (EM), immunogold EM, laser-scanning confocal microscopy, and Western blotting. Proteasome peptidase activity was studied by peptidase activity assays. EPTA EM and immunogold EM revealed that CCH led to the accumulation of protein aggregates in rat hippocampal CA1 neurons. High-resolution confocal microscopy demonstrated the presence of ubiquitin-positive protein aggregates surrounding nuclei and along dendrites. Western blotting revealed that levels of free ubiquitin were significantly reduced and that levels of ubiquitinated proteins were markedly increased in the hippocampus of CCH rats. Direct activity measurements revealed that proteasome peptidase activity in the hippocampal region of rats was decreased after CCH induction. These data suggest that reduced proteasome activity following CCH could impair the removal of abnormally folded proteins via the ubiquitin-proteasome pathway, leading to the accumulation of potentially toxic protein aggregates that could contribute to neurodegeneration.

URB597 improves cognitive impairment induced by chronic cerebral hypoperfusion by inhibiting mTOR-dependent autophagy

Chronic cerebral hypoperfusion (CCH) is associated with various ischemic cerebrovascular diseases that are characterized by cognitive impairment. The role of autophagy in cognitive dysfunction under conditions of CCH is poorly understood. To address this issue, the present study investigated the effect of the fatty acid amide hydrolase (FAAH) inhibitor URB597 on autophagy and cognition in a CCH model as well as the underlying mechanisms. Cognitive function was evaluated with the Morris water maze and by assessing long-term potentiation (LTP). The expression of autophagy-related proteins and mammalian target of rapamycin (mTOR) signaling pathway components was evaluated by immunofluorescence and western blot analyses, and ultrastructural changes were examined by transmission electron microscopy (EM). URB597 improved cognitive impairment by inhibiting CCH-induced autophagy, which was associated with mTOR signaling. Moreover, the ultrastructural deterioration resulting from CCH was improved by chronic treatment with URB597. These findings indicate that URB597 modulates autophagy in an mTOR-dependent manner, and mitigates neuronal damage and cognitive deterioration caused by CCH.

Cognitive function, depression, anxiety and quality of life in Chinese patients with untreated unruptured intracranial aneurysms.

Detected unruptured intracranial aneurysms (UIA) are becoming more common with the increased utilization of CT angiography, MR angiography and digital subtraction angiography. A proportion of patients with UIA remain untreated. We investigated to assess cognitive function, depression, anxiety and quality of life (QoL) in Chinese patients with untreated UIA. Thirty one Chinese patients with untreated UIA and 25 healthy controls were identified and matched for variables including age, sex, and living area. Cognitive function was evaluated with the Montreal Cognitive Assessment (MoCA). Depression, anxiety and QoL were screened with the Self-Rating Depression Scale, Self-Rating Anxiety Scale, and Short Form-36, respectively. Non-parametric tests were used for comparisons between groups. No patient had cognitive dysfunction at 1 month or 1 year after detection of UIA. However, a significant decrease of overall MoCA subscores was found in 30 (97%) of 31 patients 5 years after UIA discovery, suggestive of mild cognitive impairment. A significant decrease in depression and anxiety was found in patients over time. QoL in patients was reduced most prominently in psychosocial function and social activities 1 year after detection of UIA, but these improved to within normal limits at the end of the follow-up period. For Chinese patients with untreated UIA, depression, anxiety and reduced QoL may be short-term complications. Mild cognitive impairment may be a long-term complication.

Quality of life and psychological impact in adult patients with hemorrhagic moyamoya disease who received no surgical revascularization

OBJECTIVES Surgical treatment for adult hemorrhagic moyamoya disease (MMD) remains controversial. A large proportion of Chinese adult patients with hemorrhagic MMD still choose conservative treatment. In this study, we investigated to assess psychological function and quality of life (QoL) in adult patients with hemorrhagic MMD who received no surgical revascularization. METHODS 26 adult patients with hemorrhagic MMD who presented with only intraventricular hemorrhage (IVH), 20 patients with spontaneous IVH whose DSA results were negative and 30 healthy controls were identified and matched for age, gender, living area, etc. Psychological function and QoL were evaluated by Short Form-36 (SF-36), Symptom Check List 90 (SCL-90), Self-rating Depression Scale (SDS), Self-rating Anxiety Scale (SAS) and daily life questionnaire respectively one year after the initial stroke. Multiple logistic regression model was built up to screen out the independent risk factors related to depression and reduced QoL. RESULTS Heavier social and mental burden was observed in adult patients with hemorrhagic MMD compared with the patients with spontaneous IVH. The QoL of cases was particularly reduced in the psychological domains. 19 (73%) cases developed depression, indicating the probable higher incidence of psychological disorder in Asian patients. Multiple logistic regression analysis suggested the independent risks of reduced QoL and depression involved in personality types and education background. CONCLUSIONS Our data revealed that poor education background or introverted personality type may be attributed to the development of depression in Chinese adult hemorrhagic MMD patients who received no surgical revascularization associated with QoL impairment. The treatment decisions for these patients should consider the possible improvement of QoL.

The changes of signal transduction pathways in hippocampal regions and postsynaptic densities after chronic cerebral hypoperfusion in rats

The mechanisms underlying the cognitive impairment after chronic cerebral hypoperfusion (CCH) are not fully clarified. In the present study, we investigated the molecular basis for the cognitive deficits under the condition of CCH in rats. The ultrastructural changes of postsynaptic densities (PSDs) were examined by ethanolic phosphotungstic acid (EPTA) electron microscopy. Various protein kinase phosphorylation/dephosphorylation levels of the signal transduction pathways in hippocampal regions and postsynaptic densities were assessed by Western blotting. On EPTA electron microscopy, we demonstrated that proteins were highly aggregated in PSD structures of the hippocampal CA1 areas in rats at 3 months after CCH. By Western blotting, the model rats exhibited significant decrease in the levels of hippocampal Ca(2+)-calmodulin-dependent protein kinase II (CaMKII), phospho-CaMKII (p-CaMKII), phospho-extracellular regulated kinase (p-ERK), PSD CaMKII and p-ERK, with no corresponding changes in the levels of phosphorylation/dephoosphorylation protein kinase A (PKA) and protein kinase C (PKC). These results suggest that both the ultrastructural changes of PSDs and aberrant signal transduction may be involved in CCH-induced alterations in synaptic transmission underlying the cognitive dysfunction in rats of CCH.