Neuronavigated repetitive transcranial magnetic stimulation improves depression, anxiety and motor symptoms in Parkinson's disease.

Background: Repetitive transcranial magnetic stimulation (rTMS) is a potential treatment option for Parkinson's disease patients with depression (DPD), but conflicting results in previous studies have questioned its efficacy. Method: To investigate the safety and efficacy of neuronavigated high-frequency rTMS at the left DLPFC in DPD patients, we conducted a randomized, double-blind, sham-controlled study (NCT04707378). Sixty patients were randomly assigned to either a sham or active stimulation group and received rTMS for ten consecutive days. The primary outcome was HAMD, while secondary outcomes included HAMA, MMSE, MoCA and MDS-UPDRS-III. Assessments were performed at baseline, immediately after treatment, 2 weeks, and 4 weeks post-treatment. Results: The GEE analysis showed that the active stimulation group had significant improvements in depression, anxiety, and motor symptoms at various time points. Specifically, there were significant time-by-group interaction effects in depression immediately after treatment (ß, -4.34 [95% CI, -6.90 to -1.74; P = 0.001]), at 2 weeks post-treatment (ß, -3.66 [95% CI, -6.43 to -0.90; P = 0.010]), and at 4 weeks post-treatment (ß, -4.94 [95% CI, -7.60 to -2.29; P < 0.001]). Similarly, there were significant time-by-group interaction effects in anxiety at 4 weeks post-treatment (ß, -2.65 [95% CI, -4.96 to -0.34; P = 0.024]) and in motor symptoms immediately after treatment (ß, -5.72 [95% CI, -9.10 to -2.34; P = 0.001] and at 4 weeks post-treatment (ß, -5.43 [95% CI, -10.24 to -0.61; P = 0.027]). Conclusion: The study suggested that neuronavigated high-frequency rTMS at left DLPFC is effective for depression, anxiety, and motor symptoms in PD patients.

Identifying Parkinson's disease with mild cognitive impairment by using combined MR imaging and electroencephalogram.

OBJECTIVES: To analyse the changes of quantitative electroencephalogram (qEEG) and cortex structural magnetic resonance (MR) imaging in Parkinson's disease with mild cognitive impairment (PD-MCI) and to explore the "composite marker"-based machine learning model in identifying PD-MCI. METHODS: Retrospective analysis of patients with PD identified 36 PD-MCI and 35 PD with normal cognition (PD-NC). QEEG features of power spectrum and structural MR features of cortex based on surface-based morphometry (SBM) were extracted. Support vector machine (SVM) was established using combined features of structural MR and qEEG to identify PD-MCI. Feature importance evaluation algorithm of mean impact value (MIV) was established to sort the vital characteristics of qEEG and structural MR. RESULTS: Compared with PD-NC, PD-MCI showed a statistically significant difference in 5 leads and waves of qEEG and 7 cortical region features of structural MR. The SVM model based on these qEEG and structural MR features yielded an accuracy of 0.80 in the training set and had a high prediction accuracy of 0.80 in the test set (sensitivity was 0.78, specificity was 0.83, area under the receiver operating characteristic curve was 0.77), which was higher than the model built by the feature separately. QEEG features of theta wave in C3 had a marked impact on the model for classification according to the MIV algorithm. CONCLUSIONS: PD-MCI is characterized by widespread structural and EEG abnormality. "Composite markers" could be valuable for the individualized diagnosis of PD-MCI by machine learning. KEY POINTS: • Explore the brain abnormalities in Parkinson's disease with mild cognitive impairment by using the quantitative electroencephalogram and cortex structural MR simultaneously. • Multimodal features based support vector machine for identifying Parkinson's disease with mild cognitive impairment has an acceptable performance. • Theta wave in C3 is the most influential feature of qEEG and cortex structure MR imaging in identifying Parkinson's disease with mild cognitive impairment using support vector machine.

Non-pharmacological treatment for Parkinson disease patients with depression: a meta-analysis of repetitive transcranial magnetic stimulation and cognitive-behavioral treatment.

Background: Nowadays, antidepressants still are the mainstay of treatment for depression in Parkinson's disease (PD) but some recent studies report that medication might aggravate motor symptoms in PD patients. This meta-analysis aims to assess the effect of non-pharmacological treatments for depression in patients with PD.Materials and Methods: Only randomized controlled trials (RCTs) were included. The participants were PD patients with comorbid depression (dPD). The interventions had the equivalent effect of non-pharmacological treatments alone compared with control(s). Scores of depression scale were selected as the primary outcome, while scores of Unified Parkinson's Disease Rating Scale part III and the incidence of side effects were the secondary outcome. The statistics were pooled and presented as weighted mean differences (WMDs), standardized mean differences (SMDs), or risk ratios (RRs) with their 95% confidence intervals (CIs).Results: Fifteen articles were eventually included; twelve studies reported on repetitive transcranial magnetic stimulation (rTMS) and three used cognitive behavioral therapy (CBT). Other interventions failed to have qualified studies. Our data indicated that both rTMS and CBT could significantly improve depression scores in a short term (SMD = -0.621, 95% CI [-0.964, -0.278]; SMD = -1.148, 95% CI [-1.498, -0.798], respectively). In addition, rTMS could alleviate motor symptom (WMD = -2.617, 95% CI [-4.183, -1.051]) and was relatively safe (RR = 1.054, 95% CI [0.698, 1.592]).Conclusion: Our data suggest that rTMS can safely alleviate depression and motor symptoms in dPD at least for a short period. Moreover, compared with clinical monitoring, CBT can improve depressive symptoms.

Alterations in intrinsic functional networks in Parkinson's disease patients with depression: A resting-state functional magnetic resonance imaging study.

AIMS: The aim of this research was to investigate the alterations in functional brain networks and to assess the relationship between depressive impairment and topological network changes in Parkinson's disease (PD) patients with depression (DPD). METHODS: Twenty-two DPD patients, 23 PD patients without depression (NDPD), and 25 matched healthy controls (HCs) were enrolled. All participants were examined by resting-state functional magnetic resonance imaging scans. Graph theoretical analysis and network-based statistic methods were used to analyze brain network topological properties and abnormal subnetworks, respectively. RESULTS: The DPD group showed significantly decreased local efficiency compared with the HC group (P = .008, FDR corrected). In nodal metrics analyses, the degree of the right inferior occipital gyrus (P = .0001, FDR corrected) was positively correlated with the Hamilton Depression Rating Scale scores in the DPD group. Meanwhile, the temporal visual cortex, including the bilateral middle temporal gyri and right inferior temporal gyrus in the HC and NDPD groups and the left posterior cingulate gyrus in the NDPD group, was defined as hub region, but not in the DPD group. Compared with the HC group, the DPD group had extensive weakening of connections between the temporal-occipital visual cortex and the prefrontal-limbic network. CONCLUSIONS: These results suggest that PD depression is associated with disruptions in the topological organization of functional brain networks, mainly involved the temporal-occipital visual cortex and the posterior cingulate gyrus and may advance our current understanding of the pathophysiological mechanisms underlying DPD.

Changes of brain structural network connection in Parkinson's disease patients with mild cognitive dysfunction: a study based on diffusion tensor imaging.

INTRODUCTION: Previous studies have found that white matter (WM) alterations might be correlated in Parkinson's disease (PD) patients with cognitive impairment. This study aimed to investigate WM structural network connectome alterations in PD patients with mild cognitive impairment (PD-MCI) and assess the relationship between cognitive impairment and structural topological network changes in PD patients. METHODS: All 31 healthy controls (HCs) and 71 PD patients (43 PD-NC and 28 PD-MCI) matched for age, sex and education underwent 3.0 T MRI and diffusion tensor imaging (DTI) scan. Graph theoretical analyses and network-based statistical (NBS) analyses were performed to identify the structural WM networks and subnetwork changes in PD-MCI. RESULTS: PD-MCI patients showed significantly decreased global efficiency (Eglob) and increased shortest path length (Lp) compared with the HC group. Several nodal efficiencies showed significant differences in multiple brain regions among the three groups. The nodal efficiency of the orbitofrontal part was closely related to the overall cognitive ability and multiple sub-cognitive domains. Moreover, NBS analyses identified eight one-connect subnetworks, three two-connect subnetworks and two multi-connect subnetworks with reduced connectivity that characterizes the WM structural organization in PD-MCI patients. The two multi-connect subnetworks were located on the bilateral lobe, and both were centered on the orbitofrontal part. CONCLUSIONS: This study provided new evidence that PD with cognitive dysfunction is associated with WM structural alterations. The nodal efficiency and sub-network analyses focusing on the orbitofrontal part might provide new ideas to explore the physiological mechanism of PD-MCI.

Upregulation of MIF as a defense mechanism and a biomarker of Alzheimer's disease.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine. Chronic inflammation induced by amyloid ß proteins (Aß) is one prominent neuropathological feature in Alzheimer's disease (AD) brain. METHODS: Elisa, Western blot, and immunohistochemical staining analysis were performed to examine the level of MIF protein in CSF and brain tissues. MTT and LDH assays were used to examine the neurotoxicity, and the Morris Water Maze test was performed to examine the cognitive function in the MIF+/-/APP23 transgenic mice. RESULTS: MIF expression was upregulated in the brain of AD patients and AD model mice. Elevated MIF concentration was detected in the cerebrospinal fluid of AD patients but not in that of the patients suffering from mild cognitive impairment and vascular dementia. Reduced MIF expression impaired learning and memory in the AD model mice. MIF expression largely associates with Aß deposits and microglia. The binding assay revealed a direct association between MIF and Aß oligomers. Neurons instead of glial cells were responsible for the secretion of MIF upon stimulation by Aß oligomers. In addition, overexpression of MIF significantly protected neuronal cells from Aß-induced cytotoxicity. CONCLUSION: Our study suggests that neuronal secretion of MIF may serve as a defense mechanism to compensate for declined cognitive function in AD, and increased MIF level could be a potential AD biomarker.

Hippocampal damage and white matter lesions contribute to cognitive impairment in MPTP-lesioned mice with chronic cerebral hypoperfusion.

OBJECTIVES: Strong evidence has proven that cerebral hypoperfusion is closely related to Parkinson's disease (PD) with cognitive impairment. The aim of this study was to investigate the effect of chronic cerebral hypoperfusion (CCH) on cognitive dysfunction, structural abnormalities of the hippocampus and white matter (WM), and levels of inflammatory cytokines in control and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse models. METHODS: In the present study, bilateral common carotid artery stenosis (BCCAS) was performed using microcoils, and the cognitive function and WM lesions (WMLs) after BCCAS were compared between microcoil with 0.18 mm and 0.20 mm diameters. CCH and MPTP-lesioned mice were induced by intraperitoneal injection of MPTP and BCCAS. These mice were further divided into seven groups: a control group, sham-operated group, BCCAS group, PD with normal cognition (PDCN) group, PD with mild cognitive impairment (PDMCI) group, PDCN + BCCAS group, and PDMCI + BCCAS group. After 28 days of BCCAS, the mice were tested through pole-climbing experiments and by TUNEL, Nissl, and Bielschowsky silver staining. Immunohistochemistry was used to evaluate lesions in the dopaminergic (DAergic) nigrostriatal system and the number of activated microglia. Chip-based liquid chromatography was employed to measure the levels of inflammatory cytokines in the plasma. RESULTS: The results indicated that the histological results of the 0.18 mm microcoil were superior to that of the 0.20 mm microcoil. Based on these finding, BCCAS impaired the climbing ability of MPTP-lesioned PD mice. Moreover, immunohistochemistry for tyrosine hydroxylase (TH) revealed a significant reduction in the number of DAergic neurons in the substantia nigra of PD mice following BCCAS, particularly in the PDMCI + BCCAS group. In addition, Nissl, TUNEL and Bielschowsky silver staining confirmed decreased hippocampal neuron numbers, increased neuronal apoptosis and more significant WM fiber damage in the corpus callosum of the PDMCI + BCCAS group. Finally,immunohistochemistry for ionized calcium binding adaptor molecule-1 (Iba-1) and chip-based liquid chromatography revealed significantly increased microglial activation (P < 0.01) and significantly increased levels of interleukin-1ß (IL-1ß) and interferon-γ (IFN-γ) (P < 0.05) in the PDMCI + BCCAS group compared with the corresponding levels in the PDCN + BCCAS group. CONCLUSIONS: Cerebral hypoperfusion can aggravate the cognitive impairment in MPTP-lesioned PD mice. This finding may be related to the hypoperfusion-mediated deterioration of neuroinflammation, aggravation of WM damage, and induction of hippocampal neuron apoptosis in PD mice.

The clinical characteristics and cognitive features of mild cognitive impairment in Parkinson's disease and the analysis of relevant factors.

The purpose of this work is to investigate the clinical characteristics, cognitive impairment features, and subgroup types of Parkinson's disease (PD) subjects with mild cognitive impairment (PD-MCI) in the Chinese population and to analyze relevant risk factors for PD-MCI. A total of 234 non-dementia PD subjects were collected. Standardized neuropsychological assessments of overall cognitive level and four cognitive domains (memory, executive function, attention and visuospatial function) were performed using MDS Task Force diagnostic criteria for PD-MCI. PD-MCI subjects were further divided into four subgroups: nonamnestic single-domain impairment type (PD-naMCI-SD), nonamnestic multiple-domain impairment type (PD-naMCI-MD), amnestic single-domain impairment type (PD-aMCI-SD), and amnestic multiple-domain impairment type (PD-aMCI-MD). The clinical characteristics of and risk factors for all subgroups were analyzed. PD-MCI was found in 45.3% of the non-dementia PD subjects. Differences between the PD-MCI and PD with normal cognition groups with respect to age, age of onset, years of education, and motor symptom severity were significant (P < 0.05). The single-domain impairment type was the largest PD-MCI subgroup (52.83%). Memory and executive function impairment were most frequent (22.64% and 20.75%, respectively). Among the four subgroups, the number of years of education was significantly different (P = 0.003). The overall cognitive function in amnestic multiple-domain impairment type was significantly worse compared with that in those with single-domain impairment type. Regression analysis results showed that old age, high UPDRS-III score, and hyperhomocysteinemia were risk factors for PD-MCI, whereas high education level was a protective factor. Early prevention of MCI-related risk factors provides effective means to retard cognitive decline in PD patients.

Changes in Cortical Thickness in Patients With Early Parkinson's Disease at Different Hoehn and Yahr Stages.

Objectives: This study was designed to explore changes in cortical thickness in patients with early Parkinson's disease (PD) at different Hoehn and Yahr (H-Y) stages and to demonstrate the association of abnormally altered brain regions with part III of the Unified Parkinson's Disease Rating Scale (UPDRS-III). Materials and Methods: Sixty early PD patients and 29 age- and gender-matched healthy controls (HCs) were enrolled in this study. All PD patients underwent comprehensive clinical and neuropsychological evaluations and 3.0 T magnetic resonance scanning. Patients with H-Y stage ≤1.5 were included in the mild group, and all other patients were included in the moderate group. FreeSurfer software was used to calculate cortical thickness. We assessed the relationship between UPDRS-III and regional changes in cortical thinning, including the bilateral fusiform and the temporal lobe. Results: The average cortical thickness of the temporal pole, fusiform gyrus, insula of the left hemisphere and fusiform gyrus, isthmus cingulate cortex, inferior temporal gyrus, middle temporal cortex and posterior cingulate cortex of the right hemisphere exhibited significant decreasing trends in HCs group and PD groups (i.e., the mild group and moderate group). After controlling for the effects of age, gender, and disease duration, the UPDRS-III scores in patients with early PD were correlated with the cortical thickness of the left and right fusiform gyrus and the left temporal pole (p < 0.05). Conclusion: The average cortical thickness of specific brain regions reduced with increasing disease severity in early PD patients at different H-Y stages, and the UPDRS-III scores of early PD patients were correlated with cortical thickness of the bilateral fusiform gyrus and the left temporal pole.

Changes of brain structure in Parkinson's disease patients with mild cognitive impairment analyzed via VBM technology.

OBJECTIVE: To analyze changes in cerebral grey matter volume and white matter density in non-dementia Parkinson's disease patients using voxel-based morphometry (VBM) technology; to investigate features of brain structure changes in Parkinson's disease patients with mild cognitive impairment (PD-MCI), and reveal their intrinsic pathological changes. METHODS: Based on the diagnostic criteria of PD-MCI, 23 PD-MCI patients, 23 Parkinson's disease patients with normal cognition (PD-NC), and 21 age- and gender-matched healthy people were recruited for the study. Scans were performed on all subjects on a 3.0T MR scanner to obtain brain structural magnetic resonance images. Images were preprocessed using the VBM8 tool from SPM8 software package on the Matlab R2008a platform, and data were then analyzed using the SPM statistical software package to compare the differences of grey matter volume and white matter density between groups, and to evaluate the brain structural changes corresponding to the overall cognitive function. RESULTS: Compared to the control group, the PD-NC group suffered from grey matter atrophy, mainly found in the prefrontal lobe, limbic lobe and left temporal gyrus. The PD-MCI group suffered from grey matter atrophy found in the frontal lobe, limbic lobe, basal ganglia and cerebellum. Compared to the PD-NC group, the PD-MCI group suffered from grey matter atrophy found in the left-side middle temporal gyrus, inferior temporal gyrus and frontal lobe. The grey matter regions correlated with MMSE score (mainly memory related) including the right cingulate gyrus and the limbic lobe. The grey matter regions correlated with MoCA score (mainly non-memory related) including the frontal lobe, basal ganglia, parahippocampal gyrus, occipital lobe and the cerebellum. Additionally, overall cognitive function in non-dementia PD was mainly located in the frontal and limbic system, and was dominated by subcortical atrophy. CONCLUSION: Structural changes in PD-MCI patients are associated with overall cognitive function, and the atrophic areas are mainly located in the frontal and limbic system, and are dominated by subcortical atrophy. Moreover, atrophy of limbic lobes is associated with impaired memory, whereas frontal lobe atrophy is associated with executive dysfunction. In addition, the subtle brain structure of the PD early cognitive impairment stage and PD-MCI stage can be detected via VBM technology, and thus, local brain atrophy may be a neuroimaging marker for the early diagnosis of PD-MCI.

Chronic cerebral hypoperfusion independently exacerbates cognitive impairment within the pathopoiesis of Parkinson's disease via microvascular pathologys.

To date, the role of microvascular pathology and chronic cerebral hypoperfusion (CHH) in the development of mild cognitive impairment in Parkinson's disease (PD-MCI) is unclear. Here, we investigated how the combined injury through interaction of CHH and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity act as an exacerbating element to damagae cognitive fuction in a mouse model. In the present study, C57BL/6 mice underwent MPTP injection. Subjects were classified into a PD with normal cognitive performance (PDCN) group or a PD-MCI group using the Morris Water Maze test. Further, CHH was induced by stenosis of the bilateral common carotid arteries (BCCAs). Consequently, the animals were divided into 7 groups: they are control, sham, BCCAs, PDCN, PD-MCI, PDCN+BCCAs and PD-MCI+BCCAs. The Morris Water Maze test, open field test, histological investigation and western blotting were performed to analyze cerebral microvascular impairment in each group. The results showed that CHH and MPTP injection caused spatial memory and behavioral impairment, accompanied by microvascular impairment and down-regulation of ZO-1 and Occludin at the protein level compared to the control group. The above injuries were synergistically exacerbated in the PDCN+BCCAs group and the PD-MCI+BCCAs group, which paralleled the elevated expression of p-MAPK and p-Akt. In short, our data demonstrate that CHH and MPTP caused cognitive and microvascular impairment separately. Moreover, CHH may exacerbate cognitive impairment in a mouse model of PD. The study provides a new opportunity for understanding the pathogenesis of PD-MCI.

Catechol-O-methyltransferase Val158Met polymorphism influences prefrontal executive function in early Parkinson's disease.

OBJECTIVE: The catechol-O-methyltransferase (COMT) Val158Met polymorphism has been proposed to be associated with increased risk of Parkinson's disease (PD) and have a specific impact on dopamine-mediated prefrontal executive function in an inverted-U curve manner. We explored the influence of this genetic polymorphism on prefrontal executive function in a well-established Chinese cohort of early PD patients with no current or past history of motor fluctuations or dyskinesias. METHODS: Cognitive functions were assessed in 250 patients with early PD using Wechsler Adult Intelligence Scale-Chinese Revision (WAIS-RC) and Wechsler Memory Scale-Chinese Revision (WMS-RC). These patients and 300 healthy controls were subsequently genotyped for the COMT gene Val158Met polymorphism. We employed analysis of covariance (ANCOVA) and a stratified analysis to determine the associations between the COMT Val158Met genotype and cognitive functions. RESULTS: The COMT Val158Met allele frequency and genotype distributions showed no statistically significant differences between PD patients and controls. However, patients with met/met genotype performed significantly worse on WAIS-RC similarities, a measure of executive function, compared to individuals with val/val genotype. Subsequent ANCOVA analysis revealed that COMT genotype interacted with sex and daily levodopa equivalent dose (LED) to influence executive function. Further stratified analysis showed that the lower-activity COMT met/met genotype has a detrimental effect on executive function among women. CONCLUSIONS: Our results demonstrate that COMT Val158Met polymorphism is probably not associated with increased risk of PD, but has an effect on prefrontal executive function interacting with gender and dopaminergic medication.

Cognitive profile of Parkinson's disease patients: a comparative study between early-onset and late-onset Parkinson's disease.

AIM: To investigate the influence of onset age on the occurrence and progression of cognitive dysfunction using neuropsychological tests and the electrophysiological component P300 in both early-onset Parkinson's disease (EOPD) and late-onset Parkinson's disease (LOPD) patients. METHODS: A cohort of 76 EOPD patients and 166 LOPD patients was recruited for this study. Demographic information and clinical features, including age, disease duration, education level, family history, the Unified Parkinson's Disease Rating Scale, the Hoehn and Yahr stage, and depression scores were documented for each patient. The Mini-Mental State Examination, Montreal Cognitive Assessment (MoCA), Wechsler Adult Intelligence Scale - Revised, Chinese version (WAIS-RC) and Wechsler Memory Scale - Revised, Chinese version (WMS-RC) were used. In addition, P300 was also examined to assess cognitive function. RESULTS: Although EOPD patients had longer disease duration, their cognitive dysfunction progressed more slowly. The MoCA tests revealed that EOPD patients had higher scores in visuospatial function, attention, delayed recall, and orientation than the LOPD patients. The difference between the two groups on the WMS-RC test did not reach significance, whereas the scores in executive function, visuospatial function and attention as measured on the WAIS-RC test were significantly lower in the LOPD group. In addition, P300 latencies were markedly delayed and P300 amplitudes were reduced in the LOPD group. CONCLUSIONS: The current findings demonstrated that cognitive dysfunction progressed more slowly in the EOPD group. Although the LOPD patients exhibited shorter disease durations, their cognitive abilities, including executive function, visuospatial function and attention, may have been impaired.

Sex differences in cognition among Chinese people with Parkinson's disease.

To investigate sex differences in cognitive function in Parkinson's disease patients, a cohort of 172 male patients and 139 female patients were recruited for this study. Their demographic and clinical features, including age, disease duration, education level, Unified Parkinson's Disease Rating Scale-III, Hoehn-Yahr Scale, activities of daily living, Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale score were recorded. The Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Wechsler Adult Intelligence Scale-Chinese Revision (WAIS-RC) and Wechsler Memory Scale-Chinese Revision (WMS-RC) scores were compared to distinguish the cognitive properties between the two groups. The MMSE values did not show a significant difference between the groups. However, the MoCA scores of male patients were significantly higher than those of female patients (adjusted p<0.05). The male group demonstrated better performances with respect to visuospatial function, naming and abstraction (adjusted p<0.05). The WAIS-RC data showed that female patients had lower scores in information, vocabulary, picture completion, block design and picture arrangement (adjusted p<0.05), and the WMS-RC data showed that 100-1 and cumulative addition abilities were significantly weaker in females than males (adjusted p<0.05). Cognitive disturbances were more prevalent and severe in women among Chinese Parkinson's disease patients.

RIT2 polymorphism is associated with Parkinson's disease in a Han Chinese population.

Recently, a meta-analysis including 5 large genome-wide association studies has identified rs12456492 variant of RIT2 gene as a novel risk locus for Parkinson's disease (PD) in Caucasian populations. However, the association between RIT2 polymorphism and PD risk has not been positively replicated in Asian population yet. We detected the genotypes of rs12456492 in 524 PD patients and 521 control subjects from a Han Chinese population. The allele and genotype distribution of rs12456492 variant were significantly different between PD patients and controls (allele p = 0.001, genotype p = 0.002). Logistic regression analysis showed that the G-carrying genotype (AG + GG) individuals exhibited a nearly 1.4-fold increased risk for PD compared with the AA genotype carriers (OR = 1.390; 95% confidence interval = 1.079-1.791; p = 0.011). Our data support that the carriage of G allele of rs12456492 variant of RIT2 gene significantly increases the risk for PD in Han Chinese population, suggesting a potential role of RIT2 in the etiology of PD.

Cerebrospinal fluid alpha-synuclein as a biomarker for Parkinson's disease diagnosis: a systematic review and meta-analysis.

To date, there are no definitive biomarkers for Parkinson's disease (PD) diagnosis. The detection of cerebrospinal fluid (CSF) alpha (α)-synuclein in PD patients has yielded promising but inconclusive results. To determine the performance of CSF α-synuclein as a diagnostic biomarker of PD and whether CSF α-synuclein can discriminate PD from other neurodegenerative diseases, a systematic search of all relevant studies investigating reproducible CSF α-synuclein quantification methods was conducted in electronic databases. A total of 17 studies that included 3311 patients were included in this systemic review and meta-analysis. The mean CSF α-synuclein concentration was significantly lower in PD patients compared to normal/neurological controls [weighted mean difference (WMD) -0.31; 95% CI, -0.45, -0.16; p < 0.0001] and patients with Alzheimer's disease (AD) [WMD -0.15; 95% CI, -0.26, -0.04; p < 0.0001]. There was no significant difference between PD patients and dementia with Lewy bodies (DLB) patients [WMD -0.03; 95% CI, -0.16, 0.09; p = 0.58] or patients with multiple system atrophy (MSA) [WMD 0.05; 95% CI, -0.04, 0.13; p = 0.25]. Sensitivity and specificity of CSF α-synuclein in the diagnosis of PD was 0.88 (95% CI, 0.84-0.91) and 0.40 (95% CI, 0.35-0.45), respectively. The positive and negative likelihood ratios of CSF α-synuclein in the diagnosis of PD were 1.41 (95% CI, 1.24-1.60), and 0.29 (95% CI, 0.15-0.56), respectively. The corresponding summary receiver operating characteristic (SROC) curve showed an area under the curve (AUC) of 0.73. The concentration of CSF α-synuclein may be a biomarker for the diagnosis of PD. The use of α-synuclein alone however is not sufficient as a single biomarker and it must therefore be used in conjunction with other documented and reliable biomarkers.

MCP-1 and CCR2 gene polymorphisms in Parkinson's disease in a Han Chinese cohort.

Monocyte chemoattractant protein-1 (MCP-1) and its receptor CC chemokine receptor-2 (CCR2) play important roles in neuroinflammation and they have been shown to be involved in Parkinson's disease (PD) pathogenesis. In addition, several studies have suggested a role for the MCP-1 and CCR2 genotypes in cognitive impairment and depression, which are common non-motor symptoms in PD patients. In this study, a cohort of 521 PD patients and 556 cases of healthy controls were recruited to investigate the association between the MCP-1 2518A/G (rs1064211) and CCR2 V64I (rs1799864) gene polymorphisms and PD risk in the Chinese population. We also analyze the influence of these genotypes on the cognitive function and depression in PD patients by comparing Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Wechsler Adult Intelligence Scale-Chinese Revision (WAIS-RC), Wechsler Memory Scale-Chinese Revision (WMS-RC) and Hamilton Depression Rating Scale (HAMD) ratings in 217 PD patients. Our results showed no significant differences in the genotype frequency between the PD group and the control group (P > 0.05). In addition, we also failed to find an influence of the MCP-1 and CCR2 genotypes on MMSE scores, MoCA scores, WAIS-RC scores, WMS-RC scores and HAMD scores in PD patients (P > 0.05). The MCP-1 and CCR2 gene polymorphisms may not be genetic risk factors for PD in the Han Chinese population, and they do not appear to influence cognitive function and depression in PD patients.

Triggering receptor expressed on myeloid cells 2 variants are rare in Parkinson's disease in a Han Chinese cohort.

Recent studies have reported that a rare nonsynonymous variant rs75932628-T in the TREM2 gene is associated with increased risk of Alzheimer's disease and Parkinson's disease (PD) in European-descended populations. However, the association between rare TREM2 mutations and PD risk remains unknown in Chinese population. We directly sequenced exon2 of TREM2 in a cohort of 476 PD patients and 432 healthy controls from a Han Chinese population. Rs75932628-T (p.R47H) was found in 0.2% of PD cases (1/476) but in none of the controls (0/432, p = 1.000), with a minor allele frequency of 0.06% among the 908 subjects. Our findings suggest that variants in exon2 of TREM2 are extremely rare, and it is not a genetic risk factor for PD in the southern Han Chinese population.

Polymorphisms in immune/inflammatory cytokine genes are related to Parkinson's disease with cognitive impairment in the Han Chinese population.

Increasing evidence suggests that immune mediated inflammation contributes to the pathogenesis of Parkinson's disease (PD). However, whether genetic variants of genes coding for inflammatory cytokines influence the risk of cognitive impairment in PD is still unknown. In the present study, we examined whether interleukin-10 (IL-10, 1082G/A), interleukin-17A (IL-17A) rs8193036, rs2275913 and interferon-γ (IFN-γ) polymorphisms were associated with the risk of cognitive impairment in PD. The four gene polymorphisms were analyzed in 302 PD patients and results were compared to those obtained from 294 age- and gender-matched healthy controls (HC) enrolled from the Han Chinese population. PD patients were divided into two subgroups on the basis of mini mental state examination (MMSE) score: PD with cognitive impairment (MMSE scores<26) and PD without cognitive impairment (MMSE scores≥26). There was no significant difference in the distributions of genotype or allele between PD and control groups in the total population. However, the distribution of the rs8193036 (CC genotype, C allele) in PD individuals with an MMSE score<26 was significantly increased when compared to PD patients with an MMSE score≥26 (CC genotype: p=0.044; C allele: p=0.038). Also, there were significant differences in genotype and frequencies of the 1082G/A allele between PD cases with an MMSE score<26 and controls (genotype p=0.021; allele p=0.024). Logistic regression analysis showed that the 1082G/A (AA) genotype decreased (Odds ratio=0.440, p=0.042), while the rs8193036 (CC) genotype increased the risk of cognitive impairment in PD (OR=1.838, p=0.048). Based on our study, polymorphisms in immune/inflammatory-related genes such as IL-17A rs8193036 and IL-10 1082G/A might be correlated with the risk of PD with cognitive impairment in the Han Chinese population.