Novel perspective of therapeutic modules to overcome motor and nonmotor symptoms in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder that involves the loss of dopaminergic neurons, which leads to motor and non-motor symptoms that have a significant impact. The pathophysiology of PD is complex and involves environmental and genetic factors that contribute to alpha-synuclein aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammation. The current treatments of PD primarily focus on symptom management and have limitations in addressing disease progression and non-motor symptoms. Epidemiological data indicates a rise in PD cases worldwide, which highlights the need for effective treatments. Pathophysiological insights point out the involvement of various factors in PD progression, such as dopamine dysregulation, genetic mutations, oxidative stress, mitochondrial damage, alpha-synuclein aggregation, and neuroinflammation. Although current treatments, which include dopamine precursors, monoamine oxidase (MAO) inhibitors, and non-dopaminergic drugs, can alleviate motor symptoms, they are not effective in preventing disease progression or managing non-motor symptoms. Additionally, they can lead to adverse effects and become less effective over time. Novel therapeutic approaches, including cell-based therapies, gene therapies, targeted drug delivery therapies, and magnetic field therapies, are promising in improving symptom management and providing personalized treatment. Additionally, emerging therapies that target alpha-synuclein aggregation, mitochondrial dysfunction, and neuroinflammation may have potential disease-modifying effects. To sum up, for dealing with the multiple aspects of PD, there is a great need to come up with new and creative therapeutic approaches that not only relieve symptoms, but also prevent the progression of disease and non-motor symptoms. The progress made in comprehending the underlying mechanisms of PD provides optimism for developing successful treatments that can enhance the outcomes and quality of life.

Changes in fatigue of Parkinson's disease during the recurrent COVID-19 pandemic: Findings from the longitudinal analysis of the PHASE study.

BACKGROUND: According to Japanese law, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the COVID-19 pandemic falls under Category 2, implying that it necessitates hospitalization, isolation, and significant government participation. The category of infection was lowered to Category 5 in May 2023, meaning that individuals were going back to live their lives as they did before the COVID-19 pandemic. This study aimed to explore changes in the prevalence of non-motor symptoms over a longer four-year period, spanning before and after the COVID-19 pandemic. METHODS: We conducted a questionnaire survey between January and February in the following years: 2021, 2022, 2023, and 2024. RESULTS: The Parkinson's fatigue scale score in 2021 (mean: 35.3) increased significantly in 2022 (49.84), 2023 (49.33), and 2024 (54.71) (p < 0.001). After adjusting for baseline score using a mixed linear model with random intercept, the Parkinson's fatigue scale was significantly increased by 15.9 points (95 % CI: 10.9 to 20.9) in 2022, 13.1 points (7.9-18.3) in 2023, and 16.9 points (11.3-22.6) in 2024 independently of all potential confounders including other non-motor symptoms. CONCLUSIONS: The four years of longitudinal observation during the recurrent COVID-19 pandemic revealed that patients with PD experienced an increase in fatigue. Now, post-COVID-19 fatigue is attracting attention; however, the severity of fatigue may have already deteriorated during the period of recurrent COVID-19 pandemic.

Memory-Guided Saccades and Non-Motor Symptoms Improve after Botulinum Toxin Therapy in Cervical Dystonia.

Background/Objectives: Cervical dystonia (CD) is a condition characterized by involuntary activity of cervical muscles, which is often accompanied by various non-motor symptoms. Recent studies indicate impaired saccadic eye movements in CD. Local administration of botulinum toxin type A (BoNT/A), which causes temporary paralysis of the injected muscle, is the first-line treatment of focal dystonia, including CD. To our knowledge, concurrent observation of the effect of BoNT/A on smooth eye movements, voluntary saccades, memory-guided saccades, and antisaccades in CD has not yet been explored. The aim of this study was to assess the effect of BoNT/A on eye movements and non-motor symptoms in patients with CD, which, when altered, could imply a central effect of BoNT/A. Methods: Thirty patients with CD performed smooth pursuit, prosaccadic expression, memory-guided saccades, and antisaccade tasks; eye movements were recorded by an eye tracker. Motor and non-motor symptoms, including depression, anxiety, pain, disability, and cognitive changes prior to and after BoNT/A administration, were also evaluated. Results: The number of correct onward counts (p < 0.001), overall correct memory-guided saccades count (p = 0.005), motor symptoms (p = 0.001), and non-motor symptoms, i.e., anxiety (p = 0.04), depression (p = 0.02), and cognition (p < 0.001) markedly improved after BoNT/A administration. Conclusions: Memory-guided saccades, depression, and anxiety improve after BoNT/A in CD.

Invasive neurophysiological recordings in human basal ganglia. What have we learned about non-motor behaviour?

Research into the function of deep brain structures has benefited greatly from microelectrode recordings in animals. This has helped to unravel physiological processes in the healthy and malfunctioning brain. Translation to the human is necessary for improving basic understanding of subcortical structures and their implications in diseases. The use of microelectrode recordings as a standard component of deep brain stimulation surgery offers the most viable route for studying the electrophysiology of single cells and local neuronal populations in important deep structures of the human brain. Most of the studies in the basal ganglia have targeted the motor loop and movement disorder pathophysiology. In recent years, however, research has diversified to include limbic and cognitive processes. This review aims to provide an overview of advances in neuroscience made using intraoperative and post-operative recordings with a focus on non-motor activity in the basal ganglia.

Importance of focusing on subjective symptoms to maintain quality of life in patients with Parkinson's disease for over 5 years.

Parkinson's disease (PD) is a neurodegenerative disorder that causes a variety of motor and non-motor symptoms (NMS), which affect the patient's quality of life (QOL). This study aimed to compare QOL and background in patients with PD based on the disease duration and investigate the factors affecting QOL. Patients with PD were evaluated based on age, sex, disease duration (≤5 years and > 5 years groups), Mini Mental State Examination (MMSE), Japanese version of Montreal Cognitive Assessment (MoCA-J), Levodopa equivalent daily dose (LEDD), Hoehn and Yahr (HY) severity, movement disorder society-sponsored revision of the unified Parkinson's disease rating scale (MDS-UPDRS) parts I-IV, and QOL using the Parkinson's disease questionnaire (PDQ-8). Overall, 102 patients with PD (58 males; mean age = 70.0 years; mean disease duration = 7.3 years) were included in this study. QOL was significantly correlated (r > 0.30, p < 0.05) with disease duration and MDS-UPDRS parts I-IV total scores. When the PDQ-8 total score was compared with MDS-UPDRS parts I-IV total scores based on disease duration classification, it was positively correlated with the scores for parts I and II in the >5 years group. Moreover, MDS-UPDRS parts I and II total scores appeared to be the factors most significantly affecting QOL. The factors affecting QOL in patients with PD were subjective NMS and motor symptoms. Since, physician-rated motor symptoms were not associated with QOL in patients with >5 years PD, subjective symptoms should be evaluated and treated to maintain QOL.

Basal ganglia theta power indexes trait anxiety in people with Parkinson's disease.

Neuropsychiatric symptoms are common and disabling in Parkinson's disease (PD), with troublesome anxiety occurring in one-third of patients. Management of anxiety in PD is challenging, hampered by insufficient insight into underlying mechanisms, lack of objective anxiety measurements, and largely ineffective treatments. In this study, we assessed the intracranial neurophysiological correlates of anxiety in PD patients treated with deep brain stimulation (DBS) in the laboratory and at home. We hypothesized that low-frequency (theta-alpha) activity would be associated with anxiety. We recorded local field potentials (LFP) from the subthalamic nucleus (STN) or the globus pallidus pars interna (GPi) DBS implants in three PD cohorts: 1) patients with recordings (STN) performed in hospital at rest via perioperatively externalized leads, without active stimulation, both ON or OFF dopaminergic medication; 2) patients with recordings (STN or GPi) performed at home while resting, via a chronically implanted commercially available sensing-enabled neurostimulator (Medtronic PerceptTM device), ON dopaminergic medication, with stimulation both on or off; 3) patients with recordings performed at home while engaging in a behavioral task via STN and GPi leads and electrocorticography paddles over premotor cortex connected to an investigational sensing-enabled neurostimulator, ON dopaminergic medication, with stimulation both on or off. Trait anxiety was measured with validated clinical scales in all participants, and state anxiety was measured with momentary assessment scales at multiple time points in the two at-home cohorts. Power in theta (4-8 Hz) and alpha (8-12 Hz) ranges were extracted from the LFP recordings, and their relation with anxiety ratings was assessed using linear mixed-effects models. In total, 33 PD patients (59 hemispheres) were included. Across three independent cohorts, with stimulation off, basal ganglia theta power was positively related to trait anxiety (all p<0.05). Also in a naturalistic setting, with individuals at home at rest with stimulation and medication ON, basal ganglia theta power was positively related to trait anxiety (p<0.05). This relationship held regardless of the hemisphere and DBS target. There was no correlation between trait anxiety and premotor cortical theta-alpha power. There was no within-patient association between basal ganglia theta-alpha power and state anxiety. We showed that basal ganglia theta activity indexes trait anxiety in PD. Our data suggest that theta could be a possible physiomarker of neuropsychiatric symptoms and specifically of anxiety in PD, potentially suitable for guiding advanced DBS treatment tailored to the individual patient's needs, including non-motor symptoms.

Synbiotic supplementation may globally improve non-motor symptoms in patients with stable Parkinson's disease: results from an open label single-arm study.

Gut microbiota changes and brain-gut-axis (BGA) dysregulation are common in people with Parkinson's Disease (PD). Probiotics and prebiotics are emerging as a potential therapeutic approach for PD patients. The aim of this paper was to assess the neurological and gastroenterological effects in PD patients with constipation after the administration of a synbiotic product, with a focus on behavioral and cognitive symptoms. We enrolled patients with stable PD who met diagnostic criteria for functional constipation and/or irritable bowel syndrome with constipation according to Rome IV Criteria. Patients received a synbiotic treatment (Enterolactis Duo, containing the probiotic strain Lacticaseibacillus paracasei DG and the prebiotic fiber inulin) for 12 weeks. A neurological and a gastroenterological evaluation were collected before and after the treatment. In addition, 16S rRNA gene profiling and short chain fatty acid quantification were performed to characterize the microbial ecosystem of fecal samples collected before (n = 22) and after (n = 9) the synbiotic administration. 30 patients were consecutively enrolled. After treatment, patients performed better in MDS-UPDRS part 1 (p = 0.000), SCOPA-AUT (p = 0.001), TAS-20 (p = 0.014), HAM-D (p = 0.026), DIFt (p = 0.003), PAS-A (p = 0.048). Gastroenterological evaluations showed improvements in PAC-SYM score (p < 0.001), number of complete bowel movement (p < 0.001) and BSFS (p < 0.001). After the synbiotic administration, we observed a significant increase in the abundance of the order Oscillospirales, as well as the Oscillospiraceae family and the species Faecalibacterium prausnitzii within this order in fecal samples. Synbiotic treatment demonstrates potential efficacy in ameliorating non-motor features in PD patients.

Diagnostic and therapeutic challenges in PD-associated non-motor symptoms: the roles of neurologists and consultant physicians.

In addition to their motor symptoms, almost all Parkinson's disease patients report non-motor symptoms (NMS) and, in the later course of the disease, non-motor fluctuations as well. These NMS encompass e.g. neuropsychiatric, gastrointestinal, urogenital, cardiovascular symptoms and pain. For a long time, these symptoms received no or at best very little attention, but there is a growing trend towards their recognition and treatment. Despite this progress, significant gaps remain, particularly due to the sometimes-limited expertise among neurologists regarding these symptoms. The clinical need to consequently treat these NMS raises the question of whether Movement Disorder specialists should and can address them sufficiently or if additional consultant physicians have to be enrolled. Therefore, our objective is to establish benchmarking criteria to outline a potential way forward. Ideally, Movement Disorder specialists should take on greater responsibility when treating non-motor PD symptoms, integrating diagnostic and therapeutic pathways from other medical disciplines where feasible.

Cardiovascular dysautonomia and cognitive impairment in Parkinson's disease (Review).

Cognitive impairment is a prevalent non-motor symptom of Parkinson's disease (PD), which can result in significant disability and distress for patients and caregivers. There is a marked variation in the timing, characteristics and rate at which cognitive decline occurs in patients with PD. This decline can vary from normal cognition to mild cognitive impairment and dementia. Cognitive impairment is associated with several pathophysiological mechanisms, including the accumulation of ß-amyloid and tau in the brain, oxidative stress and neuroinflammation. Cardiovascular autonomic dysfunctions are commonly observed in patients with PD. These dysfunctions play a role in the progression of cognitive impairment, the incidents of falls and even in mortality. The majority of symptoms of dysautonomia arise from changes in the peripheral autonomic nervous system, including both the sympathetic and parasympathetic nervous systems. Cardiovascular changes, including orthostatic hypotension, supine hypertension and abnormal nocturnal blood pressure (BP), can occur in both the early and advanced stages of PD. These changes tend to increase as the disease advances. The present review aimed to describe the cognitive changes in the setting of cardiovascular dysautonomia and to discuss strategies through which these changes can be modified and managed. It is a multifactorial process usually involving decreased blood flow to the brain, resulting in the development of cerebral ischemic lesions, an increased presence of abnormal white matter signals in the brain, and a potential influence on the process of neurodegeneration in PD. Another possible explanation is this association being independent observations of PD progression. Patients with clinical symptoms of dysautonomia should undergo 24-h ambulatory BP monitoring, as they are frequently subtle and underdiagnosed.

Genetically stratified Parkinson's disease with freezing of gait is related to specific pattern of cognitive impairment and non-motor dominant endophenotype.

Background: Freezing of gait (FOG) is an important milestone in the individual disease trajectory of people with Parkinson's disease (PD). Based on the cognitive model of FOG etiology, the mechanism behind FOG implies higher executive dysfunction in PDFOG+. To test this model, we investigated the FOG-related phenotype and cognitive subdomains in idiopathic PD (iPD) patients without genetic variants linked to PD from the Luxembourg Parkinson's study. Methods: A cross-sectional analysis comparing iPDFOG+ (n = 118) and iPDFOG- (n = 378) individuals was performed, followed by the application of logistic regression models. Consequently, regression models were fitted for a subset of iPDFOG+ (n = 35) vs. iPDFOG- (n = 126), utilizing a detailed neuropsychological battery to assess the association between FOG and cognitive subdomains. Both regression models were adjusted for sociodemographic confounders and disease severity. Results: iPDFOG+ individuals presented with more motor complications (MDS-UPDRS IV) compared to iPDFOG- individuals. Moreover, iPDFOG+ individuals exhibited a higher non-motor burden, including a higher frequency of hallucinations, higher MDS-UPDRS I scores, and more pronounced autonomic dysfunction as measured by the SCOPA-AUT. In addition, iPDFOG+ individuals showed lower sleep quality along with lower quality of life (measured by PDSS and PDQ-39, respectively). The cognitive subdomain analysis in iPDFOG+ vs. iPDFOG- indicated lower scores in Benton's Judgment of Line Orientation test and CERAD word recognition, reflecting higher impairment in visuospatial, executive function, and memory encoding. Conclusion: We determined a significant association between FOG and a clinical endophenotype of PD with higher non-motor burden. While our results supported the cognitive model of FOG, our findings point to a more widespread cortical impairment across cognitive subdomains beyond the executive domain in PDFOG+ with additional higher impairment in visuospatial function and memory encoding.

CBD's potential impact on Parkinson's disease: An updated overview.

Background: Parkinson's disease (PD) is primarily known as a motor disorder; however, its debilitating non-motor symptoms have a significant impact on patients' quality of life. The current standard treatment, l-DOPA, is used to relieve motor symptoms, but prolonged use is often associated with severe side effects. This creates an urgent need for effective alternatives targeting both motor and non-motor symptoms. Objectives: Over the past decade, Cannabis sativa and its cannabinoids have been widely studied across various health conditions. Among these compounds, cannabidiol (CBD), a non-psychoactive component, is garnering growing interest due to its multi-targeted pleiotropic properties. This work aims to provide a comprehensive overview of CBD's efficacy in PD. Methods: This review compiles data on both motor and non-motor symptoms of PD, integrating results from preclinical animal studies and available clinical trials. Results: Preclinical research has demonstrated promising results regarding CBD's potential benefits in PD; however, the total number of clinical trials is limited (with only seven studies to date), making it difficult to draw definitive conclusions on its efficacy. Conclusions: While preclinical findings suggest that CBD may have therapeutic potential in PD, the limited number of clinical trials highlights the need for further research. This review emphasizes the gaps that need to be addressed in future studies to fully understand CBD's role in treating both motor and non-motor symptoms of PD.

Non-motor symptoms in patients with Spinocerebellar ataxia type 12.

Introduction: Spinocerebellar ataxia type 12 (SCA12) is a rare autosomal dominant neurodegenerative disorder caused by abnormal CAG repeat expansion in the PPP2R2B gene. This disease is classically characterized by action tremor, dysarthria, ataxia, and hyperreflexia. There are limited reports regarding the non-motor symptoms in patients with SCA 12. We investigated the frequency and factors associated with the selected non-motor symptoms in patients with SCA 12. Methods: Genetically diagnosed (CAG repeats > 43) and symptomatic cases of SCA 12 were included in the study. Motor severity was assessed using the Scale for the Assessment and Rating of Ataxia (SARA) and The Essential Tremor Rating Assessment Scale (TETRAS). Non-motor symptoms such as depression, autonomic function, and cognition were assessed using the Hamilton Depression Rating Scale (HAM-D), the Scales for Outcomes in Parkinson's Disease-Autonomic Dysfunction (SCOPA-AUT), and the Montreal Cognitive Assessment (MoCA), respectively. Results: The mean age of the cohort with 34 SCA12 patients was 64.87 years (standard deviation 6.844). In this study, 21 patients (61.76%) had either mild or moderate cognitive impairment, almost equally frequent in early and advanced cases. Similarly a number of patients demonstrated evidence of moderate and severe depression. The SARA score was strongly associated with the MoCA score, and CAG repeat length could independently predict the MoCA score in this cohort. Autonomic symptoms were commonly present, with the majority of the patients experiencing urinary symptoms. Discussion: Non-motor symptoms are common in SCA12 patients, even in the early stages of the condition. Timely detection and treatment of these symptoms may improve the therapeutic outcome and quality of life for SCA12 patients. The diverse symptoms of SCA12 perhaps indicate a widespread neurodegeneration beyond the cerebellum or its direct connections.

Subthalamic Stimulation Improves Short-Term Satisfaction with Life and Treatment in Parkinson's Disease.

The effect of subthalamic stimulation (STN-DBS) on patients' personal satisfaction with life and their Parkinson's disease (PD) treatment is understudied, as is its correlation with quality of life (QoL). Therefore, we tested the hypothesis that STN-DBS for PD enhances satisfaction with life and treatment. In a prospective, multicenter study with a 6-month follow-up involving 121 patients, we measured the main outcomes using the Satisfaction with Life and Treatment Scale (SLTS-7). Secondary outcomes included the eight-item PD Questionnaire (PDQ-8), European QoL Questionnaire (EQ-5D-3L), EQ-Visual Analogue Scale (VAS), Non-Motor Symptom Scale (NMSS), Hospital Anxiety and Depression Scale (HADS), and Unified PD Rating Scale (UPDRS). Longitudinal outcome changes, effect sizes (Cohen's d), and correlations between outcome changes were analyzed. SLTS-7 scores improved at the 6-month follow-up, particularly in the domains of 'satisfaction with physical health' and 'satisfaction with treatment'. Change scores correlated strongly (EQ-VAS), moderately (PDQ-8 SI and HADS), and weakly (UPDRS-activities of daily living and EQ-5D-3L) with other scales. Satisfaction with physical health, psychosocial well-being, or treatment was not related to UPDRS-motor examination. This study provides evidence that STN-DBS enhances patients' personal satisfaction with life and treatment. This satisfaction is associated with improvements in the QoL, daily activities, and neuropsychiatric aspects of PD rather than its motor aspects.

Clinical Characteristics of Patients with De Novo Parkinson's Disease and a Positive Family History.

Background/Objectives: A family history of Parkinson's disease (PD) is an important risk factor for developing PD. Because only a few studies have investigated the clinical characteristics of PD patients based on family history, this study compared the clinical characteristics of PD patients with and without a family history of PD. Methods: The study involved 356 patients with de novo PD. The data on the patients' PD family histories were obtained from the patients and their caregivers. Motor and non-motor PD symptoms were assessed using the appropriate scales. Results: Out of the 356 PD patients, 26 (7.3%) had a family history of PD. Compared with patients without a family history of PD, those with a family history of PD tended to be younger at diagnosis (67.9 years vs. 62.2 years, respectively; p = 0.009) and exhibited significantly more severe rigidity (p = 0.036). Motor subtype was not different between the PD patients with and without a family history. PD patients with a family history experienced significantly fewer falls/cardiovascular symptoms within the Non-Motor Symptoms Scale domains (p = 0.001) compared to their counterparts, although this was not statistically significant upon adjusting for age (p = 0.119). Conclusions: In de novo PD patients, having a family history of PD is associated with a younger age at diagnosis and more severe rigidity.

Pain Fluctuations in Parkinson's Disease and Their Association with Motor and Non-Motor Fluctuations.

Background: Pain fluctuations are a characteristic phenomenon in advanced Parkinson's disease (PD), but their temporal association with motor and non-motor symptom (NMS) fluctuations remains largely enigmatic. Moreover, data on their importance for disease severity perception and health-related quality-of-life (hr-QoL) is limited. Objective: To dissect pain fluctuations with respect to pain type and frequency patterns, and their association with motor and non-motor fluctuations. Methods: Prospective observational cohort study in advanced PD assessing symptom fluctuations by simultaneous hourly ratings using the PD Home diary (Off, On, Dyskinetic state), a pain diary (assessing 9 pain types) and a non-motor diary (10 key NMS) based on validated instruments. Results: Forty-seven out of 55 eligible participants with fluctuating PD (51% men, median age 65, median disease duration 10 years) had sufficient datasets (>95% of hours) from 2 consecutive days. Pain was reported in 35% of waking hours with clear circadian rhythm peaking in early morning Off periods and clustering during motor Off state (49% of Off state hours with pain). Main NMS co-fluctuating with pain were "Fatigue" and "Inner Restlessness". Simultaneous assessment of global disease severity by participants revealed that pain was associated with worse disease severity only in motor On and Dyskinetic state but not in Off state, which translated into significant correlations of daily pain times with hr-QoL only during motor On and Dyskinetic state. Conclusions: Aside from treating motor Off periods, specific recognition of pain particularly during motor On and Dyskinetic state comprises an important aspect for disease management in advanced PD.

Oscillations of the frequency and severity of pain over the day (also called pain fluctuations) are common in advanced Parkinson's disease (PD). However, their relationship with oscillations of motor and other non-motor symptoms remains unclear. Moreover, only very little data exists on how pain impacts disease severity perception and quality of life for the patients. The present study thus aimed to better understand pain fluctuations and their association with motor and non-motor symptoms in advanced PD. We conducted a prospective observational cohort study in advanced PD patients. Participants rated their symptoms hourly on two consecutive days using three diaries: the PD Home diary (for motor fluctuations), a pain diary (assessing several pain types), and a non-motor diary covering 10 key non-motor symptoms. Pain occurred during 35% of waking hours with a clear circadian rhythm peaking in the early morning and clustering during motor "Off" states as characterized by pronounced motor symptoms. The main non-motor symptoms associated with pain were "Fatigue" and "Inner Restlessness." Interestingly, pain severity correlated with health-related quality of life only during motor "On" state (defined as a state with good mobility and motor function) and "Dyskinetic" state characterized by the occurrence of involuntary movements, but not during motor "Off" periods. In conclusion, in managing advanced PD, recognizing pain during motor "On" and Dyskinetic states is crucial beyond just addressing motor "Off" periods. This understanding can significantly impact disease management and improve patients' quality of life.

Effects of Safinamide on Motor and Non-Motor Symptoms in Patients with Parkinson's Disease and Motor Fluctuations.

INTRODUCTION: Parkinson's disease (PD) involves the progressive loss of dopaminergic neurons, leading to motor and non-motor symptoms that significantly impact patients' quality of life. Safinamide modulates dopaminergic and glutamatergic systems, offering a promising treatment approach. METHODS: This meta-analysis evaluated the efficacy of safinamide as an add-on therapy to levodopa for PD patients with motor fluctuations. Following PRISMA guidelines, literature searches were conducted in PubMed and Embase (2014-2022). Inclusion criteria were studies on adult PD patients receiving safinamide with levodopa. Outcomes included on-time without troublesome dyskinesia, off-time, UPDRS Part III motor scores, UPDRS Part II activities of daily living scores, PDQ-39 emotional well-being, and GRID-HAMD scores. RESULTS: Among thirteen eligible studies, safinamide significantly improved on-time without troublesome dyskinesia at 100 mg/day (mean difference [MD]: -0.90; 95% CI: -1.12 to -0.67; p < 0.00001) and 50 mg/day (MD: -0.77; 95% CI: -1.21 to -0.34; p = 0.0005) compared to placebo. It also reduced off-time (100 mg/day: MD: -0.94; 95% CI: -1.19 to -0.70; p < 0.00001; 50 mg/day: MD: -0.72; 95% CI: -1.03 to -0.41; p < 0.00001) and improved UPDRS-III motor scores (100 mg/day: MD: -3.01; 95% CI: -4.15 to -1.86; p < 0.00001; 50 mg/day: MD: -2.93; 95% CI: -5.14 to -0.71; p = 0.001). Mood improvements were noted in PDQ-39 emotional well-being scores (MD: -5.22; 95% CI: -6.90 to -3.54) and GRID-HAMD scores (MD: -0.60; 95% CI: -0.95 to -0.25; p = 0.0009). Safinamide also positively affected pain (RR: 1.10; 95% CI: 1.03 to 1.18). CONCLUSION: Compared to placebo, safinamide significantly benefits motor and non-motor symptoms in PD patients, but further research is necessary to fully explore its therapeutic potential.

Non-motor symptoms of Parkinson`s disease-insights from genetics.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by both motor and non-motor symptoms (NMS). NMS including sleep disturbances, depression, anxiety, and constipation are diverse, can precede motor symptoms, and significantly impact patients` quality of life. The severity and type of NMS vary based on age, disease severity, and motor symptoms, and while some respond to dopaminergic treatments, others may be induced or exacerbated by such treatments. NMS also play a role in differentiating PD from drug-induced parkinsonism and are related to gait dysfunction in both early and advanced stages. Genetic factors play a significant role in the development of NMS in PD, with mutations in genes such as SNCA, LRRK2, PRKN, and GBA being associated with severe and early NMS. Familial studies and identification of susceptibility factors have provided insights into the genetic underpinnings of NMS in PD. Neurobehavioral changes, including cognitive decline, are common NMS in PD, and their genetic basis involves a spectrum of mutations shared with other neurodegenerative disorders. Further research is needed to elucidate the functional implications of these genetic factors and their contributions to the pathogenesis of NMS in PD.

Relationship of Glymphatic Function with Cognitive Impairment, Sleep Disorders, Anxiety and Depression in Patients with Parkinson's Disease.

Introduction: Previous studies have predominantly explored the relationship of the glymphatic system with motor symptoms in Parkinson's disease (PD); however, research on non-motor symptoms remains limited. Therefore, this study investigated the association between glymphatic function and non-motor symptoms, including cognitive impairment and sleep disorders, in PD patients. Methods: This study recruited 49 PD patients and 38 healthy controls (HC). Glymphatic function was evaluated using enlarged perivascular spaces (EPVS) in the basal ganglia (BG) region and diffusion tensor image analysis along the perivascular space (DTI-ALPS) index. Cognition, sleep, anxiety, and depression scales were assessed in all participants. According to the scale scores, PD patients were further divided into several groups to identify the presence of non-motor symptoms. Differences in EPVS numbers and ALPS index between PD subgroups and HC group were compared. Spearman correlation analysis was performed to investigate the association between the PD non-motor symptoms and ALPS index. Additionally, receiver operating characteristic (ROC) curves analysis was conducted for ALPS index to predict cognitive impairment and insomnia in PD patients. Results: PD patients with and without non-motor symptoms all showed more EPVS numbers than the controls, and the EPVS numbers in PD patients with cognitive impairment were also greater than those without. Notably, except for the depression subgroup, PD patients with non-motor symptoms showed significantly lower ALPS index than the controls. The Montreal Cognitive Assessment (MoCA) scores were positively correlated, whereas the Parkinson's Disease Sleep Scale (PDSS)-2 and REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ) scores were negatively correlated with the ALPS index in PD patients (r=0.3618, P=0.0053; r=-0.4146, P=0.0015; r=-0.2655, P=0.0326, respectively). The ALPS index proved to be predictive of cognitive impairment and insomnia in PD patients (AUC=0.7733, P=0.001; AUC=0.7993, P=0.0004, respectively). Conclusion: Glymphatic function is closely associated with cognition and sleep of PD patients.

Investigating the impact of socioeconomic status on amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the gradual death of motor neurons in the brain and spinal cord, leading to fatal paralysis. Socioeconomic status (SES) is a measure of an individual's shared economic and social status, which has been shown to have an association with health outcomes. Understanding the impact of SES on health conditions is crucial, as it can influence and be influenced by health-related variables. The role of socioeconomic status in influencing the risk and progression of ALS has not been established, and understanding the various factors that impact ALS is important in developing strategies for treatment and prevention. To investigate this relationship, we recruited 413 participants with definite, probable, or possible ALS according to the El Escorial criteria, from three tertiary centers in London, Sheffield, and Birmingham. Logistic regression was used to examine the association between case-control status, socioeconomic criteria, and ALS risk. Linear regression was used to examine the association between age of onset and socioeconomic variables. Two sensitivity analyses were performed, one using an alternative occupational classifier, and the other using Mendelian Randomization analysis to examine association. There was no significant relationship between any variables and ALS risk. We found an inverse relationship between mean lifetime salary and age of ALS onset (Beta = -0.157, p = 0.011), but no effect of education or occupation on the age of onset. The finding was confirmed in both sensitivity analyses and in Mendelian Randomization. We find that a higher salary is associated with a younger age of ALS onset taking into account sex, occupation, years of education, and clinical presentation.

Functional hearing impairment common in Parkinson's disease: Insights from a pilot study.

INTRODUCTION: Hearing impairments in Parkinson's Disease (PD) have received limited attention in the past, possibly because PD patients often report no perceived hearing disability, yet negative consequences of hearing impairment might aggravate communication difficulties and social withdrawal. OBJECTIVE: Our aim was to investigate functional hearing (speech in noise recognition) in PD and evaluate its relationship to neuropsychiatric symptoms, cognition and quality of life. METHODS: Participants with PD were recruited in a tertiary movement disorder clinic. Demographic, audiological, neuropsychiatric and quality of life data were collected. Participants underwent pure tone audiometry (PTA) and Hearing in Noise test (HINT) as a part of their audiological evaluation. RESULTS: A total of 29 participants (mean age: 65.8±8.3 years, M:F= 1.6:1, mean disease duration 5.2 ± 4.0 years) completed the study. All assessments were done in the ON state. 19/29 (65.5 %) participants had normal tone audiometry for age; functional hearing loss, however, was present in 17/29 (58.6 %) according to the HINT. 65 % (11/17) of the affected participants had a disease duration of <4 years. The majority (72.4 %) with poor functional hearing did not perceive any hearing impairment. Hearing deficits did not correlate with non-motor symptoms (NMS), including cognition or other quality of life measures. CONCLUSIONS: Functional hearing loss is common in PD, often presents early in the disease and the majority of PD patients are unaware of their functional hearing loss. Its potential impact on cognition, communication and quality of life requires further investigation and tailored treatment.