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Case Report
Nearly Abolished Dopamine Transporter Uptake in a Patient With a Novel FBXO7 Mutation
Eun Young Kim, Seon Young Kim, Youngduk Seo, Chaewon Shin
Received January 13, 2022  Accepted April 26, 2022  Published online July 26, 2022  
DOI: https://doi.org/10.14802/jmd.22006    [Epub ahead of print]
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AbstractAbstract PDFSupplementary Material
Mutations in the F-box only protein 7 (FBXO7) gene are the cause of autosomal recessive parkinsonian-pyramidal syndrome. Herein, we report a patient with a novel FBXO7 mutation with a unique clinical presentation. A 43-year-old male visited our hospital with complaints of progressing gait disturbance since a generalized tonic clonic seizure. There were no past neurological symptoms or familial disorders. Neurological examination revealed bradykinesia, masked face, stooped posture, parkinsonian gait, and postural instability. The bilateral uptake by dopamine transporters was nearly abolished, as determined by N-(3-[18F]fluoropropyl)- 2β-carbon ethoxy-3β-(4-iodophenyl) nortropane positron emission tomography (18F-FP-CIT PET). Next-generation sequencing revealed a heterozygous c.1066_1069delTCTG (p.Ser356ArgfsTer56) frameshift variant and a heterozygous c.80G>A (p.Arg27His) missense variant of the FBXO7 gene. The patient’s specific clinical features, medication-refractory parkinsonism and seizures further broaden the spectrum of FBXO7 mutations. The nearly abolished dopamine transporter uptake identified by 18F-FP-CIT PET is frequently found in patients with FBXO7 mutations, which is different from the usual rostrocaudal gradient that is observed in patients with Parkinson’s disease.
Review Article
Emerging Concepts of Motor Reserve in Parkinson’s Disease
Seok Jong Chung, Jae Jung Lee, Phil Hyu Lee, Young H. Sohn
J Mov Disord. 2020;13(3):171-184.   Published online August 31, 2020
DOI: https://doi.org/10.14802/jmd.20029
  • 6,473 View
  • 256 Download
  • 10 Citations
AbstractAbstract PDF
The concept of cognitive reserve (CR) in Alzheimer’s disease (AD) explains the differences between individuals in their susceptibility to AD-related pathologies. An enhanced CR may lead to less cognitive deficits despite severe pathological lesions. Parkinson’s disease (PD) is also a common neurodegenerative disease and is mainly characterized by motor dysfunction related to striatal dopaminergic depletion. The degree of motor deficits in PD is closely correlated to the degree of dopamine depletion; however, significant individual variations still exist. Therefore, we hypothesized that the presence of motor reserve (MR) in PD explains the individual differences in motor deficits despite similar levels of striatal dopamine depletion. Since 2015, we have performed a series of studies investigating MR in de novo patients with PD using the data of initial clinical presentation and dopamine transporter PET scan. In this review, we summarized the results of these published studies. In particular, some premorbid experiences (i.e., physical activity and education) and modifiable factors (i.e., body mass index and white matter hyperintensity on brain image studies) could modulate an individual’s capacity to tolerate PD pathology, which can be maintained throughout disease progression.
Original Articles
Heterogeneous Patterns of Striatal Dopamine Loss in Patients with Young- versus Old-Onset Parkinson’s Disease: Impact on Clinical Features
Seok Jong Chung, Han Soo Yoo, Yang Hyun Lee, Phil Hyu Lee, Young H. Sohn
J Mov Disord. 2019;12(2):113-119.   Published online May 30, 2019
DOI: https://doi.org/10.14802/jmd.18064
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  • 13 Citations
AbstractAbstract PDFSupplementary Material
Objective
Ample evidence has suggested that age at onset of Parkinson’s disease (PD) is associated with heterogeneous clinical features in individuals. We hypothesized that this may be attributed to different patterns of nigrostriatal dopamine loss.
Methods
A total of 205 consecutive patients with de novo PD who underwent 18F-FP-CIT PET scans (mean follow-up duration, 6.31 years) were divided into three tertile groups according to their age at onset of parkinsonian motor symptoms. Striatal dopamine transporter (DAT) availability was compared between the old- (n = 73) and young-onset (n = 66) groups. In addition, the risk of developing freezing of gait (FOG) and longitudinal requirements for dopaminergic medications were examined.
Results
The old-onset PD group (mean age at onset, 72.66 years) exhibited more severe parkinsonian motor signs than the young-onset group (52.58 years), despite comparable DAT availability in the posterior putamen; moreover, the old-onset group exhibited more severely decreased DAT availability in the caudate than the young-onset group. A Cox regression model revealed that the old-onset PD group had a higher risk for developing FOG than the young-onset group [hazard ratio 2.523, 95% confidence interval (1.239–5.140)]. The old-onset group required higher doses of dopaminergic medications for symptom control than the young-onset group over time.
Conclusion
The present study demonstrated that the old-onset PD group exhibited more severe dopamine loss in the caudate and were more likely to develop gait freezing, suggesting that age at onset may be one of the major determinants of the pattern of striatal dopamine depletion and progression of gait disturbance in PD.
Nonmotor and Dopamine Transporter Change in REM Sleep Behavior Disorder by Olfactory Impairment
Jee-Young Lee, Eun Jin Yoon, Yu Kyeong Kim, Chae Won Shin, Hyunwoo Nam, Jae Min Jeong, Han-Joon Kim, Beomseok Jeon
J Mov Disord. 2019;12(2):103-112.   Published online May 30, 2019
DOI: https://doi.org/10.14802/jmd.18061
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  • 8 Citations
AbstractAbstract PDFSupplementary Material
Objective
It is unclear whether the decline in dopamine transporters (DAT) differs among idiopathic rapid eye movement sleep behavior disorder (iRBD) patients with different levels of olfactory impairment. This study aimed to characterize DAT changes in relation to nonmotor features in iRBD patients by olfactory loss.
Methods
This prospective cohort study consisted of three age-matched groups: 30 polysomnography-confirmed iRBD patients, 30 drug-naïve Parkinson’s disease patients, and 19 healthy controls without olfactory impairment. The iRBD group was divided into two groups based on olfactory testing results. Participants were evaluated for reported prodromal markers and then underwent 18F-FP-CIT positron emission tomography and 3T MRI. Tracer uptakes were analyzed in the caudate, anterior and posterior putamen, substantia nigra, and raphe nuclei.
Results
Olfactory impairment was defined in 38.5% of iRBD patients. Mild parkinsonian signs and cognitive functions were not different between the two iRBD subgroups; however, additional prodromal features, constipation, and urinary and sexual dysfunctions were found in iRBD patients with olfactory impairment but not in those without. Tracer uptake showed significant group differences in all brain regions, except the raphe nuclei. The iRBD patients with olfactory impairment had uptake reductions in the anterior and posterior putamen, caudate, and substantia nigra (p < 0.016 in all, adjusted for age), which ranged from 0.6 to 0.8 of age-normative values. In contrast, those without olfactory impairment had insignificant changes in all regions ranging above 0.8.
Conclusion
There was a clear distinction in DAT loss and nonmotor profiles by olfactory status in iRBD.
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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  • 5 Citations
AbstractAbstract 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.
Clinical Features Indicating Nigrostriatal Dopaminergic Degeneration in Drug-Induced Parkinsonism
Seung Ha Lee, Han Kyeol Kim, Young Gun Lee, Chul Hyoung Lyoo, Sung Jun Ahn, Myung Sik Lee
J Mov Disord. 2017;10(1):35-39.   Published online December 27, 2016
DOI: https://doi.org/10.14802/jmd.16045
  • 8,115 View
  • 148 Download
  • 3 Citations
AbstractAbstract PDFSupplementary Material
Objective
Patients with drug-induced parkinsonism (DIP) may have nigrostriatal dopaminergic degeneration. We studied the clinical features that may indicate nigrostriatal dopaminergic degeneration in patients with DIP.
Methods
Forty-one DIP patients were classified into normal and abnormal [18F] FP-CIT scan groups. Differences in 32 clinical features and drug withdrawal effects were studied.
Results
Twenty-eight patients had normal (Group I) and 13 patients had abnormal (Group II) scans. Eight patients of Group I, but none of Group II, had taken calcium channel blockers (p = 0.040). Three patients of Group I and six of Group II had hyposmia (p = 0.018). After drug withdrawal, Group I showed greater improvement in Unified Parkinson’s Disease Rating Scale total motor scores and subscores for bradykinesia and tremors than Group II. Only hyposmia was an independent factor associated with abnormal scans, but it had suboptimal sensitivity.
Conclusion
None of the clinical features were practical indicators of nigrostriatal dopaminergic degeneration in patients with DIP.
Cardiovascular Autonomic Dysfunction in Mild and Advanced Parkinson’s Disease
Joong-Seok Kim, Si-Hoon Lee, Yoon-Sang Oh, Jeong-Wook Park, Jae-Young An, Sung-Kyung Park, Si-Ryung Han, Kwang-Soo Lee
J Mov Disord. 2016;9(2):97-103.   Published online March 28, 2016
DOI: https://doi.org/10.14802/jmd.16001
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  • 25 Citations
AbstractAbstract PDF
Objective
The purpose of the present study was to investigate cardiovascular autonomic dysfunction in patients with Parkinson’s disease (PD) with mild to severe stages of motor symptoms and to compare cardiovascular autonomic dysfunction between drug-naïve and dopaminergic drug-treated groups.
Methods
This study included 188 PD patients and 25 age-matched healthy controls who underwent head-up tilt-testing, 24-h ambulatory blood pressure (BP) monitoring and 24-h Holter monitoring. Autonomic function test results were evaluated among groups categorized by motor symptom severities (mild vs. moderate vs. severe) and treatment (drug-naïve or dopaminergic drug treatment).
Results
Orthostatic hypotension and supine hypertension were more frequent in patients with PD than in healthy controls. The frequencies of orthostatic hypotension, supine hypertension, nocturnal hypertension and non-dipping were not different among groups. Additionally, no significant differences were detected in supine BP, orthostatic BP change, nighttime BP, nocturnal BP dipping, or heart rate variabilities among groups.
Conclusions
Cardiovascular autonomic dysfunction is not confined to moderate to severe PD patients, and starts early in the course of the disease in a high proportion of PD patients. In addition, dopaminergic drug treatments do not affect cardiovascular autonomic function.
Gender Differences in Age-Related Striatal Dopamine Depletion in Parkinson’s Disease
Jae Jung Lee, Jee Hyun Ham, Phil Hyu Lee, Young H. Sohn
J Mov Disord. 2015;8(3):130-135.   Published online September 10, 2015
DOI: https://doi.org/10.14802/jmd.15031
  • 20,536 View
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  • 22 Citations
AbstractAbstract PDFSupplementary Material
Objective Gender differences are a well-known clinical characteristic of Parkinson’s disease (PD). In-vivo imaging studies demonstrated that women have greater striatal dopamine transporter (DAT) activity than do men, both in the normal population and in PD patients. We hypothesize that women exhibit more rapid aging-related striatal DAT reduction than do men, as the potential neuroprotective effect of estrogen wanes with age.
Methods This study included 307 de novo PD patients (152 men and 155 women) who underwent DAT scans for an initial diagnostic work-up. Gender differences in age-related DAT decline were assessed in striatal sub-regions using linear regression analysis.
Results Female patients exhibited greater DAT activity compared with male patients in all striatal sub-regions. The linear regression analysis revealed that age-related DAT decline was greater in the anterior and posterior caudate, and the anterior putamen in women compared with men; we did not observe this difference in other sub-regions.
Conclusions This study demonstrated the presence of gender differences in age-related DAT decline in striatal sub-regions, particularly in the antero-dorsal striatum, in patients with PD, presumably due to aging-related decrease in estrogen. Because this difference was not observed in the sensorimotor striatum, this finding also suggests that women may not have a greater capacity to tolerate PD pathogenesis than do men.
Case Report
Treatment of Gait Ignition Failure with Ropinirole
Alexis N. Cohen-Oram, Jonathan T. Stewart, Kim Bero, Michael W. Hoffmann
J Mov Disord. 2014;7(2):95-98.   Published online October 30, 2014
DOI: https://doi.org/10.14802/jmd.14014
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  • 1 Citations
AbstractAbstract PDF
Gait ignition failure (GIF) is a syndrome characterized by hesitation or inability to initiate gait from a static position. It may occur in a variety of conditions, including normal pressure hydrocephalus, subcortical vascular disease, parkinsonian syndromes and a variety of focal lesions. Previous information on the treatment of GIF has been primarily anecdotal, but there have been a few reports of response to dopamine agonists. We report a 63-year-old man with anoxic encephalopathy who developed GIF nine years after the initial anoxic insult. The patient’s GIF responded robustly, albeit transiently, to ropinirole. MRI was unrevealing, but a positron emission tomography scan showed hypometabolism in the deep frontal ACA/MCA watershed area; this may have disconnected the basal ganglia from the motor cortex and/or interrupted dopaminergic mesocortical transmission. Our understanding of the pathophysiology and the treatment of GIF remains limited, but there may be at least a limited therapeutic role for dopamine agonists.
Original Article
Dopamine Does Not Appear to Affect Mental Rotation in Parkinson’s Disease
Gregory P. Crucian, Sheyan Armaghani, Avan Armaghani, Paul S. Foster, David W. Burks, Barry Skoblar, Valeria Drago, Kenneth M. Heilman
J Mov Disord. 2014;7(2):77-83.   Published online October 30, 2014
DOI: https://doi.org/10.14802/jmd.14011
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  • 1 Citations
AbstractAbstract PDF
Objective Patients with Parkinson’s disease (PD) often have deficits with mental rotation (MR). The neuropathological factors underlying these deficits, however, remain to be elucidated. One hypothesis suggests that dopamine depletion in nigro-striatal systems adversely influences MR. Another hypothesis suggests that deterioration of cortical (fronto-temporo-parietal basal ganglia) networks that mediate this function are responsible for this deficit. The goal of this study was to test the dopamine hypothesis by determining if dopamine abstinence negatively influences MR performance.
Methods Thirty three non-demented right-handed individuals with PD were assess for their ability to perform a pencil and paper MR test while “on” and “off” dopaminergic medications. Dopamine abstinence followed the typical overnight withdrawal procedures.
Results No differences in mental rotation abilities were found between “on” and “off” dopaminergic medications.
Conclusions These results suggest that other neuropathological factors, such as cortical-basal ganglia neurodegeneration, or dysfunction of other neurotransmitters systems, might account for these cognitive deficits and future research will have to test these alternative hypotheses.
Review Article
Maladaptive Reward-Learning and Impulse Control Disorders in Patients with Parkinson’s Disease: A Clinical Overview and Pathophysiology Update
Jee-Young Lee, Beom Seok Jeon
J Mov Disord. 2014;7(2):67-76.   Published online October 30, 2014
DOI: https://doi.org/10.14802/jmd.14010
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  • 8 Citations
AbstractAbstract PDF
Impulse control disorders (ICD) in Parkinson’s disease (PD) are a disabling non-motor symptom with frequencies of 13–35% among patients receiving dopamine replacement therapy. ICD in PD is strongly associated with dopaminergic drug use, especially non-ergot dopamine agonists (DA). However, individual susceptibility and disease-related neural changes are also important contributors to the development of ICD. Discrepancies between nigrostriatal and mesolimbic dopaminergic degeneration and non-physiological administration of dopaminergic drugs may induce abnormal ’hyperstimulation’ of the mesolimbic system, which alters reward-learning behaviors in PD patients. In addition, DA can make patients more impulsive during decision-making and seek risk-taking behaviors. DA intake is also related to the biased representation of rewards. Ultimately, loss of negative feedback control due to dysfunctional frontostriatal connections is necessary for the establishment of ICD in PD. The subsequent behavioral and neural changes are affected by PD treatment and disease progression; thus, proper treatment guidelines for physicians are needed to prevent the development of ICD. Future studies aimed at producing novel therapeutics to control the risk factors for ICD or treat ICD behaviors in PD are warranted. This review summarizes recent advances from epidemiological and pathophysiological studies on ICD in PD. Management principles and limitations of current therapeutics are briefly discussed.
Case Report
Dopaminergic Medication-Related Repetitive Behaviors in Parkinson’s Disease
Jong Sam Baik, Sang Won Han, Jeong Yeon Kim, Jae Hyeon Park
J Mov Disord. 2008;1(2):101-103.
DOI: https://doi.org/10.14802/jmd.08020
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  • 1 Citations
AbstractAbstract PDF

A set of impulse control and repetitive behaviors presumed to be related to dopaminergic medications has been recognized in Parkinson’s disease (PD). A 68-year-old man presented with compulsive gathering of new towels for 8 months after increasing his medication dosage. After we reduced a dose of Sinemet® and ropinirole as before, and added amantadine, his repetitive behavior was gone and dyskinesia was improved.


JMD : Journal of Movement Disorders