Journal of Movement Disorders

Review Article

Fighting Against the Clock: Circadian Disruption and Parkinson’s Disease: Yen-Chung Chen, Wei-Sheng Wang, Simon J G Lewis, Shey-Lin Wu; Received October 19, 2023 Accepted November 20, 2023 Published online November 21, 2023; DOI: https://doi.org/10.14802/jmd.23216 [Accepted]

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Abstract PDF: Circadian disruption is being increasingly recognized as a critical factor in the development and progression of Parkinson's disease (PD). This review aims to provide an in-depth overview of the relationship between circadian disruption and PD, exploring the molecular, cellular, and behavioral aspects of this interaction. This will include a comprehensive understanding of how the clock gene system and transcription–translation feedback loops (TTFLs) function and how they go away in PD. The article also discusses the role of clock genes in the regulation of circadian rhythms, the impact of clock gene dysregulation on mitochondrial function, oxidative stress, and neuroinflammation, including the microbiota-gut-brain axis, which have all been proposed as crucial mechanisms in the pathophysiology of PD. Finally, this review highlights potential therapeutic strategies targeting the clock gene system and circadian rhythm for the treatment of PD.

Brief communication

Accessibility of device-aided therapies for persons with Parkinson’s disease in Poland: Katarzyna Smilowska, Tomasz Pietrzykowski, K Ray Chaudhuri, Bastiaan R. Bloem, Daniel J van Wamelen; Received September 4, 2023 Accepted November 17, 2023 Published online November 20, 2023; DOI: https://doi.org/10.14802/jmd.23172 [Accepted]

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Abstract PDF: Background
Access to care for people with Parkinson’s disease (PD), in particular to device-aided therapies (DAT), is not equally distributed.
Objectives
To analyse accessibility to DAT (deep brain stimulation; intraduodenal levodopa pump therapy; or apomorphine pump therapy) in Poland.
Methods
We analysed the distribution of DAT use in Poland by determining the number of persons with PD receiving one of the three DATs during 2015-2021.
Results
In 2021 the number of persons receiving DAT in Poland was 0.56% of the total PD population, having increased from 0.21% in 2015. Overall, deep brain stimulation was the preferred DAT in Poland, but strong regional differences in the use of the other DAT were present. Accessibility to DAT was negatively associated with average annual income (p<0.001).
Conclusions
Access to DAT for PD in Poland is still limited and accessibility showed strong regional differences, although its general increase over the last decade is encouraging.

Original Articles

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; Received March 1, 2023 Accepted November 3, 2023 Published online November 6, 2023; DOI: https://doi.org/10.14802/jmd.23042 [Accepted]

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Abstract PDF: 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
The 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 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.
Conclusions
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.

Comparative Olfactory Profiles in Parkinson’s disease and Drug-Induced Parkinsonism: In Hee Kwak, Young Eun Kim, Suk Yun Kang, Joong Seob Lee, Jeongjae Lee, Min Seung Kim, Dong A Yea, Hyeo-il Ma; Received May 29, 2023 Accepted October 6, 2023 Published online October 6, 2023; DOI: https://doi.org/10.14802/jmd.23105 [Accepted]

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Abstract PDF: Objective
Drug-induced Parkinsonism (DIP) stands as a frequently encountered diagnostic possibility when considering Parkinson’s disease (PD). While olfactory dysfunction is a common clinical feature in PD, the comparison of olfactory function between two conditions remains insufficient. This study aimed to compare the olfactory function, including threshold, discrimination, and identiﬁcation (TDI) profiles between PD and DIP.
Methods
Consecutive patients with drug-naïve PD (n=78) or DIP (n=31) confirmed through dopamine transporter image were enrolled in this study. The YSK olfactory function (YOF) test composed of TDI domains culturally familiar odorants to Koreans, was administered to all patients.
Results
In the study population, the patients with DIP were significantly older than the patients with PD. Over 70% of patients in each group had hyposmia or anosmia, and there was no significant difference in the occurrence of olfactory dysfunction between the two groups. In addition, there were no differences in the total YOF score and threshold score between the two groups. Meanwhile, the PD group had a significantly lower discrimination and identification score compared to the DIP group, after adjusting for age, sex, the existence of diabetes, disease duration, and cognitive function.
Conclusions
This study demonstrated that detailed olfactory profiles are different in PD and DIP, even though olfactory dysfunction can be observed in both conditions.

Hair Loss: A Well-Known Yet Understudied Symptom in Parkinson’s Disease Patients During Dopaminergic Therapy: Jungyeun Lee, Hwa Jung Ryu, Soon Young Hwang, Seong-Beom Koh; Received May 1, 2023 Accepted September 24, 2023 Published online September 26, 2023; DOI: https://doi.org/10.14802/jmd.23088 [Epub ahead of print]

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Abstract PDF Supplementary Material: Objective
Hair loss has been reported to occur during dopaminergic therapy in patients with Parkinson’s disease. The mechanism by which dopaminergic therapy induces hair loss is not well understood. Dopamine receptors are present in the hair follicle, where they regulate melanin production. However, the role of dopamine receptors in hair growth is still not well understood. This study aimed to evaluate the prevalence of hair loss and identify factors associated with complaints of hair loss in patients with Parkinson’s disease.
Methods
A cross-sectional design involving 495 Parkinson’s disease patients was applied to evaluate hair loss status. Patients completed a questionnaire, and scalp/hair examinations were performed. Patients with underlying conditions that could affect hair loss and those prescribed medications known to increase the risk of hair loss were excluded. Finally, 291 patients (58.8%) were included for analysis.
Results
Among the 495 patients, 138 (27.9%) reported hair loss. Interestingly, more than half of the patients who complained of hair loss (79 out of 138) did not utilize treatments such as hair products, massage, dietary modifications, or alopecia medications. Hair inspection by a single investigator revealed objective hair loss in 263 patients (53.1%). An analysis of factors associated with hair loss complaints showed that the intake of dopaminergic medications with a levodopa-equivalent daily dose > 448 mg was associated with complaints of hair loss.
Conclusion
Dopaminergic medication is associated with hair loss complaints in Parkinson’s disease patients.

Brief communication

A Survey of Perspectives on Telemedicine for Patients With Parkinson’s Disease: Jae Young Joo, Ji Young Yun, Young Eun Kim, Yu Jin Jung, Ryul Kim, Hui-Jun Yang, Woong-Woo Lee, Aryun Kim, Han-Joon Kim; Received July 12, 2023 Accepted August 21, 2023 Published online August 22, 2023; DOI: https://doi.org/10.14802/jmd.23130 [Epub ahead of print]

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Abstract PDF Supplementary Material: Objective
Parkinson’s disease (PD) patients often find it difficult to visit hospitals because of motor symptoms, distance to the hospital, or the absence of caregivers. Telemedicine is one way to solve this problem.
Methods
We surveyed 554 PD patients from eight university hospitals in Korea. The questionnaire consisted of the clinical characteristics of the participants, possible teleconferencing methods, and preferences for telemedicine.
Results
A total of 385 patients (70%) expressed interest in receiving telemedicine. Among them, 174 preferred telemedicine whereas 211 preferred in-person visits. The longer the duration of disease, and the longer the time required to visit the hospital, the more patients were interested in receiving telemedicine.
Conclusion
This is the first study on PD patients’ preferences regarding telemedicine in Korea. Although the majority of patients with PD have a positive view of telemedicine, their interest in receiving telemedicine depends on their different circumstances.

Original Article

Cervical proprioception in Parkinson's disease and its correlation with manual dexterity function: Özlem Menevşe, Büşra Kepenek-Varol, Murat Gültekin, Sevil Bilgin; J Mov Disord. 2023;16(3):295-306. Published online July 3, 2023; DOI: https://doi.org/10.14802/jmd.23039

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Abstract PDF: Objective
Cervical proprioception plays a crucial role in posture and movement control. This study aimed to determine the relationships of cervical proprioception, cervical muscle strength and endurance with manual dexterity and hand strength in individuals with idiopathic Parkinson’s disease (PD).
Methods
Twenty individuals with PD (mean age: 63.9 years) and 20 healthy individuals as a control group (mean age: 61.9 years) were recruited. Cervical joint position error (JPE), static endurance of neck muscles, activation of deep cervical flexor muscles (Craniocervical Flexion Test, CCFT), manual dexterity (Purdue Pegboard Test, PPT), cognitive and motor tasks of the PPT, finger tapping test (FTT), pinch strength, and grip strength were assessed.
Results
Cervical JPE was significantly higher in individuals with PD than in controls (p < 0.05). The strength and endurance of the cervical muscles were significantly decreased in individuals with PD (p < 0.05). Cervical JPE measurements were negatively correlated with PPT, cognitive and motor tasks of the PPT in individuals with PD (all p < 0.05). The endurance of cervical flexor muscles was negatively correlated with PPT and cognitive PPT scores in the PD group (p < 0.05). In addition, a significant positive correlation was found between cervical flexor endurance and hand strength in the PD group (p < 0.05).
Conclusion
Cervical proprioception and the strength and endurance of cervical muscles decrease in individuals with PD compared to healthy individuals. Impairment of cervical proprioception appears to be associated with poorer upper extremity performance. Detailed evaluation of the cervical region in PD may help determine the factors affecting upper extremity function.

Case Report

Rapid-Onset Dystonia and Parkinsonism in a Patient With Gaucher Disease: Ellen Hertz, Grisel Lopez, Jens Lichtenberg, Dietrich Haubenberger, Nahid Tayebi, Mark Hallett, Ellen Sidransky; J Mov Disord. 2023;16(3):321-324. Published online June 13, 2023; DOI: https://doi.org/10.14802/jmd.23074

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Abstract PDF Supplementary Material: Biallelic mutations in GBA1 cause the lysosomal storage disorder Gaucher disease, and carriers of GBA1 variants have an increased risk of Parkinson’s disease (PD). It is still unknown whether GBA1 variants are also associated with other movement disorders. We present the case of a woman with type 1 Gaucher disease who developed acute dystonia and parkinsonism at 35 years of age during a recombinant enzyme infusion treatment. She developed severe dystonia in all extremities and a bilateral pill-rolling tremor that did not respond to levodopa treatment. Despite the abrupt onset of symptoms, neither Sanger nor whole genome sequencing revealed pathogenic variants in ATP1A3 associated with rapid-onset dystonia-parkinsonism (RDP). Further examination showed hyposmia and presynaptic dopaminergic deficits in [18F]-DOPA PET, which are commonly seen in PD but not in RDP. This case extends the spectrum of movement disorders reported in patients with GBA1 mutations, suggesting an intertwined phenotype.

Review Article

GBA1 Variants and Parkinson’s Disease: Paving the Way for Targeted Therapy: Young Eun Huh, Tatiana Usnich, Clemens R. Scherzer, Christine Klein, Sun Ju Chung; J Mov Disord. 2023;16(3):261-278. Published online June 12, 2023; DOI: https://doi.org/10.14802/jmd.23023

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Abstract PDF: Glucosylceramidase beta 1 (GBA1) variants have attracted enormous attention as the most promising and important genetic candidates for precision medicine in Parkinson’s disease (PD). A substantial correlation between GBA1 genotypes and PD phenotypes could inform the prediction of disease progression and promote the development of a preventive intervention for individuals at a higher risk of a worse disease prognosis. Moreover, the GBA1-regulated pathway provides new perspectives on the pathogenesis of PD, such as dysregulated sphingolipid metabolism, impaired protein quality control, and disrupted endoplasmic reticulum-Golgi trafficking. These perspectives have led to the development of novel disease-modifying therapies for PD targeting the GBA1-regulated pathway by repositioning treatment strategies for Gaucher’s disease. This review summarizes the current hypotheses on a mechanistic link between GBA1 variants and PD and possible therapeutic options for modulating GBA1-regulated pathways in PD patients.

Original Article

Safinamide as an Adjunct to Levodopa in Asian and Caucasian Patients With Parkinson’s Disease and Motor Fluctuations: A Post Hoc Analysis of the SETTLE Study: Roongroj Bhidayasiri, Takayuki Ishida, Takanori Kamei, Ryan Edbert Husni, Ippei Suzuki, Shey Lin Wu, Jin Whan Cho; J Mov Disord. 2023;16(2):180-190. Published online April 26, 2023; DOI: https://doi.org/10.14802/jmd.22196

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Abstract PDF Supplementary Material: Objective
Safinamide is a selective, reversible monoamine oxidase B inhibitor with demonstrated efficacy and tolerability in placebo-controlled studies and is clinically useful for patients with motor fluctuations. This study evaluated the efficacy and safety of safinamide as a levodopa adjunct therapy in Asian patients with Parkinson’s disease.
Methods
Data from 173 Asian and 371 Caucasian patients from the international Phase III SETTLE study were included in this post hoc analysis. The safinamide dose was increased from 50 mg/day to 100 mg/day if no tolerability issues occurred at week 2. The primary outcome was the change from baseline to week 24 in daily ON-time without troublesome dyskinesia (i.e., ON-time). Key secondary outcomes included changes in Unified Parkinson’s Disease Rating Scale (UPDRS) scores.
Results
Safinamide significantly increased daily ON-time relative to placebo in both groups (least-squares mean: 0.83 hours, p = 0.011 [Asians]; 1.05 hours, p < 0.0001 [Caucasians]). Motor function relative to placebo (UPDRS Part III) improved significantly in Asians (-2.65 points, p = 0.012) but not Caucasians (-1.44 points, p = 0.0576). Safinamide did not worsen Dyskinesia Rating Scale scores in either subgroup, regardless of the presence or absence of dyskinesia at baseline. Dyskinesia was largely mild for Asians and moderate for Caucasians. None of the Asian patients experienced adverse events leading to treatment discontinuation.
Conclusion
Safinamide as a levodopa adjunct is well tolerated and effective in reducing motor fluctuations in both Asian and Caucasian patients. Further studies to investigate the real-world effectiveness and safety of safinamide in Asia are warranted.

Review Article

Adult-Onset Genetic Leukoencephalopathies With Movement Disorders: Mu-Hui Fu, Yung-Yee Chang; J Mov Disord. 2023;16(2):115-132. Published online March 7, 2023; DOI: https://doi.org/10.14802/jmd.22127

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Abstract PDF: Genetic leukoencephalopathies (GLEs) are a group of white matter abnormalities with heterogeneous radiological and phenotypic features. Although these conditions have mostly been described in children, adult-onset cases are increasingly recognized owing to the widespread use of neuroimaging and advances in molecular genetic testing. The disease course is often progressive with a varied spectrum of presentations, trapping neurologists in the dilemma of differential diagnosis. Movement disorders are among the most common symptoms, and their diversity makes diagnosis challenging. In this review, we focus on adult-onset GLEs with movement disorders and offer a step-by-step diagnostic approach by clarifying the phenomenology of movement, advising investigations for acquired causes, describing the clinical and radiological clues to each disease, emphasizing the limitations of advanced molecular testing, and discussing the future application of artificial intelligence. We provide a list summarizing the leukoencephalopathies associated with different categories of movement disorders. In addition to guiding clinicians on how to narrow the list of differential diagnoses with the tools currently available, another aim of this review is to emphasize the inevitable trend toward applying advanced technology in diagnosing these difficult diseases.

Original Article

The Effect of Blood Lipids, Type 2 Diabetes, and Body Mass Index on Parkinson’s Disease: A Korean Mendelian Randomization Study: Kye Won Park, Yun Su Hwang, Seung Hyun Lee, Sungyang Jo, Sun Ju Chung; J Mov Disord. 2023;16(1):79-85. Published online January 12, 2023; DOI: https://doi.org/10.14802/jmd.22175

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3 Citations

Abstract PDF Supplementary Material

Objective
Associations between various metabolic conditions and Parkinson’s disease (PD) have been previously identified in epidemiological studies. We aimed to investigate the causal effect of lipid levels, type 2 diabetes mellitus (T2DM), and body mass index (BMI) on PD in a Korean population via Mendelian randomization (MR).
Methods
Two-sample MR analyses were performed with inverse-variance weighted (IVW), weighted median, and MR-Egger regression approaches. We identified genetic variants associated with lipid concentrations, T2DM, and BMI in publicly available summary statistics, which were either collected from genome-wide association studies (GWASs) or from meta-analyses of GWAS that targeted only Korean individuals or East Asian individuals, including Korean individuals. The outcome dataset was a GWAS on PD performed in a Korean population.
Results
From previous GWASs and meta-analyses, we selected single nucleotide polymorphisms as the instrumental variables. Variants associated with serum levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides, as well as with T2DM and BMI, were selected (n = 11, 19, 17, 89, and 9, respectively). There were no statistically significant causal associations observed between the five exposures and PD using either the IVW, weighted median, or MR-Egger methods (p-values of the IVW method: 0.332, 0.610, 0.634, 0.275, and 0.860, respectively).
Conclusion
This study does not support a clinically relevant causal effect of lipid levels, T2DM, and BMI on PD risk in a Korean population.

Citations

Citations to this article as recorded by

Unraveling the link: exploring the causal relationship between diabetes, multiple sclerosis, migraine, and Alzheimer’s disease through Mendelian randomization
Hua Xue, Li Zeng, Shuangjuan Liu
Frontiers in Neuroscience.2023;[Epub] CrossRef
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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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3 Citations

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.

Citations

Citations to this article as recorded by

Potential for Therapeutic-Loaded Exosomes to Ameliorate the Pathogenic Effects of α-Synuclein in Parkinson’s Disease
David J. Rademacher
Biomedicines.2023; 11(4): 1187. CrossRef
Neural Stem Cell Therapies: Promising Treatments for Neurodegenerative Diseases
Amir Gholamzad, Hadis Sadeghi, Maryam Azizabadi Farahani, Ali Faraji, Mahya Rostami, Sajad Khonche, Shirin Kamrani, Mahsa Khatibi, Omid Moeini, Seyed Armit Hosseini, Mohammadmatin Nourikhani, Mehrdad Gholamzad
Neurology Letters.2023; 2(2): 55. CrossRef
Should continuous dopaminergic stimulation be a standard of care in advanced Parkinson’s disease?
Z. Pirtošek, V. Leta, P. Jenner, M. Vérin
Journal of Neural Transmission.2023; 130(11): 1395. CrossRef

Movement Disorders Associated With Radiotherapy and Surgical Procedures: Bharath Kumar Surisetti, Shweta Prasad, Vikram Venkappayya Holla, Nitish Kamble, Ravi Yadav, Pramod Kumar Pal; J Mov Disord. 2023;16(1):42-51. Published online January 12, 2023; DOI: https://doi.org/10.14802/jmd.22092

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Abstract PDF: Occasionally, movement disorders can occur following interventional procedures including but not limited to radiotherapy, dental procedures, and cardiac, cerebral and spinal surgeries. The majority of these disorders tend to be unexpected sequelae with variable phenomenology and latency, and they can often be far more disabling than the primary disease for which the procedure was performed. Owing to poor knowledge and awareness of the problem, delays in diagnosing the condition are common, as are misdiagnoses as functional movement disorders. This narrative review discusses the phenomenology, pathophysiology, and potential treatments of various movement disorders caused by interventional procedures such as radiotherapy and neurological and non-neurological surgeries and procedures.

Original Article

Association of Depression With Early Occurrence of Postural Instability in Parkinson’s Disease: Yun Su Hwang, Sungyang Jo, Kye Won Park, Seung Hyun Lee, Sangjin Lee, Sun Ju Chung; J Mov Disord. 2023;16(1):68-78. Published online December 20, 2022; DOI: https://doi.org/10.14802/jmd.22091

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Abstract PDF Supplementary Material: Objective
Depression in Parkinson’s disease (PD) affects the quality of life of patients. Postural instability and gait disturbance are associated with the severity and prognosis of PD. We investigated the association of depression with axial involvement in early-stage PD patients.
Methods
This study involved 95 PD patients unexposed to antiparkinsonian drugs. After a baseline assessment for depression, the subjects were divided into a depressed PD group and a nondepressed PD group. Analyses were conducted to identify an association of depression at baseline with the following outcome variables: the progression to Hoehn and Yahr scale (H-Y) stage 3, the occurrence of freezing of gait (FOG), levodopa-induced dyskinesia, and wearing-off. The follow-up period was 53.40 ± 16.79 months from baseline.
Results
Kaplan–Meier survival curves for H-Y stage 3 and FOG showed more prominent progression to H-Y stage 3 and occurrences of FOG in the depressed PD group than in the nondepressed PD group (log-rank p = 0.025 and 0.003, respectively). Depression in drug-naïve, early-stage PD patients showed a significant association with the progression to H-Y stage 3 (hazard ratio = 2.55; 95% confidence interval = 1.32–4.93; p = 0.005), as analyzed by Cox regression analyses. In contrast, the occurrence of levodopa-induced dyskinesia and wearing-off did not differ between the two groups (log-rank p = 0.903 and 0.351, respectively).
Conclusion
Depression in drug-naïve, early-stage PD patients is associated with an earlier occurrence of postural instability. This suggests shared nondopaminergic pathogenic mechanisms and potentially enables the prediction of early development of postural instability.

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