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Objective: Prior research has identified that people with Parkinson's reporting lower levels of self-efficacy exhibit worsening motor and non-motor symptomology, reduced quality of life, and self-management. Our key objective was to conduct a scoping review examining the impact of digital health technologies on self-efficacy in people with Parkinson's., Design: A scoping review using Arksey and O'Malley's (2005) framework was undertaken., Data Sources: MEDLINE, Embase, PsychINFO, CINAHL, Web of Science, IEEE Xplore, and Google Scholar principally for grey literature were searched from 1 January 2008 to the 24th of July 2024., Eligibility Criteria for Selecting Studies: Primary studies which incorporated digital health technologies, measured self-efficacy and had a sample population of people with Parkinson's were searched., Data Extraction and Synthesis: Following identification of potentially eligible records, two independent reviewers undertook title and abstract screening, followed by full-text screening. Data was extracted using our earlier published data extraction sheet which incorporated the Practical Reviews in Self-Management Support (PRISMS) taxonomy, and the template for intervention description and replication (TIDieR) checklist. Data was extracted from a Microsoft Excel spreadsheet and synthesised by describing themes, demographic data and numerical data., Results: From 33 165 unique records following screening and independent review by two reviewers, 11 eligible records were found. Of these five elevated self-efficacy to a statistically significant level, five did not and one lowered self-efficacy. Of the studies which raised self-efficacy to a statistically significant level, all adopted a multimodal approach with a variety of devices. Thematically, these devices were focused on physical activity, falls/falls prevention, or both. The level of heterogeneity precluded comparisons between studies., Conclusions: This scoping review identified significant knowledge and evidence gaps in the literature, and the limited number of eligible studies make these findings not generalisable. Future self-management research might benefit from also considering self-efficacy., Competing Interests: Competing interests: VA sits on the Statistical Advisory Board of the BMJ Open. AMH, CBC and EM have not competing interests to declare., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background: Drooling, defined as the unintentional loss of saliva from the anterior oral cavity, remains poorly understood in terms of the underlying clinical factors in people with Parkinson's disease (PwP). This study aims to clarify these factors by analyzing predictors and secondarily the correlates with the severity of drooling in PwP., Methods: We conducted a cross-sectional study involving 42 PwP with drooling and 59 without drooling. Clinical assessments were performed, and the primary outcome was the item 2.2 Saliva and drooling of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale. The Mann-Whitney test was used to compare the distribution differences in clinical variables between PwP with and without drooling. The Spearman test was used to examine correlations with drooling, and ordinal logistic regression was used to examine predictors of drooling., Results: PwP with drooling showed significantly greater impairments in axial signs, posture, facial expression, speech, swallowing, oromotor, motor and non-motor domains than PwP without drooling. Longer disease duration, higher disease severity, levodopa equivalent daily dose, axial signs, unstimulated salivary flow rate, and impairments in speech, posture, facial expression, swallowing, oromotor, motor and non-motor domains were significantly correlated with a higher score on the item 2.2. Male sex, poorer swallowing, oromotor and speech functions were strong predictors of higher scores on the item 2.2 Saliva and drooling., Conclusions: Male PwP with swallowing disorders, oromotor and speech impairments are significantly more likely to have severe drooling. Targeted interventions aimed at these swallowing, oromotor, and speech impairments may offer promising approaches to reducing drooling severity in PwP., Competing Interests: Declarations. Conflicts of interest: The authors declare no competing interests. Ethical approval: The study was conducted in agreement with the Declaration of Helsinki. This study was approved by the Health Care Ethics Committee of the Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal (Ref. No. 2284). Written consent was obtained from all participants prior to study participation., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Aggregation of alpha-synuclein (aSyn) occurs in presynaptic neurons and constitutes a key factor for the progression of Parkinson's disease, emphasising the urgency of early detection to support effective treatment. Unfortunately, a reliable, sensitive and cost-effective diagnostic tool has so far been lacking. Thus, this work presents a novel biosensor for detecting aSyn using plastic antibodies coupled to electrochemical detection. This biosensor was designed for portability and compatibility with point-of-care devices and exploits the electropolymerization of methylene blue (MB) together with aSyn on the carbon working electrode of screen-printed electrodes (SPEs). By electrochemical impedance spectroscopy (EIS) measurements, the sensor showed exceptional analytical performance in detecting aSyn monomers in human CSF samples. It showed a linear trend of response from 1 fM to 10 pM with an impressively low limit of detection of 69 aM. Selectivity tests confirmed the predominant response to aSyn monomers, a less intense response to oligomers and insensitivity to fibrils. Overall, this plastic antibody-based electrochemical sensor represents a significant breakthrough as it is the first of its kind to accurately, sensitively and selectively detect aSyn monomers with a partial response to oligomers. Its simplicity and reproducibility promise to contribute to the early and effective diagnosis of Parkinson's disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Pain is reported as one of the most troubling symptoms for people with Parkinson's (PwP); however, the literature exploring their lived experience of pain and how to manage it is limited. Pain affects PwP at all stages of their condition and can fluctuate and change over time. Therefore, it is pertinent to speak to PwP to understand their experiences of pain to inform the development of tailored behavioural interventions to manage pain. How pain interacts with other Parkinson's symptoms lacks consensus. Gaining a better understanding of this from the perspective of PwP is important to inform interventions. Exploring the behavioural determinants, including the barriers and enablers to pain management from the perspective of PwP, the role of healthcare professionals and impact of other symptoms alongside pain will inform the development of a fit for purpose, pain management toolkit for PwP., Methods and Analysis: A longitudinal qualitative study using semi structured interviews at two time points within an 18-month period will be conducted. PwP living with pain will be purposefully sampled from four NHS sites in the North of England. Data will be thematically analysed with reference to the Theoretical Domains Framework., Ethics and Dissemination: A favourable ethical opinion has been granted by the National Health Service East Midlands-Derby Research Ethics Committee (22/EM/0176) and the NHS Health Research Authority (IRAS ID 316403). Findings will be disseminated via scientific conferences, academic journals, lay summaries and public engagement events., Competing Interests: Competing interests: AY received funding from Dunhill Medical Trust, EU IMI, NIHR, Parkinson’s UK, Michael J Fox Foundation, Weston Brain Institute, Lewy Body Society and Intercept Pharmaceuticals and received funding and/or honoraria from Britannia, UCB, AbbVie, GSK, Teva-Lundbeck, GE Healthcare and Genus for attending or speaking at educational events. LR received funding from NIHR, MRC, EU, Parkinson’s UK, Dunhill Medical Trust and Cure Parkinson’s trust. CR is a named inventor on a patent for the sensory discrimination training device for the treatment of phantom limb pain, which could result in financial benefit if commercialised. CR received consultancy fees paid to his University employer for his involvement in a pain education public health campaign, and he received no personal income from this. TF was additionally funded by the National Institute for Health Research (NIHR) Applied Research Collaboration (ARC) North East and North Cumbria (NIHR200173). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The remaining authors have no competing interests to declare., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ Group.)

Isolated rapid-eye-movement sleep behavior disorder (iRBD) is a strong predictor of Parkinson's disease and Dementia with Lewy bodies. Previous studies indicate that cortical atrophy in iRBD patients may be linked to cognitive impairment, but the pattern of atrophy is inconsistently reported. This study aimed to elucidate cortical atrophy patterns in a cognitively unimpaired iRBD cohort, focusing on regions associated with cognitive functions, particularly the cuneus/precuneus, and evaluated the predictive value for future phenoconversion. We conducted voxel-based morphometry and region of interest (ROI) analysis of structural MRI scans of 36 healthy controls and 19 iRBD patients, nine of whom also received a 3-year follow-up MRI scan. The iRBD patients were followed clinically for 8 years, and time-to-event analyses, using Cox regression, were performed based on baseline ROI volumes. The iRBD patients had lower gray-matter volume in the cuneus/precuneus region as well as in subcortical structures (caudate nuclei and putamen) compared to controls. Eight iRBD patients developed either Parkinson's disease (N = 4) or Dementia with Lewy bodies (N = 4) during the follow-up period. Time-to-event analyses showed that lower right cuneus volume was associated with a higher risk of phenoconversion to alpha-synuclein-linked Parkinsonism in the iRBD patients (Hazard ratio = 13.0, CI: 1.53-110), and correlated with shorter time to conversion. In addition, lower volumes of the bilateral precuneus trended to indicate a higher risk of phenoconversion. These findings suggest a potential predictive value of cuneus and precuneus volumes in identifying iRBD patients at risk of disease progression, even before the onset of cognitive impairment., Competing Interests: Declarations. Conflicts of interest: The authors declare that they have no conflicts of interests. Consent and ethics approval: Before enrollment in the study, all study participants gave written informed consent according to the Declaration of Helsinki. The study protocol was approved by the Central Denmark Region Committee on Health Research (M-2014–397-14) and the ethics committee of the Hospital Clínic de Barcelona (HCB/2015/0186)., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Appetite dysregulation in Parkinson's Disease (PD) appears to be linked to physical and cognitive deterioration. PD patients with and without cognitive impairment (CI) were compared to an age-matched control group to explore predictors of appetite control in fasting and post-prandial conditions., Methods: Fifty-five patients were recruited and divided into three groups: twenty controls (age: 74 y, BMI: 25.8 kg/m 2 ), nineteen PD patients without CI (72.5 y, 25.1 kg/m 2 ) and sixteen PD patients with CI (74.3 y, 24.0 kg/m 2 ). Self-reported appetite perception and circulating blood metabolic biomarkers were measured in fasting and over a 3-h post-prandial period. Biomarkers included glucose, insulin, tumour necrosis factor alpha (TNF-α), leptin, acyl-ghrelin, total ghrelin, peptide YY (PYY), glucagon like peptide 1 (GLP-1), insulin growth factor 1 (IGF-1), growth factor (GF) and triglycerides. Patients were then provided with a mixed meal to eat ad libitum with the aim to evaluate links between metabolic biomarkers and control of energy intake., Results: PD patients with CI had a significant lower protein intake (7.4 ± 2.5 g, p = 0.01) compared to controls (21.9 ± 3.1 g) and PD patients without CI (14.3 ± 3.0 g). Post-prandial plasma GLP-1 concentrations were associated with decreased hunger perception (B±SE, -5.3 ± 2.4  mm·h -1 , p = 0.04). PYY concentrations were significantly associated with GLP-1 in fasting (r = 0.40, p = 0.005) and post-prandial (r = 0.46, p < 0.001) conditions. In a multivariate model, post-prandial PYY concentrations were a significant predictor of ad libitum energy intake in all subjects (B±SE, -87.5 ± 34.9 kcal, p = 0.01) and in patients with PD (B±SE, -106.8 ± 44.9 kcal, p = 0.04)., Conclusions: PYY and GLP-1 appeared to influence appetite control in PD patients and their roles merit further investigation., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The Phase II trial of Anti-alpha-Synuclein Antibody in Early Parkinson's Disease (PASADENA) is an ongoing double-blind, placebo-controlled trial evaluating the safety and efficacy of prasinezumab in early-stage Parkinson's disease (PD). During the double-blind period, prasinezumab-treated individuals showed less progression of motor signs (Movement Disorders Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III) than placebo-treated individuals. We evaluated whether the effect of prasinezumab on motor progression, assessed as a change in MDS-UPDRS Part III score in the OFF and ON states, and MDS-UPDRS Part II score, was sustained for 4 years from the start of the trial. We compared participants enrolled in the PASADENA open-label extension study with those enrolled in an external comparator arm derived from the Parkinson's Progression Markers Initiative observational study. The PASADENA delayed-start (n = 94) and early-start (n = 177) groups showed a slower decline (a smaller increase in score) in MDS-UPDRS Part III scores in the OFF state (delayed start, -51%; early start, -65%), ON state (delayed start, -94%; early start, -118%) and MDS-UPDRS Part II (delayed start, -48%; early start, -40%) than did the Parkinson's Progression Markers Initiative external comparator (n = 303). This exploratory analysis, which requires confirmation in future studies, suggested that the effect of prasinezumab in slowing motor progression in PD may be sustained long term. PASADENA ClinicalTrials.gov no. NCT03100149 ., Competing Interests: Competing interests: G.P., A.M., A.R., B.R., T.K., K.S., P.F., R.D., G.A.K., P.B., A.B. and T.N. are employees and shareholders of F. Hoffmann-La Roche Ltd. R.D. is also employed by Genentech. P.B. also has ownership interests in Acousort AB, Enterin Inc, Axial Therapeutics and Kenai Therapeutics. H.S. is an employee of Roche Diagnostics GmbH Deutschland and a shareholder of F. Hoffmann-La Roche. In the past 12 months, T.S. has served as a consultant for AskBio, Amneal, BlueRock Therapeutics, Critical Path for Parkinson’s Consortium, Denali, General Electric, Kyowa, Neuroderm/MTPA, Prevail/Lilly, Roche, Sanofi, Sinopia, Takeda and Vanqua Bio. T.S. has served on advisory boards for AskBio, Amneal, Biohaven, Denali, GAIN, General Electric, Kyowa, The Michael J. Fox Foundation, Neuron23, Parkinson Study Group, Prevail/Lilly and Roche. T.S. has also served as a member of the scientific advisory board of Koneksa, Neuroderm/MTPA, Sanofi and UCB, has received research funding from Amneal, Biogen, Neuroderm, Prevail, Roche and UCB and is an investigator for the National Institute of Neurological Disorders and Stroke, The Michael J. Fox Foundation and the Parkinson’s Foundation. R.B.P. reports grants and personal fees from Fonds de la Recherche en Sante, grants from the Canadian Institute of Health Research, grants from The Michael J. Fox Foundation, grants from Webster Foundation, personal fees from Biogen, personal fees from Curasen, personal fees from Novartis, personal fees from Eisai, other from Parkinson Canada, grants from National Institutes of Health, personal fees from International Parkinson and Movement Disorders Society, personal fees from Merck, personal fees from Vaxxinity, personal fees from Bristol Myers Squibb, personal fees from Clinilabs, personal fees from Ventus, personal fees from Korro and personal fees from Calico. R.B.P. also received consulting fees from Roche for helping to plan and interpret the study. N.P. reports participation in advisory boards for Britannia, Boston Scientific, Benevolent AI, Hoffmann-La Roche, Inc. and Abbvie. N.P. also reports receiving honoraria from Britannia, Abbvie, GE Healthcare and Boston Scientific, and grants from the Independent Research Fund Denmark, Danish Parkinson’s disease Association, Parkinson’s UK, Center of Excellence in Neurodegeneration network award, GE Healthcare Grant, Multiple System Atrophy Trust, Weston Brain Institute, EU Joint Program Neurodegenerative Disease Research, EU Horizon 2020 research, The Michael J. Fox Foundation for Parkinson’s Research and F. Hoffmann-La Roche, Inc. F.S. is a consultant for AbbVie, Bial Pharma, Biogen, F. Hoffmann-La Roche Ltd., H. Lundbeck A S, Mitsubishi Tanabe Pharma America, Inc., Sunovion Pharmaceuticals, Inc., Teva Pharmaceutical Industries, Zambon and Britannia. K.B. has received research funding from The Michael J. Fox Foundation for Parkinson’s Research, the German Society for Parkinson DPG, the Health Forum Baden Wuerttemberg, the Else Kröner Fresenius Stiftung, the University of Tuebingen and the German Research Foundation DFG. K.B. is a consultant for F. Hoffmann-La Roche Ltd., Vanqua Bio and The Michael J. Fox Foundation for Parkinson’s Research, and has received speaker honoraria from Abbvie, Lundbeck, UCB and Zambon. V.G. is a full-time employee of Excelya Germany GmbH and was an external business partner of F. Hoffmann-La Roche Ltd. K.M. is a consultant for The Michael J. Fox Foundation for Parkinson’s Research, F. Hoffmann-La Roche Ltd UCB, Denali, Takeda, Biohaven, Neuron23, Aprinoia, Prothena, Calico, Inhibikase, Invicro, Koneksa and Lilly., (© 2024. The Author(s).)

REM sleep behaviour disorder (RBD) is a parasomnia characterised by dream-enacting behaviour with loss of muscle atonia during REM sleep and is a prodromal feature of α-synucleinopathies like Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Although cortical-to-subcortical connectivity is well-studied in RBD, cerebellar and subcortical nuclei reciprocal connectivity is less established. Nonetheless, it could be relevant since RBD pathology involves brainstem structures with an ascending gradient. In this study, we utilised resting-state functional MRI to investigate 13 people with isolated RBD (iRBD), 17 with Parkinson's disease and 16 healthy controls. We investigated the connectivity between the basal ganglia, thalamus and regions of the cerebellum. The cerebellum was segmented using a functional atlas, defined by a resting-state network-based parcellation, rather than an anatomical one. Controlling for age, we found a significant group difference (F 4,82 = 5.47, p FDR = 0.017) in cerebellar-thalamic connectivity, with iRBD significantly lower compared to both control and Parkinson's disease. Specifically, cerebellar areas involved in this connectivity reduction were related to the default mode, language and fronto-parietal resting-state networks. Our findings show functional connectivity abnormalities in subcortical structures that are specific to iRBD and may be relevant from a pathophysiological standpoint. Further studies are needed to investigate how connectivity changes progress over time and whether specific changes predict disease course or phenoconversion., Competing Interests: Declarations. Ethical approval: Ethical approval was granted by the London-Surrey Research Ethics Committee Research Ethics Committee (18/LO/2123). All participants gave written informed consent. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Little is known about the relationship between parkinsonism or Parkinson's disease (PD) and frailty in Latin America., Objective: The study aimed to determine the cross-sectional and prospective associations between parkinsonism and PD with frailty in a large multi-country cohort in Latin America. Frailty was assessed using three different models to explore which definitions are more appropriate to screen for frailty in a PD population., Methods: 12,865 older adults (aged ≥65 years) from the 10/66 population-based cohort study in six Latin American countries were analyzed. Logistic regression models assessed the cross-sectional association between parkinsonism/PD with baseline frailty. Individual country analyses were combined via fixed-effect meta-analysis. In non-frail participants who were followed up for 4 years, Cox proportional hazards regression models assessed the prospective association between parkinsonism/PD with incident frailty accounting for competing risk of mortality., Results: At baseline, the prevalence of parkinsonism and PD was 7% and 2%, respectively, and the prevalence of frailty varied across the three models with rates of 18% for frailty phenotype, 20% for frailty index and 30% for multidimensional frailty model. PD was associated with baseline and incident frailty after accounting for age, sex, and education: odds ratios and 95% confidence intervals (95% CI) for frailty were 2.49 (95% CIs 1.87-3.31), 2.42 (95% CIs 1.80-3.25), and 1.57 (95% CIs 1.16-2.21), and cause-specific hazard ratios were 1.66 (95% CIs 1.07-2.56), 1.78 (95% CIs 1.05-3.03), and 1.58 (95% CIs 0.91-2.74). Similar results were found for parkinsonism., Conclusion: Parkinsonism and PD were cross-sectionally and prospectively associated with frailty in Latin America. Routine screening for frailty in PD patients may aid earlier detection of those at greater risk of adverse outcomes., (© 2024 The Author(s). Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Of the neurodegenerative diseases, Parkinson's disease is recognised to have the fastest growing prevalence. It is unclear whether this is due to the ageing global population alone, with several environmental factors increasingly implicated in changing prevalence rates. Large data sets have been used nationally and globally to help predict future disease burden. However, the reliability of such sources is yet unknown for Parkinson's disease., Summary: This review discusses the methods used in all published UK prevalence studies conducted to date. Direct comparison between prevalence figures obtained from the 10 to discussed prevalence studies is precluded due to differences in methodology for case ascertainment and diagnosis. Age adjusted estimates vary from 105/100,000 to 168/100,000., Key Messages: These studies demonstrate no overall trend in changing prevalence figures between 1961 and 2007. No difference in prevalence trends were seen for those living in rural or urban areas. Differences between ethnic groups, for example, remains an under explored area., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The accessibility of Parkinson's disease medicines is limited across sub-Saharan Africa, which can have negative health, social and financial consequences for people with Parkinson's disease and their families. However, there is a stark gap in the literature regarding the impact of poor access to medicines on individuals., Objectives: The study objective was to understand the accessibility of Parkinson's disease medicines in Kenya from the perspective of people with Parkinson's disease, their caregivers and neurologists., Methods: In-depth qualitative interviews were conducted with 55 people with Parkinson's disease, 23 caregivers and 8 neurologists to understand their experience regarding challenges with accessing Parkinson's disease medicines and the health, social and financial impact of poor availability and affordability., Results: Medicines for Parkinson's disease were deemed to be largely unavailable and unaffordable across Kenya. People with Parkinson's disease, caregivers and neurologists expressed the financial burden caused by long-term treatment in the absence of health insurance coverage. Further, barriers accessing medicines negatively impacted symptom control, social relations, and quality of life., Conclusions: Access to Parkinson's disease medicines in Kenya is limited, with severe implications for symptom management and quality of life. People with Parkinson's disease should be able to access and afford the medicines they need to manage their condition., (© 2024 The Author(s). Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

The α-synuclein seed amplification assay (αSyn-SAA) sensitively detects Lewy pathology, the amyloid state of α-synuclein, in the cerebrospinal fluid (CSF) of patients with Parkinson's disease (PD). The αSyn-SAA harnesses the physics of seeding, whereby a superconcentrated solution of recombinant α-synuclein lowers the thermodynamic threshold (nucleation barrier) for aggregated α-synuclein to act as a nucleation catalyst ("seed") to trigger the precipitation (nucleation) of monomeric α-synuclein into pathology. This laboratory setup increases the signal for identifying a catalyst if one is present in the tissue examined. The result is binary: positive, meaning precipitation occurred, and a catalyst is present, or negative, meaning no precipitation, therefore no catalyst. Since protein precipitation via seeding can only occur at a concentration many-fold higher than the human brain, laboratory-elicited seeding does not mean human brain seeding. We suggest that a positive αSyn-SAA reveals the presence of pathological α-synuclein but not the underlying etiology for the precipitation of monomeric α-synuclein into its pathological form. Thus, a positive αSyn-SAA supports a clinical diagnosis of PD but cannot inform disease pathogenesis, ascertain severity, predict the rate of progression, define biology or biological subtypes, or monitor treatment response., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interestsAlberto J Espay reports financial support was provided by NeuroDerm Ltd. Alberto J Espay reports financial support was provided by Amneal Pharmaceuticals LLC. Alberto J Espay reports financial support was provided by ACADIA Pharmaceuticals Inc. Alberto J Espay reports financial support was provided by Avion Pharmaceuticals. Alberto J Espay reports financial support was provided by Acorda Therapeutics Inc. Alberto J Espay reports financial support was provided by Kyowa Kirin Pharma BV. Alberto J Espay reports financial support was provided by Supernus Pharmaceuticals Inc. Alberto J Espay reports financial support was provided by SYNAPS Dx. Alberto J Espay reports financial support was provided by Herantis Pharma Oyj. Alberto J Espay reports a relationship with National Institutes of Health that includes: funding grants. Alberto J Espay reports a relationship with Michael J Fox Foundation for Parkinson's Research that includes: funding grants. Alberto J Espay has patent synthetic soluble nonaggregating peptide analogues as replacement treatments in proteinopathies pending to Regain Therapeutics. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Various forms of Parkinson's disease, including its common sporadic form, are characterized by prominent α-synuclein (αSyn) aggregation in affected brain regions. However, the role of αSyn in the pathogenesis and evolution of the disease remains unclear, despite vast research efforts of more than a quarter century. A better understanding of the role of αSyn, either primary or secondary, is critical for developing disease-modifying therapies. Previous attempts to hone this research have been challenged by experimental limitations, but recent technological advances may facilitate progress. The Scientific Issues Committee of the International Parkinson and Movement Disorder Society (MDS) charged a panel of experts in the field to discuss current scientific priorities and identify research strategies with potential for a breakthrough. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Parkinson disease (PD) poses emotional and financial challenges to patients, families, caregivers, and health care systems. Self-management systems show promise in empowering people with PD and enabling more control over their treatment. The collaborative nature of PD care requires communication between patients and health care professionals. While past reviews explored self-management systems in PD diagnosis and symptom management with a focus on patient portals, there is limited research addressing the interconnectivity of systems catering to the needs of both patients and clinicians. A system's acceptability and usability for clinicians are pivotal for enabling comprehensive data collection and supporting clinical decision-making, which can enhance patient care and treatment outcomes., Objective: This review study aims to assess PD self-management systems that include a clinician portal and to determine which features enhance acceptability and usability for clinicians. The primary aim is to assess evidence of clinicians' acceptability and usability of self-management systems with a focus on the integration of systems into clinical workflows, data collection points, monitoring, clinical decision-making support, and extended education and training., Methods: The review will entail 3 separate stages: a literature review following the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines, a product search, and an evaluation of the level of evidence for the identified products. For the first stage, 5 databases will be searched: PubMed, CINAHL, Scopus, ACM digital library, and IEEE Xplore. Studies eligible for inclusion will be qualitative, quantitative, and mixed methods studies examining patients' and clinician's perceptions of the acceptability and usability of digital health interventions, synthesized by a narrative qualitative analysis. A web search in the iOS Apple App Store and Android Google Play Store will identify currently available tools; the level of evidence for these will then be assessed using the Oxford Centre for Evidence-Based Medicine guidelines., Results: Literature search and screening began soon after submission of the protocol, and the review is expected to be completed by end of September 2024., Conclusions: This review will examine currently available self-management systems in PD care, focusing on their acceptability and usability. This is significant because there is limited research addressing the integration of clinicians into these systems. The findings from this study may provide critical knowledge and insight to help inform future research and will contribute to the design of self-management systems that promote collaborative efforts in PD care., International Registered Report Identifier (irrid): PRR1-10.2196/58845., (©Selina Boege, Madison Milne-Ives, Edward Meinert, Camille Carroll. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 24.09.2024.)

Traditional drug development in Parkinson's disease (PD) faces significant challenges because of its protracted timeline and high costs. In response, innovative master protocols are emerging and designed to address multiple research questions within a single overarching protocol. These trials may offer advantages such as increased efficiency, agility in adding new treatment arms, and potential cost savings. However, they also present organizational, methodological, funding, regulatory, and sponsorship challenges. We review the potential of master protocols, focusing on platform trials, for disease modifying therapies in PD. These trials share a common control group and allow for the termination or addition of treatment arms during a trial with non-predetermined end. Specific issues exist for a platform trial in the PD field considering the heterogeneity of patients in terms of phenotype, genotype and staging, the confounding effects of symptomatic treatments, and the choice of outcome measures with no consensus on a non-clinical biomarker to serve as a surrogate and the slowness of PD progression. We illustrate these aspects using the examples of the main PD platform trials currently in development with each one targeting distinct goals, populations, and outcomes. Overall, platform trials hold promise in expediting the evaluation of potential therapies for PD. However, it remains to be proven whether these theoretical benefits will translate into increased production of high-quality trial data. Success also depends on the willingness of pharmaceutical companies to engage in such trials and whether this approach will ultimately hasten the identification and licensing of effective disease-modifying drugs. © 2024 International Parkinson and Movement Disorder Society., (© 2024 International Parkinson and Movement Disorder Society.)

Neuromelanin-pigmented neurons of the substantia nigra are selectively lost during the progression of Parkinson's disease. These neurons accumulate iron in the disease state, and iron-mediated neuron damage is implicated in cell death. Animal models of Parkinson's have evidenced iron loading inside the nucleoli of nigral neurons, however the nature of intranuclear iron deposition in the melanised neurons of the human substantia nigra is not understood. Here, scanning transmission x-ray microscopy (STXM) is used to probe iron foci in relation to the surrounding ultrastructure in melanised neurons of human substantia nigra from a confirmed Parkinson's case. In addition to the expected neuromelanin-bound iron, iron deposits are also associated with the edge of the cell nucleolus. Speciation analysis confirms these deposits to be ferric (Fe 3+ ) iron. The function of intranuclear iron in these cells remains unresolved, although both damaging and protective mechanisms are considered. This finding shows that STXM is a powerful label-free tool for the in situ, nanoscale chemical characterisation of both organic and inorganic intracellular components. Future applications are likely to shed new light on incompletely understood biochemical mechanisms, such as metal dysregulation and morphological changes to cell nucleoli, that are important in understanding the pathogenesis of Parkinson's., (© 2024. The Author(s).)

Estimates of the spectrum and frequency of pathogenic variants in Parkinson's disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinson's disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The receptor for advanced glycation end products (RAGE) is a transmembrane receptor that belongs to the immunoglobulin superfamily and is extensively associated with chronic inflammation in non-transmissible diseases. As chronic inflammation is consistently present in neurodegenerative diseases, it was largely assumed that RAGE could act as a critical modulator of neuroinflammation in Parkinson's disease (PD), similar to what was reported for Alzheimer's disease (AD), where RAGE is postulated to mediate pro-inflammatory signaling in microglia by binding to amyloid-β peptide. However, accumulating evidence from studies of RAGE in PD models suggests a less obvious scenario. Here, we review physiological aspects of RAGE and address the current questions about the potential involvement of this receptor in the cellular events that may be critical for the development and progression of PD, exploring possible mechanisms beyond the classical view of the microglial activation/neuroinflammation/neurodegeneration axis that is widely assumed to be the general mechanism of RAGE action in the adult brain., (© 2023 International Society for Neurochemistry.)

Parkinson's disease is a neurodegenerative disorder primarily known for typical motor features that arise due to the loss of dopaminergic neurons in the substantia nigra. However, the precise molecular aetiology of the disease is still unclear. Several cellular pathways have been linked to Parkinson's disease, including the autophagy-lysosome pathway, α-synuclein aggregation and mitochondrial function. Interestingly, the mechanistic link between GBA1, the gene that encodes for lysosomal β-glucocerebrosidase (GCase), and Parkinson's disease lies in the interplay between GCase functions in the lysosome and mitochondria. GCase mutations alter mitochondria-lysosome contact sites. In the lysosome, reduced GCase activity leads to glycosphingolipid build-up, disrupting lysosomal function and autophagy, thereby triggering α-synuclein accumulation. Additionally, α-synuclein aggregates reduce GCase activity, creating a self-perpetuating cycle of lysosomal dysfunction and α-synuclein accumulation. GCase can also be imported into the mitochondria, where it promotes the integrity and function of mitochondrial complex I. Thus, GCase mutations that impair its normal function increase oxidative stress in mitochondria, the compartment where dopamine is oxidized. In turn, the accumulation of oxidized dopamine adducts further impairs GCase activity, creating a second cycle of GCase dysfunction. The oxidative state triggered by GCase dysfunction can also induce mitochondrial DNA damage which, in turn, can cause dopaminergic cell death. In this review, we highlight the pivotal role of GCase in Parkinson's disease pathogenesis and discuss promising examples of GCase-based therapeutics, such as gene and enzyme replacement therapies, small molecule chaperones and substrate reduction therapies, among others, as potential therapeutic interventions., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Parkinson's Disease (PD) is a progressive neurological disorder that results in potentially debilitating mobility deficits. Recently, spinal cord stimulation (SCS) has been proposed as a novel therapy for PD gait disorders. The highest levels of evidence remain limited for SCS., Objectives: In this systematic review and narrative synthesis, the literature was searched using combinations of key phrases indicating spinal cord stimulation and PD., Methods: We included pre-clinical studies and all published clinical trials, case reports, conference abstracts as well as protocols for ongoing clinical trials. Additionally, we included trials of SCS applied to atypical parkinsonism., Results: A total of 45 human studies and trials met the inclusion criteria. Based on the narrative synthesis, a number of knowledge gaps and future avenues of potential research were identified. This review demonstrated that evidence for SCS is currently not sufficient to recommend it as an evidence-based therapy for PD related gait disorders. There remain challenges and significant barriers to widespread implementation, including issues regarding patient selection, effective outcome selection, stimulation location and mode, and in programming parameter optimization. Results of early randomized controlled trials are currently pending. SCS is prone to placebo, lessebo and nocebo as well as blinding effects which may impact interpretation of outcomes, particularly when studies are underpowered., Conclusion: Therapies such as SCS may build on current evidence and be shown to improve specific gait features in PD. Early negative trials should be interpreted with caution, as more evidence will be required to develop effective methodologies in order to drive clinical outcomes., (© 2024 International Parkinson and Movement Disorder Society.)

Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by motor and non-motor symptoms. Motor symptoms include bradykinesia, resting tremors, muscular rigidity, and postural instability, while non-motor symptoms include cognitive impairments, mood disturbances, sleep disturbances, autonomic dysfunction, and sensory abnormalities. Some of these symptoms may be influenced by the proper hippocampus functioning, including adult neurogenesis. Doublecortin (DCX) is a microtubule-associated protein that plays a pivotal role in the development and differentiation of migrating neurons. This study utilized postmortem human brain tissue of PD and age-matched control individuals to investigate DCX expression in the context of adult hippocampal neurogenesis. Our findings demonstrate a significant reduction in the number of DCX-expressing cells within the subgranular zone (SGZ), as well as a decrease in the nuclear area of these DCX-positive cells in postmortem brain tissue obtained from PD cases, suggesting an impairment in the adult hippocampal neurogenesis. Additionally, we found that the nuclear area of DCX-positive cells correlates with pH levels. In summary, we provide evidence supporting that the process of hippocampal adult neurogenesis is likely to be compromised in PD patients before cognitive dysfunction, shedding light on potential mechanisms contributing to the neuropsychiatric symptoms observed in affected individuals. Understanding these mechanisms may offer novel insights into the pathophysiology of PD and possible therapeutic avenues., (© 2024 International Society for Neurochemistry.)

Falls are a major concern for people with Parkinson's disease (PwPD), but accurately assessing real-world fall risk beyond the clinic is challenging. Contemporary technologies could enable the capture of objective and high-resolution data to better inform fall risk through measurement of everyday factors (e.g., obstacles) that contribute to falls. Wearable inertial measurement units (IMUs) capture objective high-resolution walking/gait data in all environments but are limited by not providing absolute clarity on contextual information (i.e., obstacles) that could greatly influence how gait is interpreted. Video-based data could compliment IMU-based data for a comprehensive free-living fall risk assessment. The objective of this study was twofold. First, pilot work was conducted to propose a novel artificial intelligence (AI) algorithm for use with wearable video-based eye-tracking glasses to compliment IMU gait data in order to better inform free-living fall risk in PwPD. The suggested approach (based on a fine-tuned You Only Look Once version 8 (YOLOv8) object detection algorithm) can accurately detect and contextualize objects (mAP50 = 0.81) in the environment while also providing insights into where the PwPD is looking, which could better inform fall risk. Second, we investigated the perceptions of PwPD via a focus group discussion regarding the adoption of video technologies and AI during their everyday lives to better inform their own fall risk. This second aspect of the study is important as, traditionally, there may be clinical and patient apprehension due to ethical and privacy concerns on the use of wearable cameras to capture real-world video. Thematic content analysis was used to analyse transcripts and develop core themes and categories. Here, PwPD agreed on ergonomically designed wearable video-based glasses as an optimal mode of video data capture, ensuring discreteness and negating any public stigma on the use of research-style equipment. PwPD also emphasized the need for control in AI-assisted data processing to uphold privacy, which could overcome concerns with the adoption of video to better inform IMU-based gait and free-living fall risk. Contemporary technologies (wearable video glasses and AI) can provide a holistic approach to fall risk that PwPD recognise as helpful and safe to use.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Ferroptosis, an iron-dependent form of regulated cell death, may contribute to the progression of PD owing to an unbalanced brain redox status. Physical exercise is a complementary therapy that can modulate ferroptosis in PD by regulating the redox system through the activation of nuclear factor (erythroid-derived 2)-like 2 (NRF2) and brain-derived neurotrophic factor (BDNF) signaling. However, the precise effects of physical exercise on ferroptosis in PD remain unclear. In this review, we explored how physical exercise influences NRF2 and BDNF signaling and affects ferroptosis in PD. We further investigated relevant publications over the past two decades by searching the PubMed, Web of Science, and Google Scholar databases using keywords related to physical exercise, PD, ferroptosis, and neurotrophic factor antioxidant signaling. This review provides insights into current research gaps and demonstrates the necessity for future research to elucidate the specific mechanisms by which exercise regulates ferroptosis in PD, including the assessment of different exercise protocols and their long-term effects. Ultimately, exploring these aspects may lead to the development of improved exercise interventions for the better management of patients with PD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Parkinson's disease (PD) is a progressive and disabling neurodegenerative disease that rapidly worsens and results in premature mortality if left untreated. Although levodopa is the gold standard treatment for PD globally, its accessibility and affordability are severely limited in low- and middle-income countries worldwide. In this scenario, Mucuna pruriens (MP), a leguminous plant growing wild in tropical regions, emerges as a potential alternative or adjunct to levodopa-based medications due to its cost-effectiveness and global natural availability. Recent studies have demonstrated that MP can significantly ameliorate motor symptoms, although tolerability may vary. The proposition that MP could play a pivotal role in providing affordable and symptomatic relief for PD in low- and middle-income countries is grounded in its promising therapeutic profile, yet caution is warranted until more comprehensive data on the long-term safety and efficacy of MP become available. This manuscript summarizes the knowledge gained about MP by the authors, focusing on how to cultivate, store, and provide it to patients in the safest and most effective way in clinical trials. We aim to increase clinical trials investigating its safety and efficacy in PD, before promoting individual use of MP on a global scale, particularly in countries where availability and affordability of levodopa-based medications is still limited., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Roberto Cilia is an Associate Editor for Parkinsonism and Related Disorders If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: People with Parkinson's disease (PD) have an increased risk of dementia, yet patients and clinicians frequently avoid talking about it due to associated stigma, and the perception that "nothing can be done about it". However, open conversations about PD dementia may allow people with the condition to access treatment and support, and may increase participation in research aimed at understanding PD dementia., Objectives: To co-produce information resources for patients and healthcare professionals to improve conversations about PD dementia., Methods: We worked with people with PD, engagement experts, artists, and a PD charity to open up these conversations. 34 participants (16 PD; 6 PD dementia; 1 Parkinsonism, 11 caregivers) attended creative workshops to examine fears about PD dementia and develop information resources. 25 PD experts contributed to the resources., Results: While most people with PD (70%) and caregivers (81%) shared worries about cognitive changes prior to the workshops, only 38% and 30%, respectively, had raised these concerns with a healthcare professional. 91% of people with PD and 73% of caregivers agreed that PD clinicians should ask about cognitive changes routinely through direct questions and perform cognitive tests at clinic appointments. We used insights from the creative workshops, and input from a network of PD experts to co-develop two open-access resources: one for people with PD and their families, and one for healthcare professionals., Conclusion: Using artistic and creative workshops, co-learning and striving for diverse voices, we co-produced relevant resources for a wider audience to improve conversations about PD dementia., (© 2024 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Purpose: Current methods for diagnosis of PD rely on clinical examination. The accuracy of diagnosis ranges between 73 and 84%, and is influenced by the experience of the clinical assessor. Hence, an automatic, effective and interpretable supporting system for PD symptom identification would support clinicians in making more robust PD diagnostic decisions., Methods: We propose to analyze Parkinson's tremor (PT) to support the analysis of PD, since PT is one of the most typical symptoms of PD with broad generalizability. To realize the idea, we present SPA-PTA, a deep learning-based PT classification and severity estimation system that takes consumer-grade videos of front-facing humans as input. The core of the system is a novel attention module with a lightweight pyramidal channel-squeezing-fusion architecture that effectively extracts relevant PT information and filters noise. It enhances modeling performance while improving system interpretability., Results: We validate our system via individual-based leave-one-out cross-validation on two tasks: the PT classification task and the tremor severity rating estimation task. Our system presents a 91.3% accuracy and 80.0% F1-score in classifying PT with non-PT class, while providing a 76.4% accuracy and 76.7% F1-score in more complex multiclass tremor rating classification task., Conclusion: Our system offers a cost-effective PT classification and tremor severity estimation results as warning signs of PD for undiagnosed patients with PT symptoms. In addition, it provides a potential solution for supporting PD diagnosis in regions with limited clinical resources., (© 2024. The Author(s).)

Since the original description by James Parkinson, Parkinson's disease (PD) has intrigued us for over 200 years. PD is a progressive condition that is incurable so far, and affects millions of people worldwide. Over the years, our knowledge has expanded tremendously, and a range of criteria have been put forward and used to try to define PD. However, owing to the complexity of the problem, it is still not consensual how to diagnose and classify a disease that manifests with diverse features, and that responds differently to existing therapies and to those under development. We are now living a time when 'biological' information is becoming abundant, precise, and accessible enabling us to attempt to incorporate different sources of information to classify different forms of PD. These refinements are essential for basic science, as they will enable us to develop improved models for studying PD, and to implement new findings into clinical practice, as this will be the path towards effective personalized medicine., Competing Interests: Declaration of competing interest The authors have no relevant conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Sensory loss in olfaction, vision, and hearing is a risk factor for dementia, but the reasons for this are unclear. This review presents the neurobiological evidence linking each sensory modality to specific dementias and explores the potential mechanisms underlying this. Olfactory deficits can be linked to direct neuropathologic changes in the olfactory system due to Alzheimer disease and Parkinson disease, and may be a marker of disease severity. Visual deficits potentially increase dementia risk in a vulnerable individual by reducing resilience to dementia. Hearing deficits may indicate a susceptibility to Alzheimer disease through a variety of mechanisms. More generally, sensory impairment could be related to factors associated with resilience against dementia. Further research is needed to tease out the specific and synergistic effects of sensory impairment. Studying sensory loss in relation to neurodegenerative biomarkers is necessary to clarify the mechanisms involved. This could produce new monitoring and management strategies for people at risk of dementia., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Prasinezumab, a monoclonal antibody that binds aggregated α-synuclein, is being investigated as a potential disease-modifying therapy in early-stage Parkinson's disease. Although in the PASADENA phase 2 study, the primary endpoint (Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) sum of Parts I + II + III) was not met, prasinezumab-treated individuals exhibited slower progression of motor signs than placebo-treated participants (MDS-UPDRS Part III). We report here an exploratory analysis assessing whether prasinezumab showed greater benefits on motor signs progression in prespecified subgroups with faster motor progression. Prasinezumab's potential effects on disease progression were assessed in four prespecified and six exploratory subpopulations of PASADENA: use of monoamine oxidase B inhibitors at baseline (yes versus no); Hoehn and Yahr stage (2 versus 1); rapid eye movement sleep behavior disorder (yes versus no); data-driven subphenotypes (diffuse malignant versus nondiffuse malignant); age at baseline (≥60 years versus <60 years); sex (male versus female); disease duration (>12 months versus <12 months); age at diagnosis (≥60 years versus <60 years); motor subphenotypes (akinetic-rigid versus tremor-dominant); and motor subphenotypes (postural instability gait dysfunction versus tremor-dominant). In these subpopulations, the effect of prasinezumab on slowing motor signs progression (MDS-UPDRS Part III) was greater in the rapidly progressing subpopulations (for example, participants who were diffuse malignant or taking monoamine oxidase B inhibitors at baseline). This exploratory analysis suggests that, in a trial of 1-year duration, prasinezumab might reduce motor progression to a greater extent in individuals with more rapidly progressing Parkinson's disease. However, because this was a post hoc analysis, additional randomized clinical trials are needed to validate these findings., (© 2024. The Author(s).)

Parkinson's disease (PD) is among the most prevalent neurodegenerative disorders, affecting over 10 million people worldwide. The protein encoded by the SNCA gene, alpha-synuclein (ASYN), is the major component of Lewy body (LB) aggregates, a histopathological hallmark of PD. Mutations and posttranslational modifications (PTMs) in ASYN are known to influence protein aggregation and LB formation, possibly playing a crucial role in PD pathogenesis. In this work, we applied computational methods to characterize the effects of missense mutations and PTMs on the structure and function of ASYN. Missense mutations in ASYN were compiled from the literature/databases and underwent a comprehensive predictive analysis. Phosphorylation and SUMOylation sites of ASYN were retrieved from databases and predicted by algorithms. ConSurf was used to estimate the evolutionary conservation of ASYN amino acids. Molecular dynamics (MD) simulations of ASYN wild-type and variants A30G, A30P, A53T, and G51D were performed using the GROMACS package. Seventy-seven missense mutations in ASYN were compiled. Although most mutations were not predicted to affect ASYN stability, aggregation propensity, amyloid formation, and chaperone binding, the analyzed mutations received relatively high rates of deleterious predictions and predominantly occurred at evolutionarily conserved sites within the protein. Moreover, our predictive analyses suggested that the following mutations may be possibly harmful to ASYN and, consequently, potential targets for future investigation: K6N, T22I, K34E, G36R, G36S, V37F, L38P, G41D, and K102E. The MD analyses pointed to remarkable flexibility and essential dynamics alterations at nearly all domains of the studied variants, which could lead to impaired contact between NAC and the C-terminal domain triggering protein aggregation. These alterations may have functional implications for ASYN and provide important insight into the molecular mechanism of PD, supporting the design of future biomedical research and improvements in existing therapies for the disease., (© 2024 Wiley Periodicals LLC.)

Background: Inpatient prevalence of Parkinson's disease (PD) delirium varies widely across the literature. Delirium in general older populations is associated with adverse outcomes, such as increased mortality, dementia, and institutionalisation. However, to date there are no comprehensive prospective studies in PD delirium. This study aimed to determine delirium prevalence in hospitalised PD participants and the association with adverse outcomes, compared to a control group of older adults without PD., Methods: Participants were hospitalised inpatients from the 'Defining Delirium and its Impact in Parkinson's Disease' and the 'Delirium and Cognitive Impact in Dementia' studies comprising 121 PD participants and 199 older adult controls. Delirium was diagnosed prospectively using the Diagnostic and Statistical Manual of Mental Disorders 5th Edition criteria. Outcomes were determined by medical note reviews and/or home visits 12 months post hospital discharge., Results: Delirium was identified in 66.9% of PD participants compared to 38.7% of controls (p < 0.001). In PD participants only, delirium was associated with a significantly higher risk of mortality (HR = 3.3 (95% confidence interval [CI] = 1.3-8.6), p = 0.014) and institutionalisation (OR = 10.7 (95% CI = 2.1-54.6), p = 0.004) 12 months post-discharge, compared to older adult controls. However, delirium was associated with an increased risk of developing dementia 12 months post-discharge in both PD participants (OR = 6.1 (95% CI = 1.3-29.5), p = 0.024) and in controls (OR = 13.4 (95% CI = 2.5-72.6), p = 0.003)., Conclusion: Delirium is common in hospitalised PD patients, affecting two thirds of patients, and is associated with increased mortality, institutionalisation, and dementia. Further research is essential to understand how to accurately identify, prevent and manage delirium in people with PD who are in hospital., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Here, we hypothesized that the reactivity of posterior resting-state electroencephalographic (rsEEG) alpha rhythms during the transition from eyes-closed to -open condition might be lower in patients with Parkinson's disease dementia (PDD) than in patients with Alzheimer's disease dementia (ADD). A Eurasian database provided clinical-demographic-rsEEG datasets in 73 PDD patients, 35 ADD patients, and 25 matched cognitively unimpaired (Healthy) persons. The eLORETA freeware was used to estimate cortical rsEEG sources. Results showed substantial (greater than -10%) reduction (reactivity) in the posterior alpha source activities from the eyes-closed to the eyes-open condition in 88% of the Healthy seniors, 57% of the ADD patients, and only 35% of the PDD patients. In these alpha-reactive participants, there was lower reactivity in the parietal alpha source activities in the PDD group than in the healthy control seniors and the ADD patients. These results suggest that PDD patients show poor reactivity of mechanisms desynchronizing posterior rsEEG alpha rhythms in response to visual inputs. That neurophysiological biomarker may provide an endpoint for (non) pharmacological interventions for improving vigilance regulation in those patients., Competing Interests: Declaration of Competing Interest None of the authors has potential conflicts of interest to be disclosed., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: A diagnosis of Parkinson's often leads to uncertainty about the future and loss of perceived control. Peer support may offer a means to address these concerns and promote self-management., Design: A programme evaluation of the feasibility and potential effects of 'First Steps', utilising a pragmatic step wedge approach. Comparing First Steps (intervention) to (control) conditions. Setting: In the community at four sites in southern England. Participants: Newly diagnosed (≤ 12months) people with Parkinson's. Intervention: First Steps was a 2-day peer-conceived, developed and led intervention to support self-management. Main measures: At 0, 12 and 24 weeks anxiety and depression (Hospital, Anxiety and Depression Scale, HADS), daily functioning (World Health Organisation Disability Assessment Schedule, WHODAS), physical activity, quality of life (EQ5D), carer strain and service utilisation were assessed., Results: Between February 2018 and July 2019, 36 participants were enrolled into intervention and 21 to control conditions, all were included in statistical analysis. Lost to follow up was n = 1 (intervention) and n = 1 adverse event was reported (control, unrelated). Of the 36 allocated to the intervention n = 22 participants completed both days of First Steps during the study period. Completion of outcome measures was >95% at 24 weeks. Small effects favouring the intervention were found for HADS (odds ratio (OR) = 2.06, 95% confidence interval (CI) 0.24:17.84), Carer Strain Index (OR = 2.22, 95% CI 0.5:9.76) and vigorous ( d  = 0.42, 95% CI -0.12:0.97) and total physical activity ( d  = 0.41, 95% CI -0.13:0.95). EQ5D, WHOSDAS and service utilisation, was similar between groups., Conclusions: First Steps was feasible and safe and we found potential to benefit physical activity, mental health and carer strain. Further research with longer-term follow up is warranted., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Dementia with Lewy bodies (DLB), Parkinson's disease dementia (PDD), and Parkinson's disease (PD) collectively known as Lewy body diseases (LBDs) are neuropathologically characterised by α-synuclein deposits (Lewy bodies and Lewy neurites). However, LBDs also exhibit pathology associated with Alzheimer's disease (AD) (i.e. hyperphosphorylated tau and amyloid β (Aβ). Aβ can be deposited in the walls of blood vessels in the brains of individuals with AD, termed cerebral amyloid angiopathy (CAA). The aim of this study was to investigate the type and distribution of CAA in DLB, PDD, and PD and determine if this differs from AD. CAA type, severity, and topographical distribution was assessed in 94 AD, 30 DLB, 17 PDD, and 11 PD cases, and APOE genotype evaluated in a subset of cases where available. 96.3% AD cases, 70% DLB cases and 82.4% PDD cases exhibited CAA (type 1 or type 2). However only 45.5% PD cases had CAA. Type 1 CAA accounted for 37.2% of AD cases, 10% of DLB cases, and 5.9% of PDD cases, and was not observed in PD cases. There was a hierarchical topographical distribution in regions affected by CAA where AD and DLB displayed the same distribution pattern that differed from PDD and PD. APOE ε4 was associated with severity of CAA in AD cases. Topographical patterns and severity of CAA in DLB more closely resembled AD rather than PDD, and as type 1 CAA is associated with clinical dementia in AD, further investigations are warranted into whether the increased presence of type 1 CAA in DLB compared to PDD are related to the onset of cognitive symptoms and is a distinguishing factor between LBDs. Possible alignment of the the topographical distribution of CAA and microbleeds in DLB warrants further investigation. CAA in DLB more closely resembles AD rather than PDD or PD, and should be taken into consideration when stratifying patients for clinical trials or designing disease modifying therapies., (© 2024. The Author(s).)

Aims: This systematic review and meta-regression aimed to examine available literature reporting measures of physical function, anxiety, and/or depression and whether any relationships exist between these measures in individuals with Parkinson's disease., Methods: MEDLINE, CINAHL, AMED, and APA PsychInfo databases were systematically searched. Screening, quality assessment, and data extraction were completed alongside meta-regression analysis., Results: Of 1175 studies retrieved, 40 were selected for analysis with only one study assessing the relationship between physical and psychological outcomes within their cohort. A total of 27 studies were also eligible for meta-regression analysis-a total sample of 1211 participants. Meta-regressions of five combinations of paired physical and psychological outcomes showed a significant moderating effect of symptoms of depression (Beck Depression Inventory) on mobility (Timed-Up-and-Go test; coefficient = 0.37, 95% CI 0.09 to 0.65, p = 0.012) and balance (Berg Balance Score) scores (coefficient = -1.25, 95% CI -1.77 to -0.73, p < 0.001)., Conclusion: Although physical and psychological outcomes of interest were used in all included studies, only one examined their relationship. Our analysis suggests that symptoms of depression may influence measures of mobility and balance. Specifically, as the severity of symptoms of depression increases, performance on measures of mobility and balance worsens., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Background: Real-world monitoring using wearable sensors has enormous potential for assessing disease severity and symptoms among persons with Parkinson's disease (PD). Many distinct features can be extracted, reflecting multiple mobility domains. However, it is unclear which digital measures are related to PD severity and are sensitive to disease progression., Objectives: The aim was to identify real-world mobility measures that reflect PD severity and show discriminant ability and sensitivity to disease progression, compared to the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scale., Methods: Multicenter real-world continuous (24/7) digital mobility data from 587 persons with PD and 68 matched healthy controls were collected using an accelerometer adhered to the lower back. Machine learning feature selection and regression algorithms evaluated associations of the digital measures using the MDS-UPDRS (I-III). Binary logistic regression assessed discriminatory value using controls, and longitudinal observational data from a subgroup (n = 33) evaluated sensitivity to change over time., Results: Digital measures were only moderately correlated with the MDS-UPDRS (part II-r = 0.60 and parts I and III-r = 0.50). Most associated measures reflected activity quantity and distribution patterns. A model with 14 digital measures accurately distinguished recently diagnosed persons with PD from healthy controls (81.1%, area under the curve: 0.87); digital measures showed larger effect sizes (Cohen's d: [0.19-0.66]), for change over time than any of the MDS-UPDRS parts (Cohen's d: [0.04-0.12])., Conclusions: Real-world mobility measures are moderately associated with clinical assessments, suggesting that they capture different aspects of motor capacity and function. Digital mobility measures are sensitive to early-stage disease and to disease progression, to a larger degree than conventional clinical assessments, demonstrating their utility, primarily for clinical trials but ultimately also for clinical care. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

With the hope that disease-modifying treatments could target the molecular basis of Parkinson's disease, even before the onset of symptoms, we propose a biologically based classification. Our classification acknowledges the complexity and heterogeneity of the disease by use of a three-component system (SynNeurGe): presence or absence of pathological α-synuclein (S) in tissues or CSF; evidence of underlying neurodegeneration (N) defined by neuroimaging procedures; and documentation of pathogenic gene variants (G) that cause or strongly predispose to Parkinson's disease. These three components are linked to a clinical component (C), defined either by a single high-specificity clinical feature or by multiple lower-specificity clinical features. The use of a biological classification will enable advances in both basic and clinical research, and move the field closer to the precision medicine required to develop disease-modifying therapies. We emphasise the initial application of these criteria exclusively for research. We acknowledge its ethical implications, its limitations, and the need for prospective validation in future studies., Competing Interests: Declaration of interests GUH reports participation in industry-sponsored research projects from AbbVie, Bial, Biogen, Biohaven, Novartis, Sanofi, Takeda, and UCB; served as a consultant for AbbVie, Alzprotect, Aprineua, Asceneuron, Bial, Biogen, Biohaven, Kyowa Kirin, Lundbeck, Novartis, Retrotope, Roche, Sanofi, and UCB; received honoraria for scientific presentations from AbbVie, Bayer Vital, Bial, Biogen, Bristol Myers Squibb, Kyowa Kirin, Roche, Teva, UCB, and Zambon; received publication royalties from Academic Press, Kohlhammer, and Thieme; and holds a patent on the Treatment of Synucleinopathies (US patent: US 10,918,628 B2; European patent: EP 17 787 904·6–1109/3 525 788). CHA reports consultant fees from Cionic, CND Life Science, Jazz, Neurocrine, Precon Health, and XW Pharma. DB reports having served on advisory boards of UCB Pharma and ACImmune; received honoraria from Biogen, UCB Pharma, and Novartis; and her research was supported by UCB Pharma, the European Union, Novartis Pharma, and Lundbeck. CK is deputy editor of Movement Disorders and associate editor of Annals of Neurology; serves as a medical adviser to Centogene for genetic testing reports in the fields of movement disorders and dementia, excluding Parkinson's disease; serves as a medical advisor to Retromer Therapeutics; received honoraria for scientific presentations from Bial and Desitin; and does not hold any stocks or stock options with any companies that are connected to Parkinson's disease or to any of the topics in this Personal View; WP reports personal fees from AbbVie, AFFiRiS, AstraZeneca, Bial, Boston Scientific, Britannia, Intec, Ipsen, Lundbeck, NeuroDerm, Neurocrine, Denali Pharmaceuticals, Novartis, Orion Pharma, Prexton, Teva, UCB, and Zambon; royalties from Thieme, Wiley Blackwell, Oxford University Press, and Cambridge University Press. RP received personal fees as an advisor from Takeda, Roche, Biogen, AbbVie, Curasen, Lilly, Novartis, Eisai, Merck, and Vaxxinity; and received a stipend from the International Parkinson and Movement Disorder Society. AJS chairs a data safety monitoring board for Neurocrine; serves on a data safety monitoring board for AskBio; serves as an advisor to Capsidia; receives a stipend from the International Parkinson & Movement Disorder Society as editor-in-chief of Movement Disorders. AEL has served as an advisor for AbbVie, AFFiRis, Alector, Amylyx, Aprinoia, Biogen, BioAdvance, BlueRock, Biovie, Bristol MyersSquibb, CoA Therapeutics, Denali, Janssen, Jazz, Lilly, Novartis, Paladin, Pharma 2B, PsychoGenetics, Retrophin, Roche, Sun Pharma, and UCB; received honoraria from Sun Pharma, AbbVie and Sunovion; is serving as an expert witness in litigation related to paraquat and Parkinson's disease; received publishing royalties from Elsevier, Saunders, Wiley-Blackwell, Johns Hopkins Press, and Cambridge University Press; and co-shares a patent for diagnostic assays for movement disorders that includes alpha-synuclein seeding assay testing. TFO reports no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Clinical trials of disease-modifying therapies in PD require valid and responsive primary outcome measures that are relevant to patients., Objectives: The objective is to select a patient-centered primary outcome measure for disease-modification trials over three or more years., Methods: Experts in Parkinson's disease (PD), statistics, and health economics and patient and public involvement and engagement (PPIE) representatives reviewed and discussed potential outcome measures. A larger PPIE group provided input on their key considerations for such an endpoint. Feasibility, clinimetric properties, and relevance to patients were assessed and synthesized., Results: Although initial considerations favored the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III in Off, feasibility, PPIE input, and clinimetric properties supported the MDS-UPDRS Part II. However, PPIE input also highlighted the importance of nonmotor symptoms, especially in the longer term, leading to the selection of the MDS-UPDRS Parts I + II sum score., Conclusions: The MDS-UPDRS Parts I + II sum score was chosen as the primary outcome for large 3-year disease-modification trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

α-, β-, and γ-Synuclein are intrinsically disordered proteins implicated in physiological processes in the nervous system of vertebrates. α-synuclein (αSyn) is the amyloidogenic protein associated with Parkinson's disease and certain other neurodegenerative disorders. Intensive research has focused on the mechanisms that cause αSyn to form amyloid structures, identifying its NAC region as being necessary and sufficient for amyloid assembly. Recent work has shown that a 7-residue sequence (P1) is necessary for αSyn amyloid formation. Although γ-synuclein (γSyn) is 55% identical in sequence to αSyn and its pathological deposits are also observed in association with neurodegenerative conditions, γSyn is resilient to amyloid formation in vitro. Here, we report a rare single nucleotide polymorphism (SNP) in the SNCG gene encoding γSyn, found in two patients with amyotrophic lateral sclerosis (ALS). The SNP results in the substitution of Met38 with Ile in the P1 region of the protein. These individuals also had a second, common and nonpathological, SNP in SNCG resulting in the substitution of Glu110 with Val. In vitro studies demonstrate that the Ile38 variant accelerates amyloid fibril assembly. Contrastingly, Val110 retards fibril assembly and mitigates the effect of Ile38. Substitution of residue 38 with Leu had little effect, while Val retards, and Ala increases the rate of amyloid formation. Ile38 γSyn also results in the formation of γSyn-containing inclusions in cells. The results show how a single point substitution can enhance amyloid formation of γSyn and highlight the P1 region in driving amyloid formation in another synuclein family member., Competing Interests: Competing interests statement:The authors declare no competing interest.

Parkinson's disease is clinically known for the loss of dopaminergic neurons in the substantia nigra pars compacta and accumulation of intraneuronal cytoplasmic inclusions rich in alpha-synuclein called 'Lewy bodies' and 'Lewy neurites'. Together with dementia with Lewy bodies and multiple system atrophy, Parkinson's disease is part of a group of disorders called synucleinopathies. Currently, diagnosis of synucleinopathies is based on the clinical assessment which often takes place in advanced disease stages. While the causal role of alpha-synuclein aggregates in these disorders is still debatable, measuring the levels, types or seeding properties of different alpha-synuclein species hold great promise as biomarkers. Recent studies indicate significant differences in peptide, protein and RNA levels in blood samples from patients with Parkinson's disease. Seed amplification assays using CSF, blood, skin biopsy, olfactory swab samples show great promise for detecting synucleinopathies and even for discriminating between different synucleinopathies. Interestingly, small extracellular vesicles, such as exosomes, display differences in their cargoes in Parkinson's disease patients versus controls. In this update, we focus on alpha-synuclein aggregation and possible sources of disease-related species released in extracellular vesicles, which promise to revolutionize the diagnosis and the monitoring of disease progression., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Reduced cortical acetylcholinesterase activity, as measured by 11 C-donepezil positron emission tomography (PET), has been reported in patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD). However, its progression and clinical implications have not been fully investigated. Here, we explored the relationship between longitudinal changes in brain acetylcholinesterase activity and cognitive function in iRBD., Methods: Twelve iRBD patients underwent 11 C-donepezil PET at baseline and after 3 years. PET images were interrogated with statistical parametric mapping (SPM) and a regions of interest (ROI) approach. Clinical progression was assessed with the Movement Disorder Society-Unified Parkinson's Disease Rating Scale-Part III (MDS-UPDRS-III). Cognitive function was rated using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA)., Results: From baseline to follow-up, the mean 11 C-donepezil distribution volume ratio (DVR) decreased in the cortex (p = 0.006), thalamus (p = 0.013), and caudate (p = 0.013) ROI. Despite no significant changes in the group mean MMSE or MoCA scores being observed, individually, seven patients showed a decline in their scores on these cognitive tests. Subgroup analysis showed that only the subgroup of patients with a decline in cognitive scores had a significant reduction in mean cortical 11 C-donepezil DVR., Conclusions: Our results show that severity of brain cholinergic dysfunction in iRBD patients increases significantly over 3 years, and those changes are more severe in those with a decline in cognitive test scores., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Parkinson's disease (PD) is a rapidly growing neurodegenerative disorder, but up-to-date epidemiological data are lacking in Latin America. We sought to estimate the prevalence and incidence of PD and parkinsonism in Latin America., Methods: We searched Medline, Embase, Scopus, Web of Science, Scientific Electronic Library Online, and Literatura Latino-Americana e do Caribe em Ciências da Saúde or the Latin American and Caribbean Health Science Literature databases for epidemiological studies reporting the prevalence or incidence of PD or parkinsonism in Latin America from their inception to 2022. Quality of studies was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist. Data were pooled via random-effects meta-analysis and analyzed by data source (cohort studies or administrative databases), sex, and age group. Significant differences between groups were determined by meta-regression., Results: Eighteen studies from 13 Latin American countries were included in the review. Meta-analyses of 17 studies (nearly 4 million participants) found a prevalence of 472 (95% CI, 271-820) per 100,000 and three studies an incidence of 31 (95% CI, 23-40) per 100,000 person-years for PD; and seven studies found a prevalence of 4300 (95% CI, 1863-9613) per 100,000 for parkinsonism. The prevalence of PD differed by data source (cohort studies, 733 [95% CI, 427-1255] vs. administrative databases. 114 [95% CI, 63-209] per 100,000, P < 0.01), age group (P < 0.01), but not sex (P = 0.73). PD prevalence in ≥60 years also differed significantly by data source (cohort studies. 1229 [95% CI, 741-2032] vs. administrative databases, 593 [95% CI, 480-733] per 100,000, P < 0.01). Similar patterns were observed for parkinsonism., Conclusions: The overall prevalence and incidence of PD in Latin America were estimated. PD prevalence differed significantly by the data source and age, but not sex. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Aging is a major risk factor for Parkinson's disease (PD). Genetic mutations account for a small percentage of cases and the majority appears to be sporadic, with yet unclear causes. However, various environmental factors have been linked to an increased risk of developing PD and, therefore, understanding the complex interplay between genetic and environmental factors is crucial for developing effective disease-modifying therapies. Several studies identified a connection between type 2 diabetes (T2DM) and PD. T2DM is characterized by insulin resistance and failure of β-cells to compensate, leading to hyperglycemia and serious comorbidities. Both PD and T2DM share misregulated processes, including mitochondrial dysfunction, oxidative stress, chronic inflammation, altered proteostasis, protein aggregation, and misregulation of glucose metabolism. Chronic or recurring hyperglycemia is a T2DM hallmark and can lead to increased methylglyoxal (MGO) production, which is responsible for protein glycation. Glycation of alpha-synuclein (aSyn), a central player in PD pathogenesis, accelerates the deleterious aSyn effects. Interestingly, MGO blood plasma levels and aSyn glycation are significantly elevated in T2DM patients, suggesting a molecular mechanism underlying the T2DM - PD link. Compared to high constant glucose levels, glycemic variability (fluctuations in blood glucose levels), can be more detrimental for diabetic patients, causing oxidative stress, inflammation, and endothelial damage. Accordingly, it is imperative for future research to prioritize the exploration of glucose variability's influence on PD development and progression. This involves moving beyond the binary classification of patients as diabetic or non-diabetic, aiming to pave the way for the development of enhanced therapeutic interventions.

Background: There is significant unmet need for effective and efficiently delivered care for people with Parkinson's disease (PwP). We undertook a service improvement initiative to co-develop and implement a new care pathway, Home Based Care (HBC), based on supported self-management, remote monitoring and the ability to trigger a healthcare contact when needed., Objective: To evaluate feasibility, acceptability and safety of Home Based Care., Methods: We evaluated data from the first 100 patients on HBC for 6 months. Patient monitoring, performed at baseline and 6-monthly, comprised motor (MDS-UPDRS II and accelerometer), non-motor (NMSQ, PDSS-2, HADS) and quality of life (PDQ) measures. Care quality was audited against Parkinson's UK national audit standards. Process measures captured feasibility. Acceptability was assessed using a mixed-methods approach comprising questionnaires and semi-structured interviews., Results: Between October 2019 and January 2021, 108 PwP were enrolled onto HBC, with data from 100 being available at 6 months. Over 90% of all questionnaires were returned, 97% were complete or had < 3 missing items. Reporting and communications occurred within agreed timeframes. Compared with baseline, after 6m on HBC, PD symptoms were stable; more PwP felt listened to (90% vs. 79%) and able to seek help (79% vs. 68%). HBC met 93% of national audit criteria. Key themes from the interviews included autonomy and empowerment., Conclusions: We have demonstrated acceptability, feasibility and safety of our novel remotely delivered Parkinson's care pathway. Ensuring scalability will widen its reach and realize its benefits for underserved communities, enabling formal comparisons with standard care and cost-effectiveness evaluation.

While symptomatic pharmacological therapy remains the main therapeutic strategy for Parkinson's disease (PD), over the last two decades, surgical approaches have become more commonly used to control levodopa-induced motor complications and dopamine-resistant and non-motor symptoms of PD. In this paper, we discuss old and new surgical treatments for PD and the many technological innovations in this field. We have initially reviewed the relevant surgical anatomy as well as the pathological signaling considered to be the underlying cause of specific symptoms of PD. Subsequently, early attempts at surgical symptom control will be briefly reviewed. As the most well-known surgical intervention for PD is deep brain stimulation, this subject is discussed at length. As deciding on whether a patient stands to benefit from DBS can be quite difficult, the different proposed paradigms for precisely this are covered. Following this, the evidence regarding different targets, especially the subthalamic nucleus and internal globus pallidus, is reviewed as well as the evidence for newer proposed targets for specific symptoms. Due to the rapidly expanding nature of knowledge and technological capabilities, some of these new and potential future capabilities are given consideration in terms of their current and future use. Following this, we have reviewed newer treatment modalities, especially magnetic resonance-guided focused ultrasound and other potential surgical therapies, such as spinal cord stimulation for gait symptoms and others. As mentioned, the field of surgical alleviation of symptoms of PD is undergoing a rapid expansion, and this review provides a general overview of the current status and future directions in the field., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

In 2011, the UK medical research charity Cure Parkinson's set up the international Linked Clinical Trials (iLCT) committee to help expedite the clinical testing of potentially disease modifying therapies for Parkinson's disease (PD). The first committee meeting was held at the Van Andel Institute in Grand Rapids, Michigan in 2012. This group of PD experts has subsequently met annually to assess and prioritize agents that may slow the progression of this neurodegenerative condition, using a systematic approach based on preclinical, epidemiological and, where possible, clinical data. Over the last 12 years, 171 unique agents have been evaluated by the iLCT committee, and there have been 21 completed clinical studies and 20 ongoing trials associated with the initiative. In this review, we briefly outline the iLCT process as well as the clinical development and outcomes of some of the top prioritized agents. We also discuss a few of the lessons that have been learnt, and we conclude with a perspective on what the next decade may bring, including the introduction of multi-arm, multi-stage clinical trial platforms and the possibility of combination therapies for PD.

Assessing imaging biomarker in the prodromal and early phases of Parkinson's disease (PD) is of great importance to ensure an early and safe diagnosis. In the last decades, imaging modalities advanced and are now able to assess many different aspects of neurodegeneration in PD. MRI sequences can measure iron content or neuromelanin. Apart from SPECT imaging with Ioflupane, more specific PET tracers to assess degeneration of the dopaminergic system are available. Furthermore, metabolic PET patterns can be used to anticipate a phenoconversion from prodromal PD to manifest PD. In this regard, it is worth mentioning that PET imaging of inflammation will gain significance. Molecular imaging of neurotransmitters like serotonin, noradrenaline and acetylcholine shed more light on non-motor symptoms. Outside of the brain, molecular imaging of the heart and gut is used to measure PD-related degeneration of the autonomous nervous system. Moreover, optical coherence tomography can noninvasively detect degeneration of retinal fibers as a potential biomarker in PD. In this review, we describe these state-of-the-art imaging modalities in early and prodromal PD and point out in how far these techniques can and will be used in the future to pave the way towards a biomarker-based staging of PD.