Journal of Movement Disorders

Original Articles

LRRK2 G2019S impact on Parkinson disease; clinical phenotype and treatment in Tunisian patients: Guedi ALI BARREH, Ikram SGHAIER, Youssef ABIDA, Alya GHARBI, Amina NASRI, Saloua MRABET, Amira SOUISSI, Mouna BEN DJEBARA, Sameh TRABELSI, Imen KACEM, Amina GARGOURI-BERRACHI, Riadh GOUIDER; Received December 30, 2023 Accepted April 19, 2024 Published online April 23, 2024; DOI: https://doi.org/10.14802/jmd.23276 [Accepted]

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Abstract PDF: Background
LRRK2-G2019S is the most frequent mutation in North African Parkinson's disease (PD) patients.Data on its impact on disease progression and treatment response remains elusive.Therefore, we aimed to explore the clinical features,treatments,and complications through the disease course of PD Tunisian patients according to their LRRK2-G2019S profile.
Methods
Longitudinal retrospective study conducted in the department of Neurology,Razi University Hospital.We included clinically diagnosed PD patients according to the MDS criteria and reviewed their medical records for clinical,treatment, and neuropsychological assessments.LRRK2-G2019S mutation was screened among all cases using Sanger sequencing.The correlation of LRRK2-G2019S and the clinical PD features was then evaluated.
Results
We included 393 PD patients with 41.5% of cases were mutated for LRRK2-G2019S. Those with mutation exhibited an earlier age of onset(p=0.017),and female-PD cases had a higher mutation frequency (p=0.008).Mutation carriers displayed distinct clinical features,with a higher frequency of postural instability gait difficulty (PIGD)forms(adjusted-p<0.001).Throughout the disease progression,carriers showed a faster annual progression in UPDRS-III scores (adjusted-p=0.009) and a significantly higher Levodopa Equivalent Dosevalues in later stages(1060.81 vs. 877.83 for 6-8 years).Motor complications such as dyskinesia (adjusted-p<0.001) and motor fluctuations(31.9% vs. 25.7%,adjusted-p<0.001) were more prevalent in carriers,particularly in later stages.LRRK2-G2019S carriers also exhibited a lower prevalence of non-motor symptoms including cognitive disordersfor episodic memory(adjusted-p<0.001),attention(adjusted-p<0.001),and dysexecutive disorders (adjusted-p=0.039),as well asneuropsychiatric symptoms and dysautonomic signs.
Conclusion
This study demonstrated the variability of clinical profile among Tunisian PD cases explained by the incomplete penetrance of LRRK2-G2019S that increases with age.Further studies with biomarker and disease progression data are necessary to improve PD management.

Clinical and structural characteristics of NEU1 variants causing sialidosis type 1: Yingji Li, Yang Liu, Rongfei Wang, Ran Ao, Feng Xiang, Xu Zhang, Xiangqing Wang, Shengyuan Yu; Received July 27, 2023 Accepted April 9, 2024 Published online April 11, 2024; DOI: https://doi.org/10.14802/jmd.23145 [Accepted]

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Abstract PDF: Purpose
Sialidosis type 2 has variants that are both catalytically inactive (severe), while sialidosis type 1 has at least one catalytically active (mild) variant. This study aimed to discuss the structural changes associated with these variants in a newly reported family carrying NEU1 variants and explore the clinical characteristics of different combinations of variants in sialidosis type 1.
Methods
First, whole-exome sequencing and detailed clinical examination were performed on the family. Second, structural analysis, including energy, flexibility and polar contacts, was conducted for several NEU1 variants, and a sialidase activity assay was performed. Third, previous NEU1 variants were systematically reviewed, and the clinical characteristics of patients in the severe-mild and mild-mild groups with sialidosis type 1 were analyzed.
Results
We report a novel family with sialidosis type 1 and the compound heterozygous variants S182G and V143E. The newly identified V143E variant was predicted to be a mild variant through structural analysis and was confirmed by sialidase activity assay. The cherry-red spot was more prevalent in the severe-mild group, and ataxia was more common in the mild-mild group. Impaired cognition was found only in the severe-mild group. Moreover, patients with cherry-red spots and abnormal EEGs and VEPs had a relatively early age of onset, whereas patients with myoclonus had a late onset.
Conclusion
Changes in flexibility and local polar contacts may be indicators of the NEU1 pathogenicity. Sialidosis type 1 can be divided into two subgroups according to the variant combinations, and patients with these two subtypes have different clinical characteristics.

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; Received December 22, 2023 Accepted March 18, 2024 Published online March 19, 2024; DOI: https://doi.org/10.14802/jmd.23269 [Accepted]

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Abstract PDF: Objective
Physiotherapy (PT), an effective strategy for managing Parkinson’s disease (PD), can influence healthcare utilization. We analyzed trends in healthcare 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 healthcare utilization and assessed the odds ratio (OR) for receiving regular PTs.
Results
Over 10 years, 169,613 patients with PD were present. The number of patients with PD increased annually from 49,417 in 2011 to 91,841 in 2020. Patients with PD receiving PT increased from 4,847 (9.81%) in 2011 to 13,163 (14.33%) in 2020, and PT prescriptions increased from 81,220 in 2011 to 377,651 in 2019. Medical costs per patient with PD have increased from 1,686 United States Dollars (USD) in 2011 to 3,201 USD in 2020. Medical expenses for each patient with PD receiving PT increased from 6,581 USD in 2011 to 13,476 USD in 2020. Moreover, Regular PTs were administered to 31,782 patients (18.74%) and conducted only through hospitalization. Those in their 50s with disabilities demonstrated a high OR for regular PTs, while those aged 80 years or older and residing outside Seoul had a low OR.
Conclusions
The PD burden increased in South Korea between 2011 and 2020, including an increase in healthcare utilization and medical costs. The significant rise in medical expenses can be associated with increased PD prevalence and PT interventions. Regular PT applications remain restricted and have barriers to access.

Fasting plasma glucose level and longitudinal motor and cognitive outcomes in Parkinson’s disease: Ko-Eun Choi, Dong-Woo Ryu, Yoon-Sang Oh, Joong-Seok Kim; Received December 14, 2023 Accepted March 6, 2024 Published online March 6, 2024; DOI: https://doi.org/10.14802/jmd.23264 [Accepted]

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Abstract PDF: Background
Hyperglycemia and diabetes mellitus have been recognized as poor prognostic factors for motor and nonmotor outcomes in patients with Parkinson’s disease (PD), although there is some controversy. In the present study, we investigated the effects of fasting plasma glucose (FPG) level on longitudinal motor and cognitive outcomes in PD patients.
Methods
We included a total of 201 patients diagnosed with PD between January 2015 and January 2020. The patients were categorized based on FPG level: euglycemia (70< FPG <100 mg/dL), intermediate glycemia (100≤ FPG <126 mg/dL), and hyperglycemia (FPG ≥126 mg/dL), and longitudinal FPG trajectories were analyzed using group-based trajectory modeling. Survival analysis was conducted to determine the time until motor outcome (Hoehn and Yahr stage≥2) and the conversion from normal cognition to mild cognitive impairment.
Results
Among the patients studied, 82 had euglycemia, 93 had intermediate glycemia, and 26 had hyperglycemia. Intermediate glycemia (HR 1.75, 95% CI 1.08-2.81, p=0.022) and hyperglycemia (HR 3.86, 95% CI 2.00-7.48, p<0.01) emerged as significant predictors of worsening motor symptoms. However, neither intermediate glycemia (HR 1.245, 95% CI 0.764-2.029, p=0.3789) nor hyperglycemia (HR 1.602, 95% CI 0.763-3.362, p=0.2129) demonstrated associations with longitudinal progression of cognitive impairment. Diabetes mellitus defined by self-reported medical history was not related to poor motor or cognitive impairment outcomes.
Conclusions
Our results support that both impaired glucose tolerance and hyperglycemia could be associated with motor progression in PD.

Effectiveness of live-streaming tele-exercise intervention in patients with Parkinson’s disease: A pilot study: Jongmok Ha, Jung Hyun Park, Jun Seok Lee, Hye Young Kim, Ji One Song, Jiwon Yoo, Jong Hyeon Ahn, Jinyoung Youn, Jin Whan Cho; Received November 29, 2023 Accepted February 29, 2024 Published online February 29, 2024; DOI: https://doi.org/10.14802/jmd.23251 [Accepted]

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Abstract PDF: Introduction
Exercise can improve both motor and non-motor symptoms in people with Parkinson’s disease (PwP), but there is an unmet need of accessible and sustainable exercise options. This study aimed to evaluate the effect, feasibility, and safety of a regularly performed live-streaming tele-exercise intervention for PwP.
Methods
A live-streaming exercise intervention was implemented twice a week for 12 weeks in PwP. We measured the motor and nonmotor scales in these patients before and after the intervention. Changes in clinical scores from baseline to post-intervention were analyzed using a paired t-test. Factors associated with improvements in clinical scales and compliance were analyzed using Pearson’s correlation analysis.
Results
56 participants were enrolled in the study. There were significant improvements in HADS-A (p = 0.007), HADS-D (p < 0.001), UPDRS part III (p < 0.001), UPDRS total (p = 0.015), H&Y stage (p = 0.027), and PFS-16 (p = 0.026) scores following intervention. Motor improvements were associated with improvements in mood symptoms and fatigue. Higher motor impairment at baseline was associated with a higher compliance rate and better composite motor and non-motor outcomes (ΔUPDRS total score) post-intervention. Overall, the 12-week tele-exercise program was feasible and safe for PwP. No adverse event was reported. Overall adherence was 60.0% in our cohort, and 83.4% were able to participate in more than half of the exercise routines.
Conclusion
The live-streaming tele-exercise intervention is a safe, feasible, and effective non-pharmacological treatment option that can alleviate fatigue and improve mood and motor symptoms in PwP.

High levels of mutant huntingtin protein in tear fluid from Huntington’s Disease Gene Expansion Carriers: Marlies Gijs, Nynke Jorna, Nicole Datson, Chantal Beekman, Cira Dansokho, Alexander Weiss, David E J Linden, Mayke Oosterloo; Received January 18, 2024 Accepted February 21, 2024 Published online February 21, 2024; DOI: https://doi.org/10.14802/jmd.24014 [Accepted]

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Abstract PDF: Objective
Huntington's disease (HD) is an autosomal dominant, fully penetrant, neurodegenerative disease that most commonly affects adults in mid-life. HD is caused by a CAG repeat expansion in the HTT gene, resulting in the expression of mutant huntingtin (mHTT). Our aim was to detect and quantify mHTT in tear fluid, which to our knowledge has never been measured before.
Methods
We recruited 20 manifest, 13 premanifest HD gene expansion carriers (HDGECs) and 20 age-matched controls. All patients underwent detailed assessments, including Unified Huntington’s Disease Rating Scale (UHDRS) total motor score (TMS) and total function capacity score. Tear fluid was collected using paper Schirmer’s strips. The level of tear mHTT was determined using the Single Molecule Counting SMCxPRO technology.
Results
Average tear mHTT levels in manifest (67,223 ± 80,360 fM) and premanifest patients (55,561 ± 45,931 fM) were significantly higher than in controls (1622 ± 2179 fM). We noted significant correlations between tear mHTT levels and CAG repeat length, ‘estimated years to diagnosis’, disease burden score and UHDRS TMS and TFC. The ROC curve demonstrated an almost perfect score (AUC = 0.9975) when comparing controls to manifest patients. Similarly, the AUC between controls and premanifest patients was 0.9846. The optimal cut-off value to distinguish between controls and manifest patients was 4544 fM, whereas it was 6596 fM for the distinction between controls and premanifest patients.
Conclusions
Tear mHTT levels have the potential for early and non-invasive detection of alterations in HD and could be integrated into both clinical trials and clinical diagnostics.

Comparing MoCA Performance in Parkinson’s disease: Age and Education-Adjusted Cutoffs vs. Machine Learning: Kyeongmin Baek, Young Min Kim, Han Kyu Na, Junki Lee, Dong Ho Shin, Seok-Jae Heo, Seok Jong Chung, Kiyong Kim, Phil Hyu Lee, Young H Sohn, Jeehee Yoon, Yun Joong Kim; Received December 23, 2023 Accepted February 12, 2024 Published online February 13, 2024; DOI: https://doi.org/10.14802/jmd.23271 [Accepted]

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Abstract PDF: Background
and Objectives The Montreal Cognitive Assessment (MoCA) is recommended for general cognitive evaluation in Parkinson’s Disease (PD). However, age- and education-adjusted cutoffs specifically for PD have not been developed and systematically validated across PD cohorts with diverse education levels.
Methods
This retrospective analysis utilized data from 1,293 Korean patients with PD, where cognitive diagnoses were determined through comprehensive neuropsychological assessments. Age- and education-adjusted cutoffs were formulated based on 1,202 patients with PD. To identify the optimal machine learning model, clinical parameters and MoCA domain scores from 416 patients with PD were used. Comparative analyses between machine learning and different cutoffs were conducted on an additional 91 consecutive patients with PD.
Results
The cutoffs for cognitive impairment decrease with advancing age within the same education level. Similarly, lower education levels within the same age group correspond to lower cutoffs. For individuals aged 60–80, cutoffs were set as follows: 25 or 24 for those with over 12 years of education, 23 or 22 for 10–12 years, and 21 or 20 for 7–9 years. Comparisons between age- and education-adjusted cutoffs and the machine learning method showed comparable accuracies. The cutoff method demonstrated higher sensitivity (0.8627), whereas machine learning achieved higher specificity (0.8250).
Conclusions
Both the age- and education-adjusted cutoff method and machine learning demonstrated high effectiveness in detecting cognitive impairment in PD. This study highlights the necessity of tailored cutoffs and suggests the potential of machine learning to enhance cognitive assessments in PD.

Phenotypic spectrum of Progressive Supranuclear Palsy: Clinical study and APOE effect: Amina NASRI, Ikram SGHAIER, Anis NEJI, Alya GHARBI, Youssef ABIDA, Saloua MRABET, Amina GARGOURI, Mouna BEN DJEBARA, Imen KACEM, Riadh GOUIDER; Received September 9, 2023 Accepted January 30, 2024 Published online January 30, 2024; DOI: https://doi.org/10.14802/jmd.23178 [Accepted]

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Abstract PDF: Objectives
Progressive supranuclear palsy (PSP)is a rare neurodegenerative disorder encompassing several phenotypes with various motor and cognitive deficits.We aimed to study motor and cognitive characteristics across PSP phenotypes,and assess the influence of the Apolipoprotein E (APOE)gene variants on PSP phenotypic expression.
Materials and Methods
In 20-year-cross-sectional study, we retrospectively reviewed the charts of all patients classified as PSP and re-categorized them into phenotypes using the MDS-2017 criteria. Phenotypes were divided into three subgroups based on the clinical presentation during the first 3 years after symptoms’ onset, which defines the early disease stage:Richardson’s syndrome (PSP-RS), PSP-cortical (PSP-F+PSP-SL+PSP-CBS) and PSP-subcortical(PSP-P+PSP-PGF+PSP-PI+PSP-OM+PSP-C+PSP-PLS).Data on clinical and neuropsychological assessments were collected.Genotyping of APOE was performed using the RFLP-PCR and verified by Sanger sequencing.
Results
We included 112 PSP patients comprising 10 phenotypes classified into 48PSP-RS, 34PSP-cortical(17.6%PSP-CBS,9.4%PSP-F,8.2%PSP-SL)and 30 PSP-subcortical(11.6%PSP-P,8%PSP-PI, 2.6%PSP-OM,1.8%PSP-PGF,1.8%PSP-C,0.9%PSP-PLS) subgroups. PSP-RS cases had older age of onset(p=0.009)and more akinetic-rigid and levodopa resistant parkinsonism(p=0.006),while PSP-cortical cases had more tremor and asymmetric and/or levodopa responsive parkinsonism(p=0.025).Cognitive domains were significantly less altered among PSP-subcortical subgroup.Overall,PSP-APOEε4 carriers developed parkinsonism earlier (p=0.019),had earlier oculomotor dysfunction(p=0.052) and more altered cognitive profile.It was also associated with younger age of parkinsonism onset in PSP-RS phenotype(p=0.026).
Conclusion
This study demonstrated the wide phenotypic spectrum of PSP among Tunisians.Later disease onset and akinetic-rigid and levodopa resistant parkinsonism were the hallmarks of PSP-RS phenotype,while milder cognitive impairment was characteristic of PSP-subcortical subgroup.APOEε4 allele was associated to earlier parkinsonism and oculomotor dysfunction and seemed to play a role in defining a more altered cognitive profile in PSP patients.

Review Article

α-Synuclein: A Promising Biomarker for Parkinson’s Disease and Related Disorders: Taku Hatano, Ayami Okuzumi, Gen Matsumoto, Tsunemi Taiji, Nobutaka Hattori; Received March 22, 2024 Accepted April 9, 2024 Published online April 9, 2024; DOI: https://doi.org/10.14802/jmd.24075 [Accepted]

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Abstract PDF: Mutations in the SNCA gene, which encodes α-synuclein (α-syn), play a key role in the development of genetic Parkinson’s disease (PD). α-Syn is a major component of Lewy bodies in PD and glial cytoplasmic inclusions in multiple system atrophy (MSA). Rapid eye movement sleep behavior disorder (RBD) patients often progress to PD, dementia with Lewy bodies (DLB), or MSA, collectively known as α-synucleinopathies. The loss of dopaminergic neurons with Lewy bodies precedes motor dysfunction in these diseases, but the mechanisms of neurodegeneration due to α-syn aggregation are poorly understood. Monitoring α-syn aggregation in vivo could serve as a diagnostic biomarker and help elucidate the pathogenesis, necessitating a simple and accurate detection method. Seed amplification assays (SAAs), such as real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA), are used to detect small amounts of abnormally structured α-syn protofibrils, which are central to aggregation. These methods are promising for the early diagnosis of α-synucleinopathy. Differences in α-syn filament structures between α-synucleinopathies, observed through transmission electron microscopy and cryo-electron microscopy, suggest their role in the pathogenesis of neurodegeneration. SAAs may differentiate between subtypes of α-synucleinopathy and other diseases. Efforts are also being made to identify α-syn from blood using various methods. This review introduces body fluid α-syn biomarkers based on pathogenic α-syn seeds, which are expected to redefine α-synucleinopathy diagnosis and staging, improving clinical research accuracy and facilitating biomarker development.

Letters to the editor

Deep Brain Stimulation in Advanced Parkinson’s Disease: An Uncommon Case of Allergic Encephalitis: Jyun-Yi Chen, Yen-Chung Chen, Shey-Lin Wu; Received November 16, 2023 Accepted April 12, 2024 Published online April 15, 2024; DOI: https://doi.org/10.14802/jmd.23237 [Accepted]

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Haloperidol in managing DYT-TOR1A Dystonia: Unveiling a Dramatic Therapeutic Response: Pavankumar Katragadda, Vikram V Holla, Nitish Kamble, Ravi Yadav, Pramod Kumar Pal; Received February 3, 2024 Accepted April 5, 2024 Published online April 9, 2024; DOI: https://doi.org/10.14802/jmd.24029 [Accepted]

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Comments on 'Absence of Alpha-Synuclein Aggregation in Patients With Parkinson's Disease Complicated by Sigmoid Volvulus': Sabri Selcuk Atamanalp, Refik Selim Atamanalp; Received March 27, 2024 Accepted March 29, 2024 Published online March 29, 2024; DOI: https://doi.org/10.14802/jmd.24078 [Accepted]

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Knowledge, attitude and perception of genetic testing in patients with movement disorders, their caregivers and health care professionals: Sneha Kamath, Vikram V Holla, Nitish Kamble, Rohan R Mahale, Ravi Yadav, Pramod Kumar Pal; Received February 10, 2024 Accepted March 27, 2024 Published online March 27, 2024; DOI: https://doi.org/10.14802/jmd.24034 [Accepted]

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Joubert Syndrome Presenting with Levodopa Responsive Parkinsonism: Jin Hwangbo, Ki-Seok Park, Hyun Sung Kim, Jae-Hwan Choi, Jae-Hyeok Lee; Received December 29, 2023 Accepted March 27, 2024 Published online March 27, 2024; DOI: https://doi.org/10.14802/jmd.23275 [Accepted]

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Therapeutic Strategy for Improving Motor Complications of Parkinson’s Disease: Short-term Levodopa–carbidopa Intestinal Gel Therapy using a Nasogastric Tube: TAGUCHI Soutarou, NAKURA Takahiro, DOYU Manabu, SAIKI Hidemoto; Received February 8, 2024 Accepted March 20, 2024 Published online March 21, 2024; DOI: https://doi.org/10.14802/jmd.24033 [Accepted]

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