Orexin increases the neuronal excitability of several brain areas associated with maintaining of arousal.

Orexin is exclusively produced in neurons localized within the lateral hypothalamic area (LHA) and perifornical area (PFA). Orexin has been identified as a key promotor of arousal. The selective loss of orexinergic neurons results in narcolepsy. It is known that the intrinsic electrophysiological properties are critical for neurons to perform their functions in corresponding brain regions. In addition to hypothalamic orexin, other brain nuclei are involved in the regulation of sleep and wakefulness. Quite a lot of studies focus on elucidating orexin-induced regulation of sleep-wake states and modulation of neuronal electrophysiological properties in several brain regions. Here, we summarize that the orexinergic neurons exhibit spontaneous firing activity which is associated with the states of sleep-wake cycle. Orexin mainly exerts postsynaptic excitatory effects on multiple brain nuclei associated with the process of sleep and wakefulness. This review may provide a background to guide future research about the cellular mechanisms of orexin-induced maintaining of arousal.

Repetitive transcranial magnetic stimulation alleviates glial activation through suppressing HMGB1/TLR4 pathway in a rat model of Parkinson's disease.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has been demonstrated to be effective in Parkinson's disease (PD), but whether rTMS treatment has a relieving effect on neuroinflammation remains to be investigated. In this article, we explored the effects of rTMS on forelimb use asymmetry and neuroinflammation-related mechanisms in a 6-hydroxydopamine (6-OHDA)-induced PD rat model. METHODS AND RESULTS: Rats in the 6-OHDA+rTMS group received 10 Hz rTMS daily for 4 weeks. Behavioral tests (the cylinder test) were performed at the 3rd and 7th weeks after the operation. Astrocyte and microglia activation and protein levels of tyrosine hydroxylase(TH), high-mobility group box 1(HMGB1) and toll-like receptors 4(TLR4) were investigated by immunohistochemistry and Western blot analyses, respectively. After 4 weeks of treatment, forelimb use asymmetry was ameliorated in the 6-OHDA+rTMS group. Consistent with the behavioral tests, rTMS increased TH in the substantia nigra (SN) and the striatum of PD rats. High glial activation and HMGB1/TLR4 expression in the SN and the striatum were observed in the 6-OHDA group, while rTMS alleviated these changes. CONCLUSIONS: This study showed that rTMS might be a promising method for alleviating neuroinflammation in PD rat models, and the effects might be mediated through the downregulation of the HMGB1/TLR4 pathway.

Parkinson's disease peripheral immune biomarker profile: a multicentre, cross-sectional and longitudinal study.

BACKGROUND: Inflammations play crucial role in the pathogenesis of Parkinson's disease (PD), however, their possible value in the diagnosis or tracking of the progress of PD is still limited, because of discordant results in the literature and a lack of information regarding its reproducibility. Thus, overall longitudinal and cross-sectional studies are needed. This multicentre study was designed to investigate the association between multiple peripheral immune biomarkers and the development and progression of PD. METHODS: This was a longitudinal and multicentre study. First, we measured the levels of five typical cytokines and five focused chemokines in 76 PD patients and 76 healthy controls (HCs) in a discovery cohort. Then, a validation cohort of 80 PD and 80 HC participants was recruited from four multicentre locations. In addition, a prospective follow-up of early-stage PD patients was performed with significant biomarkers. Finally, we performed further verification in an exploratory set of patients with idiopathic REM sleep behaviour disorder (iRBD). RESULTS: In the discovery set, CXCL12, CX3CL1 and IL-8 levels were significantly higher in PD patients than in HCs (p < 0.05). The receiver-operating characteristic (ROC) curve for a combination of these three biomarkers produced a high area under the curve (AUC) of 0.89 (p < 0.001). Moreover, four biomarkers (the previous three and CCL15) were significantly associated with PD in the discovery and validation cohorts. Furthermore, in the prospective follow-up cohort, CX3CL1 levels were associated with motor progression after a mean interval of 43 months. In addition, CX3CL1 and IL-8 levels were higher in iRBD patients than in HCs. CONCLUSION: We showed a correlation between a profile of four peripheral immune biomarkers and PD development and progression. Our findings may provide a basis whereby PD patients with abnormal inflammatory profiles can be identified and receive timely therapeutic interventions.

Upregulation of PGC-1α Attenuates Oxygen-Glucose Deprivation-Induced Hippocampal Neuronal Injury.

Hippocampal neuronal damage likely underlies cognitive impairment in vascular dementia (VaD). PPARγ coactivator-1α (PGC-1α) is a master regulator of mitochondrial biogenesis. However, the role and the precise mechanism of how PGC-1α alleviates hippocampal neuronal injury remain unknown. To address this question, HT-22 cells, an immortalized hippocampal neuron cell line, with or without PGC-1α overexpression were subjected to oxygen-glucose deprivation (OGD), which mimics the circumstance of chronic cerebral hypoperfusion in VaD. After OGD, cell viability was assessed using the MTS assay. The mitochondrial function and reactive oxygen species (ROS) were both detected. ChIP-Seq analysis was employed to discover the underlying molecular mechanism of PGC-1α-mediated neuroprotective effects. Our results showed that mitochondrial membrane potentials were increased and ROS production was decreased in PGC-1α overexpressing cells, which increased cell viability. The further bioinformatics analysis from ChIP-Seq data indicated that PGC-1α may participate in the regulation of apoptosis, autophagy, and mitophagy pathways in HT-22 cells. We found that PGC-1α promoted the LC3-II formation and reduced the neuronal apoptosis determined by TUNEL staining. In addition, PGC-1α upregulated the expressions of mitochondrial antioxidants, including SOD2, Trx2, and Prx3. In summary, our findings indicate that PGC-1α may attenuate OGD-induced hippocampal neuronal damage by regulating multiple mechanisms, like autophagy and mitochondrial function. Thus, PGC-1α may be a potential therapeutic target for hippocampal damage associated with cognitive impairment.

BMAL1 regulation of microglia-mediated neuroinflammation in MPTP-induced Parkinson's disease mouse model.

Dysfunction of the circadian rhythm is one of most common nonmotor symptoms in Parkinson's disease (PD), but the molecular role of the circadian rhythm in PD is unclear. We here showed that inactivation of brain and muscle ARNT-like 1 (BMAL1) in 1-methyl-4-phenyl-1,2,4,5-tetrahydropyridine (MPTP)-treated mice resulted in obvious motor functional deficit, loss of dopaminergic neurons (DANs) in the substantia nigra pars compacta (SNpc), decrease of dopamine (DA) transmitter, and increased activation of microglia and astrocytes in the striatum. Time on the rotarod or calorie consumption, and food and water intake were reduced in the Bmal1-/- mice after MPTP treatment, suggesting that absence of Bmal1 may exacerbate circadian and PD motor function. We observed a significant reduction of DANs (~35%) in the SNpc, the tyrosine hydroxylase protein level in the striatum (~60%), the DA (~22%), and 3,4-dihydroxyphenylacetic acid content (~29%), respectively, in MPTP-treated Bmal1-/- mice. Loss of Bmal1 aggravated the inflammatory reaction both in vivo and in vitro. These findings suggest that BMAL1 may play an essential role in the survival of DANs and maintain normal function of the DA signaling pathway via regulating microglia-mediated neuroinflammation in the brain.

Laquinimod inhibits MMP+ induced NLRP3 inflammasome activation in human neuronal cells.

Objective: Nod-like receptor protein 3 (NLRP3) inflammasome plays anessentialrole in neuroinflammation in the Parkinson's disease (PD) progression. Laquinimodis an immunomodulator that is clinically used for the treatment of multiple sclerosis. This study aims to investigate whether laquinimod possessesa protective effect against MPP+-induced NLRP3 activation.Materials and methods: In a variety of tests on human SH-SY5Y neuronal cells, 1-methyl-4-phenyl Pyridine (MPP+) was used to mimic the microenvironment of PD. Activation of NLRP3 inflammasome was measured by western blot analysis and enzyme linked immunosorbent assay (ELISA).Results: Laquinimod had a significant protective impact against MPP+-induced neurotoxicity. Our results demonstrate that laquinimod prevented MPP+-induced reduction of cell proliferation, the release of lactate dehydrogenase (LDH), and apoptosis. Importantly, treatment with laquinimod significantly inhibited the activation of the NLRP3 inflammasome by reducing the levels of its components, including NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), and cleaved caspase 1 (P10). Consistently, laquinimod prevented MPP+-induced secretions of interleukin 1ß (IL-1ß) and interleukin-18 (IL-18). Additionally, laquinimod also reduced the expression of other related factors, such as intracellular reactive oxygen species (ROS), NADPH oxidase 4 (NOX-4), thioredoxin-interacting protein (TxNIP). Furthermore, laquinimod prevented the reduction of sirtuin 1 (SIRT1) from MPP+ stimulation. Inhibition of SIRT1 abolished the protective effects of laquinimod against the activation of the NLRP3 inflammasome, suggesting the involvement of SIRT1 in this process.Conclusion: These findings suggest that laquinimod treatment might be a possible therapeutic strategy for neuroinflammation in PD.

Determinants of diagnostic latency in Chinese people with Parkinson's disease.

BACKGROUND: Clinical diagnosis of Parkinson's disease (PD) has always lagged behind clinical symptoms. The diagnostic latency might be influenced by many factors. The diagnostic latency of Chinese people with PD has been unknown. Here we designed this cross-sectional study with the purpose to identify the diagnostic latency and its determinants in Chinese people with PD. METHODS: One hundred and thirty-one newly diagnosed people with PD were recruited into this study. Demographic and clinical characteristics as well as a detailed clinical history were collected. Motor and non-motor symptoms (NMSs) severity were assessed with appropriate assessment scales. Medical professional types in the first medical consultations were also recorded. According to the initially presenting motor phenotypes, patients would be divided into the groups of rest tremor, limb rigidity, movement slowness and walking problems. The investigated variables would be compared among the four groups. RESULTS: The PD diagnostic latency in China was around 15 months. It closely correlated to the severity of motor symptoms, anxiety and depression as well as the number of NMSs. The diagnostic latency significantly varied among the groups of different motor phenotypes of onset. Finally, initially presenting with limb rigidity, having more NMSs, motor symptoms at a more serious degree and the initial medical consultations with physicians or specialists of non-neurology were considered as determinants of a longer diagnostic latency of PD. CONCLUSIONS: Patients presenting with minor motor symptoms and disturbing NMSs as well as physicians' unfamiliarity with PD symptomology were determinants of the diagnostic delay of PD. Health education in community and improvement of the referral system might be proper strategies to shorten the diagnostic latency of PD.

Assessments of plasma ghrelin levels in the early stages of parkinson's disease.

BACKGROUND: Gastrointestinal symptoms are early events in Parkinson's disease (PD). The gastrointestinal hormone ghrelin was neuroprotective in the nigrostriatal dopamine system. The objective of this study was to assess ghrelin levels in the early stages of PD. METHODS: Plasma was collected in the fasting state in 291 PD patients in stages 1-3 and 303 age- and sex-matched healthy controls. Additional samples were taken in the glucose response test to assess nutrition-related ghrelin levels in 20 PD patients and 20 healthy controls. The enzyme-linked immunosorbent assay was used to measure total and active plasma ghrelin levels. RESULTS: We reported that total and active plasma ghrelin levels were decreased in PD, although there was no difference across progressive PD stages. Postprandial ghrelin suppression and preprandial peak responses were both attenuated in PD. CONCLUSIONS: Plasma ghrelin levels were decreased in PD; however, this event might be irrelevant to PD progression. Ghrelin responses to meals were also impaired in PD. © 2017 International Parkinson and Movement Disorder Society.

Prevalence of rapid eye movement sleep behavior disorder (RBD) in Parkinson's disease: a meta and meta-regression analysis.

Rapid eye movement sleep behavior disorder (RBD) is thought to be one of the most frequent preceding symptoms of Parkinson's disease (PD). However, the prevalence of RBD in PD stated in the published studies is still inconsistent. We conducted a meta and meta-regression analysis in this paper to estimate the pooled prevalence. We searched the electronic databases of PubMed, ScienceDirect, EMBASE and EBSCO up to June 2016 for related articles. STATA 12.0 statistics software was used to calculate the available data from each research. The prevalence of RBD in PD patients in each study was combined to a pooled prevalence with a 95 % confidence interval (CI). Subgroup analysis and meta-regression analysis were performed to search for the causes of the heterogeneity. A total of 28 studies with 6869 PD cases were deemed eligible and included in our meta-analysis based on the inclusion and exclusion criteria. The pooled prevalence of RBD in PD was 42.3 % (95 % CI 37.4-47.1 %). In subgroup analysis and meta-regression analysis, we found that the important causes of heterogeneity were the diagnosis criteria of RBD and age of PD patients (P = 0.016, P = 0.019, respectively). The results indicate that nearly half of the PD patients are suffering from RBD. Older age and longer duration are risk factors for RBD in PD. We can use the minimal diagnosis criteria for RBD according to the International Classification of Sleep Disorders to diagnose RBD patients in our daily work if polysomnography is not necessary.

Plasma levels of miR-137 and miR-124 are associated with Parkinson's disease but not with Parkinson's disease with depression.

MicroRNAs (miRNAs) are a class of small, non-coding RNAs that regulate gene expression at the post-transcriptional level. Recently, it was reported that miR-137, miR-124, and miR-184 were widely expressed in the central nervous system and were vital to neuronal regulation. In this study, we detected the circulating levels of miR-137, miR-124, and miR-184 in PD patients, and explored the potential role of miR-124, miR-137, and miR-184 in the diagnosis of PD. We further described the relationship between these miRNAs and PD with depression (PD-Dep). The study recruited 60 controls and 60 PD patients, which were further divided into two subgroups, PD with depression (PD-Dep, n = 24) and non-depressed group (PD-NDep, n = 36) according to Hamilton Rating Scale for Depression. Plasma levels of miR-137, miR-124, and miR-184 were detected by qRT-PCR. Receiver-operating characteristic (ROC) curve was used to evaluate miR-124 and miR-137 levels as potential diagnostic biomarkers for PD. The results demonstrated that there were no significant differences in levels of miR-184 between PD patients and controls (p > 0.05). However, miR-137 levels were increased significantly for PD patients compared to controls (p < 0.05), while miR-124 levels were down-regulated (p < 0.05). The areas under the ROC curve (AUC) of miR-137 and miR-124 were 0.707 (95% CI 0.615-0.789, p < 0.05) and 0.709 (95% CI 0.618-0.633, p < 0.05), respectively. Correlation analysis revealed that there was no relationship between these two miRNAs levels and UPDRS scores or H&Y stage. There were no significant differences in miR-137 and miR-124 levels between PD-Dep and PD-NDep (p > 0.05). Thus, plasma levels of miR-137 and miR-124 are associated with Parkinson's disease and might be potential biomarkers of the diagnosis of PD. There were no associations of plasma miR-137 and miR-124 with the severity of PD motor symptoms or PD-Dep.

Association of VEGF gene polymorphisms with sporadic Parkinson's disease in Chinese Han population.

Recent evidence indicates that vascular endothelial growth factor (VEGF) is capable of protecting dopaminergic (DA) neurons. Parkinson's disease (PD) is a progressive neurodegenerative disease caused by the degeneration of nigrostriatal dopaminergic neurons. To evaluate the role of VEGF single nucleotide polymorphisms (SNPs) and haplotypes in PD, we performed a case-control study including 400 PD patients and 400 healthy-matched controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis and DNA sequencing were used to detect the rs699947, rs2010963 and rs3025039 polymorphisms of the VEGF gene in cases and controls. Our study revealed that T allelic frequency of rs3025039 polymorphism was significantly higher in PD subjects (OR 1.497, 95 % CI 1.099-2.040, P = 0.013) than that in controls. Significant association for rs3025039 could be found in additive model (TT vs. CT vs. CC: OR 1.489, 95 % CI 1.018-2.177, P = 0.040) and dominant model (TT + CT vs. CC: OR 1.538, 95 % CI 1.068-2.216, P = 0.021). Subgroup analyses performed by gender suggested that this association could be found in male, but not in female. Moreover, it also demonstrated a significant association in the subgroup of late-onset PD (LOPD). However, for rs699947 and rs2010963 polymorphisms, genotype or allele frequencies did not differ between groups. No significant association could be found between rs699947 and rs2010963 polymorphism and PD risk. None of the observed haplotypes showed significant association with PD. Therefore, these results suggested that the VEGF gene might be associated with risk of developing sporadic PD in Han Chinese and the rs3025039 polymorphism may be a risk factor for sporadic PD.

Association of TLR9 polymorphisms with sporadic Parkinson's disease in Chinese Han population.

Previous studies have acknowledged that inflammatory reaction has implicated in Parkinson's disease (PD) pathogenesis nowadays. Toll-like receptors (TLRs), as key players in the inflammatory reaction, play a pivotal role in the PD pathogenesis and accumulating evidences have shown that TLRs are increased in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of PD. Therefore, the present study aimed to identify the role of the polymorphisms of rs187084 and rs352140 in TLR9 gene with PD. The genotypes were detected by polymerase chain reaction and restriction fragment length polymorphism analysis in 380 PD patients and 380 healthy matched individuals in Chinese Han population. For rs352140, our data revealed a significant difference in allele distribution in female PD group and its healthy matched control (P = 0.040). Moreover, rs352140 T allele carriers of female group were associated with a reduced risk of PD (TT + TC vs. CC, P = 0.018). However, no significant differences in genotype and allele distribution were found between the age and gender subgroups for rs187084. Therefore, our studies indicate that the rs352140 gene polymorphism may be associated with the susceptibility of female PD in Chinese Han population.

Association of TLR4 gene polymorphisms with sporadic Parkinson's disease in a Han Chinese population.

Parkinson's disease (PD) is considered as a multifactorial disorder involving complex interactions between genetic and environmental factors, while previous studies point to a pivotal role of neuroinflammation in the pathophysiology of PD. As a member of pattern recognition receptors, TLR4 plays an important role in the immune response and inflammatory responses. Growing evidences suggest that mutation of TLR4 gene may be connected with the development of PD. The objective of this study was to evaluate whether genetic polymorphisms of the TLR4 gene are associated with PD susceptibility. We genotyped three single-nucleotide polymorphisms of the TLR4 gene (rs1927911, rs1927914 and rs10116253) by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) in unrelated 380 PD patients and 380 healthy-matched controls. Our study revealed that rs1927914 C allele carriers and C allele were probably related to a decreased risk of PD (p = 0.032 and p = 0.028, respectively) as well as male PD (p = 0.034) and early-onset PD (EOPD) (p = 0.023). In addition, there were significant differences in genotype and allele distribution in male PD patients and its healthy-matched control subgroup (p = 0.035 and p = 0.012, respectively). For rs1927911 and rs10116253 polymorphisms, genotype or allele frequencies did not differ between groups. Our data suggest that the TLR4 gene might contribute to the risk of developing PD in Han Chinese and rs1927914 polymorphism may be a protective factor for sporadic PD, male PD and EOPD.

Adversarially Trained Persistent Homology Based Graph Convolutional Network for Disease Identification Using Brain Connectivity.

Brain disease propagation is associated with characteristic alterations in the structural and functional connectivity networks of the brain. To identify disease-specific network representations, graph convolutional networks (GCNs) have been used because of their powerful graph embedding ability to characterize the non-Euclidean structure of brain networks. However, existing GCNs generally focus on learning the discriminative region of interest (ROI) features, often ignoring important topological information that enables the integration of connectome patterns of brain activity. In addition, most methods fail to consider the vulnerability of GCNs to perturbations in network properties of the brain, which considerably degrades the reliability of diagnosis results. In this study, we propose an adversarially trained persistent homology-based graph convolutional network (ATPGCN) to capture disease-specific brain connectome patterns and classify brain diseases. First, the brain functional/structural connectivity is constructed using different neuroimaging modalities. Then, we develop a novel strategy that concatenates the persistent homology features from a brain algebraic topology analysis with readout features of the global pooling layer of a GCN model to collaboratively learn the individual-level representation. Finally, we simulate the adversarial perturbations by targeting the risk ROIs from clinical prior, and incorporate them into a training loop to evaluate the robustness of the model. The experimental results on three independent datasets demonstrate that ATPGCN outperforms existing classification methods in disease identification and is robust to minor perturbations in network architecture. Our code is available at https://github.com/CYB08/ATPGCN.

TMEM106B Knockdown Exhibits a Neuroprotective Effect in Parkinson's Disease via Decreasing Inflammation and Iron Deposition.

Parkinson's disease (PD) is closely related to iron accumulation and inflammation. Emerging evidence indicates that TMEM106B plays an essential role in PD. But whether TMEM106B could act on neuroinflammation and iron metabolism in PD has not yet been investigated. The aim of this study was to investigate the pathological mechanisms of inflammation and iron metabolism of TMEM106B in PD. 1-methyl-4-phenylpyridinium (MPP+)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced SH-SY5Y cells and mice were treated with LV-shTMEM106B and AAV-shTMEM106B to construct PD cellular and mouse models. Pole tests and open-field test (OFT) were performed to evaluate the locomotion of the mice. Immunohistochemistry and iron staining were used to detect TH expression and iron deposition in the SN. Iron staining was used to measure the levels of iron. Western blotting was used to detect the expression of inflammatory factors (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6)), NOD-like receptor protein 3 (NLRP3) inflammasome, divalent metal transporter 1 (DMT1), and Ferroportin1 (FPN1)). Knockdown of TMEM106B improved motor ability and rescued dopaminergic (DA) neuron loss. TMEM106B knockdown attenuated the increases of TNF-α, IL-6, NLRP3 inflammasome, and DMT1 expression in the MPP+ and MPTP-induced PD models. Furthermore, TMEM106B knockdown also increases the expression of FPN1. This study provides the first evidence that knockdown of TMEM106B prevents dopaminergic neurodegeneration by modulating neuroinflammation and iron metabolism.

Combined diagnosis for Parkinson's disease via gait and eye movement disorders.

BACKGROUND AND OBJECTIVES: With the discovery of the potential role of gait and eye movement disorders in Parkinson's disease (PD) recognition, we intend to investigate the combined diagnostic value of gait and eye movement disorders for PD. METHODS: We enrolled some Chinese PD patients and healthy controls and separated them into the training and validation sets based on enrollment time. Performance in five oculomotor paradigms and in one gait paradigm was examined using an infrared eye tracking device and a wearable gait analysis device. We developed and validated a combined model for PD diagnosis via multivariate stepwise logistic regression analysis. Furthermore, subgroup comparisons and multi-model comparison were performed to assess its applicability and advantages. RESULTS: A total of 145 PD patients and 80 healthy controls in China were recruited. The pro-saccade velocity, the trunk-sway max, and the turn mean angular velocity were finally screened out for the model development. Incorporating age factor, the ternary model demonstrated more satisfactory performance on ROC (AUC of 0.953 in the training set and AUC of 0.972 in the validation set), calibration curve, and decision curve. A nomogram was drawn to visualize the model. The combined model outperforms individual models with a broad application and the unique diagnostic value for early detection of PD patients, especially TD-PD patients. CONCLUSION: We demonstrated the presence of gait and eye movement disorders, as well as the feasibility, applicability, and superiority of employing them together to diagnose PD.

Comprehensive analysis of clinical and biological features in Parkinson's disease associated with the LRRK2 G2019S mutation: Data from the PPMI study.

The Parkinson's Progression Marker Initiative (PPMI) aims to identify biomarkers for Parkinson's disease (PD) risk, onset, and progression. This study focuses on the G2019S missense mutation in the LRRK2 gene, which is associated with hereditary and sporadic PD. Utilizing data from the PPMI database, we conducted an analysis of baseline clinical characteristics, as well as serum and cerebrospinal fluid levels in two groups: patients with PD with the G2019S mutation (PD + G2019S) and patients with PD without the mutation (PD-G2019S). Multiple linear regression and longitudinal analysis were performed, controlling for confounding factors. Compared to the PD-G2019S group, the PD + G2019S group showed more obvious initial motor dysfunction-higher baseline Movement Disorder Society-Sponsored Revision of the Unified Parkinson Disease Rating Scale (MDS-UPDRS) scores (false discovery rate [FDR]-adjusted p < 0.001), but progressed more slowly. Mechanism of Coordinated Access and activities of daily living (ADL) scores were lower at baseline (FDR-adjusted p < 0.001), whereas Scales for Outcomes of Parkinson's Disease (SCOPA)-Thermoregulatory (FDR-adjusted p = 0.015) scores were higher, emphasizing the increase of non-motor symptoms associated with LRRK2-G2019S mutation. During the follow-up period, the motor and non-motor symptoms changed dynamically with time, and there were longitudinal differences in the scores of MDS-UPDRS (FDR-adjusted PI = 0.013, PII = 0.008, PIV < 0.001), Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (FDR-adjusted p = 0.027), SCOPA-Thermoregulatory (FDR-adjusted p = 0.021), and ADL (FDR-adjusted p = 0.027) scale scores. PD associated with the LRRK2 G2019S mutation demonstrated more severe symptoms at baseline but slower progression. Motor complications and thermoregulatory disorders were more pronounced.

Association between NEK1 gene polymorphisms and the potential risk of sporadic Parkinson's disease in the Chinese Northern Han population: A case-control study.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Disease trajectories in older adults with non-AD pathologic change and comparison with Alzheimer's disease pathophysiology: A longitudinal study.

Based on the 'AT(N)' system, individuals with normal amyloid biomarkers but abnormal tauopathy or neurodegeneration biomarkers are classified as non-Alzheimer's disease (AD) pathologic change. This study aimed to assess the long-term clinical and cognitive trajectories of individuals with non-AD pathologic change among older adults without dementia, comparing them to those with normal AD biomarkers and AD pathophysiology. Analyzing Alzheimer's Disease Neuroimaging Initiative data, we evaluated clinical outcomes and conversion risk longitudinally using mixed effects models and multivariate Cox proportional hazard models. We found that compared to individuals with A-T-N-, those with abnormal tauopathy or neurodegeneration biomarkers (A-T + N-, A-T-N + , and A-T + N + ) had a faster rate of cognitive decline and disease progression. Individuals with A-T + N + had a faster rate of decline than those with A-T + N-. Additionally, in individuals with the same baseline tauopathy and neurodegeneration biomarker status, the presence of baseline amyloid could accelerate cognitive decline and clinical progression. These findings provide a foundation for future studies on non-AD pathologic change and its comparison with AD pathophysiology.

[Association of vitamin D receptor gene polymorphisms with Parkinson disease].

OBJECTIVE: Vitamin D receptor (VDR) has been proposed as a candidate gene for susceptibility to Parkinson's disease (PD). This study was set to assess the association between VDR gene Apa I and Taq I polymorphisms and PD in a Chinese Han population. METHODS: Two hundred and eighty five sporadic PD patients and 285 healthy controls were genotyped for the Apa I and Taq I polymorphisms in VDR gene using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: No significant difference was detected in genotype or allele distribution of both Apa I and Taq I polymorphisms between PD patients and controls (P U+003E 0.05). No TT genotype for Taq I was found in the studied population. For Taq I, the distribution of genotype was significantly different between male PD patients and controls (U+03C7 2=4.187, P=0.032, OR=2.149, 95%CI: 1.011-4.567), and the frequency of T allele was significantly higher in male PD patients than male controls (U+03C7 2=3.867, P=0.036, OR=2.064, 95%CI: 0.989-4.307). CONCLUSION: VDR gene Apa I polymorphisms are not associated with sporadic Parkinson's disease, but Taq I may be a risk factor for male PD.