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Neurofilament light chain (NfL) levels were reliable biomarkers of neurodegeneration in Parkinson's disease (PD). Lipoprotein-related Phospholipase A2(Lp-PLA2) levels have also been increasingly studied in PD. We aimed to explore the association of plasma NfL and Lp-PLA2 with the diagnosis, motor subtypes and disease severity of PD. Plasma NfL and Lp-PLA2 were assayed separately in 106 participants (74 PD and 32 healthy controls, HC). The motor subtypes of PD were classified according to the MDS-UPDRS components, and motor and non-motor manifestations of patients were also evaluated. Subsequently, correlation analyses were performed. The plasma NfL levels were higher in the PD than HC, and were positively correlated with age, UPDRS II, UPDRS III and the modified Hoehn and Yahr staging scale (H&Y stage) in the PD. Moreover, plasma Lp-PLA2 levels were lower in the PD than HC, and were positively correlated with Parkinson's Disease Quality of Life Questionnaire (PDQ-39) in the PD. For further distinguishing tremor-dominant (TD) from postural instability and gait difficulty-dominant (PIGD), plasma Lp-PLA2 levels were higher in the TD than PIGD, but there was no significant difference in NfL. plasma Lp-PLA2 levels were positively correlated with UPDRS I, Hamilton Anxiety Rating Scale (HAMA) and PDQ-39 in the TD. These results suggest that NfL and Lp-PLA2 may be potential biomarkers for the diagnosis of PD. We first demonstrated the potential utility of plasma Lp-PLA2 in differentiating motor subtypes. These findings deserve further evidence in larger PD cohorts. [ABSTRACT FROM AUTHOR]

Sleep macro and microstructural features have a relevant role for cognition. Although alterations in sleep macrostructure have been reported in persons with neurodegenerative disorders, including Parkinson's disease (PD), it is unknown whether there is a relationship between alterations in microstructure (sleep spindles) and global cognitive deficits in this disease. To explore the association between the macro and microstructure of sleep (sleep spindles) and the general cognitive state in persons with PD. Thirty-three patients with idiopathic PD underwent a one-night polysomnography (PSG) and a global cognitive assessment using the Montreal Cognitive Assessment (MoCA) test. PSG-based macrostructural sleep values and quantification and spectral estimation of sleep spindles were obtained. We found increases in total sleep time, latency to rapid eye movement (REM) sleep, and percentage of N1 stage, as well as a decrease in percentage of REM sleep and sleep efficiency compared to values reported in healthy adults. Compared to expected values, a decrease in the number of sleep spindles was found at frontal regions. Participants with cognitive impairment showed an even lower count of sleep spindles, as well as an increase in the amplitude of underlying sigma (12–16 Hz) waves (fast spindles). When exploring MoCA subdomains, we found a consistent relationship between the number and amplitude of sleep spindles and attention capacity. Decreased number and increased amplitude of sleep spindles are linked to cognitive impairment in persons with PD, especially in attention capacity. Therefore, sleep spindles characteristics could serve as prognostic indicators of cognitive deterioration in PD. [ABSTRACT FROM AUTHOR]

[Display omitted] Dopamine (DA) is a catecholamine neurotransmitter that works to regulate cognitive functions. Patients affected by Parkinson's Disease (PD) experience a loss of dopaminergic neurons and downregulated neural DA production. This leads to cognitive and physical decline that is the hallmark of PD for which no cure currently exists. Danio rerio , or zebrafish, have become an increasingly popular disease model used in PD pharmaceutical development. This model still requires extensive development to better characterize which PD features are adequately represented. Furthermore, the great majority of PD zebrafish models have been performed in embryos, which may not be relevant towards age-related human PD. As an improvement, mature D. rerio were treated with neurotoxic prodrug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) through intraperitoneal injection to induce parkinsonism. Behavioral analysis confirmed disparities in movement between saline-injected control and the MPTP-injected experimental group, with swim distance and speed significantly lowered seven days after MPTP injection. Simultaneously, cognitive decline was apparent in MPTP-injected zebrafish, demonstrated by decreased alternation in a y-maze. RT-qPCR confirmed trends consistent with downregulation in Parkinsonian genetic markers, specifically DA transporter (DAT), MAO-B, PINK1. In summary, mature zebrafish injected with MPTP present with similar movement and cognitive decline as compared to human disease. Despite its benefits, this model does not appear to recapitulate pathophysiology of the disease with the full profile of expected gene downregulation. Because of this, it is important that researchers looking for pharmacological interventions for PD only use this zebrafish model when targeting the human-relevant PD symptoms and causes that are represented. [ABSTRACT FROM AUTHOR]

Eye movement dysfunction is one of the non-motor symptoms of Parkinson's disease (PD). An accurate analysis method for eye movement is an effective way to gain a deeper understanding of the nervous system function of PD patients. However, currently, there are only a few assistive methods available to help physicians conveniently and consistently assess patients suspected of having PD. To solve this problem, we proposed a novel visual behavioral analysis method using eye tracking to evaluate eye movement dysfunction in PD patients automatically. This method first provided a physician task simulation to induce PD-related eye movements in Virtual Reality (VR). Subsequently, we extracted eye movement features from recorded eye videos and applied a machine learning algorithm to establish a PD diagnostic model. Then, we collected eye movement data from 66 participants (including 22 healthy controls and 44 PD patients) in a VR environment for training and testing during visual tasks. Finally, on this relatively small dataset, the results reveal that the Support Vector Machine (SVM) algorithm has better classification potential. [ABSTRACT FROM AUTHOR]

Synucleins, including α-synuclein (α-syn), β-syn, and γ-syn, have been implicated in various synucleinopathies, notably Parkinson's disease (PD), which has generated increased interest in understanding their roles. Although α-syn and β-syn have contrasting neuropathological consequences, the precise role of γ-syn remains unclear. This study validated non-motor symptoms, specifically anxiety-like behavior, along with the degradation of dopaminergic (DAergic) neurons in the nigrostriatal system and DAergic neurites in the prefrontal cortex and hippocampus of rats infused with striatal 6-hydroxydopamine (6-OHDA). Our study further investigated the alterations in γ-syn expression levels in the prefrontal cortices and hippocampi of these 6-OHDA–treated rats, aiming to establish foundational insights into the neuropathophysiology of DA depletion, a central feature of PD. Our findings revealed a significant increase in the expression of γ-syn mRNA and protein in these brain regions, in contrast to unaltered α- and β-syn expression levels. This suggests a distinct role of γ-syn within the neurobiological milieu under conditions of DA deficiency. Overall, our data shed light on the neurobiological changes observed in the hemiparkinsonian rat model induced with 6-OHDA, underscoring the potential significance of γ-syn in PD pathology. [ABSTRACT FROM AUTHOR]

PTEN-induced kinase1 (PINK1) mutation is the main cause of autosomal recessive inheritance and early-onset Parkinson's disease. Mitochondrial respiratory chain complex I (CI) functional impairment has been considered to be an important factor in the pathogenesis of PD in recent years. In addition, NDUFS3 (nicotinamide adenine dinucleotide deoxylase iron-thionein 3) is one of the core subunits of mitochondrial CI. Therefore, this study explored the role of NDUFS3 gene in PINK1B9 transgenic Drosophila and its possible related mechanisms. In this study, the PD transgenic Drosophila model of MHC-Gal4/UAS system was selected to specifically activate the expression of PINK1B9 gene in the chest muscle tissue of Drosophila melanogaster. NDUFS3 RNAi interference was used to interfere with PINK1B9 transgenic Drosophila melanogaster and its effect on PD transgenic flies was studied. The results suggest that down-regulation of NDUFS3 gene expression may have a protective effect on PINK1B9 transgenic Drosophila melanogaster, and we speculate that down-regulation of NDUFS3 gene expression to reduce oxidative stress and restore mitochondrial function may be related to mitochondrial stress response. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD), which is the second most common neurodegenerative disorder, is characterized by progressive movement impairment and loss of midbrain dopaminergic neurons in the substantia nigra. Although mutations in TMEM230 are linked to familial PD, the pathogenic mechanism underlying TMEM230-associated PD remains to be elucidated. To explore the effect of TMEM230 depletion in vivo , we created TMEM230 knockout rats using CRISPR-Cas9 technology. TMEM230 knockout rats did not exhibit any core features of PD, including impaired motor function, loss of dopaminergic neurons in the substantia nigra, or altered expression of proteins related to autophagy, the Rab family, or vesicular trafficking. In addition, no glial reactions were observed in TMEM230 knockout rats. These results indicate that depletion of TMEM230 may not lead to dopaminergic neuron degeneration in rats, further supporting that PD-associated TMEM230 mutations lead to dopaminergic neuron death by gain-of-toxic function. [ABSTRACT FROM AUTHOR]

• NEK1 gene polymorphisms may be associated with sporadic Parkinson's disease in the Chinese Northern Han population. • NEK1 rs66509122 T allele may be a protective factor for Parkinson's disease. • The rs4563461 C allele was significantly associated with sleep disorders in Parkinson's disease. • The rs66509122 C allele was associated with diabetes in female patients and depression in the early-onset of Parkinson's disease. Parkinson's disease (PD) has been identified as a genetically influenced disease linked to various genetic loci. Previous studies have suggested that neurodegenerative illnesses, including PD, Alzheimer's disease, and Amyotrophic lateral sclerosis (ALS), may share certain genetic loci. Recently, the NEK1 gene was identified as overlapping between PD and ALS. We therefore wanted to explore the potential association between the NEK1 gene single nucleotide polymorphisms (SNPs) and the clinical features and pathophysiology of sporadic PD in a northern Chinese population. A total of 510 sporadic PD patients and 510 age- and sex-matched healthy controls (HCs) were included in this study. Two SNPs (rs4563461 and rs66509122) of the NEK1 gene were genotyped using polymerase chain reaction (PCR). And we analyzed the association between NEK1 gene polymorphisms and clinical manifestations. Allele T (C vs. T, P = 0.018) and genotype TT (CC vs. TT: P = 0.021) of rs66509122 among PD group and HCs were significantly different. In addition, we discovered that the rs66509122 genotype TT was associated with depression in early-onset PD (EOPD) (P = 0.031) and diabetes in female PD (P = 0.032). Unfortunately, no distinct correlation of rs4563461 polymorphisms with sporadic PD susceptibility was found in either the overall group (C vs. T, P = 0.086) or other subgroups. However, the T allele of rs4563461 was significantly correlated with sleep disorders in the PD group, especially in the late-onset PD (LOPD) group and male PD group. This study found that the NEK1 rs66509122 polymorphism was associated with a lower risk of sporadic PD, while T allele of rs66509122 may be a protective factor for PD. The NEK1 rs4563461 and rs66509122 polymorphisms both showed correlations with some non-motor symptoms in sporadic PD patients. Further research with a larger sample and varied ethnic groups is needed to investigate the role of NEK1 gene polymorphisms in the pathophysiology of PD. [ABSTRACT FROM AUTHOR]

Neurological or neurodevelopmental disorders, such as Parkinson's disease and dyslexia, can impair rhythm perception and production. Deficits in rhythm are associated with poor performance in language, attention, and working memory tasks. Research indicates that retraining rhythmic skills may enhance these related cognitive functions. In this context, using tactile aids for rhythm training emerges as a promising approach for children who do not fully benefit from conventional audiovisual rhythm games. This is because tactile aids can compensate for sensory deficiencies and facilitate more extensive brain activation. In our study, we employed functional near-infrared spectroscopy (fNIRS) to assess the impact of tactile aids on brain cortical activation during rhythmic training in children aged 6–12 years (N = 25). We also measured the participants' spontaneous motor rhythms. The findings indicate that tactile stimulation significantly improves performance in synchronized rhythm tasks compared to audiovisual stimulation alone, particularly enhancing activation in brain regions associated with speech training such as the prefrontal cortex, motor cortex, and temporal areas. These results not only support the application of rhythm training in speech rehabilitation, but also highlight the potential of tactile aids as an effective multisensory learning strategy. [ABSTRACT FROM AUTHOR]

Although microRNA (miRNA) have important clinical prospects in the early diagnosis and treatment of PD, the functions and mechanisms of miRNAs in PD models remain poorly defined. In this study, we screened 9 miRNAs that differently expressed in PD patients and found that miR-142-3p expression was downregulated in both animal and cell models of PD. We showed that overexpression of miR-142-3p significantly alleviates the neuronal damage induced by MPP+, while knockdown of miR-142-3p exacerbates the neuronal damage caused by MPP+. We further found that miR-142-3p targets and inhibits the expression of C9orf72. Knockdown of C9orf72 mitigated neuronal autophagy dysfunction by reducing excessive activation of the AKT/mTOR pathway after MPP+ stimulation, thereby exerted neuroprotective effects. This study reveals that miR-142-3p protects neuron in PD pathogenesis via negatively regulating C9orf72 and enhancing autophagy. Our findings provides an insight into the development of potential biomarkers and therapeutic targets for PD. [ABSTRACT FROM AUTHOR]

[Display omitted] Parkinson's disease (PD) entails the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc), leading to movement-related impairments. Accurate assessment of DA neuron health is vital for research applications. Manual analysis, however, is laborious and subjective. To address this, we introduce TrueTH, a user-friendly and robust pipeline for unbiased quantification of DA neurons. Existing deep learning tools for tyrosine hydroxylase-positive (TH+) neuron counting often lack accessibility or require advanced programming skills. TrueTH bridges this gap by offering an open-sourced and user-friendly solution for PD research. We demonstrate TrueTH's performance across various PD rodent models, showcasing its accuracy and ease of use. TrueTH exhibits remarkable resilience to staining variations and extreme conditions, accurately identifying TH+ neurons even in lightly stained images and distinguishing brain section fragments from neurons. Furthermore, the evaluation of our pipeline's performance in segmenting fluorescence images shows strong correlation with ground truth and outperforms existing models in accuracy. In summary, TrueTH offers a user-friendly interface and is pretrained with a diverse range of images, providing a practical solution for DA neuron quantification in Parkinson's disease research. [ABSTRACT FROM AUTHOR]

The wearing-off phenomenon is characterized by the recurrence of motor and non-motor symptoms of Parkinsonism during a period free from levodopa. It is a pivotal aspect marking the end of the pharmacological "honeymoon" period in Parkinson's disease (PD). A growing body of literature is connecting sex with the likelihood of developing fluctuations. We investigated such an association in a post-hoc analysis of the large WORK-PD study. WORK-PD analyzed the usability of the wearing-off questionnaire 19 (WOQ19) in clinical practice and included cross-sectional data on age, disease duration, time on levodopa, Hoehn and Yahr stage, and WOQ19 scores of 532 PD patients. In the present study, we selected patients with an exposure time to levodopa of at least 1 year. A total of 380 patients were included. Women reported a higher number of wearing-off symptoms than men (6.09 ± 3.39 vs 4.96 ± 3.11, p = 0.0006). Sex groups also differed in non-motor symptoms (2 ± 1.9 vs 1.5 ± 1.5, p = 0.021), particularly behavioral wearing-off scores being higher in women (p < 0.001). The latter were primarily featured by anxiety-related phenomena. Finally, there was a significant interaction between behavioral symptoms, sex, and age at onset (df = 2, F = 9.79, p < 0.0001), whereas no such interaction was observed with levodopa exposure and motor impairment, unlike motor symptoms. Women showed a greater propensity than men to experience wearing-off, particularly non-motor fluctuations on the anxiety spectrum. The latter may demonstrate a lesser reliance on dopamine compared to motor symptoms. This observation could be underpinned by biological variances between genders at the neurotransmitter level. [ABSTRACT FROM AUTHOR]

[Display omitted] Synucleins are pivotal in neurodegenerative conditions. Beta-synuclein (β-synuclein) is part of the synuclein protein family alongside alpha-synuclein (α-synuclein) and gamma-synuclein (γ-synuclein). These proteins, found mainly in brain tissue and cancers, are soluble and unstructured. β-synuclein shares significant similarity with α-synuclein, especially in their N -terminus, with a 90% match. However, their aggregation tendencies differ significantly. While α-synuclein aggregation is believed to be counteracted by β-synuclein, which occurs in conditions like Parkinson's disease, β-synuclein may counteract α-synuclein's toxic effects on the nervous system, offering potential treatment for neurodegenerative diseases. Under normal circumstances, β-synuclein may guard against disease by interacting with α-synuclein. Yet, in pathological environments with heightened levels or toxic substances, it might contribute to disease. Our research aims to explore potential harmful mutations in the β-synuclein using computational tools to predict their destabilizing impact on protein structure. Consensus analysis revealed rs1207608813 (A63P), rs1340051870 (S72F), and rs1581178262 (G36C) as deleterious. These findings highlight the intricate relationship between nsSNPs and protein function, shedding light on their potential implications in disease pathways. Understanding the structural consequences of nsSNPs is crucial for elucidating their role in pathogenesis and developing targeted therapeutic interventions. Our results offer a robust computational framework for identifying neurodegenerative disorder-related mutations from SNP datasets, potentially reducing the costs associated with experimental characterization. [ABSTRACT FROM AUTHOR]

[Display omitted] • miRNAs as Central Regulators: Regulate multiple high-risk genes associated with PD. • Brain-Centric Expression: High presence of miRNA in the brain, particularly in regions relevant to PD. • Involvement in Vital Pathways: Intricately involved in essential metabolic and signaling pathways. • Gene Expression Patterns: high-risk PD genes in various brain regions (substantia nigra) with emphasis on spatial dynamics. • Comprehensive Regulatory Network: Shedding light on the intricate web of molecular regulation in PD. MicroRNAs (miRNAs) have emerged as critical regulators of post-transcriptional gene expression, impacting various biological processes (development, differentiation, and progression). In medicine, miRNAs are promising diagnostic biomarkers for neurodegenerative diseases, including Parkinson's disease (PD). The current study aims at exploring the role of miRNAs and transcription factors (TFs) in regulating genes-associated with PD. Deploying bioinformatics tools, the study identifies specific miRNAs and TFs involved in PD and their potential connections to the organ-disease junction. Notably, certain miRNAs are found to be highly expressed in brain, than compared to blood. Furthermore, the study explores the expression patterns of PD-related genes in different regions of the brain and attempts to construct complex network of interactions contributing to PD pathogenesis. Additionally, the regulatory relationship of two miRNAs namely hsa-miR-375-3p and hsa-miR-423-3p with TFs are well examined. Overall, the study provides a comprehensive moon-shot view of the molecular aspects of PD and their potential therapeutic targets which could be further used as diagnostic biomarkers in early detection, drug design and development attributing towards precision medicine. [ABSTRACT FROM AUTHOR]

Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder of the aging population characterized by α-synuclein accumulation in cortical and subcortical regions. Although neuropathology in advanced age has been investigated in dementias such as Alzheimer Disease (AD), severity of the neuropathology in the oldest old with DLB remains uncharacterized. For this purpose we compared characteristics of DLB cases divided into three age groups 70-79, 80-89 and ≥ 90 years (oldest old). Neuropathological indicators and levels of synaptophysin were assessed and correlated with clinical measurements of cognition and dementia severity. These studies showed that frequency and severity of DLB was lower in 80-89 and ≥ 90 year cases compared to 70-79 year old group but cognitive impairment did not vary with age. The extent of AD neuropathology correlated with dementia severity only in the 70-79 year group, while synaptophysin immunoreactivity more strongly associated with dementia severity in the older age group in both DLB and AD. Taken together these results suggest that the oldest old with DLB might represent a distinct group.

• PD-PIGD patients showed relatively weakened global topological properties. • PD-PIGD patients existed abnormal regional structural connectomes. • Dc of the cerebellar vermis was negatively correlated with the PIGD score. The Postural Instability/Gait Difficulty (PIGD) subtype of Parkinson's disease (PD) has a faster disease progression, a higher risk of cognitive and motor decline, yet the alterations of structural topological organization remain unknown. Diffusion Tensor Imaging (DTI) and 3D-TI scanning were conducted on 31 PD patients with PIGD (PD-PIGD), 30 PD patients without PIGD (PD-non-PIGD) and 35 Healthy Controls (HCs). Structural networks were constructed using DTI brain white matter fiber tractography. A graph theory approach was applied to characterize the topological properties of complex structural networks, and the relationships between significantly different network metrics and motor deficits were analyzed within the PD-PIGD group. PD-PIGD patients exhibited increased shortest path length compared with PD-non-PIGD and HCs (P < 0.05, respectively). Additionally, PD-PIGD patients exhibited decreased nodal properties, mainly in the cerebellar vermis, prefrontal cortex, paracentral lobule, and visual regions. Notably, the degree centrality of the cerebellar vermis was negatively correlated with the PIGD score (r = −0.390; P = 0.030) and Unified Parkinson's Disease Rating Scale Part III score (r = −0.436; P = 0.014) in PD-PIGD patients. Furthermore, network-based statistical analysis revealed decreased structural connectivity between the prefrontal lobe, putamen, supplementary motor area, insula, and cingulate gyrus in PD-PIGD patients. Our findings demonstrated that PD-PIGD patients existed abnormal structural connectomes in the cerebellar vermis, frontal-parietal cortex and visual regions. These topological differences can provide a topological perspective for understanding the potential pathophysiological mechanisms of PIGD in PD. [ABSTRACT FROM AUTHOR]

• NFPS protects the striatum against neurotoxicity induced by quinolinic acid. • NFPS protects the striatum against neurotoxicity induced by 6-hydroxydopamine. • NFPS reduces GluN2A and GluN2B levels after 24 h of pre-treatment. • NFPS does not alter GluN1 levels after 24 h of pre-treatment. • Inhibition of GlyT1 shows neuroprotective potential against striatal damage. The striatum, an essential component of the brain's motor and reward systems, plays a pivotal role in a wide array of cognitive processes. Its dysfunction is a hallmark of neurodegenerative diseases like Parkinson's disease (PD) and Huntington's disease (HD), leading to profound motor and cognitive deficits. These conditions are often related to excitotoxicity, primarily due to overactivation of NMDA receptors (NMDAR). In the synaptic cleft, glycine transporter type 1 (GlyT1) controls the glycine levels, a NMDAR co-agonist, which modulates NMDAR function. This research explored the neuroprotective potential of NFPS, a GlyT1 inhibitor, in murine models of striatal injury. Employing models of neurotoxicity induced by 6-hydroxydopamine (PD model) and quinolinic acid (HD model), we assessed the effectiveness of NFPS pre-treatment in maintaining the integrity of striatal neurons and averting neuronal degeneration. The results indicated that NFPS pre-treatment conferred significant neuroprotection, reducing neuronal degeneration, protecting dopaminergic neurons, and preserving dendritic spines within the striatum. Additionally, this pre-treatment notably mitigated motor impairments resulting from striatal damage. The study revealed that GlyT1 inhibition led to substantial changes in the ratios of NMDAR subunits GluN2A/GluN1 and GluN2B/GluN1, 24 h after NFPS treatment. These findings underscore the neuroprotective efficacy of GlyT1 inhibition, proposing it as a viable therapeutic strategy for striatum-related damage. [ABSTRACT FROM AUTHOR]

• KW6002 inhibits A2A receptor, benefiting neuronal injury in synucleinopathies caused by A53T-α-Syn. • KW6002 reverses A53T-α-Syn-induced inclusion bodies, astrocyte activation, apoptosis, and autophagic flux suppression. • KW6002 promotes autophagic flux, degrades A53T-α-Syn protofibrils, and reduces neuronal toxicity and apoptosis. Protein misfolding and inclusion body aggregation caused by α-Syn mutations in the brain often cause neurodegeneration and cognitive impairment, among which the A53T point mutation is more common. Inhibition of adenosine A2A receptor (A 2A R) can alleviate the pathological symptoms of brain dysfunction caused by A53T-α-Syn protofibrils, but the mechanism of action is still unclear. This studies aimed to investigate the potential therapeutic role of the A 2A R inhibitor KW6002 in a mouse model of brain synucleinopathy. A53T-α-Syn fibre precursor cell nuclear protein was injected into the bilateral prefrontal cortex of mice to establish a synucleinopathy animal model, and the A 2A R inhibitor KW6002 (5 mg/kg) was injected intraperitoneally to intervene. The intracerebral injection of A53T-α-Syn protofibrils triggers the formation of inclusion bodies in the brain, leading to astrocyte activation, an increased number of apoptotic cells, and suppression of autophagic flux. The administration of KW6002 significantly reversed these phenomena. In vitro experiments revealed that A53T-α-Syn protofibrils inhibited HT-22 autophagy in mouse hippocampal neuronal cells, whereas KW6002 increased cellular autophagic flux, upregulated the expression of LAMP2A and Hsc70 proteins and inhibited the expression of SQSTM1 protein. The present study suggests that KW6002 reduces the level of α-Syn phosphorylation by inhibiting A 2A R protein, at the same time, enhances the autophagic flux of neuronal cells, resulting in the degradation of A53T-α-Syn protofibrils and thus reducing the neuronal toxicity and apoptosis induced by A53T-α-Syn protofibrils. KW6002 has a significant protective effect on neuronal injury induced by A53T-α-Syn. [ABSTRACT FROM AUTHOR]

• Levodopa-induced dyskinesia (LID) is a common and difficult to treat symptom found in patients with Parkinson's disease. • Prior animal studies indicated that D3 receptor (DRD3) may have a role in LID. • It is reported that the SNV rs6280 (AA or serine variant) polymorphism is associated with reduced dopamine binding affinity of D3 presynaptic auto-receptor. • In the current study, we found that the AA genotype was more frequently present in PD patients with LID and healthy controls in comparison to PD patients without LID. Levodopa-induced dyskinesia (LID) is a debilitating motor feature in a subset of patients with Parkinson's disease (PD) after prolonged therapeutic administration of levodopa. Preliminary animal and human studies are suggestive of a key role of dopamine type 3 (D3) receptor polymorphism (Ser9Gly; rs6280) in LID. Its contribution to development of LID among Indian PD patients has remained relatively unexplored and merits further investigation. 200 well-characterised PD patients (100 without LID and 100 with LID) and 100 age-matched healthy controls were recruited from the outpatient department of Institute of Neurosciences Kolkata. MDS-UPDRS (Unified Parkinson's Disease Rating Scale from International Movement Disorder Society) Part III and AIMS (abnormal involuntary movement scale) were performed for estimation of severity of motor features and LID respectively in the ON state of the disease. Participants were analysed for the presence of Ser9Gly single nucleotide variant (SNV) (rs6280) by polymerase chain reaction followed by restriction fragment length polymorphism techniques. The frequency of AA genotype (serine type) was more frequently present in PD patients with LID compared to PD patients without LID (50 % vs 28 %; P = 0.002; OR = 2.57, 95 % CI: 1.43 – 4.62). The abnormal involuntary movement scale score was significantly higher in PD patients with AA genotype compared to carriers of glycine allele (AG + GG) (4.08 ± 3.35; P = 0.002). We observed a significant association of serine type SNV (rs6280) in D3 receptor gene in a cohort of PD patients with LID from India. More severe motor severity was found in patients with glycine substitution of the same SNV. The current study emphasised the role of D3 receptor in the pathogenesis of LID. [ABSTRACT FROM AUTHOR]

• aSyn density is similar in both submandibular glands of autopsied patients with Parkinson's disease. • Parkinson's disease duration correlated with submandibular gland aSyn density. • There was no evidence for significant tissue damage in previously biopsied submandibular glands. Peripheral tissue biopsy in Parkinson's disease (PD) may be valuable for clinical care, biomarker validation, and as research enrollment criteria. Determine whether submandibular gland pathologic alpha-synuclein (aSyn) density is symmetrical and whether previous needle biopsy caused tissue damage. Thirty autopsy-confirmed PD cases having fixed submandibular gland tissue from one side and frozen submandibular gland tissue from the contralateral side were studied. Tissue was stained for phosphorylated aSyn and density (0–4 semiquantitative scale) was determined. Three previously biopsied cases were also assessed for tissue damage at subsequent autopsy. Mean (SD) age was 80.9 (5.5) years and disease duration 12.5 (9.3). Submandibular gland aSyn staining had a mean score of 2.13 for both the initially fixed and the initially frozen submandibular glands. The correlation between aSyn density of the two sides was r = 0.63. Correlation of aSyn density, in the originally fixed submandibular gland, with disease duration was good (r = 0.49, p =.006). No permanent tissue damage was found in the three previously biopsied cases. This study found good correlation between aSyn density in both submandibular glands of patients with PD and found no evidence of significant tissue damage in previously biopsied subjects. [ABSTRACT FROM AUTHOR]

• Salusins are bioactive neuropeptides present in many parts of the brain. • Salusins are associated with age, lipid profile, leukocyte level. • Salusin-β is associated with Alzheimer's - Parkinson's Disease and stroke. Neuroinflammation, oxidative stress, and apoptosis play important roles in the pathophysiology of Alzheimer's Disease (AD), Parkinson's Disease (PD), and Acute Ischemic Stroke (AIS). Salusin-α and salusin-β peptides, which were shown to be present in many tissues, including the central nervous system, were also shown to be associated with apoptosis, inflammation, and oxidative stress. In the present study, the relationship between Salusin-α and salusin-β peptides and AD, PD, and AIS were investigated. A total of 179 people were included in the present study, including 46 AD, 44 PD, 42 AIS, and 47 controls. Plasma Salusin-α and salusin-β levels were measured with the ELISA Method. The plasma salusin-β levels of AD, PD, and AIS patients were lower than the control group at significant levels (p < 0.05). It was also found that there were correlations between salusin-α and salusin-β levels and age, triglyceride, LDL-c, total cholesterol, and hemoglobin levels. In this study, we found that salusin- β, an endogenous neuropeptide, was associated with AD, PD and AIS. The low level of salusin-β in these diseases in which neuronal damage occurs may be related to the neuroprotective properties of this endogenous peptide. Further studies are needed to fully understand the relationship between salusin-β and the pathophysiology of these diseases. [ABSTRACT FROM AUTHOR]

• α7 nAChR activation showed the neuroprotective effect. • α7 nAChR activation reduced the intracellular aggregates of α-Synuclein. • α7 nAChR activation by PNU282987 promotes TFEB activity. • PNU282987 reduces the intracellular α-Synuclein via the upregulation of autophagy. • Activation of α7 nAChR may possess novel therapeutic potential for PD. The α7 neuronal nicotinic acetylcholine receptor (α7 nAChR) is a potential target for the development of Parkinson's disease (PD) therapeutics. α-Synuclein (α-Syn), a principal component of Lewy bodies (cytoplasmic inclusions), is a major contributor to PD pathophysiology. Previous studies have demonstrated that activating α7 nAChR protects against nigrostriatal dopamine degeneration in acute and chronic PD animal models induced by 6-hydroxydopamine and rotenone, respectively. In the present study, we investigated the effects of PNU282987, a selective α7 nAChR agonist, against α-Syn-induced neurotoxicity in α-SynWT-, α-SynA30P-, and α-SynE46K-N2a cells. PNU282987 exhibited substantial neuroprotection against both wild-type and mutant-type α-Syn-induced toxicity. Furthermore, PNU282987 promoted transcription factor EB activity and reduced intracellular α-Syn protein levels through autophagy induction. These results highlight the therapeutic potential of α7 nAChR activation in diseases characterized by α-Syn aggregation, such as PD. [ABSTRACT FROM AUTHOR]

• TFEB transcripts are up-regulated in the temporal cortex of Lewy body diseases. • The minor SCARB2 transcript SCARB2tv2 is drastically over-expressed in the same samples. • TFEB transcript expression is modulated by female-gender and disease duration. • TFEB and SCARB2 overexpression correlates with GBA decrease. Mutations in the glucocerebrosidase (GCase) gene (GBA) and GCase deficiency are major risk factors for Lewy body diseases. Decreased GCase activity enhances alpha-synuclein aggregation and disease development. Lysosomal integral membrane protein type 2, encoded by SCARB2, binds GCase targeting it to lysosomes and transcription factor EB (Tfeb) regulates lysosomal proteostasis. Our aim was to find out if GCase deficiency in Lewy body diseases is accompanied by SCARB2 and TFEB deregulation at the transcriptional level involving alternative splicing as well. Relative mRNA expression of two SCARB2 and two TFEB transcripts was studied by real-time PCR in post-mortem brain samples of cases with pure Lewy body pathology (LBP), cases with concomitant LBP and Alzheimer disease-like pathology, and controls. TFEB expression was increased in the temporal cortex and caudate nucleus of LBP cases, and SCARB2 was differentially expressed. Female-gender associated overexpression of all transcripts was found in the caudate nucleus, and disease duration associated TFEB expression changes in the temporal cortex. SCARB2 and TFEB expression correlated negatively with GBA mRNA expression in the temporal cortex. Our findings show disease-specific deregulation of TFEB and SCARB2 expression affecting alternative promoter usage and alternative splicing in Lewy body diseases. [ABSTRACT FROM AUTHOR]

• GBA 1 knockdown increases levels of α-synuclein. • GBA 2 knockdown does not change levels of α-synuclein. • GBA 1 inhibition with CBE does not alter α-synuclein levels. • Veraglucerase Alfa can restore normal α-synuclein levels after GBA 1 siRNA treatment Mutations in the glucocerebrosidase gene are a common genetic risk factor for developing Parkinson's disease. The reasons why glucocerebrosidase mutations cause an increased life-time risk of developing Parkinson's disease are not fully understood. Here, we aimed to verify whether glucocerebrosidase activity has an effect on total α-synuclein levels. We use SH-SY5Y and primary cortical cells and expose them to either Conduritol-β-epoxide or siRNA targeting GBA 1. Unexpectedly, RNA interference towards GBA 1 and catalytic inhibition produce different effects on α-synuclein levels in cellular models. [ABSTRACT FROM AUTHOR]

• The GG genotype at SNCA rs11931074 significantly reduces the risk of PD. • The GG genotype at SNCA rs11931074 significantly increases risk of dementia in PD. • Older age, higher UPDRS III score and fewer years of education are associated with higher risk of dementia in PD. Single-nucleotide polymorphisms (SNPs) in the SNCA gene encoding alpha-synuclein have been shown to affect the PD phenotype. However, whether such polymorphisms can influence risk of dementia in PD remains unclear. To investigate possible associations between SNCA gene polymorphisms and dementia in patients with PD. A consecutive series of 291 PD patients with dementia (n = 45, 15.5%) or without it (n = 246, 84.5%) were genotyped at four SNPs in the SNCA gene. As controls, 615 healthy Han Chinese were also genotyped. Three SNPs (rs11931074, rs7684318 and rs356219) were in strong linkage disequilibrium. The GG genotype at rs11931074 significantly reduced risk of PD (p = 0.023), but it significantly increased risk of dementia after PD onset (p = 0.015) based on the recessive genetic model. Logistic regression identified the following risk factors for dementia among patients with PD: age ≥65 years (odds ratio [OR] 2.69, 95% confidence interval [CI] 1.25–5.77, p = 0.011), education ≤6 years (OR 4.66, 95% CI 2.21–9.83, p < 0.001), part III score on the Unified Parkinson's Disease Rating Scale ≥40 (OR 5.01, 95% CI 2.40–10.45, p < 0.001), and GG genotype at rs11931074 (OR 2.81, 95% CI 1.16–6.83, p = 0.022). PD patients carrying the protective GG genotype at SNCA rs11931074 may be at significantly higher risk of dementia than patients with other genotypes. Our results support the view that SNCA polymorphisms can have opposite effects on preclinical and clinical PD. [ABSTRACT FROM AUTHOR]

• Chrysin attenuated the behavioral changes in PD model induced by 6-OHDA in aged-mice. • Chrysin protects against oxidative stress in PD model induced by 6-OHDA. • Chrysin protects neuroinflammation in PD model. Parkinson's disease (PD) is an age-related neurodegenerative disorder that severely affects quality of life of patients and their families. The flavonoid chrysin (5,7-dihydroxylflavone) is a naturally occurring flavone with several pharmacological activities, including anti-inflammatory and anti-oxidative. We investigated the effects of a 28-day chrysin treatment (10 mg/kg/day, i.g.) on a model of PD induced by 6-OHDA in aged (20-month old) mice. We found a protective effect of chrysin on behavioral and cognitive alterations (rotational behavior, passive avoidance and Barnes maze tests), nitric oxide synthesis (NO x), lipid peroxidation (HNE), glutathione levels (GSH), reactive species levels (RS), neuroinflammation (interleukin-1 beta - IL-1β and tumor necrosis factor alpha - TNF-α), Na+, K+-ATPase and nicotinamide adenine dinucleotide phosphate oxidase activity (NADPH oxidase) activities. In addition, chrysin protected against changes in striatal dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels. In conclusion, chrysin improved several behavioral, cognitive and neurochemical parameters in a relevant preclinical model of PD in aged mice. [ABSTRACT FROM AUTHOR]

• G2385R and R1628P LRRK2 variants are absent in the Hungarian population. • The minor allele of the risk factor S1647T variant is more frequent among healthy male individuals compared to patients. • The protective rs356186 SNCA variant is significantly more frequent in homozygous form among controls than in PD patients. • The rs356186 SNCA variant is significantly more frequent in heterozygous form among LOPD patients compared to controls. • No significant differences were detected in the case of rs1491923, R1398H, N551K, rs2583988, rs1052553, rs10788972 variants. Parkinson's disease is the second most common neurodegenerative disease. Lifestyle, environmental effects and several genetic factors have been proposed to contribute to its development. Though the majority of PD cases do not have a family history of disease, genetic alterations are proposed to be present in 60 percent of the more common sporadic cases. The aim of this study is to evaluate the frequency of PD related specific risk variants of LRRK2 , MAPT , SNCA and PARK10 genes in the Hungarian population. Out of the ten investigated polymorphisms three are proposed to have protective effect and seven are putative risk factors. For genotyping, TaqMan allelic discrimination and restriction fragment length polymorphism method was used. LRRK2 mutations were investigated among 124 sporadic PD patients and 128 healthy controls. MAPT and SNCA variant frequencies were evaluated in a group of 123 patients and 122 controls, while PARK10 variant was studied in groups of 121 patients and 113 controls. No significant difference could be detected in the frequencies of the investigated MAPT and PARK10 variants between the studied Hungarian PD cases and controls. The minor allele of the risk factor S1647T LRRK2 variant was found to be more frequent among healthy male individuals compared to patients. Moreover, in the frequency of one of the investigated SNCA variant a significant intergroup difference was detected. The minor allele (A) of rs356186 is proposed to be protective against developing the disease. In accord with data obtained in other populations, the AA genotype was significantly more frequent among Hungarian healthy controls compared to patients. Similarly, a significant difference in genotype distribution was also found in comparison of patients with late onset disease to healthy controls, which was due to the higher frequency of AG genotype among patients. The frequencies of different gene variants show great differences in populations. Assessment of the frequency of variants of PD related genes variants is important in order to uncover the pathomechanisms underlying the disease, and to identify potential therapeutic targets. This is the first comprehensive study focusing on these genetic variants in the population of East-Central European region. Our results extend the knowledge on the world wide occurrence of these polymorphisms by demonstrating the occurrence of specific alleles and absence of others in Hungarian PD patients. [ABSTRACT FROM AUTHOR]

• Increased PHP ReHo in the TD PD subtype group indicates a compensatory performance of slow progressive cognitive decline. • Both two subtypes of PD manifest ReHo changes in the basal ganglia, thalamus. • ReHo changes in several brain areas are correlate with non-motor symptoms. Regional homogeneity (ReHo) differences in encephalic regions of Parkinson's disease (PD) patients of different subtypes were investigated to analyze its clinical significance during disease occurrence. 39 PD patients were evaluated in this study, which included 14 cases with the tremor dominant (TD) PD subtype and 23 cases with the postural instability and gait difficulty (PIGD) PD subtype, along with 28 healthy individuals, who were included as the control group. Magnetic resonance imaging (MRI) was performed for all the cases to obtain the rest-state functional magnetic resonance imaging (R-fMRI) data along with structural data. The ReHo values of the three groups were calculated and disparities in brain structures among the three groups were processed by analysis of variance. In addition, t -test analysis was used to evaluate the differences between the groups. In the end, a correlation analysis between the brain areas evaluated for ReHo differences and the clinical symptoms presented by the patients was carried out. Compared to the control group, brain areas with increased ReHo values in the TD PD subtype group, included the right putamen, right para-hippocampal gyrus, right inferior temporal gyrus, and right orbital superior frontal gyrus, while areas with decreased ReHo values, included the bilateral superior occipital gyrus and bilateral middle occipital gyrus. In contrast with the control group, areas like the right putamen, right superior temporal gyrus, left thalamus, and right superior parietal gyrus in the PIGD PD subtype group presented an increased in ReHo values, while a decreased in ReHo values was found in the right para-hippocampal gyrus, bilateral superior occipital gyrus, and middle occipital gyrus. Compared to the PIGD group, the TD group showed an increase in ReHo values in the right para-hippocampal gyrus. In the present study, ReHo values increased in the TD PD subtype group of patients, indicating a compensatory performance of slow progressive cognitive decline when compared to the PIGD PD subtype group. Two subtypes of PD manifest ReHo changes in the basal ganglia, thalamus, and in several areas of the cerebral cortex, areas that are likely to correlate with non-motor symptoms, such as cognition and emotions. [ABSTRACT FROM AUTHOR]

• DBH SNP rs129882 demonstrated significant association with East Indian PD patients. • Potential molecular basis for the association was supported by reporter gene assay. • Plasma DBH activity did not correlate with PD, maybe due to small sample size. • Replicative study using larger cohorts is likely to shed more light. • Haplotypes for 3 SNPs of DBH demonstrate variable risk/protection for PD. Parkinson's disease (PD) is the debilitating movement disorder, distinguished by dopaminergic and norepinephrinergic neurodegeneration. Apart from candidate gene mutations, several modifier loci have been reported to be associated with the disease manifestation. The Dopamine β-Hydroxylase (DBH) maintains cellular dopamine content and regulates dopamine turn over in neurons. Genetic polymorphisms of DBH are associated with PD and are found to alter plasma DBH activity in patients compared to healthy controls. Therefore, DBH activity in plasma could be a potential and easily detectable biomarkers for alteration of dopaminergic neuronal function in PD. Plasma DBH activity has been assessed among PD cases and age-matched controls to identify correlation with PD. To elucidate the role of DBH polymorphisms in Eastern Indian PD patients, three SNPs (rs1611115, rs1108580 and rs129882) were selected and screened by PCR-RFLP and DNA sequencing analysis. The T-allele of rs129882 was more prevalent among patients than controls posing risk (p -value = 0.02, OR = 1.404, 95% CI = 1.047–1.883) towards PD. The dual-Luciferase assay in SHSY5Y cell line revealed that the T-allele of rs129882 increases Luciferase signal (p = 0.0269). However, the rs1611115 and rs1108580 did not show association with PD; plasma DBH activity was not significantly different between patients and controls (p -value > 0.05). Haplotypes constructed with three SNPs showed that the CAT haplotype to pose risk, TAC haplotype to provide protection against early disease onset and CGT being protective against non-motor symptoms. These data suggest that DBH might influence the susceptibility of PD. [ABSTRACT FROM AUTHOR]

• Parkinson's disease causing mutation (DNAJC13 p.Asn855Ser) does not alter DNAJC13/RME-8 levels. • SNX1 membrane dynamics are altered in a DNAJC13 p.Asn855Ser knock-in (DKI) mouse model. • DNAJC13 p.Asn855Ser does not disrupt RME-8 binding to SNX1 or Retromer-WASH complexes. DNAJC13 (RME-8) is a core co-chaperone that facilitates membrane recycling and cargo sorting of endocytosed proteins. DNAJ/Hsp40 (heat shock protein 40) proteins are highly conserved throughout evolution and mediate the folding of nascent proteins, and the unfolding, refolding or degradation of misfolded proteins while assisting in associated-membrane translocation. DNAJC13 is one of five DNAJ 'C' class chaperone variants implicated in monogenic parkinsonism. Here we examine the effect of the DNAJC13 disease-linked mutation (p.Asn855Ser) on its interacting partners, focusing on sorting nexin 1 (SNX1) membrane dynamics in primary cortical neurons derived from a novel Dnajc13 p.Asn855Ser knock-in (DKI) mouse model. Dnajc13 p.Asn855Ser mutant and wild type protein expression were equivalent in mature heterozygous cultures (DIV21). While SNX1-positive puncta density, area, and WASH-retromer assembly were comparable between cultures derived from DKI and wild type littermates, the formation of SNX1-enriched tubules in DKI neuronal cultures was significantly increased. Thus, Dnajc13 p.Asn855Ser disrupts SNX1 membrane-tubulation and trafficking, analogous to results from RME-8 depletion studies. The data suggest the mutation confers a dominant-negative gain-of-function in RME-8. Implications for the pathogenesis of Parkinson's disease are discussed. [ABSTRACT FROM AUTHOR]

• Clinical evidence on the implication of Cystatin C in Parkinson's disease (PD) is rare. • Higher Cystatin C level in serum is associated with an increased PD risk. • Higher Cystatin C level in serum is associated with levodopa-induced dyskinesia in PD patients. • Serum Cystatin C level (1.13 mg/L) can be used as a tool for evaluating dyskinesia in PD patients. Although cystatin C (Cys C) has been implicated in the pathophysiology of Parkinson's disease (PD), whether it can be used as a tool for evaluating dyskinesia is unknown. In the present study, the association of Cys C with dyskinesia in PD patients was investigated. Fasting serum Cys C levels were measured from 120 PD patients and 156 healthy controls. Demographic information was collected for all patients. In addition, levodopa (L-dopa)-equivalent dose, Unified Parkinson's Disease Rating Scale (UPDRS) score, Hoehn and Yahr (H&Y) stage, and dyskinesia were assessed in PD patients. Receiver operating characteristic (ROC) curves were adopted to assess the evaluating accuracy of Cys C levels for distinguishing dyskinesia in PD patients. Patients with PD exhibited significantly higher serum Cys C levels compared with heathy controls. Dyskinesia was observed in 32 patients (26.7%). Multiple logistic regression showed serum Cys C levels (odds ratio, OR 12.93; 95% confidence interval, CI 1.08–54.23; p = 0.043), duration of disease (OR 1.03, 95% CI 1.01–1.05, p = 0.001) and UPDRS II score (OR 1.07, 95% CI 1.01–1.14, p = 0.019) were independently associated with dyskinesia. The ROC curve for the Cys C levels yielded a valuable accuracy for distinguishing dyskinesia in PD patients. Serum Cys C levels were independently associated with dyskinesia and may be a valuable screening tool for differentiating dyskinesia in PD patients. Although the pathophysiological mechanism of PD is complicated, the results from our study provide a better understanding of the association between Cys C and dyskinesia in PD patients and may yield insights into the pathogenesis of PD. [ABSTRACT FROM AUTHOR]

• The dopamine depletion induced excessive glutamatergic transmission in striatum is a leading cause of PD. • Exercise started after dopamine depletion could not exert neuroprotective effects on the dopamine system in PD rats. • Exercise increased mGluR2/3 and inhibited mGluR5 expression which might contribute to attenuating glutamate levels. • mGluR-mediated modulation of glutamatergic transmission in striatum might be partly related to the improvement of the motor. Hyperexcitability in the corticostriatal glutamatergic pathway may have a pivotal role in the pathogenesis of Parkinson's disease (PD). Metabotropic glutamate receptors (mGluRs) modulate glutamate transmission by both pre- and postsynaptic mechanisms, making them attractive targets for modifying pathological changes in the corticostriatal pathway. Exercise reportedly alleviates motor dysfunction and induced neuroplasticity in glutamatergic transmission. Here, the mGluR-mediated plasticity mechanism underlying behavioral improvement by exercise intervention was investigated. The experimental models were prepared by 6-hydroxydopamine injection into the right medial forebrain bundle. The models were evaluated with the apomorphine-induced rotation test. Starting 2 weeks postoperatively, exercise intervention was applied to the PD + Ex group for 4 weeks. The exercise-intervention effects on locomotor behavior, glutamate levels, and mGluR (mGluR2/3 and mGluR5) expression in hemiparkinsonian rats were investigated. The results showed that hemiparkinsonian rats have a significant increase in extracellular glutamate levels in the lesioned-lateral striatum. MGluR2/3 protein expression was reduced while mGluR5 protein expression was increased in the striatum. Notably, treadmill exercise markedly reversed these abnormal changes in the corticostriatal glutamate system and promoted motor performance in PD rats. These findings suggest that mGluR-mediated glutamatergic transmission in the corticostriatal pathway may serve as an attractive target for exercise-induced neuroplasticity in hemiparkinsonian rats. [ABSTRACT FROM AUTHOR]

• Effect of tangeritin on cognitive impairments in Drosophila model of Parkinson's disease. • The PD flies were exposed to 5, 10 and 20 μM of tangeritin. • Tangeritin reduces the cognitive impairments in PD flies. Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. As there is no permanent cure for the disease, the use of herbal compounds with antioxidant potential will be an effective approach for controlling the progression of disease. In this context the effect of tangeritin (a polymethoxy flavone concentrated in the peels of citrus fruits) was studied at final doses of 5, 10 and 20 μM on PD model flies. The doses were established in diet and the PD flies were allowed to feed on it for 24 days. The effect was studied on cognitive impairments. Immunostaining of brain sections for tyrosine hydroxylase was also performed. The docking studies were also carried out to give a plausible binding site of tangeritin on alpha synuclein molecule. The results of the study showed that tangeritin is effective in improving the cognitive impairments. [ABSTRACT FROM AUTHOR]

• Non-demented PD patients showed disrupted DMN connectivity. • Levodopa imparts a normalizing effect on the DMN integrity in PD patients. • The PCC showed decreased FC after administration of levodopa. Parkinson's disease (PD) is characterized with reduced dopamine level in the brain, resulting from the nigral degeneration. It is commonly accepted that the function of default mode network (DMN) is disturbed in PD, even in those who have no significant cognitive impairment. However, the relationship between the depletion of dopamine and DMN dysconnectivity is not fully clear. The aim of this study was to investigate the seed-based DMN connectivity and the influence of dopaminergic therapy on the DMN integrity in non-demented PD by using resting-state fMRI. Resting-state fMRI data was collected from 24 non-demented PD patients before and after taking levodopa and 36 healthy controls (HCs). Functional connectivity (FC) was examined by a seed-based correlation approach. Compared with HCs, decreased DMN connectivity in PD patients was observed, a number of which were significantly improved after taking levodopa therapy. Moreover, by directly comparing the DMN connectivity between ON- and OFF-medication conditions, we found significantly enhanced FC in a set of regions of DMN in the ON- medication condition. Conversely, we also found that the PCC revealed decreased FC with left inferior temporal. DMN connectivity was found to be impaired in no-demented PD patients, and levodopa has the ability to impart a normalizing effect on DMN connectivity. [ABSTRACT FROM AUTHOR]

• A three-year retrospective cohort study is conducted. • The different impact of STN-DBS on YOPD and OOPD patients with an onset age cut-off of 50 years is first demonstrated. • STN-DBS alleviates motor symptoms and improves quality of life equally in both YOPD and OOPD patients. To assess the role of onset age in the results of bilateral subthalamic nucleus deep brain stimulation (STN-DBS), we carried out a retrospective study of two groups of patients regarding age at disease onset. We compared, up to 3 years after surgery, the clinical effects, quality of life and the levodopa equivalent daily dose (LEDD) in patients with young-onset Parkinson's disease (onset age <50 years, YOPD) vs patients with older-onset Parkinson's disease (onset age ≥50 years, OOPD). A dramatic improvement in motor symptoms was equally observed in both groups of patients after DBS. The improvements of the Unified Parkinson's Disease Rating Scale part III motor scale (UPDRS-III) score, axial sub-score and non-axial sub-score from baseline gradually decreased over time. The benefit of STN-DBS for the axial symptoms decreased most rapidly, which directly resulted in a progressive decline in stimulation efficacy in both groups. Nevertheless, the improvement in non-axial symptoms after DBS was remarkable and long-lasting. The quality of life in both groups were also improved after DBS but were slightly decreased in the following years. The reduced LEDD were equivalent in both groups. STN-DBS alleviates motor symptoms and improves quality of life equally in both YOPD and OOPD patients with similar LEDD. The initial therapeutic benefit of STN-DBS for PD gradually decreases over time, mainly due to the progression of PD and the rapid withdrawal of the benefit for axial symptoms. [ABSTRACT FROM AUTHOR]

• Discovery of monogenic forms of Parkinson's disease provide insight into molecular mechanisms of dysfunctional mitophagy. • Several small molecule therapies are in preclinical development to enhance PINK1/Parkin mediated mitophagy. • Biomarkers for mitochondrial dysfunction and mitophagy enable clinical translation of mitophagy enhancing therapies. The discovery of rare familial monogenic forms of early-onset Parkinson's disease has led to the identification of a mitochondrial quality control process as a key player in this disease. Loss-of-function mutations in the genes encoding PINK1 or Parkin result in insufficient removal of dysfunctional mitochondria through autophagy, a process termed mitophagy. Understanding the mechanism of this process and the function of its two key players, PINK1 and Parkin, has led to the discovery of new therapeutic approaches. Small molecule activators of mitophagy, either activating PINK1 or Parkin directly or inhibiting Parkin's counterplayer, the ubiquitin-specific protease USP30, are in preclinical development. To enable clinical success of future small molecule mitophagy enhancers, biomarkers for mitochondrial integrity and mitophagy are being developed. Only a few years after the discovery of mitophagy deficits in Parkinson's disease, research of the underlying mechanisms, drug discovery of modulators for this mechanism and identification of biomarkers provide new avenues towards the development of disease-modifying therapies. [ABSTRACT FROM AUTHOR]

• Neural activation pattern throughout the mouse olfactory network was mapped for the first time. • Spatial pattern of activation was odorant-specific. • 11.7 T magnet provided high signal-to-noise ratio and resolution for imaging mouse olfactory system. Although olfactory dysfunction is an early warning sign of Alzheimer's and Parkinson's diseases, and is commonly present in a range of other neurodegenerative disorders, the mechanisms for its pathogenesis are not yet clear. Since fMRI allows the mapping of spatial and temporal patterns of activity in multiple brain regions simultaneously, it serves as a powerful tool to study olfactory dysfunction in animal models of neurodegenerative diseases. Nonetheless, there have been no reports to date of mapping odor-induced activation patterns beyond the olfactory bulb to the extended networks of olfactory and limbic archicortex, likely due to the small size of the mouse brain. Therefore, using an 11.7 T magnet and a blood volume-weighted fMRI technique, we mapped the functional neuroanatomy of the mouse olfactory system. Consistent with reports on imaging of the much larger human brain, we mapped activity in regions of the olfactory bulb, as well as olfactory and limbic archicortex. By using two distinct odorants, we further demonstrated odorant-specific activation patterns. Our work thus provides a methodological framework for fMRI studies of olfactory dysfunction in mouse models of neurodegeneration. [ABSTRACT FROM AUTHOR]

• Naturally occurring autoantibodies against human α-Syn (nAbs α-Syn) were detected in the peripheral blood of PD patients and controls in different levels. • We investigated the inhibitory effect of nAbs α-Syn on distinct α-Syn fragments induced inflammation and cytotoxicity on pr0imary microglia. • All α-Syn fragments induced the release of the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) from primary cultured microglia. • Cotreatment with nAbs α-Syn did alleviate the release of pro-inflammatory cytokines induced by the α-Syn fragments α-Syn 1–95, α-Syn 61–140, α-Syn 96–140 and α-Syn 112. • Treatment with the α-Syn fragments α-Syn 1–95, α-Syn 61–140 and α-Syn 112 impaired the viability of primary microglia. This effect could not be counteracted by cotreatment with nAbs α-Syn. Alpha-synuclein (α-Syn) is a soluble protein primarily expressed in presynaptic terminals in the central nervous system (CNS). Aggregates of fibrillated α-Syn are the major component of Lewy bodies (LB), a pathologic hallmark of idiopathic Parkinson's disease (PD). Recently, naturally occurring autoantibodies against human α-Syn (nAbs α-Syn) were detected in the peripheral blood of PD patients and controls. Here, we investigated the inhibitory effects of nAbs α-Syn on distinct α-Syn fragments, as well as inflammatory responses and cytotoxicity evoked by nAbs α-Syn in primary microglia. All α-Syn fragments induced the release of the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) from microglia in primary culture. Cotreatment with nAbs α-Syn alleviated the release of pro-inflammatory cytokines induced by α-Syn fragments α-Syn 1–95, α-Syn 61–140, α-Syn 96–140 and α-Syn 112. Treatment with the α-Syn fragments α-Syn 1–95, α-Syn 61–140 and α-Syn 112 impaired the viability of primary microglia. This effect could not be counteracted by cotreatment with nAbs α-Syn. Data suggest an important role of nAbs α-Syn in the α-Syn-induced inflammation cascade, and indicate the potential importance of nAbs in the pathogenesis of PD. This could provide an experimental therapeutic target for patients with PD. [ABSTRACT FROM AUTHOR]

• Protein degradation in cultured peripheral blood mononuclear cells is reduced in PD patients. • Macroautophagy is impaired in PBMCs of PD patients. • Chaperone-Mediated Autophagy is impaired in PBMCs of PD patients. Alpha-synuclein aggregation is considered one of the main causes of Parkinson's Disease (PD). Malfunction of autophagy-lysosomal pathways is believed to be an underlying mechanism of α-synuclein aggregation. Although such malfunction has been observed in PD brains, it is unclear whether it may also occur in extraneuronal tissues. To assess lysosome-mediated protein degradation in cultured Peripheral Blood Mononuclear Cells (PBMCs) of PD patients and healthy controls. Total protein degradation in cultured PBMCs was measured by labelling the cells with 3H-leucine using pulse-chase experiments. Different inhibitors were used to measure a range of autophagic pathways. Protein degradation through the main autophagic pathways is reduced in PD patients (n = 18) compared to age- and sex-matched healthy controls (n = 18), (macroautophagy, p =.018; Chaperone-Mediated autophagy, p =.04; and total lysosomal function, p =.007). Lysosomal dysfunction is present in cultured PBMCs of PD patients, suggesting that it may reflect a systemic feature of the disease. [ABSTRACT FROM AUTHOR]

• Nitrated α-SYN is an undesirable modification associated with oxidative and nitrative damage. • Positive nitrated α-SYN immunostaining in minor salivary gland was observed in all patients but not in control group. • The nitrated alpha-synuclein positive structures were located in periacinar stroma in PD. • Nitrated α-SYN exists in the early stage and is probably a promising biomarker for PD. Alpha-synuclein (α-SYN) is found in peripheral autonomic neuronal network apart from brain in Parkinson's disease (PD). Nitrated α-SYN is an undesirable modification associated with oxidative and nitrative damage and has been found extensively in brain, gastrointestinal(GI) tract and blood cells in PD. We aim to investigate the presence of nitrated α-SYN in minor salivary gland biopsy in PD. Patients with PD and age-matched controls underwent minor salivary gland biopsy. Motor impairment was assessed by Hoehn-Yahr (H-Y) stage and Unified Parkinson's Disease Rating Scale (UPDRS) Part III in off-state. 11C-methyl -N- 2b-carbomethoxy-3b-(4-fluorophenyl) tropane (11C-CFT) DAT-PET scan was performed in all subjects. Immunohistochemical staining for nitrated α-SYN was performed in the minor salivary gland tissues. The minor salivary gland tissues of 8 PD cases and 7 controls with early stage (H-Y stage 1-2) were detected. All PD patients showed asymmetrical and reduction of 11C-CFT uptake in the caudate, anterior and posterior putamen, while all control subjects showed normal DAT-PET scan. Positive nitrated α-SYN immunostaining was observed in all PD patients (8/8,100%) but not in control subjects (0/7). The results were consistent well with that of DAT-PET. These nitrated alpha-synuclein positive structures were mainly located in the periacinar stroma in PD patients. Our result suggests that nitrated α-SYN exists in the early stage and is probably a promising biomarker for PD. Minor salivary gland is an ideal site for α-SYN nitration detection. Despite of the small number of subjects, attention should be given to α-SYN nitration in PD and more investigations on nitrated α-SYN in different sites and large sample using should be explored in future. [ABSTRACT FROM AUTHOR]

• First instance of ALC preventing glial activation in MPTP animals. • First instance of ALC preventing Glut-1, OCL, and ZO-1 loss in MPTP animals. • ALC preventing loss of TH, DAT, and DA confirms 6-OHDA and MPTP model findings. • ALC preventing astrocytic response confirms 6-OHDA model findings. Parkinson's disease (PD) is a progressive motor disease with clinical features emerging due to degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc), which project to the caudate putamen (CPu) where they release dopamine (DA). The current study investigated whether acetyl- l -carnitine (ALC) could ameliorate the pathology seen in an in vivo in vivo chronic 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced mouse model of PD. Four treatment groups were included: 1) CONTROL receiving probenecid (PROB; 250 mg/kg) only, 2) MPTP (25 mg/kg) + PROB, 3) MPTP + ALC (100 mg/kg), and 4) ALC alone. MPTP-induced losses in tyrosine hydroxylase and DA transporter immunoreactivity in the SNc and CPu were significantly reduced by ALC. HPLC data further suggests that decreases in CPu DA levels produced by MPTP were also attenuated by ALC. Additionally, microglial activation and astrocytic reactivity induced by MPTP were greatly reduced by ALC, indicating protection against neuroinflammation. Glucose transporter-1 and the tight junction proteins occludin and zonula occludins-1 were also protected from MPTP-induced down-regulation by ALC. Together, data suggest that in this model, ALC protects against MPTP-induced damage to endothelial cells and loss of DA neurons in the SNc and CPu, suggesting that ALC therapy may have the potential to slow or ameliorate the progression of PD pathology in a clinical setting. [ABSTRACT FROM AUTHOR]

• Large case control study (2047 subjects) examines genetic associations of three risk loci with PD susceptibility. • For the first time demonstrates that rs6430538, rs199347 and rs14235 do not confer a significant risk for sporadic PD in mainland China. • We also have conducted further stratified analysis according to age at onset. Large-scale meta-analyses of genome-wide association studies have identified that polymorphisms ACMSD/TMEM163 rs6430538, GPNMB rs199347 and BCKDK /STX1B rs14235 to be the risk loci for Parkinson's disease (PD) in a Caucasian population. However, the role of these three polymorphisms in a Han Chinese population from mainland China still remains to be clarified. We conducted a large sample study to examine genetic associations of rs6430538, rs199347 and rs14235 with PD in a Han Chinese population of 989 sporadic PD patients and 1058 healthy controls. All subjects were genotyped for these loci using the Sequenom iPLEX Assay. In addition, we conducted further stratified analysis according to age at onset and compared the clinical characteristics between minor allele carriers and non-carriers for each locus. However, no significant differences were found in genotype and allele frequency distribution between PD patients and controls for the three loci, even after being stratified by age at onset. Moreover, we demonstrated that minor allele carriers cannot be distinguished from non-carriers based on their clinical features. Our study is the first to demonstrate that ACMSD/TMEM163 rs6430538, GPNMB rs199347 and BCKDK /STX1B rs14235 do not confer a significant risk for sporadic PD in mainland China. Therefore, more replication studies in additional Chinese population and other cohorts and functional studies are warranted to further clarify the role of the three loci in PD susceptibility. [ABSTRACT FROM AUTHOR]

Highlights • Auditory evoked oscillations are demonstrated first time in drug-naïve PD and controls. • Drug-naïve PD group has larger delta, alpha and theta amplitudes than controls. • Impaired dopamine metabolism may lead to an increased auditory brain activity in PD. • Decreased habituation process may result in larger oscillatory responses. Abstract Parkinson's Disease (PD) is a common neurodegenerative disorder affecting the function of dopaminergic cells in basal ganglia. Besides the motor symptoms, tremor, and dysfunction of sensory systems. In the literature, there was limited studies which investigates the basic sensorial processing in PD. Therefore, we aimed to establish the sensorial processing of simple auditory stimulations in naïve PD comparing to healthy controls (HC) via delta, theta, and alpha brain oscillatory responses. 12 naïve PD and 12 HC participated to the study. Brain responses recorded via the 64-channel electroencephalography (EEG) system in an electromagnetically and acoustically isolated room. The auditory stimuli (1500 Hz, 60 dB SPL, 500 ms) were delivered to the subjects via a headphone. The inter-stimulus interval was ranged between 2.5–4.5 s. The peak-to-peak maximum amplitudes were measured in the delta, theta and alpha frequency bands on 11 electrodes (including the frontal, central and parietal areas) for the statistical analysis in which one-way ANOVA test was employed for the comparisons between PD and HC. For the delta oscillatory responses, PD group has bigger amplitudes in frontal, central and parietal areas in comparison with HC. For the theta and alpha oscillatory responses, PD group has bigger amplitudes in parietal areas in comparison with HC. As a result, amplitudes of brain oscillatory responses in PD group were significantly bigger than the HC. In this context, decreased inhibitory mechanisms of cortical auditory processing due to the dysfunction of the dopaminergic activity may lead the increased evoked responses in PD group. [ABSTRACT FROM AUTHOR]