Journal of Parkinson's Disease - Volume 14, issue 1

Authors: van der Berg, Indy | Schootemeijer, Sabine | Overbeek, Karin | Bloem, Bastiaan R. | de Vries, Nienke M.

Article Type: Other

Abstract: Several dietary patterns and nutritional supplements have been linked to the development, progression, and symptomatic treatment of Parkinson’s disease (PD). Most of the evidence, at this point, is preliminary and based largely on observational studies. Interventional studies are scarce, so the evidence on effectiveness remains inconclusive. Dietary interventions could, analogous to exercise, potentially have a beneficial effect on disease symptoms as well as on the progression of the disease and should therefore be researched in high quality studies. Further work is also needed to study whether dietary interventions, when applied to an at-risk population, have any potential to postpone the …onset of manifest PD. In this paper, we summarize all ongoing clinical trials on dietary interventions in PD. We found 10 ongoing studies, all aimed at a different intervention. These studies are mostly exploratory in nature or represent phase I or phase II trials focusing on safety, biological responses, and symptomatic effects. Taken together, we conclude that research on dietary interventions in persons with PD is still in its early days. The results of the various ongoing trials are expected to generate new hypotheses and will help to shape the agenda for future research on this important topic. Show more

Keywords: Diet, dietary pattern, nutrition, supplements, Parkinson’s disease

DOI: 10.3233/JPD-230366

Citation: Journal of Parkinson's Disease, vol. 14, no. 1, pp. 1-16, 2024

Authors: Moors, Tim E. | Milovanovic, Dragomir

Article Type: Review Article

Abstract: Lewy bodies (LBs) are pathological hallmarks of Parkinson’s disease and dementia with Lewy bodies, characterized by the accumulation of α-synuclein (αSyn) protein in the brain. While LBs were first described a century ago, their formation and morphogenesis mechanisms remain incompletely understood. Here, we present a historical overview of LB definitions and highlight the importance of semantic clarity and precise definitions when describing brain inclusions. Recent breakthroughs in imaging revealed shared features within LB subsets and the enrichment of membrane-bound organelles in these structures, challenging the conventional LB formation model. We discuss the involvement of emerging concepts of liquid-liquid phase separation, …where biomolecules demix from a solution to form dense condensates, as a potential LB formation mechanism. Finally, we emphasize the need for the operational definitions of LBs based on morphological characteristics and detection protocols, particularly in studies investigating LB formation mechanisms. A better understanding of LB organization and ultrastructure can contribute to the development of targeted therapeutic strategies for synucleinopathies. Show more

Keywords: α-synuclein, Lewy body, Parkinson’s disease, aggregation, liquid-liquid phase separation

DOI: 10.3233/JPD-230183

Citation: Journal of Parkinson's Disease, vol. 14, no. 1, pp. 17-33, 2024

Authors: Walker, Lauren | Attems, Johannes

Article Type: Review Article

Abstract: Pathologies characteristic of Alzheimer’s disease (i.e., hyperphosphorylated tau and amyloid-β (Aβ) plaques), cardiovascular disease, and limbic predominant TDP-43 encephalopathy (LATE) often co-exist in patients with Parkinson’s disease (PD), in addition to Lewy body pathology (α-synuclein). Numerous studies point to a putative synergistic relationship between hyperphosphorylation tau, Aβ, cardiovascular lesions, and TDP-43 with α-synuclein, which may alter the stereotypical pattern of pathological progression and accelerate cognitive decline. Here we discuss the prevalence and relationships between common concomitant pathologies observed in PD. In addition, we highlight shared genetic risk factors and developing biomarkers that may provide better diagnostic accuracy for patients with …PD that have co-existing pathologies. The tremendous heterogeneity observed across the PD spectrum is most likely caused by the complex interplay between pathogenic, genetic, and environmental factors, and increasing our understanding of how these relate to idiopathic PD will drive research into finding accurate diagnostic tools and disease modifying therapies. Show more

Keywords: Parkinson’s disease, co-pathology, α-synuclein, tau, amyloid-β, TDP-43, cerebrovascular disease

DOI: 10.3233/JPD-230154

Citation: Journal of Parkinson's Disease, vol. 14, no. 1, pp. 35-52, 2024

Authors: Carroll, Camille | Clarke, Carl E. | Grosset, Donald | Rather, Arshad | Mohamed, Biju | Parry, Miriam | Reddy, Prashanth | Fackrell, Robin | Chaudhuri, Kallol Ray

Article Type: Review Article

Abstract: In the UK, guidance exists to aid clinicians and patients deciding when treatment for Parkinson’s disease (PD) should be initiated and which therapies to consider. National Institute for Health and Care Excellence (NICE) guidance recommends that before starting PD treatment clinicians should discuss the following: the patient’s individual clinical circumstances; lifestyle; preferences; needs and goals; as well as the potential benefits and harms of the different drug classes. Individualization of medicines and management in PD significantly improves patients’ outcomes and quality of life. This article aims to provide simple and practical guidance to help clinicians address common, but often overlooked, …co-morbidities. A multi-disciplinary group of PD experts discussed areas where clinical care can be improved by addressing commonly found co-morbidities in people with Parkinson’s (PwP) based on clinical experience and existing literature, in a roundtable meeting organized and funded by Bial Pharma UK Ltd. The experts identified four core areas (bone health, cardiovascular risk, anticholinergic burden, and sleep quality) that, if further standardized may improve treatment outcomes for PwP patients. Focusing on anticholinergic burden, cardiac risk, sleep, and bone health could offer a significant contribution to personalizing regimes for PwP and improving overall patient outcomes. Within this opinion-based paper, the experts offer a list of guiding factors to help practitioners in the management of PwP. Show more

Keywords: Parkinson’s disease, individualized treatment, clinical guidelines, bone density, cardiovascular risk, anticholinergics, sleep quality

DOI: 10.3233/JPD-230168

Citation: Journal of Parkinson's Disease, vol. 14, no. 1, pp. 53-63, 2024

Authors: Jong, Tiffany | Gehrlein, Alexandra | Sidransky, Ellen | Jagasia, Ravi | Chen, Yu

Article Type: Research Article

Abstract: Background: Mutations in GBA1 , which encodes the lysosome enzyme β-glucocerebrosidase (also referred to as acid β-glucosidase or GCase), are the most common genetic risk factor for Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Evidence also suggests that loss of GCase activity is implicated in PD without GBA1 mutations. Consequently, therapies targeting GCase are actively being pursued as potential strategies to modify the progression of PD and related synucleinopathies. Despite this significant interest in GCase as a therapeutic target, the lack of well-characterized GCase antibodies continues to impede progress in the development of GCase-targeted therapies. …Objective: This study aims to independently evaluate human GCase (hGCase) antibodies to provide recommendations for western blot, immunofluorescence, immunoprecipitation, and AlphaLISA (Amplified Luminescent Proximity Homogeneous Assay) assays. Methods: Two mouse monoclonal antibodies, hGCase-1/17 and hGCase-1/23, were raised against hGCase using imiglucerase, the recombinant enzyme developed to treat patients, as the antigen. These novel antibodies, alongside commonly used antibodies in the field, underwent evaluation in a variety of assays. Results: The characterization of hGCase-1/17 and hGCase-1/23 using genetic models including GBA1 loss-of-function human neuroglioma H4 line and neurons differentiated from human embryonic stem cells revealed their remarkable specificity and potency in immunofluorescence and immunoprecipitation assays. Furthermore, a hGCase AlphaLISA assay with excellent sensitivity, a broad dynamic range, and suitability for high throughput applications was developed using hGCase-1/17 and hGCase-1/23, which enabled a sandwich assay configuration. Conclusions: The hGCase immunofluorescence, immunoprecipitation, and AlphaLISA assays utilizing hGCase-1/17 and hGCase-1/23 will not only facilitate improved investigations of hGCase biology, but can also serve as tools to assess the distribution and effectiveness of GCase-targeted therapies for PD and related synucleinopathies. Show more

Keywords: Parkinson’s disease, Gaucher disease, glucocerebrosidase, monoclonal antibody

DOI: 10.3233/JPD-230295

Citation: Journal of Parkinson's Disease, vol. 14, no. 1, pp. 65-78, 2024

Authors: Dzamko, Nicolas

Article Type: Article Commentary

DOI: 10.3233/JPD-249000

Citation: Journal of Parkinson's Disease, vol. 14, no. 1, pp. 79-80, 2024

Authors: Weber, Matthew A. | Kerr, Gemma | Thangavel, Ramasamy | Conlon, Mackenzie M. | Gumusoglu, Serena B. | Gupta, Kalpana | Abdelmotilib, Hisham A. | Halhouli, Oday | Zhang, Qiang | Geerling, Joel C. | Narayanan, Nandakumar S. | Aldridge, Georgina M.

Article Type: Research Article

Abstract: Background: Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) are characterized by diffuse spread of alpha-synuclein (α -syn) throughout the brain. Patients with PDD and DLB have a neuropsychological pattern of deficits that include executive dysfunction, such as abnormalities in planning, timing, working memory, and behavioral flexibility. The prefrontal cortex (PFC) plays a major role in normal executive function and often develops α -syn aggregates in DLB and PDD. Objective: To investigate the long-term behavioral and cognitive consequences of α -syn pathology in the cortex and characterize pathological spread of α -syn. Methods: We …injected human α -syn pre-formed fibrils into the PFC of wild-type male mice. We then assessed the behavioral and cognitive effects between 12- and 21-months post-injection and characterized the spread of pathological α -syn in cortical, subcortical, and brainstem regions. Results: We report that PFC PFFs: 1) induced α -syn aggregation in multiple cortical and subcortical regions with sparse aggregation in midbrain and brainstem nuclei; 2) did not affect interval timing or spatial learning acquisition but did mildly alter behavioral flexibility as measured by intraday reversal learning; and 3) increased open field exploration. Conclusions: This model of cortical-dominant pathology aids in our understanding of how local α -syn aggregation might impact some symptoms in PDD and DLB. Show more

Keywords: Prefrontal cortex, alpha-synuclein, Parkinson’s disease, behavioral flexibility, exploratory behavior

DOI: 10.3233/JPD-230129

Citation: Journal of Parkinson's Disease, vol. 14, no. 1, pp. 81-94, 2024

Authors: Hossain, Mohammad Amran | Amenta, Francesco

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is the most prevalent neurodegenerative movement disorder and a growing health concern in demographically aging societies. The prevalence of PD among individuals over the age of 60 and 80 years has been reported to range between 1% and 4%. A timely diagnosis of PD is desirable, even though it poses challenges to medical systems. Objective: This study aimed to classify PD and healthy controls based on the analysis of voice records at different frequencies using machine learning (ML) algorithms. Methods: The voices of 252 individuals aged 33 to 87 years were recorded. …Based on the voice record data, ML algorithms can distinguish PD patients and healthy controls. One binary decision variable was associated with 756 instances and 754 attributes. Voice records data were analyzed through supervised ML algorithms and pipelines. A 10-fold cross-validation method was used to validate models. Results: In the classification of PD patients, ML models were performed with 84.21 accuracy, 93 precision, 89 Sensitivity, 89 F1-scores, and 87 AUC. The pipeline performance improved to accuracy: 85.09, precision: 92, Sensitivity:91, F1-score: 89, and AUC: 90. The Pipeline methods improved the performance of classifying PD from voice record. Conclusions: Our study demonstrated that ML classifiers and pipelines can classify PD patients based on speech biomarkers. It was found that pipelines were more effective at selecting the most relevant features from high-dimensional data and at accurately classifying PD patients and healthy controls. This approach can therefore be used for early diagnosis of initial forms of PD. Show more

Keywords: Parkinson’s disease, machine learning, pipeline, biomarkers, speech

DOI: 10.3233/JPD-230002

Citation: Journal of Parkinson's Disease, vol. 14, no. 1, pp. 95-109, 2024

Authors: Rolland, Anne-Sophie | Touzet, Gustavo | Carriere, Nicolas | Mutez, Eugenie | Kreisler, Alexandre | Simonin, Clemence | Kuchcinski, Gregory | Chalhoub, Najib | Pruvo, Jean-Pierre | Defebvre, Luc | Reyns, Nicolas | Devos, David | Moreau, Caroline

Article Type: Research Article

Abstract: Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a preferred treatment for parkinsonian patients with severe motor fluctuations. Proper targeting of the STN sensorimotor segment appears to be a crucial factor for success of the procedure. The recent introduction of directional leads theoretically increases stimulation specificity in this challenging area but also requires more precise stimulation parameters. Objective: We investigated whether commercially available software for image guided programming (IGP) could maximize the benefits of DBS by informing the clinical standard care (CSC) and improving programming workflows. Methods: We prospectively analyzed 32 consecutive parkinsonian …patients implanted with bilateral directional leads in the STN. Double blind stimulation parameters determined by CSC and IGP were assessed and compared at three months post-surgery. IGP was used to adjust stimulation parameters if further clinical refinement was required. Overall clinical efficacy was evaluated one-year post-surgery. Results: We observed 78% concordance between the two electrode levels selected by the blinded IGP prediction and CSC assessments. In 64% of cases requiring refinement, IGP improved clinical efficacy or reduced mild side effects, predominantly by facilitating the use of directional stimulation (93% of refinements). Conclusions: The use of image guided programming saves time and assists clinical refinement, which may be beneficial to the clinical standard care for STN-DBS and further improve the outcomes of DBS for PD patients. Show more

Keywords: Directional leads, clinical programming, functional mapping, timesaving, clinical refinement, Parkinson’s disease

DOI: 10.3233/JPD-225126

Citation: Journal of Parkinson's Disease, vol. 14, no. 1, pp. 111-119, 2024

Authors: Griffith, Garett | Lamotte, Guillaume | Mehta, Niyati | Fan, Peng | Nikolich, Juliana | Springman, Victoria | Suttman, Erin | Joslin, Elizabeth | Balfany, Katherine | Dunlap, MacKenzie | Kohrt, Wendy M. | Christiansen, Cory L. | Melanson, Edward L. | Josbeno, Deborah | Chahine, Lana M. | Patterson, Charity G. | Corcos, Daniel M.

Article Type: Research Article

Abstract: Background: An attenuated heart rate response to exercise, termed chronotropic incompetence, has been reported in Parkinson’s disease (PD). Chronotropic incompetence may be a marker of autonomic dysfunction and a cause of exercise intolerance in early stages of PD. Objective: To investigate the relationship between chronotropic incompetence, orthostatic blood pressure change (supine – standing), and exercise performance (maximal oxygen consumption, VO2peak ) in individuals with early PD within 5 years of diagnosis not on dopaminergic medications. Methods: We performed secondary analyses of heart rate and blood pressure data from the Study in Parkinson’s Disease of Exercise (SPARX). …Results: 128 individuals were enrolled into SPARX (63.7±9.3 years; 57.0% male, 0.4 years since diagnosis [median]). 103 individuals were not taking chronotropic medications, of which 90 had a normal maximal heart rate response to exercise testing (155.3±14.0 bpm; PDnon-chrono) and 13 showed evidence of chronotropic incompetence (121.3±11.3 bpm; PDchrono, p  < 0.05). PDchrono had decreased VO2peak compared to PDnon-chrono (19.7±4.5 mL/kg/min and 24.3±5.8 mL/kg/min, respectively, p  = 0.027). There was a positive correlation between peak heart rate during exercise and the change in systolic blood pressure from supine to standing (r  = 0.365, p  < 0.001). Conclusions: A subgroup of individuals with early PD not on dopaminergic medication had chronotropic incompetence and decreased VO2peak , which may be related to autonomic dysfunction. Evaluation of both heart rate responses to incremental exercise and orthostatic vital signs may serve as biomarkers of early autonomic impairment and guide treatment. Further studies should investigate whether cardiovascular autonomic dysfunction affects the ability to exercise and whether exercise training improves autonomic dysfunction. Show more

Keywords: Exercise, heart rate, Parkinson’s disease, autonomic nervous system, chronotropic incompetence

DOI: 10.3233/JPD-230006

Citation: Journal of Parkinson's Disease, vol. 14, no. 1, pp. 121-133, 2024