Association Between Serum Vitamin D Levels and Parkinson's Disease: A Systematic Review and Meta-Analysis

Background: Vitamin D is an important secosteroid which is involved the development and regulation of brain activity. Several studies have focused on exploring the relationship between serum vitamin D levels and Parkinson's disease (PD), but the conclusion remains ambiguous.Methods: We searched observational studies that explored the association between serum vitamin D levels and PD based on PubMed, EMBASE and Cochrane library from inception through to January 2018. The quality of included studies was evaluated by using Newcastle-Ottawa Scale (NOS). Statistical analysis of this meta-analysis was performed by Stata version 12.0 and R software.Results: Twenty studies with a total of 2,866 PD patients and 2,734 controls were included. Compared with controls, PD patients had lower serum vitamin D levels (WMD −3.96, 95%CI −5.00, −2.92), especially in higher latitude regions (WMD −4.20, 95%CI −5.66, −2.75). Assay methods contributed significantly to high heterogeneity. Furthermore, PD patients with deficient vitamin D levels had advanced risk (OR 2.08, 95%CI 1.35, 3.19) than those patients with insufficient ones (OR = 1.73, 95%CI 1.48, 2.03). In addition, serum vitamin D levels were also related to the severity of PD (WMD −5.27, 95%CI −8.14, −2.39) and the summary correlation coefficient showed strongly negative correlation (r = −0.55, 95%CI −0.73, −0.29). Moreover, the pooled correlation coefficient revealed that serum vitamin D levels were also negatively correlated to the Unified Parkinson's Disease Rating Scale III (UPDRS III) (r = −0.36, 95%CI −0.53, −0.16), but did not correlate with the duration of PD (P = 0.37) and age of patients (P = 0.49).Conclusion: Serum vitamin D levels are inversely associated with the risk and severity of PD. Our results provided an updated evidence of association between low vitamin D levels and PD and prompt the adjunctive therapeutic decisions about vitamin D replacement in PD

Extra-Cerebellar Signs and Non-motor Features in Chinese Patients With Spinocerebellar Ataxia Type 3

Objectives: Our study attempted to systematically explore the prevalence of extra-cerebellar signs and non-motor symptoms, such as anxiety, depression, fatigue, excessive daytime sleepiness (EDS) and sleep disturbances in a cohort of Chinese patients with spinocerebellar ataxia type 3 (SCA3), and further investigated the correlations between non-motor symptoms and clinical characteristics in SCA3 patients.Methods: This study included 68 molecular-proven SCA3 patients. Extra-cerebellar signs were evaluated with the Inventory of Non-Ataxia Symptoms (INAS). The INAS count indicated the number of non-ataxia signs in each patient. The severity of ataxia, fatigue, EDS, sleep quality, anxiety, and depression were assessed using the Scale for the assessment and rating of ataxia (SARA), Fatigue Severity Scale (FSS), Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), Hamilton Anxiety Rating Scale (HAMA), and the Hamilton Depression Rating Scale (HAMD) (24 items), respectively.Results: Extra-cerebellar signs were detected in 91.2% of all SCA3 patients and the mean total INAS count was 2.72 ± 1.88. Rigidity was the most frequent extra-cerebellar sign (47.1%, N = 32). Sensory symptoms (2.9%, N = 2) and chorea (5.9%, N = 4) were rare, and myoclonus (0%) was not found in this cohort. High frequencies of sleep disturbances (64.7%), fatigue (52.9%), depression (48.5%), and anxiety (42.6%) were detected in SCA3 patients. The Spearman correlation indicated that the HAMD score was associated with the CAG repeat length and HAMA score, while the PSQI score was correlated with the SARA and FSS score. In addition, multivariate linear regression analysis showed that the CAG repeat length, age of onset, sleep disturbances and depression were significant predictors of fatigue in SCA3 patients.Conclusions: Our study indicates that the vast majority of SCA3 patients display extra-cerebellar signs. Except for EDS, anxiety, depression, fatigue and impaired sleep quality are present in SCA3 patients. The CAG repeat length, age of onset, sleep disturbances and depression are predictors of fatigue in SCA3 patients

Decreased Glycogenolysis by miR-338-3p Promotes Regional Glycogen Accumulation Within the Spinal Cord of Amyotrophic Lateral Sclerosis Mice

Metabolic dysfunction is a hallmark of age-related neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). But the crosstalk between metabolic alteration and disease progression in ALS is still largely unknown. Glycogen, a branched polymer of glucose residues, is universally recognized as the energy reserve of the central nervous system (CNS), where its aberrant accumulation instigates neurodegeneration. Glycogen was reported to be accumulated in both CNS and visceral organs of SOD1G93A mice, a well-known ALS model, and contributes to the pathological process of ALS. However, the accumulative patterns and mechanisms are not well elucidated. Here, we provide extensive evidence to demonstrate that glycogen accumulated in the lumbar spinal cord of ALS mice along with the disease progression, but not in the motor cortex. This regional accumulation of glycogen was caused by deteriorated glycogenolysis, which was triggered by decreased glycogen phosphorylase, brain form (PYGB). Moreover, miR-338-3p, an elevated miRNA in the spinal cord of SOD1G93A mice, directly targeted PYGB and was responsible for the decreased glycogenolysis and subsequent glycogen accumulation. Our work is helpful for better understanding of of of metabolic dysfunctions in ALS and provides novel targets for the therapeutic intervention in the future

Prevalence and associated factors of apathy in Chinese ALS patients

ObjectivveThis study aimed to explore the prevalence and clinical correlates of apathy in amyotrophic lateral sclerosis (ALS) in a cohort of Chinese patients.MethodsA total of 1,013 ALS patients were enrolled in this study. Apathy was recorded during face-to-face interviews using Frontal Behavioral Inventory, and other patient characteristics, including depression, anxiety, and cognitive function, were collected using Hamilton Depression Rating Scale (HDRS), Hamilton Anxiety Rating Scale (HARS), and Chinese version of Addenbrooke’s Cognitive Examination-revised. Health-related quality of life of ALS patients and their caregivers was also evaluated, and the potential factors associated with apathy were explored using forward binary regression analysis. Survival was analyzed using the Cox proportional hazards model.ResultsThe prevalence of apathy in all patients was 28.9%. Patients in the late disease stage had a higher prevalence of apathy than those in the early disease stage. Furthermore, patients with apathy had a lower ALS Functional Rating Scale revised (ALSFRS-R) score, higher HDRS score, HARS score and higher proportion of reported problems in the anxiety/depression. Additionally, their caregivers had higher score of depression and higher Zarit-Burden Interview scores. Multivariate regression analysis revealed that apathy in ALS was associated with the onset region (p = 0.027), ALSFRS-R score (p = 0.007), depression (p = 0.001) and anxiety (p < 0.001). Apathy had a significant negative effect on survival in ALS patients (p = 0.032).ConclusionApathy is relatively common (28.9%) in Chinese patients with ALS. Apathy is related to both the severity of the disease, and the presentation of non-motor symptoms in ALS, such as depression and anxiety disorders. Apathy is an independent prognostic factor for survival and requires early intervention and management

Clinical Staging of Amyotrophic Lateral Sclerosis in Chinese Patients

Objective: It is important to explore the utility of clinical staging systems in the management of amyotrophic lateral sclerosis (ALS). Our aim was to assess the validity of King's College in a Chinese ALS cohort, by evaluating the duration and informativeness of each stage and examining the association between stage and prognosis.Methods: From May 2008 to December 2016, patients with a likely diagnosis of ALS were registered. We prospectively assessed the progression of the patients through the stages and calculated the duration of each stage.Results: The median duration in Stage 1 was 12.00 months, Stage 2 7.50 months, Stage 3 6.50 months, and Stage 4 4.10 months. Subset analysis revealed that the spinal-onset and early-onset patients had a longer median time in Stage 1 compared to bulbar-onset and late-onset patients, respectively. Riluzole treatment extended the durations of Stages 1 and 2, and the effect was maintained in patients with long-term use of riluzole (>6 months). Patients who initiated long-term riluzole therapy early, in Stage 1 or 2, had a longer Stage 2. Patients who received percutaneous gastrostomy endoscopy (PEG) or non-invasive positive-pressure ventilation (NIPPV) showed longer durations of Stage 4. The differences in survival time measured from each stage to death or censor date were significant.Conclusions: We validated the King's College staging system in a Chinese population, and showed this system to be useful in clinical practice. Patients with bulbar-onset or an age of onset>45 years tended to have rapidly progressing ALS. Riluzole may be more effective when initiated in an early disease stage and continued long-term. PEG and NIPPV treatments can extend disease duration of Stage 4

Cystatin C is associated with poor survival in amyotrophic lateral sclerosis patients

BackgroundCystatin C (CysC) levels in amyotrophic lateral sclerosis (ALS) have been found changes, however, the associations between serum CysC levels and the progression and survival of ALS remain largely unknown.MethodsA total of 1,086 ALS patients and 1,026 sex-age matched healthy controls (HCs) were enrolled in this study. Serum CysC, other renal function, and metabolic parameters were measured. Correlation analysis and binary logistic regression were used to explore the factors related to serum CysC. Kaplan–Meier curve and Cox regression model were used for survival analysis.ResultsCysC levels were significantly higher in ALS patients compared to HCs (0.94 vs. 0.85 mg/L, p < 0.001). Compared with ALS patients with lower CysC levels, those with higher CysC levels had an older age of onset, significantly lower ALSFRS-R scores (40.1 vs. 41.3, p < 0.001), a faster disease progression rate (0.75 vs. 0.67, p = 0.011), and lower frontal lobe function scores (15.8 vs. 16.1, p = 0.020). In the correlation analysis, CysC levels were significantly negatively correlated with ALSFRS-R scores (r = −0.16, p < 0.001). Additionally, ALS patients with higher CysC levels had significantly shorter survival time (40.0 vs. 51.8, p < 0.001) compared to patients with lower CysC levels. Higher CysC levels were associated with a higher risk of death in Cox analysis (HR: 1.204, 95% CI: 1.012–1.433). However, when treatment was included in the model, the result was no longer significant.ConclusionCysC levels in ALS patients were higher compared to HCs. Higher CysC levels were associated with greater disease severity, faster progression rate and shorter survival, needing early intervention

Freezing of gait in Parkinson’s disease with glucocerebrosidase mutations: prevalence, clinical correlates and effect on quality of life

ObjectivesMutations in glucocerebrosidase (GBA1) can change the clinical phenotype of Parkinson’s disease (PD). This study aimed to explore the clinical characteristics of freezing of gait (FOG) in PD patients with GBA1 mutations.MethodsA whole-exome sequencing analysis was used to identify the GBA1 mutations (pathogenic or likely pathogenic) and exclude other PD-related gene mutations. A forward binary logistic regression model was conducted to identify the associated factors of FOG. The stepwise multiple linear regression analysis models were used to explore the effect of FOG on quality of life.ResultsThe prevalence of FOG in patients with GBA1 mutations (30/95, 31.6%) was significantly higher than those in patients without GBA1 mutations (152/760, 20%) (p = 0.009). A higher (i.e., worse) Unified PD Rating Scale part III score (OR = 1.126, 95%CI = 1.061–1.194, p < 0.001) and a lower (i.e., worse) Montreal Cognitive Assessment score (OR = 0.830, 95%CI = 0.713–0.967, p = 0.017) were significantly associated with FOG in PD patients with GBA1 mutations. The presence of FOG was significantly associated with the decreased (i.e., worse) score of PD Questionnaire 39 after adjustment for sex, age, disease duration, motor score, and non-motor score (B = 14.981, p = 0.001).ConclusionFOG is a relatively common disabling symptom in PD patients with GBA1 mutations, which is affected by motor disability and cognitive decline. Quality of life is reduced in patients with FOG and GBA1 mutations

Dysfunction of the Default Mode Network in Drug-Naïve Parkinson’s Disease with Mild Cognitive Impairments: A Resting-State fMRI Study

Objective: Cognitive impairments are common in Parkinson’s disease (PD) and can even occur in the early stages. The default mode network (DMN) is highly relevant for cognitive processes; however, it remains largely unknown if changes in the DMN connectivity are related to the cognitive decline in drug-naïve early-stage PD patients with a mild cognitive impairment (MCI). This study used resting-state functional MRI (fMRI) to explore the brain connectivity of the DMN in early-stage drug-naïve PD patients with MCI.Method: We recruited 32 early-stage drug-naïve PD patients and 22 matched healthy controls (HC). Among the PD patients, 14 were classified as having MCI (PD-MCI) and 18 were classified as having unimpaired cognition (PD-CU). The functional integration of the DMN was evaluated by a seed-based correlation approach.Results: The brain connectivity analysis revealed reduced functional connectivity (FC) in both PD subgroups compared with HC. The PD-MCI group showed a significant reduction in FC between the DMN and a set of regions, including the precentral gyrus, middle temporal gyrus, insula, anterior inferior parietal lobule and middle frontal gyrus. Compared to the PD-CU group, the PD-MCI group demonstrated a significantly decreased FC in the middle frontal and middle temporal gyri. Additionally, compared to HC, the PD-MCI group had a significantly decreased FC within the DMN, mainly in the FC between the hippocampal formation and inferior frontal gyrus, between the posterior cingulate cortex and posterior inferior parietal lobule, and between the anterior temporal lobe and inferior frontal gyrus. Compared to the PD-CU group, the only significantly decreased FC within the DMN in the PD-MCI group was between the anterior temporal lobe and inferior frontal gyrus. In all PD patients, the decreased FC between anterior temporal lobe and middle temporal gyrus was positively correlated with attention/working performance, and the reduced FC between the hippocampal formation and inferior frontal gyrus was also positively correlated with memory function.Conclusions: Our findings suggest that an altered DMN connectivity characterizes PD-MCI patients. These findings may be helpful for facilitating the further understanding of the potential mechanisms underlying MCI in PD. However, our results are preliminary, and further investigation is needed

Functional Variant rs3135500 in NOD2 Increases the Risk of Multiple System Atrophy in a Chinese Population

Background: Given the overlap of clinical manifestations and pathological characteristics between Parkinson's disease (PD) and multiple system atrophy (MSA), we investigated the associations between five functional polymorphisms of nucleotide-binding oligomerization domain protein 2 (NOD2) which were associated with PD, and MSA in a Chinese population.Methods: A cohort of 431 MSA patients and 441 unrelated healthy controls (HCs) were included in the study. Five polymorphisms in NOD2, including P268S, R702W, G908R, 1007fs, and rs3135500, were genotyped. The mRNA expression of NOD2 in peripheral mononuclear cells (PBMCs) in 32 MSA patients were analyzed using RT-PCR, and the concentration of NOD2 and α-synuclein from plasma of 57 MSA patients were also measured by ELISA analysis.Results: No heterozygous or homozygous for R702W, G908R, and 1007fs were found in all the subjects. For rs3135500, differences in genotype distributions, dominant and additive genetic models, were found between MSA and HCs, and between MSA Parkinsonism (MSA-P) patients and HCs. Interestingly, patients carrying the “A” allele of rs3135500 had higher mRNA NOD2 level from PBMCs and NOD2 protein from plasma than patients without this allele (p = 0.028 and p = 0.036, respectively). In addition, we also found the concentration of NOD2 in plasma was positively correlated with the levels of NOD2 mRNA in PBMC and α-synuclein in plasma (R = 0.761 and 0.832, respectively).Conclusion: Our findings suggest that the rs3135500 variant in the NOD2 gene might increase the risk for MSA and might provide new evidence that inflammation mediated by NOD2 involved in the pathogenesis of MSA. Further association studies involving a larger number of participants, as well as functional studies, are needed to confirm our current findings

Essential tremor-Parkinson's disease syndrome: clinical characteristics and subtypes using cluster analysis

Abstract. Background:. Essential tremor (ET) and Parkinson's disease (PD) are common movement disorders. ET-PD syndrome is characterized by the occurrence of PD in patients with a previous history of ET, which may be an independent phenotype distinct from PD. This study aims to identify clinical characteristics and subtypes in ET-PD. Methods:. A total of 93 newly diagnosed ET-PD patients and 93 newly diagnosed PD patients matched for age, sex, education, and disease duration of PD were selected using propensity score matching analysis. The K-means cluster analysis was performed for 11 variables derived from the ET-PD group, and cluster profiles were established through statistical analysis of demographic and clinical variables. Results:. The ET-PD group consisted of a high number of patients with a family history of ET exhibiting evident tremor with milder hypokinesia and postural instability symptoms, as compared to the PD group. Through the cluster analysis, two clusters of ET-PD patients were identified. The ET-PD cluster 1 (n = 34) had a shorter ET duration before PD onset, lower number of patients with a family history of ET, higher unified PD rating scale instability scores, higher non-motor symptoms scores (non-motor symptoms scale D1 scores, Hamilton depression scale scores, Hamilton anxiety scale scores, and PD sleep scale-2 scores), and higher Chinese version of the PD questionnaire-39 scores relative to the ET-PD cluster 2 (n = 59). Conclusion:. ET-PD patients had significantly different characteristics for motor symptoms as compared to PD patients, and may be distinctly divided into two clinical subtypes, namely, the ET-PD complex type and the ET-PD simple type