Reduction of white matter integrity correlates with apathy in Parkinson's disease.

BACKGROUND: Apathy is a common non-motor symptom in Parkinson's disease (PD), but little is known about apathy and white matter (WM) change. In this study, we investigated whether fractional anisotropy (FA) of the WM can distinguish apathetic patients from non-apathetic PD patients, and whether the FA value correlates with the severity of apathy in PD. METHODS: Thirty-nine PD patients participated in our study, of which 18 participants were with apathy symptom, and 21 without apathy symptom. Diffusion tensor imaging was performed on all the subjects. RESULTS: Compared to non-apathetic PD patients, the apathetic group had reduced FA values in the genu and body of corpus callosum, bilateral anterior corona radiata, left superior corona radiata and left cingulum. Furthermore, in these WM regions, the FA values were negatively correlated with the Lille Apathy Rating Scale scores in apathetic subjects. CONCLUSION: The WM change is associated with apathy in PD patients. In addition, the FA values of specific regions of WM could be a promising marker to predict the severity of apathy.

Abnormalities of regional brain function in Parkinson's disease: a meta-analysis of resting state functional magnetic resonance imaging studies.

There is convincing evidence that abnormalities of regional brain function exist in Parkinson's disease (PD). However, many resting-state functional magnetic resonance imaging (rs-fMRI) studies using amplitude of low-frequency fluctuations (ALFF) have reported inconsistent results about regional spontaneous neuronal activity in PD. Therefore, we conducted a comprehensive meta-analysis using the Seed-based d Mapping and several complementary analyses. We searched PubMed, Embase, and Web of Science databases for eligible whole-brain rs-fMRI studies that measured ALFF differences between patients with PD and healthy controls published from January 1st, 2000 until June 24, 2016. Eleven studies reporting 14 comparisons, comparing 421 patients and 381 healthy controls, were included. The most consistent and replicable findings in patients with PD compared with healthy controls were identified, including the decreased ALFFs in the bilateral supplementary motor areas, left putamen, left premotor cortex, and left inferior parietal gyrus, and increased ALFFs in the right inferior parietal gyrus. The altered ALFFs in these brain regions are related to motor deficits and compensation in PD, which contribute to understanding its neurobiological underpinnings and could serve as specific regions of interest for further studies.

Aberrant regional homogeneity in Parkinson's disease: A voxel-wise meta-analysis of resting-state functional magnetic resonance imaging studies.

Studies of abnormal regional homogeneity (ReHo) in Parkinson's disease (PD) have reported inconsistent results. Therefore, we conducted a meta-analysis using the Seed-based d Mapping software package to identify the most consistent and replicable findings. A systematic literature search was performed to identify eligible whole-brain resting-state functional magnetic resonance imaging studies that had measured differences in ReHo between patients with PD and healthy controls between January 2000 and June 4, 2016. A total of ten studies reporting 11 comparisons (212 patients; 182 controls) were included. Increased ReHo was consistently identified in the bilateral inferior parietal lobules, bilateral medial prefrontal cortices, and left cerebellum of patients with PD when compared to healthy controls, while decreased ReHo was observed in the right putamen, right precentral gyrus, and left lingual gyrus. The results of the current meta-analysis demonstrate a consistent and coexistent pattern of impairment and compensation of intrinsic brain activity that predominantly involves the default mode and motor networks, which may advance our understanding of the pathophysiological mechanisms underlying PD.

[Change and significance of blood lipids during the course of carotid artery plaque formation induced by diabetes mellitus in patients with ischemic cerebral vascular disease].

OBJECTIVE: To explore the change and possible role of blood lipids during the course of plaque formation induced by diabetes mellitus in patients with ischemic cerebral vascular disease. METHODS: A total of 1 464 hospitalized patients with a diagnosis of ischemic cerebral vascular disease at our department from February 2008 to May 2012. They were distinguished as plaque (n = 332) or not (n = 132) based on carotid artery intima-media thickness (IMT) on B-mode ultrasound. And there were diabetics (n = 153) and non-diabetics (n = 311). Also blood glucose, blood lipids and new infarction or not were recorded. Comparisons of positive carotid artery plaque and the level of blood glucose and lipids were made between diabetics and non-diabetics. And the level-risk relationship between plaque formation and diabetes mellitus or blood lipids were performed through Logistic regression. RESULTS: The positive rate of carotid artery plaque was higher in diabetics versus non-diabetics (80% vs 67%, P = 0.003), OR (95% CI, P value) was 2.001 (1.258-3.182, 0.001) through Logistic regression; after adjusting for cerebral infarction, 1.875 (1.172-3.000, 0.009). It had a lower level of high-density lipoprotein-cholesterol (HDL-C) in diabetics versus non-diabetics (1.1 ± 0.3 vs 1.2 ± 0.3 mmol/L, P = 0.001). HDL-C was correlated with plaque formation while OR (95% CI, P value) was 0.416 (0.210-0.823, 0.012) through Logistic regression. And there has no correlation between plaque formation and other subtypes of blood lipids. CONCLUSION: A decrease of HDL-C may play an important role in the course of carotid artery plaque induced by diabetes mellitus in patients with ischemic cerebral vascular disease.

TL-2 attenuates ß-amyloid induced neuronal apoptosis through the AKT/GSK-3ß/ß-catenin pathway.

ß-amyloid (Aß)-mediated neuronal apoptosis contributes to the progression of Alzheimer's disease (AD), although the exact mechanism remains unclear. This study aimed to investigate whether Dalesconol B (TL-2), a potent immunosuppressive agent with an unusual carbon skeleton, could inhibit Aß-induced apoptosis in vitro and in vivo and to explore the underlying mechanisms. Aß(1-42) was injected to bilateral hippocampus of mice to make the AD models in vivo. TL-2 was able to cross the blood-brain barrier and attenuate memory deficits in the AD mice. TL-2 also inhibited Aß(1-42)-induced neuronal apoptosis in vitro and in vivo. In addition, TL-2 could activate the AKT/GSK-3ß pathway, and inhibition of AKT and activation of GSK-3ß partially eliminated the neuroprotective effects of TL-2. Furthermore, TL-2 induced the nuclear translocation of ß-catenin and enhanced its transcriptional activity through the AKT/GSK-3ß pathway to promote neuronal survival. These results suggest that TL-2 might be a potential drug for AD treatment.

Cervicocranial arterial dissection: an analysis of the clinical features, prognosis, and treatment efficacy.

Clinical features and therapeutic strategies of cervicocranial arterial dissection (CCAD) are still unclear. A retrospective review was conducted on 71 CCAD patients. Diagnosed by DSA and outcome evaluation was through mRS scores follow-up 12 months. All patients were allocated into three groups according to clinical situation: 1) subarachnoid hemorrhage (SAH), 2) ischemic symptoms and 3) mass effect. CCAD with anterior circulation arterial dissection (ACAD) had higher ischemia than that with posterior circulation arterial dissection (PCAD) (p=0.023). The non-aneurysmal dissection (NAD) patients were susceptible to ischemia (p=0.00) and patients with aneurismal dissection (AD) were more susceptible to SAH (p=0.001); The outcome of patients with SAH was significantly worse than patients with other manifestations (p=0.012). Following up one year, the outcome of CCAD involving posterior inferior cerebellar artery (PICA) was significantly worse than the other area (p=0.035). There was no statistically significant difference in mRS scores between endovascular treatment and conservative treatment (p=0.052) at one year follow-up. Patients suffering from SAH that received endovascular treatment experienced improved outcomes than patients with conservative treatment (p=0.033). The patients in the ACAD, NAD and extracranial CCAD groups were more likely to suffer from ischemia, while patients in the AD group were susceptible to SAH. CCAD with SAH or involving PICA had poor prognoses. The therapeutic efficacy of conservative treatment is nearly equal to endovascular treatment in CCAD patients follow up 12 months; however, endovascular treatment may decrease the risk of mortality for the patient with SAH.

Hopeahainol A attenuates memory deficits by targeting ß-amyloid in APP/PS1 transgenic mice.

Increasing evidence demonstrates that amyloid beta (Aß) elicits mitochondrial dysfunction and oxidative stress, which contributes to the pathogenesis of Alzheimer's disease (AD). Identification of the molecules targeting Aß is thus of particular significance in the treatment of AD. Hopeahainol A (HopA), a polyphenol with a novel skeleton obtained from Hopea hainanensis, is potentially acetylcholinesterase-inhibitory and anti-oxidative in H(2)O(2)-treated PC12 cells. In this study, we reported that HopA might bind to Aß(1-42) directly and inhibit the Aß(1-42) aggregation using a combination of molecular dynamics simulation, binding assay, transmission electron microscopic analysis and staining technique. We also demonstrated that HopA decreased the interaction between Aß(1-42) and Aß-binding alcohol dehydrogenase, which in turn reduced mitochondrial dysfunction and oxidative stress in vivo and in vitro. In addition, HopA was able to rescue the long-term potentiation induction by protecting synaptic function and attenuate memory deficits in APP/PS1 mice. Our data suggest that HopA might be a promising drug for therapeutic intervention in AD.

Safety and efficacy of umbilical cord mesenchymal stem cell therapy in hereditary spinocerebellar ataxia.

Hereditary spinocerebellar ataxia (SCA) is a devastating, incurable disease. Stem-cell-based therapies represent new promise for clinical research in neurology. The objectives of this study were to assess the feasibility, efficacy, and potential toxicity of human umbilical cord mesenchymal stem cells (UCMSCs) therapy in patients with SCA. Sixteen genomically diagnosed SCA patients were enrolled and received intravenous and intrathecal infusion of UCMSCs. Clinical, laboratory, and radiographic evaluations were conducted to assess the safety of UCMSC therapy. Efficacy was evaluated by the Berg Balance Scale (BBS) and International Cooperative Ataxia Rating Scale (ICARS) scores. Among the 16 cases, there were no serious transplant-related adverse events happened in 12 months follow-up. The majority of patients showed improved BBS and ICARS scores continuing for at least 6 months which indicated UCMSC therapy could alleviate SCA symptoms. This study suggested that UCMSC transplantation was safe and might delay the progression of SCA. This may represent a new therapeutic strategy for SCA and other genetic neurological diseases.

Human umbilical cord mesenchymal stem cell therapy on neuromyelitis optica.

Stem cell transplantation is a promising therapy for neuromyelitis optica (NMO). Among stem cell varieties, human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) possess many advantages, add a differential potential into neural cells, secrete a set of trophic factors and cytokines, regulate immunological function, and have therapeutic potential for neurological diseases. In this study, hUC-MSCs transplantation was used to treat five NMO patients with follow-up for 18 months including evaluation of Expanded Disability Status Scale (EDSS) levels, clinical course, magnetic resonance imaging (MRI) characteristics, adverse events, and so on. Among the five cases, four showed therapeutic improvement after hUC-MSCs treatment. Both symptoms and signs improved and relapse frequencies were reduced. MRI characteristics also showed decreased volume and severity of lesions, while few adverse events occurred. The results suggest that hUC-MSCs transplantation appear safe and might be effective for NMO treatment in the near future. In addition, according to flow cytometry assay (FACS) results, B cells of blood were inhibited while T cells increased after treatment, indicating an immune-related mechanism.

Serum bilirubin after acute ischemic stroke is associated with stroke severity.

Elevated serum bilirubin was prevalent in the acute ischemic stroke (AIS), which was induced in response to oxidative stress and could display the intensity of oxidative stress. As more severe stroke is linked with higher level of oxidative stress, we hypothesized that bilirubin may be associated with the severity of stroke. In this study, bilirubin and other biochemical indexes were measured in 531 enrolled patients with AIS, and NIH Stroke Scale (NIHSS) scores were assessed simultaneous with blood collection. The association between bilirubin and the severity of stroke was performed by Spearman correlation analyze, and the level-risk relationship of bilirubin in different level of NIHSS score was performed through Multinomial logistic regression analysis. We performed multivariable logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) of severe stroke dichotomized as NIHSS≥8 with adjustment for other stroke risk factors, the level-risk relationship of severe stroke in different level of bilirubin was also performed through Multinomial logistic regression analysis. We found that NIHSS score was significantly positively correlated with both serum direct bilirubin (Dbil, R=0.229 and P=0.000) and total bilirubin (Tbil, R=0.224 and P=0.000), higher level of serum bilirubin linked to the higher NIHSS score with OR(95% CI) in upper level of NIHSS score group was 1.12(1.01-1.24), 1.23(1.11-1.36), 1.31(1.15-1.51) in Dbil and 1.01(0.99-1.31), 1.05(1.03-1.08), 1.07(1.03-1.11) in Tbil compared to the lowest level group. In unadjusted or adjusted logistic regression analyses, serum Dbil and Tbil still have a significant association with the severe stroke. When both the Dbil and Tbil concentrations were grouped into 4 levels, participants with higher levels of bilirubin showed higher risk with severe stroke compared with the lowest level of bilirubin, with OR(95% CI) 1.881(1.04-3.404) of Dbil in level 3 and 3.702(1.979-6.927) of Tbil, 3.352(1.572-7.147) of total bilirubin in level 4. As a conclusion, serum bilirubins were in significant correlation with severity of AIS, which may be served as useful markers to reflect the degree of illness.

Diammonium glycyrrhizinate upregulates PGC-1α and protects against Aß1-42-induced neurotoxicity.

Mitochondrial dysfunction is a hallmark of beta-amyloid (Aß)-induced neurotoxicity in Alzheimer's disease (AD), and is considered an early event in AD pathology. Diammonium glycyrrhizinate (DG), the salt form of Glycyrrhizin, is known for its anti-inflammatory effects, resistance to biologic oxidation and membranous protection. In the present study, the neuroprotective effects of DG on Aß(1-42)-induced toxicity and its potential mechanisms in primary cortical neurons were investigated. Exposure of neurons to 2 µM Aß(1-42) resulted in significant viability loss and cell apoptosis. Accumulation of reactive oxygen species (ROS), decreased mitochondrial membrane potential, and activation of caspase-9 and caspase-3 were also observed after Aß(1-42) exposure. All these effects induced by Aß(1-42) were markedly reversed by DG treatment. In addition, DG could alleviate lipid peroxidation and partially restore the mitochondrial function in Aß(1-42)-induced AD mice. DG also significantly increased the PGC-1α expression in vivo and in vitro, while knocking down PGC-1α partially blocked the protective effects, which indicated that PGC-1α contributed to the neuroprotective effects of DG. Furthermore, DG significantly decreased the escape latency and search distance and increased the target crossing times of Aß(1-42)-induced AD mice in the Morris water maze test. Therefore, these results demonstrated that DG could attenuate Aß(1-42)-induced neuronal injury by preventing mitochondrial dysfunction and oxidative stress and improved cognitive impairment in Aß(1-42)-induced AD mice, indicating that DG exerted potential beneficial effects on AD.

Early biomarkers for post-stroke cognitive impairment.

The aim of this study was to investigate whether some biomarkers could predict cognitive impairment after stroke. One hundred fifty-two first-ever stroke patients were recruited within 6-72 h after the onset of symptoms. Blood was drawn within 1 h after admission for determining biomarkers. Cognitive function was assayed 2 weeks after stroke. The patients were divided into four groups: stroke, vascular cognitive impairment with no dementia (VCIND), vascular dementia (VaD), and mixed dementia (MD). Forty healthy subjects were used as controls. The results indicated that lower soluble receptor levels for advanced glycation end products (sRAGE) and higher ß-secretase enzyme (BACE1) and neprilysin (NEP) levels were found in the VCIND, VaD, and MD groups. In addition, the percentages of ε3/ε4 genotypes and ε4 alleles in the VCIND, VaD, and MD groups were higher than in the stroke group. Correlation analysis determined that sRAGE, BACE1, and NEP were significantly related to the results of neuropsychological assessments. Logistic regression analysis, however, suggested that only sRAGE and BACE1 changed ahead of cognitive impairment after stroke. In conclusion, only BACE1 and sRAGE, not NEP or APOE genotypes, may be biomarkers diagnosing post-stroke cognitive impairment.

[Management of symptomatic cerebral arterial stenoses with coincidental intracranial aneurysms].

OBJECTIVE: To explore the clinical features and management strategies of patients with symptomatic intracranial stenosis associated with unruptured intracranial aneurysms. METHODS: From 2005 to 2011, 24 patients of symptomatic intracranial stenosis with coincidental intracranial aneurysm were divided into two groups of angioplasty and aneurysm embolization (A, n = 12) and non-embolization (B, n = 12). All patients were followed up by phone or at outpatient services. Ten patients were re-assessed with digital subtraction angiography (DSA). RESULTS: The patients of group A were followed up without stroke or death, but one patient had restenosis asymptomatically. Two patients of group B died of subarachnoid hemorrhage. CONCLUSION: Angioplasty or antiplatelet therapy may increase the rupturing risk of aneurysm. Dissecting aneurysms should be handled by coiling positively and in a timely manner by coiling to prevent rebleeding. Coincidental intracranial aneurysms should be handled by coiling actively.

[Granulocytic sarcoma of oral cavity: report of two cases].

Granulocytic sarcoma of oral cavity is a kind of isolated tumor constructed by immature myeloid cells. Two cases of granulocytic sarcoma of oral cavity were analyzed. The literatures about granulocytic sarcoma were overviewed.

Altered expression of Abeta metabolism-associated molecules from D-galactose/AlCl(3) induced mouse brain.

Cerebral deposition of amyloid-beta peptide (Abeta) is a critical feature of Alzheimer's disease (AD). Either aluminium trichloride (Al) or D-galactose (D-gal) induces Abeta overproduction in rat or mouse brain and has been used to produce models of aging and AD. Here it is shown that mice treated with Al plus D-gal represent a good model of AD with altered expression of Abeta metabolism-associated molecules. The work shows that Al/D-gal causes memory impairment and high Abeta levels in the cortex (Co) and hippocampus (Hi). Then, we found that beta-site APP cleavage enzyme 1 (BACE1) was increased in mouse Co and Hi. Al or Al plus D-gal suppressed mRNA of the low-density lipoprotein receptor-related protein 1(LRP1). D-gal also decreased the LRP expression in Hi, but not in Co. However, Al/D-gal did not affect the receptor for advanced glycation end products (RAGE) expression in mouse brains. Furthermore, Al/D-gal reduced the expression of neprilysin (NEP), but not the insulin degrading enzyme (IDE). This study indicates that Al/D-gal affects the expression of Abeta metabolism-associated molecules that are responsible for Abeta deposition during AD, suggesting that this mouse model can be a useful model for studying the mechanisms and biomarkers of AD and for drug screening.

Estrogen inhibits Fas-mediated apoptosis in experimental stroke.

Estrogen is protective in experimental cerebral ischemia, yet the mechanism remains unclear. Fas-mediated apoptosis has been shown to be induced after cerebral ischemia and significantly contribute to ischemic brain damage. In this study, we tested if estrogen is protective against cerebral ischemia by suppressing Fas-mediated apoptosis. 17Beta-estradiol-treated and untreated ovariectomized (OVX) female mice were subjected to 2 h middle cerebral artery occlusion (MCAO). Expression of Fas and Fas-associated death domain (FADD) were measured at 3, 6 and 12 h of reperfusion by RT-PCR and Western blot, respectively. Post-ischemic activities of caspase-8 and -3 activities, the two downstream effectors of Fas-induced apoptosis, were also assayed at same time points by ELISA. Finally, Fas antibody-induced cell death in primary cortical neurons was assayed by fluorescence activated cell sorter (FACS) in the presence and absence of estradiol. Our data showed that estradiol-treated OVX female mice sustained smaller infarct compared to untreated OVX mice. Ischemia upregulated Fas and FADD expression, and increased caspase-8 and -3 activities in OVX female mouse cortex, which were significantly attenuated by estradiol. Estradiol also significantly inhibited Fas antibody-induced neuronal cell apoptosis. Our data suggests that inhibition of ischemia-induced Fas-mediated apoptosis is an important mechanism of neuroprotection by estrogen in cerebral ischemia.