Journal of Parkinson's Disease - Volume 14, issue 5

Authors: McFarthing, Kevin | Buff, Sue | Rafaloff, Gary | Pitzer, Kenneth | Fiske, Brian | Navangul, Anaya | Beissert, Katelyn | Pilcicka, Aleksandra | Fuest, Rosie | Wyse, Richard K. | Stott, Simon R.W.

Article Type: Other

Abstract: Background: For the past five years, our annual reports have been tracking the clinical development of new drug-based therapies for the neurodegenerative condition of Parkinson’s disease (PD). These reviews have followed the progress both of “symptomatic treatments” (ST – improves/reduces symptoms of the condition) and “disease-modifying treatments” (DMT – attempts to delay/slow progression by addressing the underlying biology of PD). Efforts have also been made to further categorize these experimental treatments based on their mechanisms of action and class of drug. Methods: A dataset of clinical trials for drug therapies in PD using trial data downloaded from the …ClinicalTrials.gov online registry was generated. A breakdown analysis of all the studies that were active as of January 31st, 2024, was conducted. This analysis involved categorizing the trials based on both the mechanism of action (MOA) and the drug target. Results: There were 136 active Phase 1–3 trials evaluating drug therapies for PD registered on ClinicalTrials.gov, as of January 31, 2024. Of these trials, 76 (56%) were classified as ST trials and 60 (44%) were designated DMT. More than half (58%) of the trials were in Phase 2 testing stage, followed by Phase 1 (30%) and Phase 3 (12%). 35 of the trials were registered since our last report, with the remaining 101 trials appearing in at least one earlier report. Conclusions: The drug development pipeline for PD remains in a robust state with a wide variety of approaches being developed and evaluated in Phase 1 and 2. Yet again, however, only a limited number of DMTs are transitioning to Phase 3. Show more

Keywords: Clinical trials, studies, Parkinson’s, disease modification, neuroprotection, immunotherapy, inflammation, gene therapy

DOI: 10.3233/JPD-240272

Citation: Journal of Parkinson's Disease, vol. 14, no. 5, pp. 899-912, 2024

Authors: Beckers, Milan | Coburn, Bryan | Kalia, Lorraine V. | Bloem, Bastiaan R.

Article Type: Editorial

DOI: 10.3233/JPD-249007

Citation: Journal of Parkinson's Disease, vol. 14, no. 5, pp. 913-915, 2024

Authors: König, Annekatrin | Outeiro, Tiago F.

Article Type: Review Article

Abstract: 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. Show more

Keywords: Parkinson’s disease, diabetes, alpha-synuclein, neurodegeneration, glycation

DOI: 10.3233/JPD-230104

Citation: Journal of Parkinson's Disease, vol. 14, no. 5, pp. 917-924, 2024

Authors: Demailly, Alexandre | Moreau, Caroline | Devos, David

Article Type: Review Article

Abstract: Background: Parkinson’s disease (PD) is characterized by striatal dopamine deficiency. Since dopamine cannot cross the digestive and blood-brain barriers, its precursor, levodopa (L-DOPA), remains the mainstay of treatment. However, the significant pharmacokinetic (Pk) and pharmacodynamic (Pd) limitations of L-DOPA, combined with the severity of PD, may trigger motor and non-motor complications, for which continuous dopaminergic delivery therapies have been developed. Objective: The aim of this study was to review the literature on the Pk/Pd limitations of L-DOPA and how current treatments of continuous dopaminergic administration ameliorate these problems, in order to identify the need for new therapeutic avenues. …Methods: A comprehensive literature search was carried out using PubMed and 75 articles were initially extracted. Following independent screening by two reviewers and consideration of eligibility, 10 articles were chosen for further analysis. Information concerning the Pk/Pd of L-DOPA was classified for each article. Results: Pk/Pd problems notably include: (i) restricted digestive and cerebral absorption; (ii) unnecessary peripheral distribution; (iii) short half-life; (iv) age- and PD-induced decline of central aromatic L-amino acid decarboxylase; (v) misdistribution in many cells; and (vii) pulsatile stimulation of dopaminergic receptors. Current treatments only slightly ameliorate some of these problems. Conclusions: Many Pk/Pd constraints are not resolved by existing continuous dopaminergic delivery therapies. This highlights the significant gap between these treatments and the ideal of continuous dopaminergic stimulation. Show more

Keywords: Parkinson’s disease, dopamine, continuous dopaminergic stimulation, motor fluctuations and dyskinesia, apomorphine

DOI: 10.3233/JPD-230372

Citation: Journal of Parkinson's Disease, vol. 14, no. 5, pp. 925-939, 2024

Authors: Chen, Yuan-Hao | Kuo, Tung-Tai | Wang, Vicki | Cheng, Pin-Wen | Huang, Eagle Yi-Kung | Ma, Kuo-Hsing | Greig, Nigel H. | Olson, Lars | Hoffer, Barry J. | Tseng, Kuan-Yin

Article Type: Research Article

Abstract: Background: The serotonin (5-HT) system can manipulate the processing of exogenous L-DOPA in the DA-denervated striatum, resulting in the modulation of L-DOPA-induced dyskinesia (LID). Objective: To characterize the effects of the serotonin precursor 5-hydroxy-tryptophan (5-HTP) or the serotonin transporter (SERT) inhibitor, Citalopram on L-DOPA-induced behavior, neurochemical signals, and underlying protein expressions in an animal model of Parkinson’s disease. Methods: MitoPark (MP) mice at 20 weeks of age, subjected to a 14-day administration of L-DOPA/Carbidopa, displayed dyskinesia, referred to as LID. Subsequent investigations explored the effects of 5-HT-modifying agents, such as 5-HTP and Citalopram, on abnormal involuntary …movements (AIMs), locomotor activity, neurochemical signals, serotonin transporter activity, and protein expression in the DA-denervated striatum of LID MP mice. Results: 5-HTP exhibited duration-dependent suppressive effects on developing and established LID, especially related to abnormal limb movements observed in L-DOPA-primed MP mice. However, Citalopram, predominantly suppressed abnormal axial movement induced by L-DOPA in LID MP mice. We demonstrated that 5-HTP could decrease L-DOPA-upregulation of DA turnover rates while concurrently upregulating 5-HT metabolism. Additionally, 5-HTP was shown to reduce the expressions of p-ERK and p-DARPP-32 in the striatum of LID MP mice. The effect of Citalopram in alleviating LID development may be attributed to downregulation of SERT activity in the dorsal striatum of LID MP mice. Conclusions: While both single injection of 5-HTP and Citalopram effectively mitigated the development of LID, the difference in mitigation of AIM subtypes may be linked to the unique effects of these two serotonergic agents on L-DOPA-derived DA and 5-HT metabolism. Show more

Keywords: Serotonin system, Parkinson’s disease, dopamine, L-DOPA-induced dyskinesia, 5-HTP, Citalopram

DOI: 10.3233/JPD-240080

Citation: Journal of Parkinson's Disease, vol. 14, no. 5, pp. 941-964, 2024

Authors: Scholefield, Melissa | Church, Stephanie J. | Xu, Jingshu | Patassini, Stefano | Cooper, Garth J.S.

Article Type: Research Article

Abstract: Background: Localized pantothenic acid deficiencies have been observed in several neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease dementia (PDD), and Huntington’s disease (HD), indicating downstream energetic pathway perturbations. However, no studies have yet been performed to see whether such deficiencies occur across the dementia with Lewy bodies (DLB) brain, or what the pattern of such dysregulation may be. Objective: Firstly, this study aimed to quantify pantothenic acid levels across ten regions of the brain in order to determine the localization of any pantothenic acid dysregulation in DLB. Secondly, the localization of pantothenic acid alterations was compared …to that previously in AD, PDD, and HD brains. Methods: Pantothenic acid levels were determined in 20 individuals with DLB and 19 controls by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC–MS/MS) across ten brain regions. Case–control differences were determined by nonparametric Mann–Whitney U test, with the calculation of S-values, risk ratios, E-values, and effect sizes. The results were compared with those previously obtained in DLB, AD, and HD. Results: Pantothenic acid levels were significantly decreased in six of the ten investigated brain regions: the pons, substantia nigra, motor cortex, middle temporal gyrus, primary visual cortex, and hippocampus. This level of pantothenic acid dysregulation is most similar to that of the AD brain, in which pantothenic acid is also decreased in the motor cortex, middle temporal gyrus, primary visual cortex, and hippocampus. DLB appears to differ from other neurodegenerative diseases in being the only of the four to not show pantothenic acid dysregulation in the cerebellum. Conclusions: Pantothenic acid deficiency appears to be a shared mechanism of several neurodegenerative diseases, although differences in the localization of this dysregulation may contribute to the differing clinical pathways observed in these conditions. Show more

Keywords: Pantothenic acid, vitamin B5, dementia with Lewy bodies, mass spectrometry, metabolomics, UHPLC–MS/MS, Lewy body dementia

DOI: 10.3233/JPD-240075

Citation: Journal of Parkinson's Disease, vol. 14, no. 5, pp. 965-976, 2024

Authors: Braunger, Luca Jannik | Knab, Felix | Gasser, Thomas

Article Type: Research Article

Abstract: Background: Mutations in the Leucine Rich Repeat Kinase 2 gene are highly relevant in both sporadic and familial cases of Parkinson’s disease. Specific therapies are entering clinical trials but patient stratification remains challenging. Dysregulated microRNA expression levels have been proposed as biomarker candidates in sporadic Parkinson’s disease. Objective: In this proof-of concept study we evaluate the potential of extracellular miRNA signatures to identify LRRK2-driven molecular patterns in Parkinson’s disease. Methods: We measured expression levels of 91 miRNAs via RT-qPCR in ten individuals with sporadic Parkinson’s disease, ten LRRK2 mutation carriers and eleven healthy controls using …both plasma and cerebrospinal fluid. We compared miRNA signatures using heatmaps and t -tests. Next, we applied group sorting algorithms and tested sensitivity and specificity of their group predictions. Results: miR-29c-3p was differentially expressed between LRRK2 mutation carriers and sporadic cases, with miR-425-5p trending towards significance. Individuals clustered in principal component analysis along mutation status. Group affiliation was predicted with high accuracy in the prediction models (sensitivity up to 89%, specificity up to 70%). miRs-128-3p, 29c-3p, 223-3p, and 424-5p were identified as promising discriminators among all analyses. Conclusions: LRRK2 mutation status impacts the extracellular miRNA signature measured in plasma and separates mutation carriers from sporadic Parkinson’s disease patients. Monitoring LRRK2 miRNA signatures could be an interesting approach to test drug efficacy of LRRK2-targeting therapies. In light of small sample size, the suggested approach needs to be validated in larger cohorts. Show more

Keywords: Parkinson’s disease, LRRK2, microRNA, miRNA, biomarker

DOI: 10.3233/JPD-230408

Citation: Journal of Parkinson's Disease, vol. 14, no. 5, pp. 977-991, 2024

Authors: Francis, Michaela | Zirra, Alexandra | Haque, Tahrina | Gallagher, David | Budu, Caroline | Lees, Andrew J. | Schrag, Anette | Noyce, Alastair J. | Simonet, Cristina

Article Type: Short Communication

Abstract: Reduced spontaneous blinking is a recognized Parkinson’s disease (PD) feature. In contrast, voluntary blinking has been less studied and might serve as a measurable marker of facial bradykinesia. We tested 31 PD patients and 31 controls. Participants were filmed during conversation and a rapid blinking task. Both tasks were videorecorded to count the number of blinks per second. PD patients had lower blink rates. Rapid blinking accurately discriminated between groups with 77% sensitivity and 71% specificity. To conclude, rapid blinking may be a simple and quantifiable task of facial bradykinesia.

Keywords: Blinking, hypomimia, bradykinesia, Parkinson’s disease

DOI: 10.3233/JPD-240005

Citation: Journal of Parkinson's Disease, vol. 14, no. 5, pp. 993-997, 2024

Authors: Lelo de Larrea-Mancera, E. Sebastian | Correa-Medina, Erick I. | Padilla-Bustos, Katia | Romero Terán, Diana Paulina | Hernández-Medrano, Ana Jimena | Cerda-Hernández, Gloria Itzel | Cervantes-Arriaga, Amin | Rodríguez-Violante, Mayela | Gallun, Frederick J. | Seitz, Aaron R. | Solís-Vivanco, Rodolfo

Article Type: Research Article

Abstract: Background: Research indicates that people with Parkinson’s disease (PwPs) may experience challenges in both peripheral and central auditory processing, although findings are inconsistent across studies. Due to the diversity of auditory measures used, there is a need for standardized, replicable hearing assessments to clarify which aspects of audition are impacted in PWPs and whether they are linked to motor and non-motor symptoms. Objective: To characterize auditory processes and their possible alteration in PwPs. To address this, we collected a comprehensive set of standardized measures of audition using PART, a digital testing platform designed to facilitate replication. Additionally, we …examined the relationship between auditory, cognitive, and clinical variables in PwPs. Methods: We included 44 PwPs and 54 age and education matched healthy controls. Assessments included detection of diotic and dichotic frequency modulation, temporal gaps, spectro-temporal broad-band modulation, and speech-on-speech masking. Results: We found no statistically significant differences in auditory processing measures between PwPs and the comparison group (ps > 0.07). In PwPs, an auditory processing composite score showed significant medium size correlations with cognitive measures (0.39 < r<0.41, ps < 0.02) and clinical variables of motor symptom severity, quality of life, depression, and caretaker burden (0.33 < r<0.52, ps < 0.03). Conclusions: While larger datasets are needed to clarify whether PwPs experience more auditory difficulties than healthy controls, our results underscore the importance of considering auditory processing on the symptomatic spectrum of Parkinson’s disease using standardized replicable methodologies. Show more

Keywords: Psychometrics, hearing, auditory processing, Parkinson’s disease, digital assessment, cognition, non-motor symptoms, Mexico

DOI: 10.3233/JPD-230458

Citation: Journal of Parkinson's Disease, vol. 14, no. 5, pp. 999-1013, 2024

Authors: De Groote, Clara | Dujardin, Kathy | Defebvre, Luc | Flinois, Bérengère | Herlin, Virginie | Carrière, Nicolas | Wawrziczny, Emilie

Article Type: Research Article

Abstract: Background: People with Parkinson’s disease (PwPD) exhibit various sexual difficulties (SDs) that may be due to motor and/or nonmotor symptoms or the use of antiparkinsonian medication. SDs are often underreported by PwPD and underexplored by physicians. Objective: This study aimed to explore the SDs experienced by PwPD and create a scale for assessing them. Methods: A corpus of items was generated from semistructured interviews to represent the experience of PwPD as closely as possible. The number of items was reduced according to the psychometric properties, and the scale’s structure was subsequently examined. The final phase consisted …of measuring the scale’s validity and reliability. Results: After assessment of the original corpus of 59 items by PwPD and clinicians, a 25-item version was obtained. The analysis of item properties led to the removal of fifteen items. An exploratory factor analysis of the first 10-item version with a first PwPD sample identified four components of the SDs among PwPD: “low sexual esteem,” “sexual displeasure,” “impact on sexual position” and “hypersexuality.” With a second PwPD sample, a confirmatory factor analysis demonstrated a satisfactory fit between the model with four components and the data. The 10-item scale had good internal consistency and good temporal reliability. Conclusions: The Parkinson’s Disease Sexual Difficulties Scale (PD-SDS) is a valid screening tool that facilitates the investigation of and communication about PD-related SDs. It is intended to improve the identification of vulnerable PwPD and to target the domain of sexual experience impacted by PD to better support PwPD. Show more

Keywords: Parkinson’s disease, sexual difficulties, screening tool, scale

DOI: 10.3233/JPD-240063

Citation: Journal of Parkinson's Disease, vol. 14, no. 5, pp. 1015-1025, 2024