Motor Symptoms Research Articles

Mobilenet, inception ResNet and GoogleNet for epilepsy detection using spectrogram images

Epilepsy is considered the most common cerebral disorder, around 1% of the worldwide population suffer from it. Recently, detection of epilepsy has attracted more and more attention. It has become a hastily increasing problem that can worsen their conditions which necessitate a specific and crucial attention where the symptoms can be an impaired awareness or motor symptoms. Besides that, the difficult process of manual inspection of electroencephalography electroencephalogram (EEG). This paper proposes using transfer learning models to detect both normal and epileptic brain activity and auto-classify signals from the brain. The models considered for this study are GoogleNet, MobileNet, and inception residual neural network inception ResNet. These models were associated with seven different classifiers such as discriminant. These classifiers were tested, analyzed and compared with each other. The efficiency of models is comparatively evaluated through result using multiple metrics. We therefore attained an accuracy of 96.53%, a precision of 97.18%, a false positive rate of 2.78% and an F1-score of 96.50%. Finally, comparison of the suggested approach with existing research shows that the performance of epilepsy classification has been markedly enhanced.

Lifestyle modulators of neuroplasticity in Parkinson's disease: evidence in human neuroimaging studies.

Parkinson's disease is a neurodegenerative disease characterized by both motor and non-motor symptoms. A progressive neuronal loss and the consequent clinical impairment lead to deleterious effects on daily living and quality of life. Despite effective symptomatic therapeutic approaches, no disease-modifying therapies are currently available. Emerging evidence suggests that adopting a healthy lifestyle can improve the quality of life of Parkinson's disease patients. In addition, modulating lifestyle factors can positively affect the microstructural and macrostructural brain levels, corresponding to clinical improvement. Neuroimaging studies may help to identify the mechanisms through which physical exercise, dietary changes, cognitive enrichment, and exposure to substances modulate neuroprotection. All these factors have been associated with a modified risk of developing PD, with attenuation or exacerbation of motor and non-motor symptomatology, and possibly with structural and molecular changes. In the present work, we review the current knowledge on how lifestyle factors influence Parkinson's disease development and progression and the neuroimaging evidence for the brain structural, functional, and molecular changes induced by the adoption of positive or negative lifestyle behaviours.

Does Parkinson's disease affect sleep quality?

Parkinson's disease (PD) is a common neurodegenerative disease that is linked to several motor and nonmotor symptoms, including sleep disturbances. Patient quality of life has been shown to be disproportionally impacted by disease. To investigate sleep quality among individuals with PD, and to assess the severity of sleep disturbances and their impact on daytime activities. A case‒control with 44 patients with Parkinson's disease and 80 apparently healthy control participants was recruited from several hospitals and clinics. Each participant provided a thorough medical history and underwent a physical examination, and a questionnaire comprising the standard PSQI was used to assess sleep quality. Independent samples t test and Spearman's correlation analysis were used with a p value equal to or less than 0.05 which was considered significant. The mean global PSQI score was 11.55 ± 4.412 for PD patients and 5.73 ± 3.22 for the control group with significant p value, Sleep latency onset was 75.57min for PD patients and 22.81min for the control group with significant p value. There was no significant correlation between age and other sleep-related variables. A total of 86.4% of patients with Parkinson's disease suffered from varying degrees of daytime dysfunction compared to 61.25% of the controls. Parkinson's disease patients had poorer sleep quality than the controls. Age and sex were not found to be expected as a factor for sleep quality in patients with Parkinson's disease. Daytime dysfunction rates are high in patients with Parkinson's disease.

Spectral Domain and Angiography Optical Coherence Tomography in Parkinson’s Disease: Structural And Vascular Changes in the Retina Correlate with Disease Severity and Progression

Background. Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by bradykinesia, resting tremor, and muscle rigidity. Visual disturbances have been also described among non-motor features. Objective. We aimed to investigate the structural and vascular changes in the retinal and choroidal vascular networks, and to assess any relationship with motor and non-motor symptoms (NMS) in PD patients. Methods. Ganglion cell complex (GCC), retinal nerve fiber layer (RNFL), and subfoveal choroidal thickness (SFCT) were examined using spectral domain-optical coherence tomography (SD-OCT). The vessel density (VD) of retinal and choriocapillary vascular networks in macular area and the foveal avascular zone (FAZ) area were evaluated by OCT angiography (OCTA). All patients underwent clinical evaluation using motor section of the Unified PD Rating Scale (UPDRS-III) and the Hoehn and Yahr (HY) scale. Results. A total of 48 eyes from 24 PD patients and 50 eyes from 25 controls were assessed. At SD-OCT, GCC and RNFL were more significantly thin in patients compared to controls. At OCTA exam, PD subjects showed lower values in VD of superficial capillary plexus (SCP) and radial peripapillary capillary plexus in comparison to controls, whereas FAZ area resulted in a significant increase in the patient group. We found a negative correlation between the age at onset and VD of SCP, and between HY score and RNFL thickness and FAZ. UPDRS-III score was negatively correlated with VD of deep capillary plexus. Discussion. The impairment of retinal structure and microvasculature seems to correlate with disease severity and progression in PD. Retinal anomalies can be considered as non-motor manifestations that could occur already in the early stage of the disease.

Remote exercise classes are associated with better quality of life in people with Parkinson’s during the Covid-19 pandemic.

Background The classical hallmarks of Parkinson’s Disease (PD) include motor and non-motor symptoms. People with Parkinson’s (PwP) report that the non-motor symptoms, such as memory problems, anxiety, depression and sleep disturbances, have a greater impact on their overall quality of life (QOL). Factors that improve wellbeing for PwP may also lead to improved QOL for their carers. The benefits of exercise in slowing disease decline and improving overall QOL in PwP have been well documented, but online exercise methods have not been extensively studied. Methods Our observational cross-sectional study recruited n=91 PwP and n=23 individuals acting as caregivers, during the COVID-19 pandemic. We used online surveys with validated clinical questionnaires, including the Parkinson’s Disease Questionnaire (PDQ-39), Hospital Anxiety and Depression Scale (HADS), Beck’s Depression Inventory (BDI) and Pittsburgh Sleep Quality Index (PSQI), to assess the impact of different remote online exercise classes on PD symptoms. We also assessed the wellbeing of the PwP’s caregivers using the Parkinson’s Disease Questionnaire - Carer (PDQ-C) at the same time. Results PwP who exercised daily had better QOL scores (45.67 ± 4.34) compared to PwP who exercised once a week or less (123.50 ± 14.56; p<0.001). Those who undertook daily exercise also had lower depression scores (9.37 ± 1.68) than those who exercised less frequently (23.50 ± 3.65; p=0.002). We also found that people who maintained their exercise regimes during the restrictive lockdown period had better QOL scores, ie. lower PDQ-39 scores, (44.64 ± 5.57) compared to those who decreased their frequency of exercise (76.81 ± 7.75; p=0.001). When we assessed caregivers at this timepoint, we found that these individuals had QOL scores within the normal range. Conclusion Remote exercise classes were associated with lower depression scores and better QOL in PwP. PwP who partook in remote classes during lockdowns maintained physical activity and this had positive impacts on their wellbeing.

Impulse Control Disorders in Parkinson's Disease: An Overview of Risk Factors, Pathogenesis and Pharmacological Management.

Impulse control disorders in Parkinson's disease are relatively common drug-induced addictive behaviours that are usually triggered by the dopamine agonists pramipexole, ropinirole and rotigotine. This narrative review aimed to provide a comprehensive overview of the current knowledge of impulse control disorders in Parkinson's disease. We summarised the prevalence, clinical features, risk factors and potential underlying mechanisms of impulse control disorders in Parkinson's disease. Moreover, recent advances in behavioural and imaging characteristics and management strategies are discussed. Early detection as well as a tailored multidisciplinary approach, which typically includes careful adjustment of the dopaminergic therapy and the treatment of associated neuropsychiatric symptoms, are necessary. In some cases, a continuous delivery of levodopa via a pump or the dopamine D1 receptor agonist, apomorphine, can be considered. In selected patients without cognitive or speech impairment, deep brain stimulation of the subthalamic nucleus can also improve addictions. Finding the right balance of tapering dopaminergic dose (usually dopamine agonists) without worsening motor symptoms is essential for a beneficial long-term outcome.

Effects of dopaminergic therapy on sleep quality in fluctuating Parkinson's disease patients.

Sleep disorders negatively impact quality of life in Parkinson's disease (PD), yet the role of antiparkinsonian drugs on sleep quality is still unclear. We aimed to explore the correlation between sleep dysfunction and dopaminergic therapy in a large cohort of advanced PD patients. Patients consecutively evaluated for device-aided therapies eligibility were evaluated by means of the PD Sleep Scale (PDSS-2; score ≥ 18 indicates poor sleep quality), and the Epworth Sleepiness Scale (ESS score ≥ 10 indicates excessive daytime sleepiness-EDS). Binary logistic regression analysis, adjusting for age, sex, disease duration, motor impairment, and sleep drugs, was employed to evaluate the association between dopaminergic therapy and PDSS-2 and ESS scores. Analysis of covariance assessed differences in PDSS-2 and ESS scores between patients without DA, and between patients treated with low or high doses of DA (cut-off: DA-LEDD = 180mg). In a cohort of 281 patients, 66.2% reported poor sleep quality, and 34.5% reported EDS. DA treatment demonstrated twofold lower odds of reporting relevant sleep disturbances (OR 0.498; p = 0.035), while DA-LEDD, levodopa-LEDD, total LEDD, and extended-release levodopa were not associated with disturbed sleep. EDS was not influenced by dopaminergic therapy. Patients with DA intake reported significant lower PDSS-2 total score (p = 0.027) and "motor symptoms at night" domain score (p = 0.044). Patients with higher doses of DA showed lower PDSS-2 total score (p = 0.043). Our study highlights the positive influence of DA add-on treatment on sleep quality in this group of advanced fluctuating PD patients.

Sensorimotor Network Segregation Predicts Long-Term Learning of Writing Skills in Parkinson’s Disease

The prediction of motor learning in Parkinson’s disease (PD) is vastly understudied. Here, we investigated which clinical and neural factors predict better long-term gains after an intensive 6-week motor learning program to ameliorate micrographia. We computed a composite score of learning through principal component analysis, reflecting better writing accuracy on a tablet in single and dual task conditions. Three endpoints were studied—acquisition (pre- to post-training), retention (post-training to 6-week follow-up), and overall learning (acquisition plus retention). Baseline writing, clinical characteristics, as well as resting-state network segregation were used as predictors. We included 28 patients with PD (13 freezers and 15 non-freezers), with an average disease duration of 7 (±3.9) years. We found that worse baseline writing accuracy predicted larger gains for acquisition and overall learning. After correcting for baseline writing accuracy, we found female sex to predict better acquisition, and shorter disease duration to help retention. Additionally, absence of FOG, less severe motor symptoms, female sex, better unimanual dexterity, and better sensorimotor network segregation impacted overall learning positively. Importantly, three factors were retained in a multivariable model predicting overall learning, namely baseline accuracy, female sex, and sensorimotor network segregation. Besides the room to improve and female sex, sensorimotor network segregation seems to be a valuable measure to predict long-term motor learning potential in PD.

Optimization of Zebrafish Larvae 6-OHDA Exposure for Neurotoxin Induced Dopaminergic Marker Reduction.

Parkinson's disease (PD) is a neurodegenerative disorder that is clinically assessed by motor symptoms associated with the loss of midbrain dopaminergic neurons affecting the quality of life for over 8.5 million people worldwide. The neurotoxin 6-hydroxydopamine (6-OHDA) has been used to chemically induce a PD-like state in zebrafish larvae by several laboratories; however, highly variable concentration, methodology, and reagents have resulted in conflicting results suggesting a need to investigate these issues of reproducibility. We propose a protocol that addresses the differences in methodology and induces changes in 6 days postfertilization (dpf) larvae utilizing a 24-h exposure at 3 dpf with 30 μM 6-OHDA. Despite ∼50% lethality, no morphological or development differences in surviving fish are observed. Definition of our model is defined by downregulation of the expression of th1 by reverse transcriptase-quantitative polymerase chain reaction, a marker for dopaminergic neurons and a reduction in movement. Additionally, we observed a downregulation of pink1 and an upregulation of sod1 and sod2, indicators of mitochondrial dysfunction and response to reactive oxygen species, respectively.

Evidence of heat sensitivity in people with Parkinson's disease.

Examining how heat affects people with Parkinson's disease is essential for informing clinical decision-making, safety, well-being, and healthcare planning. While there is evidence that the neuropathology associated with Parkinson's disease affects thermoregulatory mechanisms, little attention has been given to the association of heat sensitivity to worsening symptoms and restricted daily activities in people with this progressive disease. Using a cross-sectional study design, we examined the experiences of people diagnosed with Parkinson's disease in the heat. Two-hundred and forty-seven people completed an online survey (age: 66.0 ± 9.2 years; sex: male = 102 (41.3%), female = 145 (58.7%)), of which 195 (78.9%) reported becoming more sensitive to heat with Parkinson's disease. Motor and nonmotor symptoms worsened with heat in 182 (73.7%) and 203 (82.2%) respondents, respectively. The most commonly reported symptoms to worsen included walking difficulties, balance impairment, stiffness, tremor, fatigue, sleep disturbances, excess sweating, difficulty concentrating, and light-headedness when standing. Concerningly, over half indicated an inability to work effectively in the heat, and nearly half reported that heat impacted their ability to perform household tasks and social activities. Overall, heat sensitivity was common in people with Parkinson's disease and had a significant impact on symptomology, day-to-day activities and quality of life.

Characterisation of RT-QuIC negative cases from the UK National CJD Research and Surveillance programme.

Incorporation of the real-time quaking-induced conversion (RT-QuIC) assays for diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) has transformed diagnosis largely related to its extremely high specificity. However, the test has a c.10% false-negative result and we aim to characterize the clinical features, investigation profile, and molecular subtype in this cohort of patients. 250 individuals diagnosed with definite sporadic CJD were identified from the UK National CJD Research and Surveillance Unit from 2012 to 2023. We compared the clinical features and investigation profile in those with a negative CSF RT-QuIC to those with a positive RT-QuIC. 27 individuals (10.8%) were CSF RT-QuIC negative. Median age of onset was younger (62years vs 68years, p = 0.002), median disease duration was longer (4.4months vs 10.5months, p < 0.001), and these individuals were less likely to present with gait difficulties (73% vs 93%, p = 0.003) or motor symptoms (62% vs 80%, p = 0.04). The sensitivity of electroencephalography and diffusion-weighted MRI were similar in both groups. In those who were RT-QuIC negative, there was an overrepresentation of the VV1 (32% vs 1%) and MM2 molecular subtypes (21% vs 3%). Co-occurring neurodegenerative disease was found in 33% (9/27) of those who were RT-QuIC negative. Individuals with sporadic CJD and a negative CSF RT-QuIC present with younger age of onset, different clinical features and are over-represented with the VV1 and MM2 subtypes of sporadic CJD. Further work is required to better understand the biochemical properties contributing to RT-QuIC negative results in these cases.

Blood Mitochondrial DNA Copy Number Is Associated with Motor Symptoms and Dementia in Parkinson’s Disease (S26.008)

Blood Mitochondrial DNA Copy Number Is Associated with Motor Symptoms and Dementia in Parkinson’s Disease (S26.008)

Exploratory Analysis of PASADENA Open-label Extension Evaluating the Effect of Prasinezumab on the Progression of Motor Signs and Symptoms (S30.006)

Exploratory Analysis of PASADENA Open-label Extension Evaluating the Effect of Prasinezumab on the Progression of Motor Signs and Symptoms (S30.006)

Clinical and neuroimaging characterization of the first frontotemporal dementia family carrying the MAPT p.K298E mutation.

We present an in-depth clinical and neuroimaging analysis of a family carrying the MAPT K298E mutation associated with frontotemporal dementia (FTD). Initial identification of this mutation in a single clinical case led to a comprehensive investigation involving four affected siblings allowing to elucidate the mutation's phenotypic expression.A 60-year-old male presented with significant behavioral changes and progressed rapidly, exhibiting speech difficulties and cognitive decline. Neuroimaging via FDG-PET revealed asymmetrical frontotemporal hypometabolism. Three siblings subsequently showed varied but consistent clinical manifestations, including abnormal behavior, speech impairments, memory deficits, and motor symptoms correlating with asymmetric frontotemporal atrophy observed in MRI scans.Based on the genotype-phenotype correlation, we propose that the p.K298E mutation results in early-onset behavioral variant FTD, accompanied by a various constellation of speech and motor impairment.This detailed characterization expands the understanding of the p.K298E mutation's clinical and neuroimaging features, underlining its role in the pathogenesis of FTD. Further research is crucial to comprehensively delineate the clinical and epidemiological implications of the MAPT p.K298E mutation.

The grasp reflex in patients with idiopathic normal pressure hydrocephalus.

To investigate the prevalence and intensity of grasp reflexes and to examine changes in these reflexes after shunt surgery in patients with idiopathic normal pressure hydrocephalus (iNPH). We enrolled 147 patients with probable iNPH. A standard procedure was used to determine the presence of grasp reflexes, and the intensity of these reflexes was assessed using a four-category classification. Clinical rating scales and their correlation with grasp reflexes were also evaluated. Grasp reflexes were reassessed in 72 patients 1year after surgery. We found that approximately 50.3% of patients with iNPH exhibited a positive grasp reflex. Among these patients, 69% exhibited bilateral positivity, while the remaining patients showed unilateral positivity. Furthermore, the intensity of the grasp reflex was significantly correlated with the severity of gait and with cognitive, urinary, motor, and behavioural symptoms. Surgical interventions led to a reduction (41.7%) or maintenance (30.6%) of the reflex intensity in 72.3% of iNPH patients. The changes in reflex intensity showed significant positive correlations with changes in the number of steps of the Timed Up and Go test and Trail Making Test-A scores but not with changes in total scores on the iNPH Grading Scale. This retrospective study identified grasp reflexes as a highly prevalent phenomenon in patients with iNPH. These reflexes can assist in evaluating the severity of various symptoms, including cognitive, gait, urinary, motor and emotional symptoms.

Online cognitive testing in Parkinson’s disease: advantages and challenges

Parkinson’s disease (PD) is primarily characterized by motor symptoms. Yet, many people with PD experience cognitive decline, which is often unnoticed by clinicians, although it may have a significant impact on quality of life. For over half a century, traditional in-person PD cognitive assessment lacked accessibility, scalability, and specificity due to its inherent limitations. In this review, we propose that novel methods of online cognitive assessment could potentially address these limitations. We first outline the challenges of traditional in-person cognitive testing in PD. We then summarize the existing literature on online cognitive testing in PD. Finally, we explore the advantages, but also the limitations, of three major processes involved in online PD cognitive testing: recruitment and sampling methods, measurement and participation, and disease monitoring and management. Taking the limitations into account, we aim to highlight the potential of online cognitive testing as a more accessible and efficient approach to cognitive testing in PD.

On the Optimal Diagnosis and the Evolving Role of Pimavanserin in Parkinson's Disease Psychosis.

Parkinson's disease (PD) is associated with the development of psychosis (PDP), including hallucinations and delusions, in more than half of the patient population. Optimal PD management must therefore involve considerations about both motor and non-motor symptoms. Often, clinicians fail to diagnosis psychosis in patients with PD and, when it is recognized, treat it suboptimally, despite the availability of multiple interventions. In this paper, we provide a summary of the current guidelines and clinical evidence for treating PDP with antipsychotics. We also provide recommendations for diagnosis and follow-up. Finally, an updated treatment algorithm for PDP that incorporates the use of pimavanserin, the only US FDA-approved drug for the treatment of PDP, was developed by extrapolating from a limited evidence base to bridge to clinical practice using expert opinion and experience. Because pimavanserin is only approved for the treatment of PDP in the US, in other parts of the world other recommendations and algorithms must be considered.

The Interaction Between Nutraceuticals and Gut Microbiota: a Novel Therapeutic Approach to Prevent and Treatment Parkinson's Disease.

Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons, leading to motor and non-motor symptoms. Emerging research has shed light on the role of gut microbiota in the pathogenesis and progression of PD. Nutraceuticals such as curcumin, berberine, phytoestrogens, polyphenols (e.g., resveratrol, EGCG, and fisetin), dietary fibers have been shown to influence gut microbiota composition and function, restoring microbial balance and enhancing the gut-brain axis. The mechanisms underlying these benefits involve microbial metabolite production, restoration of gut barrier integrity, and modulation of neuroinflammatory pathways. Additionally, probiotics and prebiotics have shown potential in promoting gut health, influencing the gut microbiome, and alleviating PD symptoms. They can enhance the gut's antioxidant capacity of the gut, reduce inflammation, and maintain immune homeostasis, contributing to a neuroprotective environment. This paper provides an overview of the current state of knowledge regarding the potential of nutraceuticals and gut microbiota modulation in the prevention and management of Parkinson's disease, emphasizing the need for further research and clinical trials to validate their effectiveness and safety. The findings suggest that a multifaceted approach involving nutraceuticals and gut microbiota may open new avenues for addressing the challenges of PD and improving the quality of life for affected individuals.

Bodily Maps of Symptoms and Emotions in Parkinson's Disease.

Emotions are reflected in bodily sensations, and these reflections are abnormal in psychiatric conditions. However, emotion-related bodily sensations have not been studied in neurological disorders. The aim of this study was to investigate whether Parkinson's disease (PD) is associated with altered bodily representations of emotions. Symptoms and emotion-related sensations were investigated in 380 patients with PD and 79 control subjects, using a topographical self-report method, termed body sensation mapping. The bodily mapping data were analyzed with pixelwise generalized linear models and principal component analyses. Bodily maps of symptoms showed characteristic patterns of PD motor symptom distributions. Compared with control subjects, PD patients showed decreased parasternal sensation of anger, and longer PD symptom duration was associated with increased abdominal sensation of anger (PFWE < 0.05). The PD-related sensation patterns were abnormal across all basic emotions (P < 0.05). The results demonstrate altered bodily maps of emotions in PD, providing novel insight into the nonmotor effects of PD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Physical exercise for people with Parkinson's disease: a systematic review and network meta-analysis.

Physical exercise is effective in managing Parkinson's disease (PD), but the relative benefit of different exercise types remains unclear. To compare the effects of different types of physical exercise in adults with PD on the severity of motor signs, quality of life (QoL), and the occurrence of adverse events, and to generate a clinically meaningful treatment ranking using network meta-analyses (NMAs). An experienced information specialist performed a systematic search for relevant articles in CENTRAL, MEDLINE, Embase, and five other databases to 17 May 2021. We also searched trial registries, conference proceedings, and reference lists of identified studies up to this date. We included randomized controlled trials (RCTs) comparing one type of physical exercise for adults with PD to another type of exercise, a control group, or both. Two review authors independently extracted data. A third author was involved in case of disagreements. We categorized the interventions and analyzed their effects on the severity of motor signs, QoL, freezing of gait, and functional mobility and balance up to six weeks after the intervention using NMAs. Two review authors independently assessed the risk of bias using the risk of bias 2 (RoB 2) tool and rated the confidence in the evidence using the CINeMA approach for results on the severity of motor signs and QoL. We consulted a third review author to resolve any disagreements. Due to heterogeneous reporting of adverse events, we summarized safety data narratively and rated our confidence in the evidence using the GRADE approach. We included 154 RCTs with a total of 7837 participants with mostly mild to moderate disease and no major cognitive impairment. The number of participants per study was small (mean 51, range from 10 to 474). The NMAs on the severity of motor signs and QoL included data from 60 (2721 participants), and 48 (3029 participants) trials, respectively. Eighty-five studies (5192 participants) provided safety data. Here, we present the main results. We observed evidence of beneficial effects for most types of physical exercise included in our review compared to a passive control group. The effects on the severity of motor signs and QoL are expressed as scores on the motor scale of the Unified Parkinson's Disease Rating Scale (UPDRS-M) and the Parkinson's Disease Questionnaire 39 (PDQ-39), respectively. For both scales, higher scores denote higher symptom burden. Therefore, negative estimates reflect improvement (minimum clinically important difference: -2.5 for UPDRS-M and -4.72 for PDQ-39). Severity of motor signs The evidence from the NMA (60 studies; 2721 participants) suggests that dance and gait/balance/functional training probably have a moderate beneficial effect on the severity of motor signs (dance: mean difference (MD) -10.18, 95% confidence interval (CI) -14.87 to -5.36; gait/balance/functional training: MD -7.50, 95% CI -11.39 to -3.48; moderate confidence), and multi-domain training probably has a small beneficial effect on the severity of motor signs (MD -5.90, 95% CI -9.11 to -2.68; moderate confidence). The evidence also suggests that endurance, aqua-based, strength/resistance, and mind-body training might have a small beneficial effect on the severity of motor signs (endurance training: MD -5.76, 95% CI -9.78 to -1.74; aqua-based training: MD -5.09, 95% CI -10.45 to 0.40; strength/resistance training: MD -4.96, 95% CI -9.51 to -0.40; mind-body training: MD -3.62, 95% CI -7.24 to 0.00; low confidence). The evidence is very uncertain about the effects of "Lee Silverman Voice training BIG" (LSVT BIG) and flexibility training on the severity of motor signs (LSVT BIG: MD -6.70, 95% CI -16.48 to 3.08; flexibility training: MD 4.20, 95% CI -1.61 to 9.92; very low confidence). Quality of life The evidence from the NMA (48 studies; 3029 participants) suggests that aqua-based training probably has a large beneficial effect on QoL (MD -15.15, 95% CI -23.43 to -6.87; moderate confidence). The evidence also suggests that mind-body, gait/balance/functional, and multi-domain training and dance might have a small beneficial effect on QoL (mind-body training: MD -7.22, 95% CI -13.57 to -0.70; gait/balance/functional training: MD -6.17, 95% CI -10.75 to -1.59; multi-domain training: MD -5.29, 95% CI -9.51 to -1.06; dance: MD -3.88, 95% CI -10.92 to 3.00; low confidence). The evidence is very uncertain about the effects of gaming, strength/resistance, endurance, and flexibility training on QoL (gaming: MD -8.99, 95% CI -23.43 to 5.46; strength/resistance training: MD -6.70, 95% CI -12.86 to -0.35; endurance training: MD -6.52, 95% CI -13.74 to 0.88; flexibility training: MD 1.94, 95% CI -10.40 to 14.27; very low confidence). Adverse events Only 85 studies (5192 participants) provided some kind of safety data, mostly only for the intervention groups. No adverse events (AEs) occurred in 40 studies and no serious AEs occurred in four studies. AEs occurred in 28 studies. The most frequently reported events were falls (18 studies) and pain (10 studies). The evidence is very uncertain about the effect of physical exercise on the risk of adverse events (very low confidence). Across outcomes, we observed little evidence of differences between exercise types. We found evidence of beneficial effects on the severity of motor signs and QoL for most types of physical exercise for people with PD included in this review, but little evidence of differences between these interventions. Thus, our review highlights the importance of physical exercise regarding our primary outcomes severity of motor signs and QoL, while the exact exercise type might be secondary. Notably, this conclusion is consistent with the possibility that specific motor symptoms may be treated most effectively by PD-specific programs. Although the evidence is very uncertain about the effect of exercise on the risk of adverse events, the interventions included in our review were described as relatively safe. Larger, well-conducted studies are needed to increase confidence in the evidence. Additional studies recruiting people with advanced disease severity and cognitive impairment might help extend the generalizability of our findings to a broader range of people with PD.