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Background: Fatigue is a common and disabling non-motor symptom (NMS) in Parkinson's disease (PD) patients. However, the effect of subthalamic nucleus (STN) deep brain stimulation (DBS) on fatigue has not been widely studied., Objective: To determine the effect of STN DBS on fatigue in PD patients, measured by the Non-motor symptoms scale (NMSS)., Methods: Cross-sectional analysis of 50 patients with PD who underwent STN DBS at King's College Hospital and Salford Royal Hospital with fatigue scores (measured by question number 4 from domain 2 (sleep/fatigue) of the NMSS as the primary outcome measure. Secondary outcome measures included the PD Sleep Scale (PDSS), Scales for Outcome in PD (SCOPA)-motor examination, activities of daily living, motor complications, Hoehn and Yahr (HY) stage and changes in Levodopa Equivalent Daily Dose (LEDD)., Results: 50 patients with a mean follow-up period of 1.98 ± 1.36 years were studied. Significant improvement in median fatigue scores (4.00 (0.75-9.00) to 1.00 (0.00-4.50); p  = .001) was observed. In addition, improvements in question 5 (sleep maintenance and fragmentation; 8.00 (4.00-12.00) to 0.00 (0.00-4.00); p  < .001) and in domain 2 total score (sleep/fatigue; 20.00 (8.75-27.25) to 6.00 (0.75-16.00); p  < .001) were also significant, together with improvements in NMSS total score, SCOPA scores and HY stage ( p ≤ .02). Moreover, LEDD but especially dopamine agonists LEDD was significantly reduced after DBS (310.00 (0.00-480.00) to 150.00 (0.00-300.00); p  < .020)., Conclusions: Even though open label and not using a validated fatigue scale, this observational analysis suggest that fatigue improves significantly after STN DBS with persisting benefits at two years follow-up.

MRI-guided focused ultrasound (MRgFUS) lesioning is an innovative, safe and effective treatment which provides an innovative development in the field of minimally invasive stereotactic neurosurgery. Based on the application of focused ultrasound energy under full MR planning and thermal imaging control, unilateral lesioning of the thalamus, subthalamic nucleus, and globus pallidus is indicated for the treatment of movement disorders, including essential tremor, Parkinson's disease, and dystonia. We started to apply this technique in February 2019 for the treatment of patients with movement disorders. The authors developed a diagnostic therapeutic care pathway, which is herewith proposed and applied as an explication of standard clinical practice in use. The project was the result of the application of different methods such as Health Technology Assessment (HTA), Strengths, Weaknesses, Opportunities and Threats analysis (SWOT) and Demin -Plan, Do, Check, Act (PDCA) cycle. The aim of this project was to standardize the MRgFUS diagnostic-therapeutic pathway (DTP), describe its application and the appropriateness of different phases (patient selection, intervention phase and follow-up). Here, we described in detail our experience in the DTP application from 2019 up to now in 610 patients with movement disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Rinaldo, Cilia, Leta, Gammone, Andreasi, Colucci, Braccia, Telese, Poli, Levi, Romito, Ghilemetti, De Martin, Fumagalli, Epifani, Prioni, Amami, Piacentini, Elia, Devigili, Nazzi, Ciceri, Stanziano, Grisoli, Caldiera, Catotti, DiMeco, Moreschi and Eleopra.)

Non-motor symptoms (NMS) of Parkinson's disease (PD) are well described in both clinical practice and the literature, enabling their management and enhancing our understanding of PD. NMS can dominate the clinical pictures and NMS subtypes have recently been proposed, initially based on clinical observations, and later confirmed in data driven analyses of large datasets and in biomarker-based studies. In this chapter, we provide an update on what is known about three common subtypes of NMS in PD. The pain (Park-pain), sleep dysfunction (Park-sleep), and autonomic dysfunction (Park-autonomic), providing an overview of their individual classification, clinical manifestation, pathophysiology, diagnosis, and potential treatments., (Copyright © 2024. Published by Elsevier Inc.)

The symptomatic treatment of Parkinson's disease (PD) has been dominated by the use of dopaminergic medication, but significant unmet need remains, much of which is related to non-motor symptoms and the involvement of non-dopaminergic transmitter systems. As such, little has changed in the past decades that has led to milestone advances in therapy and significantly improved treatment paradigms and patient outcomes, particularly in relation to symptoms unresponsive to levodopa. This review has looked at how pharmacological approaches to treatment are likely to develop in the near and distant future and will focus on two areas: 1) novel non-dopaminergic pharmacological strategies to control motor symptoms; and 2) novel non-dopaminergic approaches for the treatment of non-motor symptoms. The overall objective of this review is to use a 'crystal ball' approach to the future of drug discovery in PD and move away from the more traditional dopamine-based treatments. Here, we discuss promising non-dopaminergic and 'dirty drugs' that have the potential to become new key players in the field of Parkinson's disease treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Heterozygous mutations in the GBA gene, encoding the lysosomal enzyme β-glucocerebrosidase (GCase), are the most frequent genetic risk factor for Parkinson's disease (PD). GBA -related PD (GBA-PD) patients have higher risk of dementia and reduced survival than non-carriers. Preclinical studies and one open-label trial in humans demonstrated that the chaperone ambroxol (ABX) increases GCase levels and modulates α-synuclein levels in the blood and cerebrospinal fluid (CSF)., Methods and Analysis: In this multicentre, double-blind, placebo-controlled, phase II clinical trial, we randomise patients with GBA-PD in a 1:1 ratio to either oral ABX 1.2 g/day or placebo. The duration of treatment is 52 weeks. Each participant is assessed at baseline and weeks 12, 26, 38, 52 and 78. Changes in the Montreal Cognitive Assessment score and the frequency of mild cognitive impairment and dementia between baseline and weeks 52 are the primary outcome measures. Secondary outcome measures include changes in validated scales/questionnaires assessing motor and non-motor symptoms. Neuroimaging features and CSF neurodegeneration markers are used as surrogate markers of disease progression. GCase activity, ABX and α-synuclein levels are also analysed in blood and CSF. A repeated-measures analysis of variance will be used for elaborating results. The primary analysis will be by intention to treat., Ethics and Dissemination: The study and protocols have been approved by the ethics committee of centres. The study is conducted according to good clinical practice and the Declaration of Helsinki. The trial findings will be published in peer-reviewed journals and presented at conferences., Trial Registration Numbers: NCT05287503, EudraCT 2021-004565-13., Competing Interests: Competing interests: RC has received speaking honoraria from Zambon Italia; Zambon SAU; Bial Italia Srl; advisory board fees from Bial; research support from the Italian Ministry of Health; he is Editor-in-Chief of the neuromuscular and movement disorders section of Brain Sciences (MDPI); Associate Editor of Parkinsonism and Related Disorders (Elsevier) and Frontiers in Ageing Neuroscience., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has been discussed in the context of Parkinson's disease (PD) over the last three years. Now that we are entering the long-term phase of this pandemic, we are intrigued to look back and see how and why the community of patients with PD was impacted and what knowledge we have collected so far. The relationship between COVID-19 and PD is likely multifactorial in nature. Similar to other systemic infections, a probable worsening of PD symptoms secondary to COVID-19, either transient or persistent (long COVID), has been demonstrated, while the COVID-19-related mortality of PD patients may be increased compared to the general population. These observations could be attributed to direct or indirect damage from SARS-CoV-2 in the central nervous system (CNS) or could result from general infection-related parameters (e.g., hospitalization or drugs) and the sequelae of the COVID-19 pandemic (e.g., quarantine). A growing number of cases of new-onset parkinsonism or PD following SARS-CoV-2 infection have been reported, either closely (post-infectious) or remotely (para-infectious) after a COVID-19 diagnosis, although such a link remains hypothetical. The pathophysiological substrate of these phenomena remains elusive; however, research studies, particularly pathology studies, have suggested various COVID-19-induced degenerative changes with potential associations with PD/parkinsonism. We review the literature to date for answers considering the relationship between SARS-CoV-2 infection and PD/parkinsonism, examining pathophysiology, clinical manifestations, vaccination, and future directions.

Background: Recent concepts suggest that the neuropathological hallmark of Parkinson's disease (PD) may in part originate from the enteric nervous system. We evaluated the frequency of functional gastrointestinal disorders in PD patients using Rome IV criteria and correlated the clinical severity of PD., Methods: PD patients and matched controls were recruited between January 2020 and December 2021. Rome IV criteria were used to diagnose constipation and irritable bowel syndrome (IBS). Severity of PD motor symptoms was evaluated using UPDRS part III scores and non-motor symptoms using Non-motor Symptoms Scale (NMSS)., Results: A total of 99 PD patients and 64 controls were enrolled. The prevalence of constipation (65.7% vs. 34.3%, P < 0.001) and IBS (18.1% vs 5%, P = 0.02) were significantly higher in PD patients than controls. The prevalence of IBS was higher in early-stage PD than advanced-stage PD (14.43% vs. 8.25%, P = 0.02), whereas constipation was more common in advanced stages (71.43% vs. 18.56%, P < 0.001). PD patients with IBS had higher NMSS total scores (P < 0.01) than those without IBS. The severity of IBS correlated with NMSS scores (r = 0.71, P < 0.001), especially subscores in domain 3 assessing mood disorders (r = 0.83, P < 0.001), but not UPDRS part III scores (r = 0.06, P = 0.45). The severity of constipation correlated with the UPDRS part III scores (r = 0.59, P < 0.001) but not the domain 3 mood subscores (r = 0.15, P = 0.07)., Conclusion: The prevalence of IBS and constipation was higher in PD patients than controls and phenotypic correlation supported the occurrence of IBS with higher non-motor symptom burden, especially mood symptoms, in PD patients., Competing Interests: Declaration of competing interest All authors report no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Parkinson's disease has been identified as a risk factor for severe Coronavirus disease 2019 (COVID-19) outcomes. However, whether the significant high risk of death from COVID-19 in people with Parkinson's disease is specific to the disease itself or driven by other concomitant and known risk factors such as comorbidities, age, and frailty remains unclear., Objective: To investigate clinical profiles and outcomes of people with Parkinson's disease and atypical parkinsonian syndromes who tested positive for COVID-19 in the hospital setting in a multicentre UK-based study., Methods: A retrospective cohort study of Parkinson's disease patients with a positive SARS-CoV-2 test admitted to hospital between February 2020 and July 2021. An online survey was used to collect data from clinical care records, recording patient, Parkinson's disease and COVID-19 characteristics. Associations with time-to-mortality and severe outcomes were analysed using either the Cox proportional hazards model or logistic regression models, as appropriate., Results: Data from 552 admissions were collected: 365 (66%) male; median (inter-quartile range) age 80 (74-85) years. The 34-day all-cause mortality rate was 38.4%; male sex, increased age and frailty, Parkinson's dementia syndrome, requirement for respiratory support and no vaccination were associated with increased mortality risk. Community-acquired COVID-19 and co-morbid chronic neurological disorder were associated with increased odds of requiring respiratory support. Hospital-acquired COVID-19 and delirium were associated with requiring an increase in care level post-discharge., Conclusions: This first, multicentre, UK-based study on people with Parkinson's disease or atypical parkinsonian syndromes, hospitalised with COVID-19, adds and expands previous findings on clinical profiles and outcomes in this population., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Sorrell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To evaluate the long-term, real-life effects on non-motor symptoms (NMS) of opicapone compared to entacapone in levodopa-treated people with Parkinson's disease (PwP)., Methods: A retrospective data analysis, with pre- and post-opicapone initiation data of 17 PwP with motor fluctuations compared to a comparable group of 18 PwP introduced on entacapone. The primary outcome was changes in the NMS Scale (NMSS) total score after 1-year follow-up. Secondary outcomes included changes in the NMSS domains, and Parkinson's Disease Sleep Scale (PDSS) total and item scores after the same time span., Results: Groups were comparable for baseline demographics and Parkinson's-related features (p ≥ 0.314) as well as duration of follow-up (1.33 ± 0.66 years for PwP on opicapone and 1.23 ± 0.49 years for those on entacapone; p = 0.858). PwP who were introduced on opicapone showed no changes in NMSS and PDSS total scores after 1 year (p = 0.605 and p = 0.507, respectively), whereas PwP who were introduced on entacapone showed significant worsening of NMSS and PDSS total scores at follow-up (p = 0.005 and p = 0.001, respectively). In neither group changes in individual NMSS domains from baseline to follow-up were observed (p ≥ 0.288 for entacapone and p ≥ 0.816 for opicapone, respectively). In PwP on entacapone significant worsening was seen in the distressing dreams, hallucinations, and limb numbness items of the PDSS (p ≤ 0.05)., Conclusions: Introduction of opicapone in real-life PwP with motor fluctuations seems to stabilise NMS burden and aspects of sleep dysfunction, in contrast to entacapone where there was a worsening of NMS burden and PDSS scores over 1 year follow-up., (© 2023. The Author(s).)

People with Parkinson's Disease (PwP) experience a significant deterioration of their daily life quality due to non-motor symptoms, with gastrointestinal dysfunctions manifesting as a vanguard of the latter. Electrogastrography (EGG) is a noninvasive diagnostic tool that can potentially provide biomarkers for the monitoring of dynamic gastric alterations that are related to daily lifestyle and treatment regimens. In this work, a robust analysis of EGG dynamics is introduced to evaluate the effect of probiotic treatment on PwP. The proposed framework, namely biSEGG, introduces a Swarm Decomposition-based enhancement of the EGG, combined with Bispectral feature engineering to model the underlying Quadratic Phase Coupling interactions between the gastric activity oscillatory components of EGG. The biSEGG features are benchmarked against the conventional Power Spectrum-based ones and evaluated through machine learning classifiers. The experimental results, when biSEGG was applied on data epochs from 11 PwP (probiotic vs placebo, AUROC: 0.67, Sensitivity/Specificity: 75/58%), indicate the superiority of biSEGG over Power Spectrum-based approaches and justify the efficiency of biSEGG in capturing and explaining intervention- and meal consumption-related alterations of the gastric activity in PwP.Clinical relevance- biSEGG holds potential for dynamic monitoring of gastrointestinal dysfunction and health status of PwP across diverse daily life scenarios.

Many advances in understanding the pathophysiology of Parkinson disease (PD) have been based on research addressing its motor symptoms and phenotypes. Various data-driven clinical phenotyping studies supported by neuropathological and in vivo neuroimaging data suggest the existence of distinct non-motor endophenotypes of PD even at diagnosis, a concept further strengthened by the predominantly non-motor spectrum of symptoms in prodromal PD. Preclinical and clinical studies support early dysfunction of noradrenergic transmission in both the CNS and peripheral nervous system circuits in patients with PD that results in a specific cluster of non-motor symptoms, including rapid eye movement sleep behaviour disorder, pain, anxiety and dysautonomia (particularly orthostatic hypotension and urinary dysfunction). Cluster analyses of large independent cohorts of patients with PD and phenotype-focused studies have confirmed the existence of a noradrenergic subtype of PD, which had been previously postulated but not fully characterized. This Review discusses the translational work that unravelled the clinical and neuropathological processes underpinning the noradrenergic PD subtype. Although some overlap with other PD subtypes is inevitable as the disease progresses, recognition of noradrenergic PD as a distinct early disease subtype represents an important advance towards the delivery of personalized medicine for patients with PD., (© 2023. Springer Nature Limited.)

Levodopa is the gold standard for the symptomatic treatment of Parkinson's disease (PD). There are well documented motor and non-motor fluctuations, however, that occur almost inevitably once levodopa is started after a variable period in people with PD. Whilst brain neurodegenerative processes play a part in the pathogenesis of these fluctuations, a range of barriers across the gastrointestinal (GI) tract can alter levodopa pharmacokinetics, ultimately contributing to non-optimal levodopa response and symptoms fluctuations. GI barriers to levodopa transport and absorption include dysphagia, delayed gastric emptying, constipation, Helicobacter pylori infection, small intestinal bacterial overgrowth and gut dysbiosis. In addition, a protein-rich diet and concomitant medication intake can further alter levodopa pharmacokinetics. This can result in unpredictable or sub-optimal levodopa response, 'delayed on' or 'no on' phenomena. In this narrative review, we provided an overview on the plethora of GI obstacles to levodopa transport and absorption in PD and their implications on levodopa pharmacokinetics and development of motor fluctuations. In addition, management strategies to address GI dysfunction in PD are highlighted, including use of non-oral therapies to bypass the GI tract., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Continuous drug delivery (CDD) is used in moderately advanced and late-stage Parkinson's disease (PD) to control motor and non-motor fluctuations ('OFF' periods). Transdermal rotigotine is indicated for early fluctuations, while subcutaneous apomorphine infusion and levodopa-carbidopa intestinal gel are utilised in advanced PD. All three strategies are considered examples of continuous dopaminergic stimulation achieved through CDD. A central premise of the CDD is to achieve stable control of the parkinsonian motor and non-motor states and avoid emergence of 'OFF' periods. However, data suggest that despite their efficacy in reducing the number and duration of 'OFF' periods, these strategies still do not prevent 'OFF' periods in the middle to late stages of PD, thus contradicting the widely held concepts of continuous drug delivery and continuous dopaminergic stimulation. Why these emergent 'OFF' periods still occur is unknown. In this review, we analyse the potential reasons for their persistence. The contribution of drug- and device-related involvement, and the problems related to site-specific drug delivery are analysed. We propose that changes in dopaminergic and non-dopaminergic mechanisms in the basal ganglia might render these persistent 'OFF' periods unresponsive to dopaminergic therapy delivered via CDD., (© 2022. The Author(s).)

Parkinsonism secondary to viral infections is not an uncommon occurrence and has been brought under the spotlight with the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A variety of viruses have been described with a potential of inducing or contributing to the occurrence of parkinsonism and Parkinson's disease (PD), although the relationship between the two remains a matter of debate originating with the description of encephalitis lethargica in the aftermath of the Spanish flu in 1918. While some viral infections have been linked to an increased risk for the development of PD, others seem to have a causal link with the occurrence of parkinsonism. Here, we review the currently available evidence on viral-induced parkinsonism with a focus on potential pathophysiological mechanisms and clinical features. We also review the evidence on viral infections as a risk factor for developing PD and the link between SARS-CoV-2 and parkinsonism, which might have important implications for future research and treatments., (© 2022. The Author(s).)

Background: Progressive supranuclear palsy (PSP) is a progressive neurodegenerative condition presenting with different clinical endophenotypes. The parkinsonian variant of PSP (PSP-P) is characterised by early but fading responsiveness to high-dose levodopa therapy; however, high-dose oral therapy is often associated with intolerance due to dopaminergic side effects and so doses may have to be capped despite clinical benefits. Evidence from animal models and real-life registries suggest far higher doses of levodopa can be tolerated if given in a continuous drug delivery (CDD) manner. We investigated tolerance and possible clinical benefits in patients with PSP-P still responsive to levodopa after initiating CDD in the form of intrajejunal levodopa infusion (IJLI) therapy as part of a compassionate usage program (CU)., Methods: This is an observational clinical data report from the IJLI implementation program undertaken in regional tertiary referral Parkinson's centres in India and at King's College Hospital London, Dubai as part of a CU. Four patients with PSP-P receiving IJLI as a part of a CU underwent evaluations of liver and renal function, motor and nonmotor function, quality of life, sleep dysfunction, fatigue, anxiety and depression, and cognitive impairment at baseline and 6 and 12 months post-IJLI initiation., Results: In total, three out of four patients successfully completed 12 months of treatment (6 months in one patient). All four patients showed good tolerability to IJLI even at higher doses (1400 and 1960 mg at 6 and 12 months, respectively) when compared to oral levodopa (812.5 ± 103 levodopa equivalent daily dose [LEDD]) and presented with overall persistent improvements in motor and nonmotor scores and quality-of-life scores at 6 and 12 months post-IJLI. All patients showed improvement in estimated glomerular filtration rate (43.50 ml/min/1.73 m 2 to 67.5 ml/min/1.73 m 2 and 79.5 ml/min/1.73 m 2 at 6 and 12 months, respectively)., Conclusions: IJLI led to persistent beneficial effects on motor and some nonmotor aspects in patients with PSP-P at up to 12 months after treatment with associated improvement in overall renal function., (© 2022 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Gastrointestinal (GI) issues are commonly experienced by patients with Parkinson's disease (PD). Those that affect the lower GI tract, such as constipation, are the most frequently reported GI problems among patients with PD. Upper GI issues, such as swallowing dysfunction (dysphagia) and delayed gastric emptying (gastroparesis), are also common in PD but are less well recognized by both patients and clinicians and, therefore, often overlooked. These GI issues may also be perceived by the healthcare team as less of a priority than management of PD motor symptoms. However, if left untreated, both dysphagia and gastroparesis can have a significant impact on the quality of life of patients with PD and on the effectiveness on oral PD medications, with negative consequences for motor control. Holistic management of PD should therefore include timely and effective management of upper GI issues by utilizing both non-pharmacological and pharmacological approaches. This dual approach is key as many pharmacological strategies have limited efficacy in this setting, so non-pharmacological approaches are often the best option. Although a multidisciplinary approach to the management of GI issues in PD is ideal, resource constraints may mean this is not always feasible. In 'real-world' practice, neurologists and PD care teams often need to make initial assessments and treatment or referral recommendations for their patients with PD who are experiencing these problems. To provide guidance in these cases, this article reviews the published evidence for diagnostic and therapeutic management of dysphagia and gastroparesis, including recommendations for timely and appropriate referral to GI specialists when needed and guidance on the development of an effective management plan., Competing Interests: Author RB received consultancy and/or honoraria/lecture fees from Abbott, Boehringer Ingelheim, Britannia, Ipsen, Novartis, Teva-Lundbeck, Takeda, and Otsuka Pharmaceutical; he has received research funding from the Newton Fund, the UK Government, Thailand Science and Research Innovation Bureau, Thailand Research Fund, Crown Property Bureau, Chulalongkorn University, and the National Science and Technology Development Agency; he holds patents for laser-guided walking stick, portable tremor device, nocturnal monitoring, and electronic Parkinson’s disease symptom diary as well as copyright on dopamine lyrics and teaching video clips for common nocturnal and gastrointestinal symptoms for Parkinson’s disease. Author WP was supported by The Second Century Fund (C2F), Chulalongkorn University. Author AT received research funding from The Michael J. Fox Foundation, the Toray Science Foundation, and the Malaysian Ministry of Education Fundamental Research Grant Scheme. Author VL received grants from NIHR BRC, Parkinson’s UK, travel and congress grants from Bial Pharma UK Ltd., speaker-related activity fees from Britannia Pharmaceuticals, Bial Pharma UK, Profile, and consultancy fees from Invisio Pharmaceuticals and Bial Pharma UK, all outside the submitted work. Author KC served as an advisory board member of AbbVie, UCB, GKC, Bial, Cynapsus, Lobsor, Stada, Zambon, Profile Pharma, Synovion, Roche, Theravance, Scion, Britannia, Acadia, 4D Pharma, has received speaker-related activity fees from AbbVie, Britannia, UCB, Zambon, Novartis, Boehringer Ingelheim, Bial, Kyowa Kirin, SK Pharma, research grant from Bial Pharma UK, and royalties from Oxford (book), Cambridge publishers (book), MAPI institute (KPPS, PDSS 2). Author PP received honoraria for delivering lectures in teaching programs conducted by International Parkinson Disease and Movement Disorders Society (MDS). He has received research funding from Indian Council of Medical Research (ICMR), Department of Biotechnology (DBT), Department of Science and Technology-Cognitive Science Research Initiative (DST-CSRI), Department of Science and Technology-Science and Engineering Research Board (DST-SERB), Michael J. Fox Foundation (United States), and Scientific Knowledge for Ageing and Neurological ailments (SKAN). The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bhidayasiri, Phuenpathom, Tan, Leta, Phumphid, Chaudhuri and Pal.)

Unexplained weight changes that occur in Parkinson's disease (PD), are often neglected and remain a poorly understood non-motor feature in patients with PD. A specific 'Park-weight' phenotype with low body weight has been described, and our aim was to evaluate the clinical and prognostic trajectories and biomarkers of weight variability in PD. We evaluated body weight-related biomarkers in 405 de novo PD patients and 187 healthy controls (HC) over a 5-year follow-up period from the PPMI database. Body-weight variability was defined as intra-individual variability in body weight between visits. PD patients were categorized as weight losers, gainers, or patients with stable weight. The differential progression of motor and non-motor clinical variables between groups was explored using linear mixed-effects models. Finally, we estimated longitudinal changes in weight as a function of baseline and longitudinal striatal presynaptic dopaminergic transporter imaging. PD patients presented a greater weight variability compared to HC (p = 0.003). Patients who developed weight loss had lower CSF amyloid-beta 1-42 (p = 0.009) at baseline. In addition, patients with weight loss showed a faster cognitive decline (p = 0.001), whereas patients with weight gain showed a slower motor progression (p = 0.001), compared to patients with stable weight. Baseline right striatal denervation was a predictor of weight variability in both PD patients and HC (p < 0.001). Similarly, weight variability in PD patients was associated with the progression of right striatal denervation (p < 0.001). Weight variability and specifically weight loss are more frequent in PD compared to HC, and are associated with specific motor, non-motor and cognitive progression patterns. A greater CSF amyloid burden was present at baseline in patients with subsequent weight loss. Presynaptic dopaminergic imaging in the right striatum may serve as a predictor of future weight changes in PD and HC., (© 2022. The Author(s).)

Background: Twenty-four-hour treatment options could provide a continuous drug delivery strategy in advanced Parkinson's disease and can ameliorate motor and non-motor complications. Use of levodopa infusion is often limited to 12-16 h/day due to its cost. Adjunctive overnight rotigotine transdermal patch is a continuous drug delivery option successfully used in clinical practice coupled with apomorphine infusion. However, real-life data addressing the tolerability of transdermal dopamine agonist therapy with concomitant use of intrajejunal levodopa infusion in advanced Parkinson's disease are not available., Objective: To evaluate the tolerability and beneficial effects of combined therapy with overnight rotigotine transdermal patch and intrajejunal levodopa infusion over a follow-up period of 12 months in advanced Parkinson's disease., Method: In this retrospective data analysis, data before and after the initiation of the continuous drug delivery combined therapy using overnight rotigotine transdermal patch and intrajejunal levodopa infusion were collected from the ongoing non-motor-international-longitudinal study (NILS) and local clinical practice at King's College Hospital (London, United Kingdom). 12 advanced Parkinson's disease patients on intrajejunal levodopa therapy who were additionally treated with overnight rotigotine transdermal patch (mean dose 5.67 ± 4.19 mg) are included. Tolerability over a 12-month period was assessed. In addition, changes in motor symptoms (SCales for Outcomes in Parkinson's disease, SCOPA-Motor), non-motor symptoms (Non-Motor Symptoms Scale, NMSS) and quality of life (Parkinson's disease Questionnaire-8, PDQ-8) before and 12-month after continuous drug delivery combined therapy initiation are evaluated., Results: Tolerability was 100% irrespective of age, disease duration, stages of disease. (Treatment with overnight rotigotine transdermal patch that was maintained for a minimum of 6 months was considered "tolerated", primary tolerability). In addition, we noted a significant reduction of the NMSS total score (p = 0.009) and the NMSS domain 3 score (mood and apathy domain) (p = 0.028), although the latter did not remain statistically significant after correction for multiple testing (p2 = 0.252) at 12 months., Conclusion: Combination of intrajejunal levodopa infusion with overnight rotigotine transdermal patch is well tolerated and extend the beneficial effects of infusion with excellent tolerability; and also improved aspects of mood and apathy sustained at 12 months in advanced Parkinson's disease., (© 2022. Crown.)

Competing Interests: KRC declares grant support from Bial, Britannia, AbbVie, UCB, GKC, EU Horizon 2020, Parkinson's UK, NIHR, Parkinson's Foundation, Wellcome Trust, Kirby Laing Foundation, and MRC; has served as an advisory board member for, received consultancy and speaking fees from, and declares travel support from, AbbVie, UCB, GKC, Bial, Cynapsus, Lobsor, Stada, Zambon, Profile Pharma, Synovion, Roche, Theravance, Scion, Britannia, Acadia, 4D Pharma, and Medtronic; reports royalties or licenses from Oxford and Cambridge publishers (books) and the Mapi Institute (KPPS, PDSS 2); and has received payment for expert testimony from GMC. VL declares honoraria for speaking and manuscript writing from Britannia.

Non-motor symptoms (NMSs) are highly prevalent throughout the course of Parkinson's disease (PD). Pain, autonomic dysfunction and sleep disturbances remain at the forefront of the most common NMSs; their treatment is challenging and their effect on the quality of life of both patients and caregivers detrimental. Yet, the landscape of clinical trials in PD is still dominated by therapeutic strategies seeking to ameliorate motor symptoms; subsequently, effective strategies to successfully treat NMSs remain a huge unmet need. Wider awareness among industry and researchers is thus essential to give rise to development and delivery of high-quality, large-scale clinical trials in enriched populations of patients with PD-related pain, autonomic dysfunction and sleep. In this review, we discuss recent developments in the field of pharmacological treatment strategies designed or re-purposed to target three key NMSs: pain, autonomic dysfunction and sleep disturbances. We focus on emerging evidence from recent clinical trials and outline some exciting and intriguing findings that call for further investigations. This article is part of the Special Issue on 'New therapeutic approaches to Parkinson's disease'., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Gastrointestinal symptoms and gut dysbiosis may occur before the onset of motor symptoms in Parkinson's disease (PD). Prediagnostic and prodromal features, such as constipation and α-synuclein pathology, can be detected several years before the clinical diagnosis of PD and have the potential to develop as early PD biomarkers. Environmental toxins and gut dysbiosis may trigger oxidative stress and mucosal inflammation, and initiate α-synuclein accumulation in the enteric nervous system, early in PD. Chronic gut inflammation can lead to a leaky gut and systemic inflammation, neuro inflammation, and neuro degeneration via gut-vagus-brain signaling or through blood-brain barrier permeability. Concepts regarding the gut-brain signaling in PD pathogenesis are changing rapidly and more investigation is required. The gut microbiota interacts with the human body by modulating the enteric and central nervous systems, and immune activity. Understanding the immune responses between gut microbiota and human body might help in elucidating the PD pathogenesis. As changes in gut microbiota composition might be associated with different clinical phenotypes of PD, gut microbiota-modulating interventions, such as probiotics and fecal microbiota transplantation (FMT), have the potential to restore the gut dysbiosis, reduce inflammation, and possibly modulate the clinical PD phenotype., (© 2021. Crown.)

Background: Postural Instability and Gait difficulties (PIGD) subtype has been associated with worse cognitive performance in Parkinson's disease (PD)., Objective: To investigate whether PIGD subtype classification or PIGD-related clinical features predict the development of cognitive decline in de novo PD patients., Methods: Data from 422 PD patients with de novo PD were obtained from the PPMI database. At follow-up (up to 6 years), patients were categorized as having cognitive impairment or not. Multivariate Cox survival analysis was carried out including motor subtype and individual MDS-UPDRS items defining PIGD phenotype as predictors. Previously validated clinical predictors of cognitive impairment were included in the model as covariates. Occurrence of cognitive impairment at follow-up was used as the time-to-event and Kaplan-Meier curve was generated., Results: At baseline, 76 patients were classified as PIGD, 299 tremor-dominant and 47 as indeterminate. Development of cognitive impairment was not associated with PIGD subtype (p = 0.252). When individual MDS-UPDRS items were interrogated in the model, postural instability proved to be an independent predictor of cognitive impairment (HR = 2.045; 95%CI: 1.068-3.918; p = 0.031), while gait difficulties were not associated with cognitive decline (p = 0.870)., Conclusions: Our findings suggest that postural instability, as assessed by MDS-UPDRS III, may serve as a possible indicator of the risk of developing cognitive impairment in de novo PD patients rather than the PIGD phenotype., (© 2021. The Author(s).)