Preoperative Attention/Memory Problem Affects the Quality of Life of Parkinson’s Disease Patients after Deep Brain Stimulation: A Cohort StudyRead the full article
Parkinson’s Disease publishes research related to the epidemiology, etiology, pathogenesis, genetics, cellular, molecular and neurophysiology, as well as the diagnosis and treatment of Parkinson’s disease.
Chief Editor Dr Cristine Alves da Costa is based at Centre National de la Research Scientifique, France. Her research is focuses on Parkinson’s molecular and cell biology.
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A Systematic Review and Meta-Analysis of the Efficacy and Safety of Rasagiline or Pramipexole in the Treatment of Early Parkinson’s Disease
Background. Rasagiline or pramipexole monotherapy has been suggested for the management of early Parkinson’s disease (PD). The aim of this research was to systematically review the clinical efficacy and safety of rasagiline or pramipexole in early PD (defined as disease duration ≤5 years and Hoehn and Yahr stage of ≤3). Methods. Randomized controlled trials (RCTs) of rasagiline or pramipexole for early PD published up to September 2021 were retrieved. Outcomes of interest included changes in the Unified Parkinson’s Disease Rating Scale (UPDRS) Parts II and III and the incidence of adverse events. Standardized mean difference (SMD), odds ratio (OR), and 95% confidence interval (CI) were calculated, and heterogeneity was measured with the I2 test. Results. Nine rasagiline and eleven pramipexole RCTs were included. One post hoc analysis of one rasagiline study was included. Five studies for each drug were included in meta-analyses of the UPDRS scores. The rasagiline meta-analysis focused on patients receiving 1 mg/day. Rasagiline and pramipexole significantly improved UPDRS Part II and III scores when compared to placebo. Significant heterogeneity among the studies was present (I2 > 70%). Neither rasagiline nor pramipexole increased the relative risk for any adverse events, serious adverse events, or adverse events leading to withdrawal when compared with placebo. Conclusion. Applying a Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach to summarize the evidence, we found moderate confidence in the body of evidence for the efficacy of rasagiline or pramipexole in early PD, suggesting further well-designed, multicenter comparative RCTs remain needed.
Alprazolam Reduces Freezing of Gait (FOG) and Improves FOG-Related Gait Deficiencies
Background. Freezing of gait (FOG) is an intractable motor symptom in Parkinson’s disease (PD) that increases fall risk and impairs the quality of life. FOG has been associated with anxiety, with experimental support for the notion that anxiety itself provokes FOG. We investigated the effect of acute anxiety reduction via alprazolam on FOG in PD. Methods. In ten patients with PD, FOG, and normal cognition, we administered 0.25 mg alprazolam in one session and placebo in another, in counterbalanced order. At each session, on separate days, patients walked on a pressure-sensitive walkway. Using Oculus Rift virtual-reality goggles, patients walked along a plank that appeared to be (a) level with the floor, in the low-anxiety condition or (b) raised high above the ground, in the high-anxiety conditions. In this way, we assessed the impacts of anxiety and alprazolam (i.e., anxiety reduction) on FOG frequency and other gait parameters. Results. FOG events appeared only in the high-anxiety conditions. Alprazolam significantly reduced subjective and objective measures of anxiety, as well as the prevalence of FOG (). Furthermore, alprazolam improved swing time () and gait variability in all conditions, particularly during the elevated plank trials. Interpretation. Our results suggest that (1) anxiety induces FOG, and (2) alprazolam concomitantly reduces anxiety and FOG. Alprazolam further improved gait stability (i.e., swing time and gait variability). These findings reveal that anxiety triggers FOG in PD. Treating anxiety can reduce FOG and improve gait stability, potentially offering new therapeutic avenues for this intractable and disabling symptom in PD.
Single-Cell Analyses Reveal Necroptosis’s Potential Role in Neuron Degeneration and Show Enhanced Neuron-Immune Cell Interaction in Parkinson’s Disease Progression
Parkinson’s disease (PD) is a common neuron degenerative disease among the old, characterized by uncontrollable movements and an impaired posture. Although widely investigated on its pathology and treatment, the disease remains incompletely understood. Single-cell RNA sequencing (scRNA-seq) has been applied to the area of PD, providing valuable data for related research. However, few works have taken deeper insights into the causes of neuron death and cell-cell interaction between the cell types in the brain. Our bioinformatics analyses revealed necroptosis-related genes (NRGs) enrichment in neuron degeneration and selecting the cells by NRGs levels showed two subtypes within the main degenerative cell types in the midbrain. NRG-low subtype was largely replaced by NRG-high subtype in the patients, indicating the striking change of cell state related to necroptosis in PD progression. Moreover, we carried out cell-cell interaction analyses between cell types and found that microglia (MG)’s interaction strength with glutamatergic neuron (GLU), GABAergic neuron (GABA), and dopaminergic neuron (DA) was significantly upregulated in PD. Also, MG show much stronger interaction with NRG-high subtypes and a stronger cell killing function in PD samples. Additionally, we identified CLDN11 as a novel interaction pattern specific to necroptosis neurons and MG. We also found LEF1 and TCF4 as key transcriptional regulators in neuron degeneration. These findings suggest that MG were significantly overactivated in PD patients to clear abnormal neurons, especially the NRG-high cells, explaining the neuron inflammation in PD. Our analyses provide insights into the causes of neuron death and inflammation in PD from single-cell resolution, which could be seriously considered in clinical trials.
Sex Differences in the Allele Distribution of PGLYRP2 Variant rs892145 in Parkinson’s Disease
Introduction. Parkinson’s disease (PD) is a complex multifactorial disease, involving genetic susceptibility, environmental risk factors, and gene-environmental interactions. The microbiota-gut-brain axis is hypothesized to play a role in the pathophysiology of PD, and peptidoglycan recognition proteins (PGLYRPs), which modulate the gut microbiota, are, therefore, relevant candidate genes for PD. Methods. Using quantitative real-time PCR, we genotyped three PGLYRP variants (rs892145, rs959117, and rs10888557) and performed an association analysis in 508 PD patients and 585 control individuals. We further conducted a meta-analysis of rs892145 and analyzed PGLYRP2 gene expression in lymphocytes from patients with PD and controls. Results. Although initial analysis of the three variants rs892145, rs959117, and rs10888557 and a meta-analysis of rs892145 did not reveal any association between the selected variants and PD, we found an interaction between sex and genotype for rs892145, with a marked difference in the allele distribution of rs892145 between male and female patients. As compared to controls, the T allele was less common in female patients (odds ratio = 0.76, = 0.04) and more common in male patients (odds ratio = 1.29, = 0.04). No difference was found in PGLYRP2 gene expression between PD patients and controls ( = 0.38), nor between sexes ( = 0.07). Discussion. Overall, this genetic screening in Swedish PD patients does not support previous results demonstrating associations of PGLYRP variants with the risk of PD. Meta-analysis of rs892145 revealed pronounced heterogeneity between previously published studies which is likely to have influenced the results. Taken together, the genetic and gene expression analyses suggest a possible link between genetic variants in PGLYRP2 and sex differences in PD. Because of the limited sample size in our study, these results need to be verified in independent cohorts before concluding.
The Role of Muscle Strength in the Sit-to-Stand Task in Parkinson’s Disease
Background. Rising from a chair or the sit-to-stand (STS) task is frequently impaired in individuals with Parkinson’s disease (PD). These patients commonly attribute such difficulties to weakness in the lower extremities. However, the role of muscle strength in the STS transfer task has not been fully elucidated. Objective. We aim at determining the role of muscle strength in the STS task. Methods. We studied 90 consecutive patients with PD and 52 sex- and age-matched controls. Lower limb strength was determined in both legs by clinical examination using the Medical Research Council Scale, dynamometric (leg flexion) and weighting machine (leg pressure) measures. Patients were interrogated regarding the presence of subjective lower limb weakness or allied sensations. Results. There were 20 patients (22.2%) with abnormal STS task (item 3.9 of the MDS-UPDRS-III ≥2 points). These patients had higher modified Hoehn and Yahr stage and higher total motor scores of the MDS-UPDRS, compared with 70 PD patients with normal STS task. Patients with abnormal STS task endorsed lower limb weakness more frequently and had lower muscle strength in the proximal lower extremities, compared to PD patients with normal STS task and normal controls. The presence of perceived lower limb weakness increased the risk of an abnormal STS task, OR: 11.93 (95% C.I. 1.51–94.32), whereas a hip extension strength ≤9 kg/pressure also increased the risk of abnormal STS task, OR: 4.45 (95% C.I. 1.49–13.23). In the multivariate regression analysis, bradykinesia and decreased hip strength were related to abnormal STS task. Conclusions. Patients with PD and abnormal STS task complain more commonly of lower limb weakness and have decreased proximal lower limb strength compared to patients with PD and normal STS task, likely contributing to abnormalities in performing the STS task.
Protective Role of AMPK against PINK1B9 Flies’ Neurodegeneration with Improved Mitochondrial Function
Adenosine 5′-monophosphate-activated protein kinase (AMPK)’s effect in PTEN-induced kinase 1 (PINK1) mutant Parkinson’s disease (PD) transgenic flies and the related mechanism is seldom studied. The classic MHC-Gal4/UAS PD transgenic flies was utilized to generate the disease characteristics specifically expressed in flies’ muscles, and Western blot (WB) was used to measure the expression of the activated form of AMPK to investigate whether activated AMPK alters in PINK1B9 PD flies. MHC-Gal4 was used to drive AMPK overexpression in PINK1B9 flies to demonstrate the crucial role of AMPK in PD pathogenesis. The abnormal wing posture and climbing ability of PINK1B9 PD transgenic flies were recorded. Mitochondrial morphology via transmission electron microscopy (TEM) and ATP and NADH: ubiquinone oxidoreductase core subunit S3 (NDUFS3) protein levels were tested to evaluate the alteration of the mitochondrial function in PINK1B9 PD flies. Phosphorylated AMPKα dropped significantly in PINK1B9 flies compared to controls, and AMPK overexpression rescued PINKB9 flies’ abnormal wing posture rate. The elevated dopaminergic neuron number in PPL1 via immunofluorescent staining was observed. Mitochondrial dysfunction in PINK1B9 flies has been ameliorated with increased ATP level, restored mitochondrial morphology in muscle, and increased NDUFS3 protein expression. Conclusively, AMPK overexpression could partially rescue the PD flies via improving PINK1B9 flies’ mitochondrial function.