Mutations in the glucocerebrosidase gene are responsible for Chinese patients with Parkinson's disease.

Pathological mutations in the glucocerebrosidase gene (GBA) have been suggested to be associated with Parkinson's disease (PD) in various ethnic populations. Most studies on Chinese PD patients have only screened the N370S and L444P mutations in the GBA gene. To investigate the GBA mutations in Chinese population, we performed complete sequencing of the GBA gene in 184 Chinese PD patients and 130 Chinese control individuals. As a result, we identified three novel and nine reported GBA mutations. The novel mutations include 5-bp deletion (c.334_338delCAGAA), L264I and L314V and the nine reported GBA mutations are R163Q, F213I, E326K, S364S, F347L, V375L, L444P, RecNciI and Q497R. The novel 5-bp deletion (CAGAA) produces a short truncated GBA protein of 142 amino acids, which loses major function domains of the 536 amino acids. Our data also reveals that the frequency of GBA mutations within this Chinese PD cohort was 8.7%, which is significantly higher than 1.54% observed in the Chinese control cohort (χ(2) = 7.22, P = 0.0072; odds ratio (OR) = 6.095, 95% confidence interval of OR = 1.546-24.030). The most common L444P mutation accounts 2.74%, which confer more genetic risk for PD in this Chinese population. In conclusion, novel and known GBA mutations were identified and were found to be associated to PD in this Chinese population.

Osthole Upregulates BDNF to Enhance Adult Hippocampal Neurogenesis in APP/PS1 Transgenic Mice.

Adult hippocampal neurogenesis occurs in the dentate gyrus (DG) of the mouse hippocampus, and plays roles in learning and memory progresses. In amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mice, a rodent model of Alzheimer's disease (AD), severe impairment of neurogenesis in the dentate subgranular zone (SGZ) of the DG has been reported. Osthole, an active constituent of Cnidium monnieri (L.) CUSSON, has been reported to exert neuroprotective effects and may promote neural stem cell proliferation. However, whether osthole ameliorates spatial memory deficits and improves hippocampal neurogenesis in APP/PS1 mice remains unknown. In this study we found that osthole (30 mg/kg intraperitoneally (i.p.) once daily) treatment dramatically ameliorated the cognitive impairments by Morris Water Maze test and passive avoidance test, and augmented neurogenesis in the DG of hippocampus in APP/PS1 mice. Furthermore, osthole treatment upregulated expression of brain-derived neurotrophic factor (BDNF) and enhanced activation of the BDNF receptor tyrosine receptor kinase B (TrkB) following increased phosphorylation of cyclic AMP response element-binding protein (CREB), indicating that osthole improves neurogenesis via stimulating BDNF/TrkB/CREB signaling in APP/PS1 transgenic mice.

Preliminary results of cord blood mononuclear cell therapy for multiple system atrophy: a report of three cases.

OBJECTIVES: This study was designed to evaluate the effects of cord blood mononuclear cell transplantation in multiple system atrophy (MSA). CLINICAL PRESENTATION AND INTERVENTION: Cord blood mononuclear cells (1-2 × 10(8) cells/6 ml) were injected into the subarachnoid space using lumbar puncture in patients 1 and 2 and cisterna magna puncture in patient 3 in the 3 patients with MSA. The cord blood mononuclear cell transplantation was repeated 30 days after the first treatment in patients 1 and 2; it was repeated twice in patient 3. The clinical outcomes of treatment were used to assess the Unified Multiple System Atrophy Rating Scale (UMSARS) before, 90 and 180 days after the cell transplantation. There were no clinically noticeable side effects from the cord blood mononuclear cells. The UMSARS scores improved after 90 days of the cord blood mononuclear cell therapy in all 3 patients, the most significant improvement being that in urinary incontinence and ability to walk. CONCLUSIONS: Cord blood mononuclear cell transplantation was safe and potentially effective in the treatment of MSA in the 3 patients.

Impaired glymphatic clearance in multiple system atrophy: A diffusion spectrum imaging study.

INTRODUCTION: Impaired α-synuclein clearance is pivotal in the pathogenesis of neurodegenerative diseases. We evaluated glymphatic clearance in multiple system atrophy (MSA) patients using advanced imaging. METHODS: Forty-four MSA patients (11 with MSA-parkinsonian type [MSA-P] and 33 with MSA-cerebellar type [MSA-C]) and 30 healthy controls were studied using diffusion spectrum magnetic resonance imaging (DSI-MRI). Diffusivities were measured along the x-, y-, and z-axes to calculate the Analysis Along the Perivascular Space (ALPS) index. Comparisons of the ALPS index were conducted between MSA patients and controls and among MSA subtypes. The ALPS index correlation with the Unified Multiple System Atrophy Rating Scale (UMSARS) scores was also analyzed. RESULTS: The ALPS index differed significantly between patients with MSA and healthy controls, with lower values observed in the former (1.46 ± 0.17 versus1.63 ± 0.12, p < 0.001). Both MSA-P and MSA-C patients had lower ALPS-index (1.40 ± 0.13, p < 0.001; 1.47 ± 0.18, p = 0.003, respectively), but there was no significant difference between the two (p = 0.22). No correlation was found between the ALPS index and clinical scores for UMASRS I (r = -0.08, p = 0.61), UMASRS II (r = -0.04, p = 0.81), or UMASRS I + II (r = -0.05, p = 0.74). CONCLUSION: MSA patients show reduced glymphatic clearance as measured by the ALPS index, underscoring the utility of this imaging method in neurodegenerative disease research.

Long-Term Clinical Efficacy of Human Umbilical Cord Blood Mononuclear Cell Transplantation by Lateral Atlanto-Occipital Space Puncture (Gong's Puncture) for the Treatment of Multiple System Atrophy.

Multiple system atrophy (MSA) is a sporadic, progressive neurodegenerative disease characterized by autonomic nervous dysfunction with parkinsonism or cerebellar ataxia. Mesenchymal stem cell therapy or transplantation of human umbilical cord blood mononuclear cells (hUCB-MCs) may inhibit progression in MSA, but long-term studies are lacking. In addition, injection of stem cells via lateral atlanto-occipital space puncture (LASP, or Gong's puncture) may efficiently target areas of brain injury and avoid the disadvantages of other methods. This prospective study investigated the long-term clinical efficacy of transplantation of hUCB-MCs via LASP for the treatment of MSA. Seven patients with MSA who received hUCB-MC transplantation via LASP were followed for 3 to 5 years. Neurological function was evaluated before (baseline), at 3, 6, and 12 months, and annually after the first transplantation using the Unified MSA Rating Scale (UMSARS); a lower score indicated improvement. Adverse events were recorded. The best therapeutic effect was observed 3 to 6 months after the first hUCB-MC transplantation. The total UMSARS score at the timepoint of best effect (25.71 ± 11.87) was significantly lower than the score before treatment (42.57 ± 7.96; P = 0.001), but also significantly lower than at the end of follow-up (35.14 ± 18.21; P = 0.038). The UMSARS II score (findings on neurological examination) at the timepoint of best effect was significantly lower than before treatment (P = 0.001). There were no serious adverse events. In conclusion, transplantation of hUCB-MCs via LASP is a safe and effective treatment for MSA.

Progressive hemifacial atrophy in a Chinese patient: A case report.

BACKGROUND: Progressive hemifacial atrophy (PHA) is a rare and progressive condition of unknown etiology that is characterized by chronic progressive atrophy of the skin, subcutaneous tissue, muscle, and bone on 1 side of the face. However, its precise pathogenesis remains poorly understood. CASE PRESENTATION: Here, we report a case of PHA, which manifested as left-sided facial atrophy. Whole-exome sequencing of peripheral blood samples from the patient and his parents, together with bioinformatics analyses, led to the identification of mutations in ARHGAP4 and CFAP47. CONCLUSION: This report is the first to describe ARHGAP4 and CFAP47 mutations in a patient with PHA. These mutations may be related to the occurrence of hemifacial atrophy, although further studies are needed to clarify the role of ARHGAP4 and CFAP47 in the context of PHA pathogenesis.

Efficacy of Human Umbilical Cord Blood-Mononuclear Cell Transplantation for MSA Treatment and Its Effects on Changes in T-Cell Subsets in Peripheral Blood and Inflammatory Factors.

OBJECTIVE: This study is aimed at examining the efficacy of human umbilical cord blood-mononuclear cell (hUCB-MNCs) transplantation through lateral atlanto-occipital space puncture in multiple system atrophy (MSA) treatment and investigating changes in T-cell subsets in peripheral blood and inflammatory factors in patients before and after treatment. METHODS: A total of 20 patients with MSA who underwent hUCB-MNC transplantation through lateral atlanto-occipital space puncture in the Liaocheng People's Hospital were enrolled. Patients were followed up at 0, 1, 3, and 6 months after treatment, and the Unified Multiple System Atrophy Rating Scale (UMSARS) scores, TNF-α in the peripheral blood, IL-6, percentage of CD4, and CD4/CD8 ratio were evaluated and compared for each follow-up point; any adverse effects were recorded. RESULTS: UMSARS Part I scores were 20.55 ± 3.80, 19.20 ± 3.78, and 19.40 ± 4.11, 1, 3, and 6 months, respectively, after treatment and were significantly lower as compared to that before treatment (23.50 ± 4.72; P < 0.05). Similarly, UMSARS Part II scores 1, 3, and 6 months after treatment were 25.50 ± 5.01, 24.05 ± 5.01, and 24.25 ± 5.05, respectively, significantly lower as compared to that before treatment (30.15 ± 5.63; P < 0.05). The IL-6 values in the peripheral blood 1, 3, and 6 months after treatment were 5.25 ± 2.70 pg/m, 2.96 ± 1.75 pg/m, and 3.31 ± 1.62 pg/m, respectively, which were significantly lower (P < 0.05) than that before treatment (8.22 ± 4.69) pg/m. The TNF-α levels at 3 and 6 months after treatment were 13.08 ± 6.13 pg/m and 12.24 ± 4.76 pg/m, respectively, which were significantly lower than that before treatment (22.99 ± 13.30; P < 0.01). The CD4/CD8 ratios in the peripheral blood 1, 3, and 6 months after treatment were 1.09 ± 0.25, 1.30 ± 0.24, and 1.43 ± 0.22, respectively, which were significantly different than that before treatment (0.81 ± 0.24, P < 0.01). Similarly, the CD4 percentages 1, 3, and 6 months after treatment were 34.09 ± 1.79, 36.05 ± 1.50, and 36.47 ± 1.47, respectively, which were significantly different than that before treatment (0.81 ± 0.24; P < 0.01). CONCLUSION: hUCB-MNC transplantation through lateral atlanto-occipital space puncture could significantly improve the symptoms and signs in patients with MSA and delay the disease progression. Thus, hUCB-MNCs may modulate immune activity and reduce the inflammatory response.

A new method of subarachnoid puncture for clinical diagnosis and treatment: lateral atlanto-occipital space puncture.

OBJECTIVE Lumbar puncture may not be suitable for some patients needing subarachnoid puncture, while lateral C1-2 puncture and cisterna magna puncture have safety concerns. This study investigated lateral atlanto-occipital space puncture (also called lateral cisterna magna puncture) in patients who needed subarachnoid puncture for clinical diagnosis or treatment. The purpose of the study was to provide information on the complications and feasibility of this technique and its potential advantages over traditional subarachnoid puncture techniques. METHODS In total, 1008 lateral atlanto-occipital space puncture procedures performed in 667 patients were retrospectively analyzed. The success rate and complications were also analyzed. All patients were followed up for 1 week after puncture. RESULTS Of 1008 lateral atlanto-occipital space punctures, 991 succeeded and 17 failed (1.7%). Fifteen patients (2.25%) reported pain in the ipsilateral external auditory canal or deep soft tissue, 32 patients (4.80%) had a transient increase in blood pressure, and 1 patient (0.15%) had intracranial hypotension after the puncture. These complications resolved fully in all cases. There were no serious complications. CONCLUSIONS Lateral atlanto-occipital space puncture is a feasible technique of subarachnoid puncture for clinical diagnosis and treatment. It is associated with a lower rate of complications than lateral C1-2 puncture or traditional (suboccipital) cisterna magna puncture. It may have potential in the neurological diagnostic and treatment fields.

Treatment of multiple system atrophy - the past, present and future.

Multiple system atrophy is a sporadic progressive degenerative disease which is characterized by multiple central nervous systems involved. So far, there is no effective medicine to cure MSA. The main research direction of treatment includes immunization transplantation and cytotherapy. Human umbilical cord blood is the residue of blood in the placenta and umbilical cord after fetal delivery. It is the most abundant cell bank and its usage is not limited to treat hematological diseases. The researches about hUCB-MNC treatment on MSA are increasing gradually. The potential of other MSC is also discussed. Lateral atlanto-occipital space puncture is an ingenious way created by Professor Dianrong Gong. More than 30 cases of MSA have been treated by this method with fine clinical effect and without serious complications. It indicates that stem cells treatment is a valid method for refractory nerve system diseases.

Prior transient ischemic attacks may have a neuroprotective effect in patients with ischemic stroke.

INTRODUCTION: Although functional recovery and survival after ischemic infarction seem to improve in patients with prior transient ischemic attack (TIA), little is known about the role of characteristics of prior TIA in subsequent cerebral infarction. Thus, the objective of this study was to explore how the characteristics of prior TIA have a neuroprotective effect on patients with ischemic stroke. MATERIAL AND METHODS: A total of 221 patients admitted consecutively to a primary care center for first-ever ischemic stroke were divided into two groups on the basis of the presence or absence of prior TIAs. The initial NIHSS modified Rankin Scale was used to measure the severity and disability after the stroke. Subgroups were based on the TIA duration (< 10 min, 10 to 60 min, and > 60 min), TIA frequency (1 time, 2-3 times, more than 3 times), and the interval of stroke (< 1 week, 1-4 weeks, > 4 weeks). The severity of the neurologic picture on admission and functional disability after stroke were compared between patients with and without TIAs and subgroups as well. RESULTS: A total of 132 (59.73%) of the 221 patients had prior TIAs before stroke. Risk factors and the initial clinical picture did not differ between patients with or without TIAs. Patients with prior TIA had a more favorable outcome than those without TIA (59.09% vs. 43.82%), and a significant difference between the two groups was observed (χ² = 4.976, p = 0.026). Furthermore, neurological outcome in patients with prior TIA lasting for 60 min, less than 3 times and shorter intervals within 4 weeks was significantly different from that in the non-TIA group (p < 0.05). CONCLUSIONS: Prior transient ischemic attacks may have a neuroprotective effect on the subsequent ischemic stroke, and this effect might be affected by the characteristics of TIAs. Patients with TIAs of low frequency, short duration and short interval are considered to have better neurological outcomes.

(2R,3S)-Pinobanksin-3-cinnamate improves cognition and reduces oxidative stress in rats with vascular dementia.

This study investigated the neuroprotective effects of (2R,3S)-pinobanksin-3-cinnamate (PNC) in rats with occlusion-damaged bilateral common carotid arteries. Administration with PNC (5 and 10 mg/kg/day) for 5 weeks significantly improved the behavioral performance of rats with vascular dementia, as showed in the Morris water maze test by shortening the escape latency and latency of crossing, completing more platform crossings, as well as spending more time in the target zone. Further evaluations found that PNC could markedly decrease malondialdehyde levels, enhance superoxide dismutase activity and glutathione levels, and decrease the release of cytochrome c as well as the activities of caspases. Moreover, PNC increased Nrf2 and anti-apoptotic bcl-2 protein expression, while Nox1 and pro-apopotic bax protein expression was decreased. PNC may exert its neuroprotective effects through counteracting oxidative stress and has the potential to treat vascular dementia.

Baicalein ameliorated the upregulation of striatal glutamatergic transmission in the mice model of Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disorder, which is characterized by a loss of projecting dopaminergic neurons in the substantia nigra and diminished dopamine level in the striatum. Dopaminergic deficit consequently leads to the alterations of striatal basal glutamatergic synaptic transmission and plasticity in the medium spiny neurons. The cytokines and neurotoxins released from the reactive immune cells induced the loss of the projecting dopaminergic neurons in the substantia nigra, which triggering the pathogenesis of PD. The present study investigated the effect of treatment with baicalein (5,6,7-trihydroxyflavone) on the central cytokine synthesis, striatal glutamatergic transmission, and behavioral performance in the rotarod task in the mice injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Treatment with baicalein significantly attenuated the upregulation of striatal basal glutamatergic strength by decreasing the presynaptic glutamate release and recovering the insertion of postsynaptic glutamate receptor subunit GluR1 induced by MPTP. It also significantly improved the behavioral performance in the rotarod task in the mice injected with MPTP. Treatment with baicalein decreased the upregulation of cytokines (tumor necrosis factor-α and interleukin-1ß) in the substantia nigra and striatum in the mice injected with MPTP. These results indicated that baicalein might serve as novel approach for the treatment of the patients with PD.