SNCA rs11931074 polymorphism correlates with spontaneous brain activity and motor symptoms in Chinese patients with Parkinson's disease.

The α-synuclein (SNCA) gene is thought to be involved in levels of α-synuclein and influence the susceptibility for the development of Parkinson's disease (PD). The aim of the present study is to explore the association among SNCA rs1193074 polymorphism, spontaneous brain activity and clinical symptoms in PD patients. 62 PD patients and 47 healthy controls (HC) were recruited and underwent resting-state functional magnetic resonance imaging (rs-fMRI) scans. Also blood sample of each participant was genotyped for rs11931074 polymorphism (PD: TT = 19, GT = 32, GG = 11; HC: TT = 10, GT = 25, GG = 12) and then examined to ascertain the influence of different genotypes on regional brain activity with amplitude low-frequency fluctuation analysis (ALFF). Furthermore, we evaluated the relationship among genotypes, interactive brain region and clinical symptoms in PD. Compared with HC subjects, PD patients showed decreased ALFF values in right lingual gyrus and increased ALFF values in right cerebellum posterior lobe. Significant interaction of ''groups × genotypes'' was found in the right angular gyrus, where there were higher ALFF values in TT genotype than in GT or GG genotype in the PD group and there was a contrary trend in the HC group. And further Spearman's correlative analyses revealed that ALFF values in right angular gyrus were negatively associated with unified Parkinson's disease rating scale (UPDRS) III score in PD-TT genotype. Our study shows for the first time that SNCA rs11931074 polymorphism might modulate brain functional alterations and correlate with motor symptoms in Chinese PD patients.

Neurology practice and stroke services across East China: a multi-site, county-level hospital-based survey.

BACKGROUND: Neurological disorders are an economic and public health burden which requires efficient and adequate medical resources. Currently, little is known about the status of the quality of neurological care services available in China. As neurological primary care is mostly provided at the county hospital level, investigation of this geographical level is required. The aim of this study is to evaluate currently available neurology care services in Yangtze River Delta Urban Agglomerations in east China. METHODS: A multi-site, county-level hospital-based observational survey was conducted in east China from January 2017 to December 2017. A questionnaire was made to assess hospital and the departmental patient care capabilities, human resources and technical capacity in neurology departments. RESULTS: Of 228 hospitals across the Yangtze River Delta Urban Agglomerations, 217 documents were returned. Of these, 22 were excluded due to invalid hospital information or duplicate submission. Overall, most hospitals have neurology departments (162, 83.1%) while less than half of the hospitals have a stroke center (80, 41.0%) and neurology emergency department (46, 23.6%). Among 162 hospitals with neurology department, 5 were excluded due to inadequate sharing, leaving 157 hospitals for analysis. About 84.1% of these neurology departments can administer intravenous thrombolysis while about one third of them has the ability to perform arterial thrombectomy (36.9%). In addition, 46.2% of hospitals can carry out computed tomography angiography (CTA) in emergency room. Tertiary care hospitals are much more equipped with modern medical resources compared to the secondary hospitals. In four administrative regions, the neurology services are better in more economically advanced regions. CONCLUSIONS: Neurological care services need to be enhanced at the county-level hospitals to improve health care delivery.

PM2.5 induces liver fibrosis via triggering ROS-mediated mitophagy.

BACKGROUND: The increasing epidemic of fine particulate matter (PM2.5) is a serious threat to human health. It induces the occurrence of liver fibrosis, but its molecular mechanism is not yet clear. The molecular mechanisms of PM2.5 inducing liver fibrosis were investigated in this study. METHODS: The cell viability of LX-2 cells and primary hepatic stellate cells (HSCs) was detected using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In vitro enzyme-linked immune sorbent assay (ELISA) kits were used to detect the concentrations of antioxidant enzymes and reactive oxygen species (ROS). The mitochondrial transmembrane potential (MTP) was determined by JC-1 dye. Knockdown of Parkin was carried out by Parkin-specific siRNA transfection. Relative mRNA and protein expressions were evaluated by qRT-PCR, Western blotting, and immunofluorescence analysis. RESULTS: PM2.5 activated LX-2 cells and primary HSCs, inducing the liver fibrosis along with down-regulation of the gelatinases MMP-2, and up-regulation of myofibroblast markers collagen type I and α-SMA. The levels of ROS and reactive nitrogen species (RNS), as well as the lipid peroxidation marker malondialdehyde (MDA) were significantly up-regulated in LX-2 cells and primary HSCs treated with PM2.5. Also, the enzymatic antioxidants levels were disturbed by PM2.5. Furthermore, PM2.5 decreased the MTP, releasing cytochrome c from the mitochondria to the cytosol. The dynamics of mitochondria were regulated by PM2.5 via facilitating mitochondrial fission. The excess ROS induced by PM2.5 triggered the mitophagy by activating PINK1/Parkin pathway, and inhibition of mitophagy induced by PM2.5 diminished the liver fibrosis. CONCLUSION: PM2.5 may induce mitophagy via activating PINK1/Parking signal pathway by increasing ROS, thereby activating HSCs and causing liver fibrosis.

The association between clinically relevant anxiety and other non-motor symptoms in Parkinson's disease.

Anxiety disorders in patients with Parkinson's disease (PD) are often missed due to an overlap with other non-motor symptoms. The relationships between anxiety and other non-motor symptoms in PD still remain unclear. We used the Hamilton anxiety rating scale and the Non-motor Symptoms Questionnaire to measure anxiety and the complex range of non-motor symptoms in 99 PD patients. The relationships between anxiety and other PD-related non-motor symptoms were examined through regression analyses. 25 % of PD patients were diagnosed with clinically relevant anxiety. Non-motor symptoms were more prominent in patients with anxiety. Depression, urinary disorders, and sleep disruption were the factors most likely to influence anxiety in PD. Our findings have revealed a strong interplay between anxiety and other non-motor symptoms of PD and have highlighted the need for a holistic approach towards the clinical treatment of this disabling condition.

Transcutaneous auricular vagus nerve stimulation improves anxiety symptoms and cortical activity during verbal fluency task in Parkinson's disease with anxiety.

OBJECTIVE: To investigate the effect of 20/4Hz transcutaneous auricular vagus nerve stimulation (taVNS) on anxiety symptoms in Parkinson's disease (PD) and the potential neural mechanism. METHODS: In the current randomized, double-blind, sham-controlled trial, 30 PD patients with anxiety (PD-A), 30 PD patients without anxiety (PD-nA), and 30 healthy controls (HCs) were enrolled. PD-A patients were randomly (1:1) allotted to real taVNS stimulation group (RS) or sham stimulation group (SS) to explore the efficacy of a two-week treatment of taVNS to promote anxiety recovery. Simultaneously, all participants were measured activation in the bilateral prefrontal cortex during verbal fluency task (VFT) using functional near-infrared spectroscopy. RESULTS: PD-A patients showed significantly decreased oxyhemoglobin in the left triangle part of the inferior frontal gyrus (IFG) during VFT, which was negatively related to the severity of anxiety symptoms. After two-week treatment of taVNS, the interaction of group and time had significant effect on HAMA scores (F = 18.476, p < 0.001, η2 = 0.398). In RS group, compared with baseline, HAMA scores decreased significantly in the post-treatment and follow-up condition (both p < 0.001). Meanwhile, in RS group, HAMA scores were lower than those in SS group in the post-treatment and follow-up condition (p = 0.006, <0.001, respectively). Furthermore, the 20/4Hz taVNS remarkably ameliorated anxiety symptoms in PD patients, directly correlated with the increased activation of the left triangle part of the IFG during VFT in RS group. CONCLUSION: Our results depicted that taVNS could ameliorate the anxiety symptoms of PD-A patients and regulated the function of the left triangle part of the IFG.

Advancements in autologous stem cell transplantation for Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative disease marked by comparatively focal dopaminergic neuron degeneration in the substantia nigra of the midbrain and dopamine loss in the striatum, which causes motor and non-motor symptoms. Currently, pharmacological therapy and deep brain stimulation(DBS) are the primary treatment modalities for PD in clinical practice. While these approaches offer temporary symptom control, they do not address the underlying neurodegenerative process, and complications often arise. Stem cell replacement therapy is anticipated to prevent further progression of the disease due to its regenerative capacity, and considering the cost of immunosuppression and the potential immune dysfunctions, autologous stem cell transplantation holds promise as a significant method against allogeneic one to treat Parkinson's disease. In this review, the safety concerns surrounding tumorigenicity and complications associated with transplantation are discussed, along with methods utilized to evaluate the efficacy of such procedures. Subsequently, we summarize the preclinical and clinical studies involving autologous stem cell transplantation for PD, and finally talk about the benefits of autologous stem cell transplantation against allogeneic transplants.

Transcutaneous auricular vagus nerve stimulation improves gait and cortical activity in Parkinson's disease: A pilot randomized study.

OBJECTIVE: In this randomized, double-blind, sham-controlled trial, we explored the effect of 20 Hz transcutaneous auricular vagus nerve stimulation (taVNS) on gait impairments in Parkinson's disease (PD) patients and investigated the underlying neural mechanism. METHODS: In total, 22 PD patients and 14 healthy controls were enrolled. PD patients were randomized (1:1) to receive active or sham taVNS (same position as active taVNS group but without releasing current) twice a day for 1 week. Meanwhile, all subjects were measured activation in the bilateral frontal and sensorimotor cortex during usual walking by functional near-infrared spectroscopy. RESULTS: PD patients showed instable gait with insufficient range of motion during usual walking. Active taVNS improved gait characteristics including step length, stride velocity, stride length, and step length variability compared with sham taVNS after completion of the 7-day therapy. No difference was found in the Unified Parkinson's Disease Rating Scale III, Timed Up and Go, Tinetti Balance, and Gait scores. Moreover, PD patients had higher relative change of oxyhemoglobin in the left dorsolateral prefrontal cortex, pre-motor area, supplementary motor area, primary motor cortex, and primary somatosensory cortex than HCs group during usual walking. Hemodynamic responses in the left primary somatosensory cortex were significantly decreased after taVNS therapy. CONCLUSION: taVNS can relieve gait impairments and remodel sensorimotor integration in PD patients.

BDNF rs6265 single-nucleotide polymorphism is involved in levodopa-induced dyskinesia in Parkinson's disease via its regulation of the cortical thickness of the left postcentral gyrus.

Background: Brain-derived neurotrophic factor (BDNF) gene rs6265 single-nucleotide polymorphism (SNP) is thought to be involved in neuroplasticity and influence the development of levodopa-induced dyskinesia (LID) in Parkinson's disease (PD). This study aimed to determine how the BDNF rs6265 SNP regulates cortical thickness and to investigate the association between BDNF and the pathological mechanisms of LID in PD. Methods: This cross-sectional study recruited 75 patients with PD, including 37 patients with LID and 38 patients without LID, and 33 healthy controls. All the participants underwent T1-weighted magnetic resonance imaging (MRI) scans, clinical evaluations, and BDNF rs6265 genotyping. Two-way factorial analysis of covariance (ANCOVA) was used to explore the primary effects of disease status, rs6265 genotype, and their interactions on cortical thickness. Associations between cortical thickness in the regions of the brain affected by disease status-genotype interactions and clinical symptoms were detected using Spearman's rank-order correlation. Receiver operating characteristic (ROC) curve analysis was used to test cortical thickness measurements as an indicator of LID. Results: The main effects of disease status were observed in the right pars orbitalis (F=4.229, P=0.017), medial orbitofrontal cortex (F=3.639, P=0.030), and left banks superior temporal sulcus (F=3.172, P=0.046). The left pars orbitalis (F=4.541, P=0.036) and lingual gyrus (F=4.307, P=0.041) were thicker in carriers of the CC genotype than in carriers of the TC/TT genotype. Interaction between disease status and genotype showed that in the LID group, carriers of the CC genotype had a thicker left postcentral gyrus (mean difference =0.103, 95% confidence interval, 0.036 to 0.107, Bonferroni-corrected P<0.005) than did carriers of the TC/TT genotype, whereas no difference was found in the non-LID and healthy control (HC) groups. In carriers of the CC genotype, the cortical thickness of the left postcentral gyrus could identify whether patients with PD had LID, with an area under the receiver operating curve (AUC) of 0.757 (P=0.033, optimal cut-off =2.102). The cortical thickness of the left postcentral gyrus was also positively correlated with the Unified Dyskinesia Rating Scale (UDysRS) score in the LID-CC subgroup (r=0.825, P=0.001). Conclusions: The BDNF rs6265 SNP might be associated with dyskinesia symptoms in patients with PD and LID through its regulation of cortical thickness in the left postcentral gyrus.

Impaired Interhemispheric Synchrony in Parkinson's Disease with Fatigue.

The characteristics of interhemispheric resting-state functional connectivity (FC) in Parkinson's disease (PD) with fatigue remain unclear; therefore, we aimed to explore the changes in interhemispheric FC in PD patients with fatigue. Sixteen PD patients with fatigue (PDF), 16 PD patients without fatigue (PDNF) and 15 matched healthy controls (HCs) were enrolled in the retrospective cross-sectional study. We used voxel-mirrored homotopic connectivity (VMHC) to analyze the resting-state functional magnetic resonance imaging (fMRI) data of these subjects. Compared to PDNF, PDF patients had decreased VMHC values in the supramarginal gyri (SMG). Furthermore, the mean VMHC values of the SMG were negatively correlated with the mean fatigue severity scale (FSS/9) scores (r = -0.754, p = 0.001). Compared to HCs, PDF patients had decreased VMHC in the SMG and in the opercular parts of the inferior frontal gyri (IFG operc). The VMHC values in the IFG operc and middle frontal gyri (MFG) were notably decreased in PDNF patients compared with HCs. Our findings suggest that the reduced VMHC values within the bilateral SMG may be the unique imaging features of fatigue in PD, and may illuminate the neural mechanisms of fatigue in PD.

Impaired interhemispheric synchrony in Parkinson's disease patients with apathy.

BACKGROUND: Apathy is a common non-motor symptom in Parkinson's disease (PD), yet the neural mechanism remains unknown. It has been reported that the lateralization of dopamine levels is correlated with apathetic symptoms. We aimed to ascertain the role of lateralization in the neuropathogenesis of apathy in PD. METHODS: Twenty-six apathetic PD patients (PD-A), twenty-seven nonapathetic PD patients (PD-NA), and twenty-three healthy controls (HCs) were recruited. All subjects underwent T1-weighted and resting state functional MRI scanning during OFF medication state. Voxel-mirrored Homotopic Connectivity (VMHC) and asymmetry voxel-based morphometry (asymmetry VBM) analysis were applied to detect the synchrony of homotopic connections between hemispheres and grey matter asymmetry index. RESULTS: Compared with both PD-NA and HCs groups, the PD-A group showed excessively decreased z-VMHC values in the nucleus accumbens (NAcc) and putamen. Additionally, both PD subgroups exhibited decreased z-VMHC values in the cerebellum lobule VIII compared with controls. However, no corresponding alteration in grey matter asymmetry index was found. Further, a negative correlation between the z-VMHC values of the NAcc and the Apathy Scale (AS) was confirmed in the PD-A group. Meanwhile, the same relationship was also confirmed between the putamen and AS. Notably, ROC curve analyses uncovered that the z-VMHC values of the NAcc and putamen could be a potential neuroimaging feature discerning apathetic PD patient, respectively. LIMITATIONS: This is a cross-sectional study. CONCLUSION: Our findings demonstrated that the asymmetric functional connectivity in the mesocorticolimbic and nigrostriatal systems might induce the pathophysiological mechanisms of apathy in PD.

Phosphorylated α-synuclein aggregated in Schwann cells exacerbates peripheral neuroinflammation and nerve dysfunction in Parkinson's disease through TLR2/NF-κB pathway.

To investigate the mechanism of peripheral neuropathy in Parkinson's disease (PD), we prepared a PD mice model by long-term exposure of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to mimic PD pathology in humans and the sciatic nerves were taken for further research. It turned out that phosphorylated α-synuclein (p-α-syn) was significantly deposited in Schwann cells (SCs) of sciatic nerves possibly contributing to degenerated myelin SCs and atrophied axons in MPTP group. Further analysis confirmed that toll-like receptors (TLRs) were implicated with PD peripheral neuropathy, in which TLR2 exhibits the predominant expression. Increased expression of inflammatory factors about TLR2/nuclear factor kappa-B (NF-κB) pathway was noted in MPTP group compared to saline group, with proteins on other pathways showing no changes. Moreover, MPTP-challenged mice exhibited worse motor ability and damaged nerve conduction, implicating that p-α-syn neurotoxicity might be relevant to impairments of motor and sensory nerves. After the treatment of CU-CPT22, a TLR2 antagonist, p-α-syn accumulation, motor and sensory function were ameliorated in CU-CPT22 combined with MPTP group. Thus, we demonstrated that pathological p-α-syn might combine TLR2 to affect SCs activation, inflammatory response as well as motor and sensory function through TLR2/nuclear factor kappa-B (NF-κB) signaling pathway. This study firstly demonstrates a novel mechanism of p-α-syn accumulated in SCs of peripheral nerves, which extends our understanding on SCs-mediated peripheral neuroinflammation related to TLR2/NF-κB signaling pathway and sheds light on potential new therapeutic avenues for PD.

Dysfunction in superior frontal gyrus associated with diphasic dyskinesia in Parkinson's disease.

Alterations in brain function in Parkinson's disease (PD) patients with diphasic dyskinesia have not been investigated. We aimed to explore the alterations in regional brain function. Each of 53 levodopa (LD)-treated PD patients had two resting-state functional magnetic resonance imaging (rs-fMRI) scans in the same morning, before and after taking LD. The regional homogeneity (ReHo) approach was used to reveal local synchronization changes. Two-way factorial repeated measures analysis of covariance, with group as a between-subject factor and LD effect as a within-subject factor, was performed to explore the two main effects and interaction. Interactive analysis was used to show outcomes that combined disease status and LD effect. Spearman's correlations were used to detect associations between interactive brain regions and severity of dyskinetic symptoms, assessed by the Unified Dyskinesia Rating Scale (UDyRS) scores, along with moderation analyses. There was no significant difference in the main group effect analysis. Significantly different clusters obtained from main LD effect analysis were in left caudate nucleus and putamen. ReHo values decreased in the caudate nucleus and increased in the putamen during the ON state after taking LD. Interaction between group and LD effect was found in left medial superior frontal gyrus (mSFG), where there were the lowest ReHo values, and was negatively correlated with UDyRS scores in the diphasic dyskinetic group during the ON state. The relationship was independent of LD dose. Abnormal local synchronization in the mSFG is closely associated with the development of diphasic dyskinesia in PD patients.

Activated Schwann cells and increased inflammatory cytokines IL-1ß, IL-6, and TNF-α in patients' sural nerve are lack of tight relationship with specific sensory disturbances in Parkinson's disease.

AIMS: Neuroinflammation is one of the most important processes in the pathogenesis of Parkinson's disease (PD). Sensory disturbances are common in patients with PD, but the underlying pathophysiological mechanisms remain unknown. This study aimed to characterize the activation of Schwann cells (SCs) and the increase of expression of inflammatory cytokines IL-1ß, IL-6, and TNF-α in the sural nerve of PD, and further explore whether peripheral nerve inflammation is the cause of PD sensory disturbances. METHODS: A total of 14 patients with PD (including 5 with sensory disturbances and 9 without sensory disturbances) and 6 controls were included. The excitation and conduction function of sural nerve was detected by sural nerve electrophysiological examination. With sural nerve biopsy samples, ultrastructural changes of sural nerve were observed by electron microscopy; Schwann cell biomarker glial fibrillary acid protein (GFAP) and inflammatory cytokines including interleukin-1beta (IL-1ß), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-α) were detected by immunohistochemistry, and the outcome of immunostaining slice was semiquantitatively counted; double immunofluorescence was used to identify the locus immunoreactive for inflammatory cytokines. RESULTS: Compared with healthy controls, nerve conduction velocity (NCV) slowed down and sensory nerve action potential (SNAP) amplitude decreased in PD patients, accompanied by axonal degeneration and demyelinating lesions, and expression of GFAP and inflammatory cytokines was increased. Inflammatory cytokines were significantly colocalized with GFAP and slightly colocalized with NF. These indicators did not differ significantly between PD patients with and without sensory disturbances. CONCLUSION: Our study results suggest that peripheral sensory nerve injury exists in PD patients, accompanied by Schwann cell activation and inflammation, thus demonstrate peripheral nerve inflammation participates in the pathophysiological process of PD but it is not necessarily related to the patient's sensory disturbance.

The increased gray matter volumes of precentral gyri in Parkinson's disease patients with diphasic dyskinesia.

Abnormal dopaminergic modulation of the cortico-basal ganglia motor loops results in the emergence of levodopa-induced dyskinesia (LID). We focused on alterations in the gray matter (GM) volume and the cortical thickness of the brain, especially in cortico-basal ganglia motor loops, in Parkinson's disease (PD) with diphasic dyskinesia. 48 PD patients with diphasic dyskinesia, 60 PD patients without dyskinesia and 48 healthy controls (HC) were included. Voxel-based morphometry (VBM) was applied to get GM images from MRI brain images. FreeSurfer was used to get cortical thickness. Distinct analyses of covariance (ANCOVA) and linear contrasts were performed for early- and late-onset PD groups. The severity of diphasic dyskinesia was evaluated by the Unified Dyskinesia Rating Scale (UDysRS). Finally, the correlations between mean volumes of clusters showing differences and the UDysRS scores were performed by Pearson's correlation. The GM volumes of precentral gyri were increased in PD patients with diphasic dyskinesia when compared with those without dyskinesia, which were positively correlated with UDysRS scores in PD patients with diphasic dyskinesia. However, there was no significant difference in cortical thickness among groups. The increased precentral gyri GM volumes might be associated with the pathogenesis and the severity of diphasic dyskinesia.

BST1 rs4698412 allelic variant increases the risk of gait or balance deficits in patients with Parkinson's disease.

AIMS: We aimed to explore effects of bone marrow stromal cell antigen-1 (BST1) rs4698412 allelic variant on brain activation and associative clinical symptoms in Parkinson's disease (PD). METHODS: A total of 49 PD patients and 47 healthy control (HC) subjects were recruited for clinical evaluations, blood samples collection for genotypes, and resting-state functional MRI (rs-fMRI) scans. Based on BST1 rs4698412 allelic variant (G â†’ A), participants were further divided into 18 PD-GG, 31 PD-GA/AA, 20 HC-GG, and 27 HC-GA/AA carriers, which respectively indicated subjects carrying ancestral or risk allele in that locus in PD or HC. Two-way analysis of covariance (ANCOVA) was applied to investigate main effects and interactions between PD and BST1 rs4698412 allelic variant on brain function via amplitude of low-frequency fluctuations (ALFF). Spearman's correlations were then utilized to detect associations between interactive brain regions and clinical symptoms. RESULTS: Compared to HC subjects, PD patients exhibited increased ALFF values in left cerebellum_8 and cerebellum_9. Significant interaction was in right lingual gyrus, where there were the lowest ALFF values and ALFF values were only negatively associated with Timed Up and Go (TUG) test time in PD-GA/AA subgroup. CONCLUSION: BST1 rs4698412-modulated lingual gyrus functional alterations could be related to gait and balance dysfunction in PD.

Phosphorylated α-synuclein deposits in sural nerve deriving from Schwann cells: A biomarker for Parkinson's disease.

INTRODUCTION: Paresthesia is common in Parkinson's disease (PD) patients. We assumed that peripheral nerve might be implicated. This study aimed to investigate whether phosphorylated α-synuclein (pSNCA) pathology occurred in sural nerve fibers and to explore the underlying pathogenesis of paresthesia of lower limbs associated with PD. METHODS: Clinical assessments and sural nerve biopsy were performed to evaluate clinical characteristics and the deposition of total α-synuclein (tSNCA) and pSNCA in biopsy pieces using immunochemistry methods on 16 PD patients and 15 controls. In addition, immunofluorescence staining was performed using certain antibodies to characterize the component of sural nerve and to localize the expression of pSNCA. RESULTS: Deposition of pSNCA was found in 16/16 PD patients with a high positive percentage of 100% but in 0/15 controls, however, all biopsy pieces showed positive response to tSNCA immunohistological staining in nerve fibers. pSNCA was expressed mainly in Schwann cells but scarcely in axons, demonstrating a novel pattern of pSNCA expression in peripheral nervous system. CONCLUSION: Our findings suggest that peripheral somatic sensory nerve is also involved in SNCA pathology in PD. The search for pSNCA in sural nerve might serve as a novel biomarker for early diagnosis of PD and pSNCA in sural nerve may derive from Schwann cells rather than propagate retrograde along the primary sensory neurons from the central nervous system.

Disrupted amplitude of low-frequency fluctuations and causal connectivity in Parkinson's disease with apathy.

Apathy is a common non-motor symptom in Parkinson's disease (PD). We aimed to explore its associated neural substrates changes via amplitude of low-frequency fluctuations (ALFF) and granger causality analysis (GCA). Resting-state functional magnetic resonance imaging (rs-fMRI) scans were performed in 20 PD patients with apathy (PD-A), 22 PD patients without apathy (PD-NA) and 19 healthy volunteers. GCA, a new method exploring direction from one brain region to another, was based on brain regions showing alterations of neural activity as seeds, which were examined utilizing ALFF approach. The relationships between ALFF or GCA and apathetic symptoms were also assessed. Relative to PD-NA group, PD-A group indicated decreased ALFF in left orbital middle frontal gyrus and bilateral superior frontal gyrus (SFG). Only ALFF values in right SFG were negatively correlated with Apathy Scale (AS) scores. Then GCA with the seed of right SFG showed a positive feedback from right thalamus to ipsilateral SFG, which was positively correlated with AS scores. In conclusion, dysfunction in SFG and a positive feedback from thalamus to ipsilateral SFG contributed to presence of PD-related apathy, providing a new perspective for future studies on apathy in PD.

Protective effect of inducible nitric oxide synthase inhibitor on pancreas transplantation in rats.

AIM: To investigate the effect of inducible nitric oxide synthase inhibitor, aminoguanidine, on pancreas transplantation in rats. METHODS: A model of pancreas transplantation was established in rats. Streptozotocin-induced diabetic male Wistar rats were randomly assigned to sham-operation control group (n = 6), transplant control group (n = 6), and aminoguanidine (AG) treatment group (n = 18). In the AG group, aminoguanidine was added to intravascular infusion as the onset of reperfusion at the dose of 60 mg/kg, 80 mg/kg, 100 mg/kg body weight, respectively. Serum nitric oxide (NO) level, blood sugar and amylase activity were detected. Nitric oxide synthase (NOS) test kit was used to detect the pancreas cNOS and inducible NOS (iNOS) activity. Pancreas sections stained with HE and immunohistochemistry were evaluated under a light microscope. RESULTS: As compared with the transplant control group, the serum NO level and amylase activity decreased obviously and the evidence for pancreas injury was much less in the AG group. The AG (80 mg/kg body weight) group showed the most significant difference in NO and amylase (NO: 66.0 +/- 16.6 vs 192.3 +/- 60.0, P < 0.01 and amylase: 1426 +/- 177 vs 4477 +/- 630, P < 0.01). The expression and activity of tissue iNOS, and blood sugar in the AG (80 mg/kg body weight) group were much lower than those in the transplant control group (iNOS: 2.01 +/- 0.23 vs 26.59 +/- 5.78, P < 0.01 and blood sugar: 14.2 +/- 0.9 vs 16.8 +/- 1.1, P < 0.01). CONCLUSION: Selective iNOS inhibitor, aminoguanidine as a free radical, has a protective effect on pancreas transplantation in rats by inhibiting NO and reducing its toxicity.

Abnormal Resting-State Neural Activity and Connectivity of Fatigue in Parkinson's Disease.

AIMS: Fatigue is a common burdensome problem in patients with Parkinson's disease (PD), but its pathophysiological mechanisms are poorly understood. This study aimed at investigating the neural substrates of fatigue in patients with PD. METHODS: A total of 17 PD patients with fatigue, 32 PD patients without fatigue, and 25 matched healthy controls were recruited. The 9-item fatigue severity scale (FSS) was used for fatigue screening and severity rating. Resting-state functional magnetic resonance imaging (RS-fMRI) data were obtained from all subjects. Amplitude of low-frequency fluctuations (ALFF) was used to measure regional brain activity, and functional connectivity (FC) was applied to investigate functional connectivity at a network level. RESULTS: PD-related fatigue was associated with ALFF changes in right middle frontal gyrus within the attention network and in left insula as well as right midcingulate cortex within the salience network. FC analysis revealed that above three regions showing ALFF differences had altered functional connectivity mainly in the temporal, parietal, and motor cortices. CONCLUSION: Our findings do reveal that abnormal regional brain activity within attention and salience network and altered FC of above abnormal regions are involved in neural mechanism of fatigue in patients with PD.

MicroRNA-7 targets Nod-like receptor protein 3 inflammasome to modulate neuroinflammation in the pathogenesis of Parkinson's disease.

BACKGROUND: α-Synuclein (α-Syn), a pathological hallmark of Parkinson's disease (PD), has been recognized to induce the production of interleukin-1ß in a process that depends, at least in vitro, on nod-like receptor protein 3 (NLRP3) inflammasome in monocytes. However, the role of NLRP3 inflammasome activation in the onset of PD has not yet been fully established. RESULTS: In this study, we showed that NLRP3 inflammasomes were activated in the serum of PD patients and the midbrain of PD model mice. We further clarified that α-syn activated the NLRP3 inflammasome through microglial endocytosis and subsequent lysosomal cathepsin B release. Deficiency of caspase-1, an important component of NLRP3 inflammasome, significantly inhibited α-syn-induced microglia activation and interleukin-1ß production, which in turn alleviated the reduction of mesencephalic dopaminergic neurons treated by microglia medium. Specifically, we demonstrated for the first time that Nlrp3 is a target gene of microRNA-7 (miR-7). Transfection of miR-7 inhibited microglial NLRP3 inflammasome activation whereas anti-miR-7 aggravated inflammasome activation in vitro. Notably, stereotactical injection of miR-7 mimics into mouse striatum attenuated dopaminergic neuron degeneration accompanied by the amelioration of microglial activation in MPTP-induced PD model mice. CONCLUSIONS: Our study provides a direct link between miR-7 and NLRP3 inflammasome-mediated neuroinflammation in the pathogenesis of PD. These findings will give us an insight into the potential of miR-7 and NLRP3 inflammasome in terms of opening up novel therapeutic avenues for PD.