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More and more evidence suggests that dopamine receptor D3 gene (DRD3) plays an important role in the clinical manifestations and the treatment of Parkinson's disease (PD). DRD3 Ser9Gly polymorphism is the most frequently studied variant point. Our aim was to investigate the potential effect of DRD3 Ser9Gly polymorphism on modulating resting-state brain function and associative clinical manifestations in PD patients. We consecutively recruited 61 idiopathic PD patients and 47 healthy controls (HC) who were evaluated by clinical scales, genotyped for variant Ser9Gly in DRD3, and underwent resting-state functional magnetic resonance imaging. Based on DRD3 Ser9Gly polymorphism, PD patients and HCs were divided into four subgroups. Then, two-way analysis of covariance (ANCOVA) was applied to investigate main effects and interactions of PD and DRD3 Ser9Gly polymorphism on the brain function via amplitude of low-frequency fluctuations (ALFF) approach. The association between DRD3 Ser9Gly-modulated significantly different brain regions, and clinical manifestations were detected by Spearman's correlations. PD patients exhibited decreased ALFF values in the right inferior occipital gyrus, lingual gyrus, and fusiform gyrus. A significant difference in the interaction of "groups × genotypes" was observed in the right medial frontal gyrus. The ALFF value of the cluster showing significant interactions was positively correlated with HAMD-17 scores (r=0.489, p=0.011) and anhedonia scores (r=0.512, p=0.008) in PD patients with the Ser/Gly or Gly/Gly genotypes. Therefore, D3 gene Ser9Gly polymorphism might be associated with the severity of depression characterized by anhedonia in PD patients. [ABSTRACT FROM AUTHOR]

Introduction: Freezing of gait is a common complaint in patients with Parkinson's disease (PD). However, the neural bases of freezing of gait in PD remain uncertain. Existing studies on PD patients with freezing of gait (PD-FOG+) have reported damage of the corpus callosum, the largest commissural bundle of the brain. Thus, in this study we explored homotopic connectivity to investigate FOG-related interehemispheric alterations METHODS: A total of 21 PD-FOG + patients, 33 PD patients without freezing of gait (PD-FOG-), and 24 matched healthy controls were recruited. All PD patients were evaluated via the FOG questionnaire (FOGQ) and all subjects had a resting state functional magnetic resonance imaging (rs-fMRI) scan. The pattern of the homotopic connectivity was measured with the voxel-mirrored homotopic connectivity (VMHC) approach.Result: The PD-FOG + patients showed decreased VMHC values in the inferior parietal lobe (IPL) compared to both PD-FOG-patients and healthy controls. In PD-FOG + patients, the mean VMHC values in the IPL were negatively correlated with the FOGQ scores. Receiver operating characteristic curves analyses revealed that the VMHC in the IPL had discriminatory function distinguishing PD-FOG + patients from PD-FOG-patients or healthy controls.Conclusion: Decreased VMHC values of PD-FOG + patients relative to PD-FOG- and healthy controls in IPL maybe a unique feature for PD-FOG+ and it may have the ability to separate PD-FOG + patients from PD-FOG- and healthy controls. [ABSTRACT FROM AUTHOR]

Fatigue is a common complaint in patients with Parkinson's disease (PD). However, the neural bases of fatigue in PD remain uncertain. In this cross-sectional study, our aim was to study the change of the local brain function in PD patients with fatigue. Among 49 patients with PD, 17 of them had fatigue and the remaining 32 patients without fatigue, and 25 age- and gender-matched healthy controls were enrolled. All subjects were evaluated with Fatigue Severity Scale (FSS) and had a resting-state functional magnetic resonance imaging (rs-fMRI) scan. The fMRI images were analyzed using regional homogeneity (ReHo) to study the change of the local brain function. ReHo analysis controlling for gray matter volume, age, gender, and education showed decreased ReHo in the left anterior cingulate cortex (ACC) and the right superior frontal gyrus (dorsolateral part), and increased ReHo in the left postcentral gyrus and the right inferior frontal gyrus (orbital and triangular part), compared PD-F with PD-NF; In PD patients, the regional activity in the left ACC and the right superior frontal gyrus (dorsolateral part) was negatively correlated with the FSS scores, while that in the left postcentral gyrus, the right inferior frontal gyrus (orbital and triangular part) was positively correlated with the FSS scores. This study demonstrates that brain areas including frontal, postcentral and ACC regions indicative of sensory, motor, and cognitive systems are involved in fatigue in PD patients. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to evaluate the level of taurine in plasma, and its association with the severity of motor and non-motor symptoms (NMS) and chronic levodopa treatment in Parkinson's disease (PD).Patients and methods: Plasma taurine level was measured in treated PD (tPD), untreated PD (ntPD) and control groups. Motor symptoms and NMS were assessed using the Unified Parkinson's Disease Rating Scale, the short form of the McGill Pain Questionnaire, the Hamilton Depression Scale, the Scale for Outcomes in Parkinson's disease for Autonomic Symptoms and the Pittsburgh Sleep Quality Index. Longtime exposure to levodopa was indicated by its approximate cumulative dosage.Results: The plasma taurine levels of PD patients were decreased when compared with controls and negatively associated with motor severity but not NMS. Moreover, tPD patients exhibited lower levels of plasma taurine than ntPD patients. Interestingly, plasma taurine levels negatively correlated with cumulative levodopa dosage in tPD. After controlling for potential confounders, the association between taurine and levodopa remained significant.Conclusion: Our study supports that taurine may play important roles in the pathophysiology of PD and the disturbances caused by chronic levodopa administration. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to explore plasma antioxidant status inde novoChinese Parkinson's disease (PD) patients and investigate its relationship with specific motor features of PD.Patients and methods: Sixty-fourde novoChinese PD patients and 40 age- and sex-matched healthy controls were recruited. Each motor feature of PD patients was assessed by unified Parkinson's disease rating scale. Plasma antioxidant status, including plasma level of glutathione (GSH) and plasma activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), was detected using enzyme-linked immunosorbent assay. The relationship between the plasma antioxidant status and motor features of PD was evaluated by Spearman's coefficient.Results: Plasma GSH level and plasma activities of GSH-Px, CAT and SOD of PD patients were lower than those of healthy controls. Moreover, the declining activity of plasma CAT was related with the increasing mean postural instability and gait disorder (PIGD) score and growing age. In contrast, the severity of tremor was positively correlated with plasma SOD activity.Conclusion: Our study demonstrates that the plasma antioxidant status is impaired inde novoChinese PD patients. The complex relationship between the plasma antioxidant status and different motor features indicates that the antioxidant mechanisms underlying tremor and PIGD of PD may be different. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence suggests that patients with Parkinson's disease (PD) present with peripheral autonomic dysfunction (AutD) that even precedes motor deficits, through which α-synuclein can spread to the central nervous system. However, the pathological mechanisms underlying AutD in prodromal PD remain unclear. Here, we investigated the role of α-synuclein and its interplay with the activation of Schwann cells (SCs) of the vagus nerve in AutD. Methods: Rats were subjected to injection with adeno-associated viruses containing the human mutated A53T gene (AAV-A53T) or an empty vector into the left cervical vagus nerve and evaluated for gastrointestinal symptoms, locomotor functions, intestinal blood flow, and nerve electrophysiology. Further, we examined the impact of α-synucleinopathy on vagus nerves, SCs, and central nervous system neurons using electron microscopy, immunofluorescence, immunohistochemistry, and western blot. Finally, the role of Toll-like receptor 2 (TLR2) in regulating the neuroinflammation in the vagus nerve via MyD88 and NF-κB pathway was determined using genetic knockdown. Results: We found that rats injected with AAV-A53T in the vagus nerve exhibited prominent signs of AutD, preceding the onset of motor deficits and central dopaminergic abnormalities by at least 3 months, which could serve as a model for prodromal PD. In addition, reduced intestinal blood flow and decreased nerve conduction velocity were identified in AAV-A53T-injected rats, accompanied by disrupted myelin sheaths and swollen SCs in the vagus nerve. Furthermore, our data demonstrated that p-α-synuclein was deposited in SCs but not in axons, activating the TLR2/MyD88/NF-κB signaling pathway and leading to neuroinflammatory responses. In contrast, silencing the TLR2 gene not only reduced inflammatory cytokine expression but also ameliorated vagal demyelination and secondary axonal loss, consequently improving autonomic function in rats. Conclusions: These observations suggest that overexpression of α-synuclein in the vagus nerve can induce symptoms of AutD in prodromal PD, and provide support for a deeper understanding of the pathological mechanisms underlying AutD and the emergence of effective therapeutic strategies for PD. [ABSTRACT FROM AUTHOR]

Abstract: Previous studies on the association between glycogen synthase kinase 3 beta (GSK3-β) polymorphisms (rs334558 and rs6438552) and Parkinson's disease (PD) susceptibility remained inconsistent. Thus, the goal of this study was to re-examine their exact association by a meta-analysis. All eligible studies were identified by a systematic literature search of multiple databases. Six studies (3105 cases and 4387 controls) on rs334558 and six studies (2579 cases and 4091 controls) on rs6438552 were included. The quality of these studies was generally good according to the Newcastle–Ottawa Scale (NOS). The meta-analysis showed null association between the two variants and PD susceptibility in all genetic models from the overall or Caucasian population. However, the analysis of rs334558 revealed that the risk of PD decreased in heterozygote, dominant or additive models (OR=0.60, 95% CI: 0.48, 0.74; OR=0.63, 95% CI: 0.51, 0.78; OR=0.82, 95% CI: 0.71, 0.94, respectively) from the Eastern Asian population. Moreover, the analysis on the homozygote, heterozygote, dominant or additive models suggested that rs6438552 also reduced the PD risk (OR=0.45, 95% CI: 0.24, 0.84; OR=0.62, 95% CI: 0.39, 0.97; OR=0.57, 95% CI: 0.37, 0.87; OR=0.66, 95% CI: 0.49, 0.88, respectively) in the Eastern Asian population. Together, the findings suggest that the two variants both reduced the risk of PD in the Eastern Asian subgroup but not in the overall and Caucasian populations, which should be cautiously interpreted because of limited number of included studies. [Copyright &y& Elsevier]

Hsisosuchus, with three known species, was the most common genus of crocodyliforms in the Sichuan Basin during the Jurassic. However, the overall shape of the ventral trunk shield of osteoderms has not been clarified due to the lack of complete specimens. A new specimen of Hsisosuchus recently recovered from the Upper Jurassic of Yunnan has the nearly complete ventral trunk shield preserved. This specimen provides an example for the first time for us to understand the shape and the way of the arrangement of the osteoderms in the ventral trunk shield in the genus. Compared with the articulated part of the ventral trunk shield preserved in two of the three species of the genus, the osteoderms of the ventral trunk shield of the new specimen are different in both shape and way of arrangement, indicating that the pattern of the ventral trunk shield is not constant within Hsisosuchus. With no skull and much of the postcranial skeleton poorly preserved as well as no corresponding element that can be used to compare with all the three species, the new specimen was considered as an indeterminate species of Hsisosuchus, awaiting more materials to clarify the problem. [ABSTRACT FROM AUTHOR]

Background: Dysfunction of the primary motor cortex, participating in regulation of posture and gait, is implicated in freezing of gait (FOG) in Parkinson's disease (PD). Objective: The aim was to reveal the mechanisms of "OFF‐period" FOG (OFF‐FOG) and "levodopa‐unresponsive" FOG (ONOFF‐FOG) in PD. Methods: We measured the transcranial magnetic stimulation (TMS) indicators and gait parameters in 21 healthy controls (HCs), 15 PD patients with ONOFF‐FOG, 15 PD patients with OFF‐FOG, and 15 PD patients without FOG (Non‐FOG) in "ON" and "OFF" medication conditions. Difference of TMS indicators in the four groups and two conditions and its correlations with gait parameters were explored. Additionally, we explored the effect of 10 Hz repetitive TMS on gait and TMS indicators in ONOFF‐FOG patients. Results: In "OFF" condition, short interval intracortical inhibition (SICI) exhibited remarkable attenuation in FOG patients (both ONOFF‐FOG and OFF‐FOG) compared to Non‐FOG patients and HCs. The weakening of SICI correlated with impaired gait characteristics in FOG. However, in "ON" condition, SICI in ONOFF‐FOG patients reduced compared to OFF‐FOG patients. Pharmacological treatment significantly improved SICI and gait in OFF‐FOG patients, and high‐frequency repetitive TMS distinctly improved gait in ONOFF‐FOG patients, accompanied by enhanced SICI. Conclusions: Motor cortex disinhibition, represented by decreased SICI, is related to FOG in PD. Refractory freezing in ONOFF‐FOG patients correlated with the their reduced SICI insensitive to dopaminergic medication. SICI can serve as an indicator of the severity of impaired gait characteristics in FOG and reflect treatments efficacy for FOG in PD patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Different gas-solids flow phenomenas have been observed during start-up of fluidized beds of different particulate materials. • Forces on a horizontal slat during start-up of fluidized beds of different particulate materials were measured. • The immersed internals will be subject to more severe during start-up of fluidized beds of small particle size. • Different gas–solids flow phenomenas have been observed during start-up of fluidized beds of different particulate materials To study the effect of particle properties on forces acting on immersed internals during start-up of fluidized bed reactors, forces on a horizontal slat were measured in fluidized beds of four types of particulate materials (i.e. FCC catalyst particles and three silica sands of different sizes). The forces were measured by strain gauges adhered on the slat surface. Transient pressure signals were also measured synchronously by pressure transducers. The experimental results show that a high upward stress impulse appears in the measured stress signals during start-up of the fluidized beds of FCC particles and the two smaller-size silica sands. The peak stress impulse was several times larger than the magnitude of stress signals measured during steady state operation. However, in the fluidized bed of the coarsest silica sand, the peak stress impulse during start-up was much smaller, which is close to the magnitudes measured during steady state fluidization. For the three sizes of silica sands, the effective peak load densities on the slat decreased significantly with increasing particle size and were approximately proportional to the calculated fixed bed pressure drops of these beds based on Ergun equation. On the other hand, during start-up of the fluidized bed of FCC particles, particles near the bottom of the bed were difficult to mobilize and collapse, resulting in the bed expanding considerably and requiring more time to transform into a fluidized state. Potentially, internals immersed in the fluidized beds of small particles are easier to damage during the start-up stage. Effective measures (e.g. starting up the bed gradually with small increments of superficial gas velocity) must be implemented to reduce the possible risks for internals immersed in these fluidized beds. [ABSTRACT FROM AUTHOR]

Aims: The study aimed to investigate alterations in the inherent connectivity pattern of global functional networks in Parkinson's disease (PD) patients with fatigue. Methods: Eighteen PD patients with fatigue (PD‐F), 20 PD patients without fatigue (PD‐NF), and 23 healthy controls (HCs) were recruited and analyzed by the voxel‐wise degree centrality (DC) and the seed‐based functional connectivity (FC) analysis. Meanwhile, the surface‐based morphometry (SBM) analysis was also commanded to explore the structural alternations among groups. Results: PD‐F patients displayed reduced DC values in the left postcentral gyrus relative to PD‐NF and HCs groups, while increased DC values in the bilateral precuneus compared to HCs. Simultaneously, altered DC value in the left postcentral gyrus negatively corresponded to the mean fatigue severity scale (FSS) in PD‐F patients. Additionally, the receiver operating characteristic (ROC) curves uncovered that the reduced DC value of the left postcentral gyrus could discriminate PD‐F from PD‐NF and HCs groups. Our FC analysis further revealed that altered FC was located predominantly in the sensorimotor network in the PD‐F group. Moreover, we discovered no statistically significant differences between the three groups concerning cortical thickness. Conclusion: Our findings indicated that the altered functional connectivity in the sensorimotor network centering on the left postcentral gyrus and the bilateral precuneus might be the potential pathogenesis of PD with fatigue. [ABSTRACT FROM AUTHOR]

Background: Mounting research support that cholinergic dysfunction plays a prominent role in freezing of gait (FOG), which commonly occurs in Parkinson's disease (PD). Basal forebrain (BF), especially the cholinergic nuclei 4 (Ch4), provides the primary source of the brain cholinergic input. However, whether the degeneration of BF and its innervated cortex contribute to the pathogenesis of FOG is unknown. Objective: To explore the role of structural alterations of BF and its innervated cortical brain regions in the pathogenesis of PD patients with freezing. Methods: Magnetic resonance imaging assessments and neurological assessments were performed on 20 PD patients with FOG (PD‐FOG), 20 without FOG (PD‐NFOG), and 21 healthy participants. Subregion volumes of the BF were compared among groups. Local gyrification index (LGI) was computed to reveal the cortical alternations. Relationships among subregional BF volumes, LGI, and the severity of FOG were evaluated by multiple linear regression. Results: Our study discovered that, compared to PD‐NFOG, PD‐FOG exhibited significant Ch4 atrophy (p = 4.6 × 10−5), accompanied by decreased LGI values in the left entorhinal cortex (p = 3.00 × 10−5) and parahippocampal gyrus (p = 2.90 × 10−5). Based on the regression analysis, Ch4 volume was negatively associated with FOG severity in PD‐FOG group (β = −12.224, T = −2.556, p = 0.031). Interpretation: Our results imply that Ch4 degeneration and microstructural disorganization of its innervated cortical brain regions may play important roles in PD‐FOG. [ABSTRACT FROM AUTHOR]

Despite a growing body of evidence suggests that abnormal iron metabolism plays an important role in the pathogenesis of Parkinson’s disease (PD), few studies explored its role in non-motor symptoms (NMS) of PD. The present study aimed to investigate the relationship between abnormal iron metabolism and NMS of PD. Seventy PD patients and 64 healthy controls were consecutively recruited to compare serum iron, ceruloplasmin, ferritin, and transferrin levels. We evaluated five classic NMS, including depression, anxiety, pain, sleep disorder, and autonomic dysfunction in PD patients using the Hamilton Depression Scale (HAMD), the Hamilton Anxiety Scale (HAMA), the short form of the McGill Pain Questionnaire, the Pittsburgh Sleep Quality Index and the Scale for Outcomes in Parkinson’s disease for Autonomic Symptoms, respectively. Hierarchical multiple regression analysis was used to investigate the correlations between abnormal iron metabolism and NMS. No differences in serum ceruloplasmin and ferritin levels were examined between PD patients and healthy controls, but we observed significantly decreased serum iron levels and increased serum transferrin levels in PD patients in comparison with healthy controls. After eliminating confounding factors, HAMD scores and HAMA scores were both negatively correlated with serum iron levels and positively correlated with serum transferrin levels. In summary, abnormal iron metabolism might play a crucial role in the pathogenesis of depression and anxiety in PD. Serums levels of iron and transferrin could be peripheral markers for depression and anxiety in PD. [ABSTRACT FROM AUTHOR]

Purpose: The neural bases of fatigue in Parkinson's disease (PD) remain uncertain. We aimed to assess the brain metabolic correlates of fatigue in patients with PD. Patients and methods: Twenty-seven PD patients without clinically relevant depression (17-item Hamilton Depression Rating Scale (HAMD) score ≥ 14), apathy (Apathy Scale (AS) score ≥ 14) and excessive daytime somnolence (Epworth Sleepiness Scale (ESS) score ≥ 10) were evaluated with Fatigue Severity Scale (FSS). Each patient had an F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) scan. Motor symptoms were measured with the Unified Parkinson's Disease Rating Scale motor part. Levodopa equivalent daily dose for each patient was also calculated. The PET images were analyzed using statistical parametric mapping software. We introduced the age, educational level, HAMD scores, AS scores and ESS scores as covariates. Results: High FSS scores were associated with brain hypermetabolism in areas including the right middle temporal gyrus (Brodmann area (BA) 37) and left middle occipital gyrus (BA 19). Increased FSS scores correlated with hypometabolism in regions such as the right precuneus (BA 23), left inferior frontal gyrus (BA 45) and left superior frontal gyrus (orbital part, BA 11). Conclusion: This study demonstrates that brain areas including frontal, temporal and parietal regions indicative of emotion, motivation and cognitive functions are involved in fatigue in PD patients. [ABSTRACT FROM AUTHOR]

Object To detect the cerebral metabolic bases of Parkinson’s disease (PD) patients with anxiety. Methods Totally 28 idiopathic PD patients without depression (17-item Hamilton Depression Rating Scale, HAMD score <14) were enrolled in our study. All subjects were classified into PD with anxiety (PD-A) (n = 13) and PD without anxiety (PD-NA) (n = 15) by cutoff score of 11 according to Hamilton Anxiety Rating Scale (HAMA). Besides, age- and gender- matched healthy controls (HCs) (n = 15) were selected. A resting-state F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) scan was applied to estimate cerebral metabolic activity. All statistical analyses were performed using IBM SPSS Statistics V20.0.0 software, while statistical parametric mapping software (SPM) was used to analyze the FDG-PET images. Results PD-A showed decreased glucose metabolism in the bilateral orbitofrontal cortex (OFC, BA10 and BA11) when compared with PD-NA. Significant decrease of cerebral glucose metabolism in the bilateral OFC, bilateral supplementary motor area (SMA, BA6), bilateral dorsal anterior cingulate cortex (dACC, BA32), right dorsolateral prefrontal cortex (dlPFC, BA9), right ventrolateral prefrontal cortex (vlPFC, BA44), right putamen and left caudatum was detected in PD-A compared with HCs. There was significant reduced glucose metabolism of the bilateral SMA in PD-NA when compared with HCs (uncorrected p < 0.005). Conclusion The anxiety of PD was associated with the metabolic reductions of PFC and striatal areas. OFC, part of PFC, could be taken as a characteristic feature for anxiety in PD. This metabolic pattern suggested that deficits of prefrontostriatal pathways might affect anxiety mood in PD. [ABSTRACT FROM AUTHOR]

This study assessed the patterns of functional and structural connectivity abnormalities in patients with Parkinson's disease with freezing of gait (PD FOG+) compared with those without freezing (PD FOG−) and healthy controls (HCs). Resting state functional MRI (rs-fMRI) and diffusion tensor imaging (DTI) scans were obtained from 14 PD FOG+, 16 PD FOG− and 16HCs. Between-group difference in pedunculopontine nucleus (PPN) functional connectivity (FC) was performed to assess FC dysfunction. Tract-based spatial statistics (TBSS) was applied to compare white matter (WM) impairment across the whole brain between groups. PD FOG+ patients exhibited abnormal PPN FC, compared with HCs and with PD FOG−, mainly in the corticopontine-cerebellar pathways (in the bilateral cerebellum and in the pons), as well as the visual temporal areas (in the right middle temporal gyrus and in the right inferior temporal gyrus). Moreover, PD FOG+ patients, showed more pronounced WM abnormalities, relative to controls, including the interhemispheric connections of corpus callosum, the cortico-cortical WM tracts of the cingulum, the superior longitudinal fasciculus and inferior fronto-occipital fasciculus, the corticofugal tract (cerebral peduncles, internal capsule, corona radiata), as well as tracts connecting the thalamus (thalamic radiation). This study suggests that FOG in PD is associated with abnormal PPN FC network, mainly affecting the corticopontine-cerebellar pathways as well as visual temporal areas involved in visual processing, and with diffuse WM deficits extending to motor, sensory and cognitive regions. Combining rs-fMRI and DTI method, our study should advance the understanding of neural mechanisms underlying FOG in PD. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to clarify the dynamic neural activity of levodopa‐induced dyskinesia (LID) in Parkinson's disease (PD). Methods: Using dynamic functional network connectivity (dFNC) analysis, we evaluated 41 PD patients with LID (LID group) and 34 PD patients without LID (No‐LID group). Group spatial independent component analysis and sliding‐window approach were employed. Moreover, we applied a k‐means clustering algorithm on windowed functional connectivity (FC) matrices to identify reoccurring FC patterns (i.e., states). Results: The optimal number of states was determined to be five, the so‐called State 1, 2, 3, 4, and 5. In ON phase, compared with No‐LID group, LID group occurred more frequently and dwelled longer in strongly connected State 1, characterized by strong positive connections between visual network (VIS) and sensorimotor network (SMN). When switching from OFF to ON phase, LID group occurred less frequently in State 3 and State 4. Meanwhile, LID group dwelled longer in State 2 and shorter in State 3. No‐LID group occurred more frequently in State 5 and less frequently in State 3. Additionally, correlation analysis demonstrated that dyskinesia's severity was associated with frequency of occurrence and dwell time in State 2, dominated by inferior frontal cortex in cognitive executive network (CEN). Conclusion: Using dFNC analysis, we found that dyskinesia may be related to the dysfunctional inhibition of CEN on motor loops and excessive excitation of VIS and SMN, which provided evidence of the changes in brain dynamics associated with the occurrence of dyskinesia. [ABSTRACT FROM AUTHOR]

Background: Freezing of gait (FOG) in Parkinson's disease (PD), especially the "L-dopa-unresponsive" subtype, is associated with the dysfunction of non-dopaminergic circuits. Objective: We sought to determine whether cortical sensorimotor inhibition evaluated by short-latency afferent inhibition (SAI) related to cholinergic and gamma-aminobutyric acid (GABA)-ergic activities is impaired in PD patients with L-dopa-unresponsive FOG (ONOFF-FOG). Methods: SAI protocol was performed in 28 PD patients with ONOFF-FOG, 15 PD patients with "off" FOG (OFF-FOG), and 25 PD patients without FOG during medication "on" state. Additionally, 10 ONOFF-FOG patients underwent SAI testing during both "off" and "on" states. Twenty healthy controls participated in this study. Gait was measured objectively using a portable Inertial Measurement Unit system, and participants performed 5-meter Timed Up and Go single- and dual-task conditions. Spatiotemporal gait characteristics and their variability were determined. FOG manifestations and cognition were assessed with clinical scales. Results: Compared to controls, PD patients without FOG and with OFF-FOG, ONOFF-FOG PD patients showed significantly reduced SAI. Further, dopaminergic therapy had no remarkable effect on this SAI alterations in ONOFF-FOG. Meanwhile, OFF-FOG patients presented decreased SAI only relative to controls. PD patients with ONOFF-FOG exhibited decreased gait speed, stride length, and increased gait variability relative to PD patients without FOG and controls under both walking conditions. For ONOFF-FOG patients, significant associations were found between SAI and FOG severity, gait characteristics and variability. Conclusion: Reduced SAI was associated with severe FOG manifestations, impaired gait characteristics and variability in PD patients with ONOFF-FOG, suggesting the impaired thalamocortical cholinergic-GABAergic SAI pathways underlying ONOFF-FOG. [ABSTRACT FROM AUTHOR]

Background Accumulating evidence suggests that serotonergic system may be implicated in the pathophysiology of Parkinson's disease (PD), and particularly in nonmotor symptoms such as depression, fatigue, sleep disorders, sensory and autonomic dysfunction. This study aimed to evaluate plasma levels of serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in PD patients, and investigate their associations with nonmotor symptoms. Methods Eighty-two PD patients and sixty-four controls underwent a series of clinical assessments, including Hamilton Depression Scale, Fatigue Severity Scale, Pittsburgh Sleep Quality Index, Visual Analog Scale for Pain, and Scale for Outcomes in PD for Autonomic Symptoms. Plasma 5-HT and 5-HIAA levels were measured by HPLC-ECD. Results PD patients exhibited worse performance on nonmotor symptom scales (all P -values <0.001) and presented lower plasma levels of 5-HT ( P < 0.001) and 5-HIAA ( P < 0.001) than control individuals. Within the PD group, decreased concentrations of plasma 5-HT and 5-HIAA were correlated with more severe depression (r = −0.447, P < 0.001; r = −0.407, P < 0.001, respectively) and pain (r = −0.485, P < 0.001; r = −0.416, P < 0.001, respectively). After performing multiple linear regression, plasma 5-HT ( P = 0.01) and 5-HIAA ( P = 0.006) remained significantly associated with depression. Conclusions Our results suggest that serotonergic dysfunction might exist in PD, and specifically correlated with depression and pain in PD. Plasma levels of 5-HT and 5-HIAA may be considered as peripheral markers for depression in PD. [ABSTRACT FROM AUTHOR]

Impulse control disorders (ICD) in Parkinson's disease (PD) is highly multifactorial in etiology and has intricate neural mechanisms. Our multimodal neuroimaging study aimed to investigate the specific patterns of structure-function-neurotransmitter interactions underlying ICD. Thirty PD patients with ICD (PD-ICD), 30 without ICD (PD-NICD) and 32 healthy controls (HCs) were recruited. Gyrification and perivascular spaces (PVS) were computed to capture the alternations of cortical surface morphology and glymphatic function. Seed-based functional connectivity (FC) were performed to identify the corresponding functional changes. Further, JuSpace toolbox were employed for cross-modal correlations to evaluate whether the spatial patterns of functional alterations in ICD patients were associated with specific neurotransmitter system. Compared to PD-NICD, PD-ICD patients showed hypogyrification and enlarged PVS volume fraction in the left orbitofrontal gyrus (OFG), as well as decreased FC between interhemispheric OFG. The interhemispheric OFG connectivity reduction was associated with spatial distribution of μ-opioid pathway (r = −0.186, p = 0.029, false discovery rate corrected). ICD severity was positively associated with the PVS volume fraction of left OFG (r = 0.422, p = 0.032). Furthermore, gyrification index (LGI) and percent PVS (pPVS) in OFG and their combined indicator showed good performance in differentiating PD-ICD from PD-NICD. Our findings indicated that the co-altered structure-function-neurotransmitter interactions of OFG might be involved in the pathogenesis of ICD. • Structure-function-neurotransmitter interaction • Enlarged PVS • OFG hypogyrification [ABSTRACT FROM AUTHOR]

Objectives: In this study, the alterations of structural topological properties in Parkinson's disease (PD) patients with levodopa-induced dyskinesias (LIDs) were explored using white matter structural network connectome derived from diffusion tensor imaging (DTI).Methods: 21 dyskinetic PD patients, 21 non-dyskinetic PD patients and 25 healthy controls were studied in global and nodal topological properties of structural networks after controlling age, gender and education. Afterwards, post hoc analyses were performed to explore further differences. Finally, multiple linear regression analysis was employed to test the associations between significant different properties and the severity of dyskinesias in PD.Results: Dyskinetic PD patients exhibited significant increased global efficiency, local efficiency, clustering coefficient, but decreased shortest path length compared with the non-dyskinetic. Additionally, increased nodal efficiency in bilateral inferior frontal gyrus (IFG), right putamen, right thalamus, and decreased nodal shortest path length in bilateral IFG and right thalamus, were discovered in dyskinetic PD in comparison with non-dyskinetic PD. Notably, a negative correlation between the Abnormal Involuntary Movement Scale (AIMS) scores and shortest path length of whole-brain network was found in PD with LIDs.Conclusions: Our results indicated excessively optimized topological organization of whole-brain structural connectome in PD patients with LIDs. These findings also illustrated that excessively strengthened basal ganglia-thalamocortical nodal structural connections played an important role in the presence of LIDs. [ABSTRACT FROM AUTHOR]

Freezing of gait (FOG) is an intractable and paroxysmal gait disorder that seriously affects the quality of life of Parkinson's disease (PD) patients. Emerging studies have reported abnormal brain activity of distributed networks in FOG patients, whereas ignoring the intrinsic dynamic fluctuations of functional connectivity. The purpose of this study was to examine the dynamic functional network connectivity (dFNC) of PD-FOG. In total, 52 PD patients with FOG (PD-FOG), 73 without FOG (PD-NFOG) and 38 healthy controls (HCs) received resting state functional magnetic resonance imaging (rs-fMRI). Sliding window method, k-means clustering and graph theory analysis were employed to retrieve dynamic characteristics of PD-FOG. Partial correlation analysis was conducted to verify whether the dFNC was related to freezing gait severity. Seven brain networks were identified and configured into seven states. Compared to PD-NFOG, significant spatial pattern was identified for state 2 in freezers, showing increased functional coupling between default mode network (DMN) and basal ganglia network (BG), as a concrete manifestation of increased precuneus-caudate coupling. The mean dwell time and fractional window of state 2 had a positive correlation with FOG severity. Furthermore, PD-FOG group exhibited lower variance in nodal efficiency of independent components (IC) 7 (left precuneus). Our study suggested that aberrant coupling of precuneus-caudate and disrupted variability of precuneus efficiency might be associated to the neural mechanisms of FOG. • altered coupling of DMN-BG. • decreased variance in Ne of precuneus. • visuospatial overload. [ABSTRACT FROM AUTHOR]

Object Anxiety disorders are very common in Parkinson’s disease (PD), but neural mechanisms underlying these symptoms still remain elusive. In the present study, we aim to investigate the neural substrates in anxiety disorders in PD. Methods The present study comprised 48 PD patients and 19 healthy subjects. According to a Hamilton Anxiety Rating Scale cutoff score of 12, we divided PD patients into PD with anxiety groups (n = 15) and PD without anxiety groups (n = 33). Patients with apparent depressive symptoms and cognitive decline were excluded. All subjects were evaluated for demographic and clinical characteristics and performed 3.0 T MRI scans. The alterations of neural activity were examined utilizing resting-state fMRI (rs-fMRI) combined with the amplitude of low-frequency fluctuations (ALFF) approach. Results Results of the analysis of covariance indicated that PD patients with anxiety displayed increased ALFF mainly in right cerebellar posterior lobe (CPL), bilateral brainstem and right orbitofrontal gyrus (OFG). Subsequently, the Spearman correlation demonstrated negative correlation between ALFF values in right cerebellum_9 and the Hamilton Anxiety Rating Scale scores. Conclusion Our findings demonstrated that anxiety disorders in PD were associated with increased activities in anxiety-related brain regions, including OFG, brainstem and CPL, using the ALFF approach. [ABSTRACT FROM AUTHOR]

The aim of our study is to examine the plasma levels of the four kinds of neurodegenerative proteins in plasma: α-syn, T-tau, P-tau and Aβ-42 in Parkinson's disease (PD) and to evaluate the relationship between their plasma levels and PD motor subtypes. 84 patients with PD were enrolled in our study, and finally, 73 of them were classified into the tremor-dominant subtype (TD) and the postural instability gait difficulty subtype (PIGD). Their motor performance was evaluated by a series of clinical assessments: Freezing of Gait Questionnaire (FOGQ), Timed Up and Go (TUGs), Tinetti balance, and Tinetti gait. Plasma levels of these proteins were measured by enzyme-linked immunosorbent assay (ELISA). The plasma level of α-syn was significantly higher in PD patients when compared to controls ( p = 0.004), and significantly higher in the PIGD group when compared to the TD group ( p = 0.03). While the plasma level of Aβ-42 was significantly lower in PD patients than in controls ( p = 0.002), and significantly lower in the PIGD group than in the TD group ( p = 0.05). In PD patients, the plasma level of α-syn ( r = −0.355, p < 0.001) was significantly related to the severity of Tenitti Gait score, even after performing multiple linear regression ( p = 0.002). While the plasma level of Aβ-42 ( r = −0.261, p < 0.05) was significantly associated with the severity of PIGD score and remained correlate when performed multiple linear regression ( p = 0.005). The patients with PIGD subtype are characterized with a lower level of plasma Aβ-42 and a higher plasma level of α-syn, which may be used as biomarkers for diagnosis and progression of the subtypes of PD. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most common malignant brain tumor with poor prognosis and limited treatment options. Tumor suppressor candidate 1 (TUSC1) was recently identified as a potential tumor suppressor in human cancers. However, the expression and potential function of TUSC1 in GBM remain unclear. Herein, we report that TUSC1 is significantly decreased in GBM tissues and cell lines. Patients with high levels of TUSC1 displayed a significant better survival compared with those with low levels of TUSC1. Functional experiments demonstrated that exogenous expression of TUSC1 inhibited GBM cell proliferation and induced G1 phase arrest by down-regulating CDK4. Moreover, overexpression of TUSC1 retarded tumor growth in vivo. Together, our findings revealed that TUSC1 might be a crucial tumor suppressor gene and a novel therapeutic target for GBM. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) can be classified into the tremor dominant (TD) subtype and the postural instability gait difficulty (PIGD) subtype, which present with different clinical courses and prognoses. However, the symptom-specific intrinsic neural mechanisms underlying the subtypes of PD still remain elusive. In the current study, we utilized resting-state fMRI (rs-fMRI) combined with the regional homogeneity (ReHo) method to investigate the modulations of neural activity in 13 patients with predominantly PIGD (p-PIGD) and 15 patients with predominantly TD (p-TD) in the resting state. Compared with healthy controls, the p-PIGD and the p-TD groups both displayed ReHo changes in the default mode network (DMN). By contrast, the p-TD group exhibited more ReHo alterations in the cerebellum involved in the cerebello-thalamo-cortical (CTC) loops, whilst the p-PIGD group in extensive cortical and sub-cortical areas, including the frontal, parietal, occipital, temporal, limbic lobes, basal ganglia and thalamus, which are involved in the striatal-thalamo-cortical (STC) loops. Direct comparison between the two groups showed significant ReHo alterations in the primary visual cortex. Our findings underscore the differential involvement of the STC and CTC circuits underlying the two subtypes of PD. Moreover, relatively widespread neural activity abnormality, especially in the motor-related regions as well as the visual network, is apparently a characteristic feature of PIGD symptoms. This study could shed light on the underlying pathophysiology and clinical heterogeneity of PD presentation. [ABSTRACT FROM AUTHOR]

Converging evidence suggests that changes in plasma levels of amino acids are involved in Parkinson's disease (PD), but their roles in nonmotor symptoms (NMS) of PD remain unclear. The aim of this study was to evaluate the correlations between plasma amino acids and NMS of PD. Plasma levels of aspartate (Asp), glutamate (Glu), glycine (Gly) and γ-aminobutyric acid (GABA) were measured in 92 PD patients and 60 healthy controls. Four NMS, including depression, pain, sleep disturbances and autonomic dysfunction were assessed in enrolled subjects using the Hamilton Depression Scale, the short form of the McGill Pain Questionnaire, the Pittsburgh Sleep Quality Index and the Scale for Outcomes in Parkinson's disease for Autonomic Symptoms, respectively. Hierarchical multiple regression analysis was used to evaluate the correlations between plasma levels of amino acids and NMS. PD patients exhibited significantly higher scores of NMS scales and lower plasma levels of amino acids compared to healthy controls. Within the PD group, plasma levels of Asp and Glu were negatively associated with the severity of depression and sleep disturbances. Moreover, decreased plasma level of GABA was correlated with more severe symptoms of sleep disturbances. After controlling for gender, disease duration, severity of motor symptoms and anti-parkinsonian medications, Glu but not Asp remained significantly associated with depression, along with Asp, GABA but not Glu remained negatively associated with sleep disturbances. The altered plasma levels of amino acids may be implicated in the pathogenesis of NMS of PD. [ABSTRACT FROM AUTHOR]

• DFC in state IV differed between PD-pRBD and PD-npRBD. • FC among DMN, VIS and BG had abnormalities in pRBD. • Temporal metrics altered in RBD. Rapid eye movement (REM) sleep behavior disorder (RBD) is one of the common nonmotor symptoms of Parkinson's disease (PD), characterized by frequently occurring REM sleep without muscle atonia. Our aim was to explore dynamic network connection changes in PD patients with RBD. On the basis of RBD screening questionnaire (RBDSQ), 126 PD patients were classified into those with probable RBD symptoms (PD-pRBD) and without probable RBD (PD-npRBD). We applied independent component analysis, sliding window approach and k-means clustering methods to clarify dynamic functional connectivity alterations. In contrast to PD-npRBD, PD-pRBD patients were liable to engage in a brain pattern mainly marked by weaker positive couplings between visual network (VIS) and default mode network (DMN), DMN and basal ganglia network (BG), and within DMN (State IV). In addition, we discovered that both PD patients with or without pRBD had shorter dwell time and fewer occurrences in State III, characterized by positive correlations between VIS and DMN, BG and DMN, and positive within-network coupling of sensorimotor network (SMN), relative to healthy controls. Our study suggested that the weaker positive couplings between VIS and DMN, DMN and BG, and within DMN in State IV could be involved in the pathogenesis of PD patients with probable RBD on an overall level. [ABSTRACT FROM AUTHOR]

[Display omitted] • Peripheral sensory nerve was impaired in PD, MSA and PSP. • p-α-syn and p-tau in sural nerve may serve as novel biomarkers for differential diagnosis of PD, MSA and PSP. • Schwann cells might perform an important role in peripheral pathophysiological processes of PD, MSA and PSP. Differential diagnosis of Parkinson's disease (PD), multiple system atrophy (MSA) and progressive supranuclear paralysis (PSP) is challenging. This study aimed to investigate the expression of phosphorylated α-synuclein (p-α-syn) and phosphorylated tau-protein (p-tau) in sural nerves from patients with PD, MSA and PSP to find biomarkers for differential diagnosis. Clinical evaluations and sural nerve biopsies were performed on 8 PD patients, 8 MSA patients, 6 PSP patients and 8 controls (CTRs). Toluidine blue staining was used to observe morphological changes in sural nerves. The deposition of p-α-syn and p-tau was detected by immunohistochemistry with semiquantitative evaluation. Locations of p-α-syn and p-tau were identified by double immunofluorescent staining. In case groups, the density of nerve fibres decreased with swollen or fragmented Schwann cells (SCs). All cases (22/22) but no CTRs (0/8) presented p-α-syn immunoreactivity with gradually decreasing semiquantitative levels among the PD (6.00 ± 2.07), MSA (5.00 ± 2.33) and PSP (3.50 ± 1.52) groups. p-tau aggregates were found in 7/8 MSA (1.88 ± 1.46) and 6/6 PSP (1.67 ± 0.52) patients but not in PD patients or CTRs. There were different expression patterns of p-α-syn and p-tau in PD, MSA and PSP patients. These findings suggest that peripheral sensory nerve injury exists in PD, MSA and PSP patients. With a different expression pattern and level, p-α-syn and p-tau in sural nerves may serve as novel biomarkers for differential diagnosis of PD, MSA and PSP. [ABSTRACT FROM AUTHOR]