Journal of Movement Disorders

Review Article

Non-Motor Fluctuations in Parkinson’s Disease: Underdiagnosed Yet Important: Iro Boura, Karolina Poplawska-Domaszewicz, Cleanthe Spanaki, Rosabel Chen, Daniele Urso, Riaan van Coller, Alexander Storch, Kallol Ray Chaudhuri; J Mov Disord. 2025;18(1):1-16. Published online December 20, 2024; DOI: https://doi.org/10.14802/jmd.24227

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Abstract PDF: Non-motor fluctuations (NMFs) in Parkinson’s disease (PD) significantly affect patients’ well-being. Despite being identified over two decades ago, NMFs remain largely underrecognized, undertreated, and poorly understood. While they are often temporally associated with motor fluctuations (MFs) and can share common risk factors and pathophysiologic mechanisms, NMFs and MFs are currently considered distinct entities. The prevalence and severity of NMFs, often categorized into neuropsychiatric, sensory, and autonomic subtypes, vary significantly across studies due to the heterogeneous PD populations screened and the diverse evaluation tools applied. The consistent negative impact of NMFs on PD patients’ quality of life underscores the importance of further investigations via focused and controlled studies, validated assessment instruments and novel digital technologies. High-quality research is essential to illuminate the complex pathophysiology and clinical nuances of NMFs, ultimately enhancing clinicians’ diagnostic and treatment options in routine clinical practice.

Original Articles

Trends in Physiotherapy Interventions and Medical Costs for Parkinson’s Disease in South Korea, 2011–2020: Dong-Woo Ryu, Jinse Park, Myung Jun Lee, Dallah Yoo, Sang-Myung Cheon; J Mov Disord. 2024;17(3):270-281. Published online March 19, 2024; DOI: https://doi.org/10.14802/jmd.23269

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Abstract PDF Supplementary Material: Objective
Physiotherapy (PT), which is an effective strategy for managing Parkinson’s disease (PD), can influence health care utilization. We analyzed trends in health care utilization, PT interventions, and medical costs among patients with PD.
Methods
Using data from the Korean National Health Insurance Service from 2011 to 2020, we analyzed the number of patients with PD and their health care utilization and assessed the odds ratio (OR) for receiving regular PTs.
Results
Over 10 years, 169,613 patients with PD were included in the analysis. The number of patients with PD increased annually from 49,417 in 2011 to 91,841 in 2020. The number of patients with PD receiving PT increased from 4,847 (9.81%) in 2011 to 13,163 (14.33%) in 2020, and the number of PT prescriptions increased from 81,220 in 2011 to 377,651 in 2019. Medical costs per patient with PD increased from 1,686 United States dollars (USD) in 2011 to 3,202 USD in 2020. The medical expenses for each patient with PD receiving PT increased from 6,582 USD in 2011 to 13,475 USD in 2020. Moreover, regular PTs were administered to 31,782 patients (18.74%) and were administered only through hospitalization. Those patients in their 50s with disabilities demonstrated a high OR for regular PTs, whereas those aged 80 years or older and residing outside of Seoul had a low OR.
Conclusion
The PD burden increased in South Korea between 2011 and 2020, as did health care utilization and medical costs. A significant increase in medical expenses can be associated with increased PD incidence and PT interventions. Regular PT applications remain restricted and have barriers to access.

Parkinson’s Disease, Impulsive-Compulsive Behaviors, and Health-Related Quality of Life: Marie Grall-Bronnec, Audrey Verholleman, Caroline Victorri-Vigneau, Juliette Leboucher, Elsa Thiabaud, Jean-Benoit Hardouin, Benoit Schreck, Tiphaine Rouaud, Monica Roy, Pascal Derkinderen, Gaëlle Challet-Bouju; J Mov Disord. 2024;17(1):82-88. Published online November 6, 2023; DOI: https://doi.org/10.14802/jmd.23042

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Abstract PDF Supplementary Material

Objective
A large body of literature has examined the links between the use of dopamine replacement therapy (DRT) in Parkinson’s disease (PD) and the development of “impulsive-compulsive behaviors (ICBs).” Little is known regarding the link between the development of ICBs and health-related quality of life (HRQOL). We aimed to explore the factors that are associated with poorer HRQOL, especially in relation to DRT-induced ICBs, in a sample of PD patients.
Methods
This PARKADD (PARK: PARKinson’s disease; ADD: behavioral ADDictions) study was a prospective case‒control study initially designed to assess the factors associated with ICBs in PD patients. A prospective clinical follow-up was added, aiming to capture the long-term evolution of HRQOL in relation to ICBs occurring or worsening after the beginning of PD. We focused on sociodemographic and PD characteristics and the history or presence of ICBs. HRQOL was measured using the Parkinson’s Disease Questionnaire-8. A multivariate linear regression was performed to identify factors related to poorer HRQOL.
Results
A total of 169 patients were eligible for the follow-up study. The presence of an ICB, a higher levodopa equivalent daily dose (LEDD) and a longer PD duration were significantly associated with poorer HRQOL, with an interaction between LEDD and PD duration.
Conclusion
The presence of an ICB was related to poorer HRQOL and should be considered a crucial factor for the management of PD patients. Several studies were recently published that provide guidelines for the management of these patients, with recommendations based on two key principles: prevention and specific treatment.

Citations

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Review Articles

Current Status and Future Perspectives on Stem Cell-Based Therapies for Parkinson’s Disease: Young Cha, Tae-Yoon Park, Pierre Leblanc, Kwang-Soo Kim; J Mov Disord. 2023;16(1):22-41. Published online January 12, 2023; DOI: https://doi.org/10.14802/jmd.22141

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Abstract PDF

Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease, affecting 1%–2% of the population over the age of 65. As the population ages, it is anticipated that the burden on society will significantly escalate. Although symptom reduction by currently available pharmacological and/or surgical treatments improves the quality of life of many PD patients, there are no treatments that can slow down, halt, or reverse disease progression. Because the loss of a specific cell type, midbrain dopamine neurons in the substantia nigra, is the main cause of motor dysfunction in PD, it is considered a promising target for cell replacement therapy. Indeed, numerous preclinical and clinical studies using fetal cell transplantation have provided proof of concept that cell replacement therapy may be a viable therapeutic approach for PD. However, the use of human fetal cells remains fraught with controversy due to fundamental ethical, practical, and clinical limitations. Groundbreaking work on human pluripotent stem cells (hPSCs), including human embryonic stem cells and human induced pluripotent stem cells, coupled with extensive basic research in the stem cell field offers promising potential for hPSC-based cell replacement to become a realistic treatment regimen for PD once several major issues can be successfully addressed. In this review, we will discuss the prospects and challenges of hPSC-based cell therapy for PD.

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Multiple System Atrophy: Advances in Diagnosis and Therapy: Hirohisa Watanabe, Sayuri Shima, Yasuaki Mizutani, Akihiro Ueda, Mizuki Ito; J Mov Disord. 2023;16(1):13-21. Published online December 20, 2022; DOI: https://doi.org/10.14802/jmd.22082

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Abstract PDF

This review summarizes improvements in understanding the pathophysiology and early clinical symptoms of multiple system atrophy (MSA) and advancements in diagnostic methods and disease-modifying therapies for the condition. In 2022, the Movement Disorder Society proposed new diagnostic criteria to develop disease-modifying therapies and promote clinical trials of MSA since the second consensus was proposed in 2008. Regarding pathogenesis, cutting-edge findings have accumulated on the interactions of α-synuclein, neuroinflammation, and oligodendroglia with neurons. In neuroimaging, introducing artificial intelligence, machine learning, and deep learning has notably improved diagnostic accuracy and individual analyses. Advancements in treatment have also been achieved, including immunotherapy therapy against α-synuclein and serotonin-targeted and mesenchymal stem cell therapies, which are thought to affect several aspects of the disease, including neuroinflammation. The accelerated progress in clarifying the pathogenesis of MSA over the past few years and the development of diagnostic techniques for detecting early-stage MSA are expected to facilitate the development of disease-modifying therapies for one of the most intractable neurodegenerative diseases.

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Case Report

Effect of Chelation Therapy on a Korean Patient With Brain Manganese Deposition Resulting From a Compound Heterozygous Mutation in the SLC39A14 Gene: Jae-Hyeok Lee, Jin-Hong Shin; J Mov Disord. 2022;15(2):171-174. Published online March 22, 2022; DOI: https://doi.org/10.14802/jmd.21143

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Abstract PDF

Mutations in the manganese transporter gene SLC39A14 lead to inherited disorders of manganese metabolism. Chelation therapy with edetate calcium disodium (CaNa2EDTA) is known to effectively reduce manganese deposition. We describe the first identified Korean case of SLC39A14-associated manganism and the treatment response to a 5-year chelation therapy. An 18-year-old female presented with childhood-onset dystonia. Magnetic resonance imaging showed T1 hyperintensity throughout the basal ganglia, brainstem, cerebellum, cerebral and cerebellar white matter, and pituitary gland. Blood manganese levels were elevated, and whole-exome sequencing revealed compound heterozygous mutations in SLC39A14. Treatment with intravenous CaNa₂EDTA led to a significant reduction in serum manganese levels and T1 hyperintensities. However, her dystonia improved insignificantly. Hence, early diagnosis of this genetic disorder is essential because it is potentially treatable. Even though our treatment did not significantly reverse the establish deficits, chelation therapy could have been more effective if it was started at an earlier stage of the disease.

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Mechanisms of manganese-induced neurotoxicity and the pursuit of neurotherapeutic strategies
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Review Articles

Manganese and Movement Disorders: A Review: Dinkar Kulshreshtha, Jacky Ganguly, Mandar Jog; J Mov Disord. 2021;14(2):93-102. Published online April 6, 2021; DOI: https://doi.org/10.14802/jmd.20123

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Abstract PDF

Scientific and technological advances achieved with industrial expansion have led to an ever-increasing demand for heavy metals. This demand has, in turn, led to increased contamination of soil, water and air with these metals. Chronic exposure to metals may be detrimental not only to occupational workers but also to the nonoccupational population exposed to these metals. Manganese (Mn), a commonly used heavy metal, is an essential cofactor for many enzymatic processes that drive biological functions. However, it is also a potential source of neurotoxicity, particularly in the field of movement disorders. The typical manifestation of Mn overexposure is parkinsonism, which may be difficult to differentiate from the more common idiopathic Parkinson’s disease. In addition to environmental exposure to Mn, other potential etiologies causing hypermanganesemia include systemic health conditions, total parenteral nutrition and genetic mutations causing Mn dyshomeostasis. In this review, we critically analyze Mn and discuss its sources of exposure, pathophysiology and clinical manifestations. We have highlighted the global public health impact of Mn and emphasize that movement disorder specialists should record a detailed social and occupational history to ensure that a toxic etiology is not misdiagnosed as a neurodegenerative disease. In the absence of a definite therapeutic option, early diagnosis and timely institution of preventive measures are the keys to managing its toxic effects.

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Update on Current Technologies for Deep Brain Stimulation in Parkinson’s Disease: Michelle Paff, Aaron Loh, Can Sarica, Andres M. Lozano, Alfonso Fasano; J Mov Disord. 2020;13(3):185-198. Published online August 31, 2020; DOI: https://doi.org/10.14802/jmd.20052

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Abstract PDF

Deep brain stimulation (DBS) is becoming increasingly central in the treatment of patients with Parkinson’s disease and other movement disorders. Recent developments in DBS lead and implantable pulse generator design provide increased flexibility for programming, potentially improving the therapeutic benefit of stimulation. Directional DBS leads may increase the therapeutic window of stimulation by providing a means of avoiding current spread to structures that might give rise to stimulation-related side effects. Similarly, control of current to individual contacts on a DBS lead allows for shaping of the electric field produced between multiple active contacts. The following review aims to describe the recent developments in DBS system technology and the features of each commercially available DBS system. The advantages of each system are reviewed, and general considerations for choosing the most appropriate system are discussed.

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Immunotherapy Targeting Neurodegenerative Proteinopathies: α-Synucleinopathies and Tauopathies: Junghwan Shin, Han-Joon Kim, Beomseok Jeon; J Mov Disord. 2020;13(1):11-19. Published online December 19, 2019; DOI: https://doi.org/10.14802/jmd.19057

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Abstract PDF

α-Synuclein and tau deposition in the central nervous system is responsible for various parkinsonian syndromes, including Parkinson’s disease, multiple system atrophy, dementia with Lewy bodies, progressive supranuclear palsy and corticobasal degeneration. Emerging evidence has suggested that pathologic α-synuclein and tau are transmitted from cell to cell and further accelerate the aggregation of pathologic proteins in neighboring cells. Furthermore, extracellular pathologic proteins have also been reported to provoke inflammatory responses that lead to neurodegeneration. Therefore, immunotherapies targeting extracellular α-synuclein and tau have been proposed as potential disease-modifying strategies. In this review, we summarize completed phase I trials and ongoing phase II trials of immunotherapies against α-synuclein and tau and further discuss concerns and hurdles to overcome in the future.

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Original Articles

Less Pulsatile Levodopa Therapy (6 Doses Daily) Is Associated with a Reduced Incidence of Dyskinesia: Mark M. Lin, Robert Laureno; J Mov Disord. 2019;12(1):37-42. Published online January 30, 2019; DOI: https://doi.org/10.14802/jmd.18046

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299 Download
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Abstract PDF

Objective
To evaluate whether less pulsatile levodopa therapy (LPT) can reduce the development of levodopa-induced dyskinesia (LID).
Methods
This is a retrospective cohort study of patients with Parkinson’s disease at the movement disorders clinic of Medstar Washington Hospital Center. The study was not blinded or randomized. Patients were seen between August 2002 and August 2018. During these years, we treated patients with less pulsatile (6 doses daily) levodopa treatment to reduce LID. Occurrence of LID was recorded.
Results
Ninety-five patients with Parkinson’s disease taking levodopa were divided into two groups: 1) patients who were initially managed on LPT or who switched from traditional therapy (TT) (n = 61) (mean disease duration: 7.7 ± 4.8 years, mean levodopa duration: 5.6 ± 4.5 years and mean observation time: 4.3 ± 3.4 years), and 2) patients on TT throughout the observation period or until they developed dyskinesia (n = 34) (mean disease duration: 8.3 ± 3.8 years, mean levodopa duration: 6.2 ± 4.2 years and mean observation time: 4.1 ± 3.4 years). Three of the 61 LPT patients developed dyskinesia during the observation period. One of the patients developed dyskinesia after being switched to pulsatile doses by another doctor. In the other two, dyskinesia was minimal. In contrast to this 4.9% cumulative incidence, dyskinesia occurred in 50% (17/34) of TT patients, an incidence similar to that in published data (p < 0.001).
Conclusion
Less pulsatile levodopa with 6 daily doses was associated with a low incidence of LID. Further study of this method of treatment is warranted.

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Individual Therapeutic Singing Program for Vocal Quality and Depression in Parkinson’s Disease: Eun Young Han, Ji Young Yun, Hyun Ju Chong, Kyoung-Gyu Choi; J Mov Disord. 2018;11(3):121-128. Published online August 9, 2018; DOI: https://doi.org/10.14802/jmd.17078

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Objective
Patients with Parkinson’s disease (PD) frequently experience depression associated with voice problems. Singing involves the use of similar muscles and the neural networks associated with vocal function and emotional response. The purpose of this study is to enhance vocal quality and depressive symptoms of patients with PD using individual singing program.
Methods
The Individual Therapeutic Singing Program for PD (ITSP-PD) was conducted by a certified music therapist. In total, nine PD patients with a subjective voice problem or depression participated in 6 sessions over 2 weeks. We measured the Maximum Phonation Time (MPT) via the Praat test, the Voice Handicap Index (VHI), the Voice-Related Quality of Life (V-RQOL) and the Geriatric Depression Scale (GDS).
Results
In total, 8 out of 9 patients completed all the sessions; 6 out of 8 patients participated in the follow-up test after 6 months. A statistically significant change in MPT (p = 0.011) was observed between the pre- and post-tests. The VHI (p = 0.035) and the GDS (p = 0.018) were significantly lower in the post-test. In the pre-, post-, and follow-up tests, the MPT (p = 0.030), V-RQOL (p = 0.008), and GDS (p = 0.009) were significantly changed.
Conclusion
The ITSP-PD based on neurological singing therapy for PD showed therapeutic possibility for vocal function and depression in patients with PD. Our findings suggest the need for a randomized study to examine the continuing positive effects of the ITSP-PD over a longer period of time.

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Psychodynamic Psychotherapy for Functional (Psychogenic) Movement Disorders: Vibhash D. Sharma, Randi Jones, Stewart A. Factor; J Mov Disord. 2017;10(1):40-44. Published online December 27, 2016; DOI: https://doi.org/10.14802/jmd.16038

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Objective
As the literature for the treatment of functional (psychogenic) movement disorders (FMD) is sparse, we assessed clinical outcomes in patients with FMD who underwent treatment with psychodynamic psychotherapy (PDP).
Methods
A retrospective analysis of the data of patients with FMD who were referred for PDP from 2008−2014 at Emory University Medical Center was performed.
Results
Thirty patients were included, mean age at presentation was 50 years (SD 13.9) and majority were female (27/30). Most common movement disorder was involuntary shaking/jerky movements (50%) and tremor (43%). Mean duration of symptoms was 3.2 years and mean number of PDP visits was 4.9. PDP lead to good outcomes in 10, modest in 8, and poor in 9. Three patients lost to follow up. Mean duration of symptoms between two groups (good vs. poor) was not statistically significant (p = 0.11), mean number of PDP visits showed a trend towards significance (p = 0.053). In all cases of good outcomes precipitants of the movement disorder were identified and a majority (60%) was receptive of the diagnosis and had good insight.
Conclusion
PDP lead to improvement in 60% of the patients which is encouraging as the treatment is challenging. This study supports heterogeneous causes of FMD including varied roles of past/recent events and demonstrates importance of psychological approaches such as PDP. Treatment with PDP should be considered in some patients with FMD but predicting who will respond remains a challenge. Further long term prospective studies with large sample size and placebo control are needed.

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Applications of CRISPR/Cas9 for Gene Editing in Hereditary Movement Disorders: Wooseok Im, Jangsup Moon, Manho Kim; J Mov Disord. 2016;9(3):136-143. Published online September 21, 2016; DOI: https://doi.org/10.14802/jmd.16029

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Abstract PDF

Gene therapy is a potential therapeutic strategy for treating hereditary movement disorders, including hereditary ataxia, dystonia, Huntington’s disease, and Parkinson’s disease. Genome editing is a type of genetic engineering in which DNA is inserted, deleted or replaced in the genome using modified nucleases. Recently, clustered regularly interspaced short palindromic repeat/CRISPR associated protein 9 (CRISPR/Cas9) has been used as an essential tool in biotechnology. Cas9 is an RNA-guided DNA endonuclease enzyme that was originally associated with the adaptive immune system of Streptococcus pyogenes and is now being utilized as a genome editing tool to induce double strand breaks in DNA. CRISPR/Cas9 has advantages in terms of clinical applicability over other genome editing technologies such as zinc-finger nucleases and transcription activator-like effector nucleases because of easy in vivo delivery. Here, we review and discuss the applicability of CRISPR/Cas9 to preclinical studies or gene therapy in hereditary movement disorders.

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Abstract PDF

Immunization therapy targeting α-synuclein has emerged as a promising approach for Parkinson’s disease and perhaps for other synucleinopathies. Several antibodies have shown therapeutic effects in mouse models of synucleinopathies and have alleviated the pathological and behavioral phenotypes of these mice. The mechanisms through which the immunization therapy works were initially puzzling, especially given that α-synuclein is a typical cytosolic protein. Recent studies, however, suggested that extracellular α-synuclein is an important pathogenic entity, and hence, a target for immunotherapy. Here, we review the literature describing immunization therapy for synucleinopathies in mouse models and provide current thoughts on the potential mechanisms underlying the therapeutic effects of α-synuclein immunotherapy.

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Cell Therapy Strategies vs. Paracrine Effect in Huntington’s Disease: Wooseok Im, Manho Kim; J Mov Disord. 2014;7(1):1-6. Published online April 30, 2014; DOI: https://doi.org/10.14802/jmd.14001

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Abstract PDF

Huntington’s disease (HD) is a genetic neurodegenerative disorder. The most common symptom of HD is abnormal involuntary writhing movements, called chorea. Antipsychotics and tetrabenazine are used to alleviate the signs and symptoms of HD. Stem cells have been investigated for use in neurodegenerative disorders to develop cell therapy strategies. Recent evidence indicates that the beneficial effects of stem cell therapies are actually mediated by secretory molecules, as well as cell replacement. Although stem cell studies show that cell transplantation provides cellular improvement around lesions in in vivo models, further work is required to elucidate some issues before the clinical application of stem cells. These issues include the precise mechanism of action, delivery method, toxicity and safety. With a focus on HD, this review summarizes cell therapy strategies and the paracrine effect of stem cells.

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