Journal of Parkinson's Disease - Volume 14, issue 6

Authors: Björklund, Anders | Mattsson, Bengt

Article Type: Review Article

Abstract: Targeted delivery of α-synuclein using AAV vectors has over the two decades since its introduction developed into a versatile tool for modeling different aspects of synucleinopathy, mimicking those seen in Parkinson’s disease and related Lewy body disorders. The viral vector approach to disease modeling is attractive in that the expression of α-synuclein, wild-type or mutated, can be confined to defined anatomical structures and targeted to selected cell populations using either cell-type specific promoter constructs or different natural or engineered AAV serotypes. AAV-α-synuclein was initially used to model progressive α-synuclein pathology in nigral dopamine neurons, and, like the standard 6-OHDA model, …it has most commonly been applied unilaterally, using the non-injected side as a reference and control. In recent years, however, the AAV-α-synuclein model has become more widely used to induce Parkinson-like synuclein pathology in other relevant neuronal systems, such as the brainstem noradrenergic and serotonergic neurons, the vagal motor neurons, as well as in oligodendrocytes, the prime target relevant to the pathology seen in multiple system atrophy. The purpose of this review is to give an overview of the progress made in the use of the AAV-α-synuclein model over the last two decades and summarize the state-of-the art in the use of the AAV-α-synuclein model for disease modeling in rats and mice. Show more

Keywords: Adeno-associated virus, substantia nigra, locus coeruleus, raphe nucleus, pre-formed fibrils, multiple system atrophy, rotenone, glucocerebrosidase 1, LRRK2

DOI: 10.3233/JPD-240207

Citation: Journal of Parkinson's Disease, vol. 14, no. 6, pp. 1077-1094, 2024

Authors: Woerman, Amanda L. | Luk, Kelvin C.

Article Type: Position Paper

Abstract:  Pre-formed fibrils (PFFs) made from recombinant α -synuclein are broadly used throughout the field in cellular and animal models of Parkinson’s disease. However, their ability to successfully recapitulate disease biology is a controversial topic. In this article, two researchers debate this issue with Amanda Woerman taking the view that PFFs are a model of synucleinopathy but not Parkinson’s disease, while Kelvin Luk defends their use as an important tool in the field.

Keywords: Alpha-synuclein, Parkinson’s disease, synucleinopathies

DOI: 10.3233/JPD-240228

Citation: Journal of Parkinson's Disease, vol. 14, no. 6, pp. 1095-1103, 2024

Authors: Kopil, Catherine M. | Asis, Angelica | Campbell, Clyde | Chowdhury, Sohini | Dexter, David T. | Fargo, Keith N. | Lee, Karen K. | Matthews, Helen | Taylor, Angela | Xiao, Yuge | Stephenson, Diane

Article Type: Position Paper

Abstract: Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) share underlying neuropathology. Despite overlapping biology, therapeutic development has been approached separately for these clinical syndromes and there remains no treatment to slow, stop or prevent progression of clinical symptoms and development disability for people living with PD or DLB. Recent advances in biomarker tools, however, have paved new paths for biologic definition and staging of PD and DLB under a shared research framework. Patient-centered research funding organizations see the opportunity for a novel biological staging system for PD and DLB to accelerate and increase success of therapeutic development for the …patient communities they serve. Amid growing momentum in the field to develop biological definitions for these neurodegenerative diseases, 7 international nonprofit organizations focused on PD and DLB came together to drive multistakeholder discussion and input on a biological staging system for research. The impact of these convenings to date can be seen in changes incorporated into a proposed biological staging system and growing alignment within the field to rapidly apply new scientific knowledge and biomarker tools to inform clinical trial design. In working together, likeminded nonprofit partners who were initially catalyzed by the significant potential for a biological staging system also realized the power of a shared voice in calling the field to action and have since worked together to establish a coalition to advance precompetitive progress and reduce hurdles to developing better treatments for PD, DLB and biologically related disorders. Show more

Keywords: Parkinson’s disease, Lewy body dementia, Lewy body disease, synucleinopathies, biomarkers, nonprofit organizations

DOI: 10.3233/JPD-230257

Citation: Journal of Parkinson's Disease, vol. 14, no. 6, pp. 1105-1114, 2024

Authors: Kurpershoek, Elisabeth | Visser, Leonie N.C. | Malekzadeh, Arjan | de Bie, Rob M.A. | Dijk, Joke M. | Hillen, Marij A.

Article Type: Review Article

Abstract: Background: Patients with Parkinson’s disease (PD) need to receive adequate information to manage their disease. However, little is known about how information provision affects patients. Objective: To conduct a scoping review of the literature on the relationship between content, timing, manner of delivery, and source of PD-specific information on the one hand, and patient outcomes on the other. Methods: All literature reporting about original data and published until April 2024 in peer-reviewed journals was searched in MEDLINE (Ovid), Embase (Ovid) and PsychInfo (Ovid). Subsequently, data were extracted and synthesized. Results: 40 publications describing the …effects of information provision or patients’ evaluation thereof were retrieved. Four categories of patient outcomes were described, namely 1) evaluation and experience of information provision; 2) physical functioning; 3) psychosocial well-being; and 4) quality of life. In intervention studies, patients generally valued the provided information. Findings from cross-sectional and qualitative studies showed the importance of tailoring information to individuals’ needs and capabilities. Due to variation in study designs and outcomes, no unambiguous conclusions could be drawn regarding the relationship between information and outcomes. Conclusions: This scoping review identified how PD patients acquire information and revealed a lack of systematic research into the effect of information on patient outcomes. Future studies should assess 1) what information is currently provided by clinicians; 2) what additional information might be beneficial to provide; and 3) how information can be effectively aligned to benefit patients. This will eventually yield insight into how information might optimally empower PD patients. Show more

Keywords: Parkinson’s disease, patient education, information sources, patient outcome

DOI: 10.3233/JPD-240073

Citation: Journal of Parkinson's Disease, vol. 14, no. 6, pp. 1115-1127, 2024

Authors: Yan, Zhenzhen | Zhao, Guohua

Article Type: Research Article

Abstract: Background: In experimental and observational studies, the characteristics of gut microbiota have been associated with Parkinson’s disease (PD), among which metabolic pathways played an important role. However, the causality remained unclear. Objective: Herein, we aimed to determine the potential impact of gut microbiota and gut microbiota-derived metabolites on PD risk using a Mendelian randomization (MR) approach. Methods: We included as exposures gut microbial taxa abundance and gut-derived metabolites (branched chain amino acids [BCAAs]), with PD as the outcome. In addition, we explored whether BCAAs act as a mediating factor in the pathway from gut microbiota to …PD. Results: We found evidence of a causality of 15 microbial taxa and PD before and after sensitivity analyses, but not after multiple testing correction. There was significant association between BCAAs levels and the risk of PD, especially isoleucine (OR = 0.995, 95% CI 0.992–0.999, p  = 0.004, pFDR  = 0.012). In addition, the causality of gut microbiota and BCAAs was also explored that the increased g_Coprococcus abundance can result in the decrease in isoleucine level (OR = 1.046; 95% CI, 1.009–1.085; p  = 0.016). Conclusions: Our findings indicated suggestive association between gut microbiota and its metabolites and PD. Furthermore, higher BCAAs levels were associated with the decreased PD risk. This study may provide new targets for PD treatment, such as dietary BCAAs supplementation. Show more

Keywords: Mendelian randomization, gut microbiota, branched chain amino acids, Parkinson’s disease

DOI: 10.3233/JPD-240244

Citation: Journal of Parkinson's Disease, vol. 14, no. 6, pp. 1129-1138, 2024

Authors: Lamotte, Guillaume | McKee, Kathleen E. | Luthra, Nijee S. | Corcos, Daniel M.

Article Type: Article Commentary

Abstract: Orthostatic hypotension (OH) is the most common manifestation of cardiovascular autonomic dysfunction in Parkinson’s disease. In this viewpoint, we discuss five practical questions regarding OH in Parkinson’s disease: 1) How common is the problem? 2) Why should people with Parkinson’s disease and providers care about OH? 3) What are the symptoms of OH? 4) How to confirm a diagnosis of OH? And 5) How to treat OH? OH is an important non-motor symptom of Parkinson’s disease for which we have available treatments to significantly mitigate morbidity and possibly positively impact the disease course.

Keywords: Parkinson’s disease, autonomic nervous system, hypotension, orthostatic hypotension, autonomic failure

DOI: 10.3233/JPD-240149

Citation: Journal of Parkinson's Disease, vol. 14, no. 6, pp. 1139-1146, 2024

Authors: Silbergleit, Alice K. | LeWitt, Peter A.

Article Type: Other

DOI: 10.3233/JPD-230435

Citation: Journal of Parkinson's Disease, vol. 14, no. 6, pp. 1147-1148, 2024

Authors: Eijsvogel, Pepijn P.N.M. | Borghans, Laura G.J.M. | Prins, Samantha | Moss, Laurence | van Kraaij, Sebastiaan J.W. | van Brummelen, Emilie | Klaassen, Erica | Martin, Renee S. | Bautista, Edgar | Ford, Anthony P. | Kremer, Philip H.C. | Groeneveld, Geert Jan | Vargas, Gabriel A.

Article Type: Research Article

Abstract: Background: Noradrenergic signaling declines in Parkinson’s disease (PD) following locus coeruleus neurodegeneration. Epidemiologic studies demonstrate that β-acting drugs slow PD progression. Objective: The primary objective was to compare the safety and effects of 3 β-adrenoceptor (β-AR) acting drugs on central nervous system (CNS) function after a single dose in healthy volunteers (HVs) and evaluate the effects of multiple doses of β-AR acting drugs in HVs and PD-patients. Methods: In Part A, HVs received single doses of 32 mg salbutamol, 160μ g clenbuterol, 60 mg pindolol and placebo administered in a randomized, 4-way cross-over study. In Part B (randomized …cross-over) and Part C (parallel, 2:1 randomized), placebo and/or clenbuterol (20μ g on Day 1, 40μ g on Day 2, 80μ g on Days 3–7) were administered. CNS functions were assessed using the NeuroCart test battery, including pupillometry, adaptive tracking and recall tests. Results: Twenty-seven HVs and 12 PD-patients completed the study. Clenbuterol improved and pindolol reduced the adaptive tracking and immediate verbal recall performance. Clenbuterol and salbutamol increased and pindolol decreased pupil-to-iris ratios. Clenbuterol was selected for Parts B and C. In Part B, clenbuterol significantly increased performance in adaptive tracking with a tendency toward improved performance in immediate and delayed verbal recall. In Part C trends toward improved performance in immediate and delayed verbal recall were observed in PD-patients. Typical cardiovascular peripheral β2 -AR effects were observed with clenbuterol. Conclusions: This study demonstrates the pro-cognitive effects of clenbuterol in HVs with similar trends in PD-patients. The mechanism of action is likely activation of β2-ARs in the CNS. Show more

Keywords: Parkinson’s disease, adrenergic beta-agonist, electroencephalography, central nervous system agents, disease progression, phase 1 clinical trial, pharmacology

DOI: 10.3233/JPD-240039

Citation: Journal of Parkinson's Disease, vol. 14, no. 6, pp. 1149-1161, 2024

Authors: Zoetewei, Demi | Ginis, Pieter | Goris, Maaike | Gilat, Moran | Herman, Talia | Brozgol, Marina | Thumm, Pablo Cornejo | Hausdorff, Jeffrey M. | Nieuwboer, Alice | D’Cruz, Nicholas

Article Type: Research Article

Abstract: Background: Measurement of freezing of gait (FOG) relies on the sensitivity and reliability of tasks to provoke FOG. It is currently unclear which tasks provide the best outcomes and how medication state plays into this. Objective: To establish the sensitivity and test-retest reliability of various FOG-provoking tasks for presence and severity of FOG, with (ON) and without (OFF) dopaminergic medication. Methods: FOG-presence and percentage time frozen (% TF) were derived from video annotations of a home-based FOG-provoking protocol performed in OFF and ON. This included: the four meter walk (4MW), Timed Up and Go (TUG) single …(ST) and dual task (DT), 360° turns in ST and DT, a doorway condition, and a personalized condition. Sensitivity was tested at baseline in 63 definite freezers. Test-retest reliability was evaluated over 5 weeks in 26 freezers. Results: Sensitivity and test-retest reliability were highest for 360° turns and higher in OFF than ON. Test-retest intra-class correlation coefficients of % TF varied between 0.63–0.90 in OFF and 0.18–0.87 in ON, and minimal detectable changes (MDCs) were high. The optimal protocol included TUG ST, 360° turns ST, 360° turns DT and a doorway condition, provoking FOG in all freezers in OFF and 91.9% in ON and this could be done reliably in 95.8% (OFF) and 84.0% (ON) of the sample. Combining OFF and ON further improved outcomes. Conclusions: The highest sensitivity and reliability was achieved with a multi-trigger protocol performed in OFF + ON. However, the high MDCs for % TF underscore the need for further optimization of FOG measurement. Show more

Keywords: Outcome measures, sensitivity, test-retest reliability, dopaminergic effect, freezing of gait, Parkinson’s disease, FOG detection, FOG severity

DOI: 10.3233/JPD-240134

Citation: Journal of Parkinson's Disease, vol. 14, no. 6, pp. 1163-1174, 2024

Authors: Astalosch, Melanie | Mousavi, Mahta | Ribeiro, Luísa Martins | Schneider, Gerd-Helge | Stuke, Heiner | Haufe, Stefan | Borchers, Friedrich | Spies, Claudia | von Hofen-Hohloch, Judith | Al-Fatly, Bassam | Ebersbach, Georg | Franke, Christiana | Kühn, Andrea A. | Kübler-Weller, Dorothee

Article Type: Research Article

Abstract: Background: Postoperative delirium (POD) is a serious complication following deep brain stimulation (DBS) but only received little attention. Its main risk factors are higher age and preoperative cognitive deficits. These are also main risk factors for long-term cognitive decline after DBS in Parkinson’s disease (PD). Objective: To identify risk factors for POD severity after DBS surgery in PD. Methods: 57 patients underwent DBS (21 female; age 60.2±8.2; disease duration 10.5±5.9 years). Preoperatively, general, PD– and surgery-specific predictors were recorded. Montreal Cognitive Assessment and the neuropsychological test battery CANTAB ConnectTM were used to test domain-specific cognition. …Volumes of the cholinergic basal forebrain were calculated with voxel-based morphometry. POD severity was recorded with the delirium scales Confusion Assessment Method for Intensive Care Unit (CAM-ICU) and Nursing Delirium Scale (NU-DESC). Spearman correlations were calculated for univariate analysis of predictors and POD severity and linear regression with elastic net regularization and leave-one-out cross-validation was performed to fit a multivariable model. Results: 21 patients (36.8%) showed mainly mild courses of POD following DBS. Correlation between predicted and true POD severity was significant (spearman rho = 0.365, p  = 0.001). Influential predictors were age (p  < 0.001), deficits in attention and motor speed (p  = 0.002), visual learning (p  = 0.036) as well as working memory (p  < 0.001), Nucleus basalis of Meynert volumes (p  = 0.003) and burst suppression (p  = 0.005). Conclusions: General but also PD– and surgery-specific factors were predictive of POD severity. These findings underline the multifaceted etiology of POD after DBS in PD. Valid predictive models must therefore consider general, PD– and surgery-specific factors. Show more

Keywords: Parkinson’s disease, deep brain stimulation, postoperative delirium, cognition, risk prediction, personalized therapy, outcome

DOI: 10.3233/JPD-230276

Citation: Journal of Parkinson's Disease, vol. 14, no. 6, pp. 1175-1192, 2024