Myung Jun Lee

Impaired finger dexterity in patients with parkinson's disease correlates with discriminative cutaneous sensory dysfunction†

To study the influence of discriminative cutaneous sensory dysfunction on impaired finger dexterity in Parkinsons disease (PD), we evaluated 48 right‐handed PD patients during a practically defined off‐medication period and 24 healthy age‐matched controls. With visual deprivation, a finger tapping task (FTT) was performed to assess the speed of simple repetitive finger movements and a coin rotation task (CRT) was used to assess finger dexterity. The tasks were performed with the right hand. We measured the somesthetic temporal discrimination threshold (sTDT) in the right index finger. The mean ± SD FTT score of the patient group was lower than that of the control group (24.0 ± 8.0 vs. 29.8 ± 7.8; P < 0.01). The patient group performed worse on the CRT than the control group (8.5 ± 3.5 vs. 12.6 ± 1.7; P < 0.001). The mean sTDT value of the patient group was longer than that of the control group (124.0 ± 44.8 vs. 78.1 ± 26.2 ms; P < 0.001). The CRT scores correlated with the sTDT values (Pearsons correlation coefficient = −0.43; P < 0.01), but not with the Unified Parkinsons Disease Rating Scale (UPDRS) finger bradykinesia scores or FTT scores. Multiple regression analysis showed that the sTDT values (parameter estimate = −0.03, SE = 0.01; P < 0.01), but not patient age, UPDRS finger bradykinesia score, or FTT score, affected the CRT score. Slowness of simple repetitive finger movements did not have a strong impact on the impaired manual dexterity of PD. Discriminative sensory dysfunction and consequent abnormal sensorimotor integration seem to be involved in the impaired finger dexterity of PD.

Cognitive impairments associated with morphological changes in cortical and subcortical structures in multiple system atrophy of the cerebellar type

Patients with the cerebellar variant of multiple system atrophy (MSA‐C) often show cognitive deficits in various cognitive domains. The association between morphometric changes in cortical and subcortical structures and cognitive impairments in MSA‐C were investigated to explore the neural correlates responsible for cognitive deficits in MSA‐C patients.

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia linked CSF1R mutation: Report of four Korean cases.

We describe detailed clinical, biochemical, neuroimaging and neuropathological features in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), encompassing hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD), linked to colony-stimulating factor 1 receptor (CSF1R) mutations in four Korean cases. Clinical, biochemical, neuroimaging and neuropathological findings were obtained by direct evaluation and from previous medical records. The genetic analysis of the CSF1R gene was done in two autopsy-confirmed ALSP cases and two cases where ALSP was suspected based on the clinical and neuroimaging characteristics. We identified two known mutations: c.2342C>T (p.A781V) in one autopsy-proven HDLS and clinically ALSP-suspected case and c.2345G>A (p.R782H) in another autopsy-proven POLD case. We also found a novel mutation (c.2296A>G; p.M766V) in a patient presenting with hand tremor, stuttering and hesitant speech, and abnormal behavior whose father died from a possible diagnosis of spinocerebellar ataxia. To the best of our knowledge, this is the first documented ALSP-linked CSF1R mutation in Korea and supports the suggestion that HDLS and POLD, with pathological characteristics that are somewhat different but which are caused by CSF1R mutations, are the same spectrum of disease, ALSP.

Expansion of the clinicopathological and mutational spectrum of Perry syndrome

BACKGROUND Perry syndrome (PS) caused by DCTN1 gene mutation is clinically characterized by autosomal dominant parkinsonism, depression, severe weight loss, and hypoventilation. Previous pathological studies have reported relative sparing of the cerebral cortex in this syndrome. Here, we characterize novel clinical and neuroimaging features in 3 patients with PS. METHODS (18)F-fluorinated N-3-fluoropropyl-2-ß-carboxymethoxy-3-β-(4-iodophenyl) nortropane ([(18)F]FP-CIT) PET, [(18)F]fluorodeoxyglucose PET, or volumetric MRI was performed in probands, and imaging data were analyzed and compared with those of control subjects. RESULTS We identified 2 novel mutations of DCTN1. Oculogyric crisis that presented before levodopa treatment was observed in 1 case. One patient had supranuclear gaze palsy. In 2 cases, [(18)F]FP-CIT showed marked loss of dopamine transporter binding with only mild parkinsonism. Areas of hypometabolism or cortical thickness change were observed in dorsolateral frontal, anterior cingulate, lateral temporal, and inferior parietal cortices. CONCLUSION Oculomotor manifestations are not uncommon in PS. Neuroimaging studies suggest involvement of the frontotemporoparietal cortex, which may be the clinical correlate of apathy and depression, as well as pathological changes in subcortical structures.

Clinical Heterogeneity of Atypical Pantothenate Kinase-Associated Neurodegeneration in Koreans

Objective Neurodegeneration with brain iron accumulation (NBIA) represents a group of inherited movement disorders characterized by iron accumulation in the basal ganglia. Recent advances have included the identification of new causative genes and highlighted the wide phenotypic variation between and within the specific NBIA subtypes. This study aimed to investigate the current status of NBIA in Korea. Methods We collected genetically confirmed NBIA patients from twelve nationwide referral hospitals and from a review of the literature. We conducted a study to describe the phenotypic and genotypic characteristics of Korean adults with atypical pantothenate kinase-associated neurodegeneration (PKAN). Results Four subtypes of NBIA including PKAN (n = 30), PLA2G6-related neurodegeneration (n = 2), beta-propeller protein-associated neurodegeneration (n = 1), and aceruloplasminemia (n = 1) have been identified in the Korean population. The clinical features of fifteen adults with atypical PKAN included early focal limb dystonia, parkinsonism-predominant feature, oromandibular dystonia, and isolated freezing of gait (FOG). Patients with a higher age of onset tended to present with parkinsonism and FOG. The p.R440P and p.D378G mutations are two major mutations that represent approximately 50% of the mutated alleles. Although there were no specific genotype-phenotype correlations, most patients carrying the p.D378G mutation had a late-onset, atypical form of PKAN. Conclusions We found considerable phenotypic heterogeneity in Korean adults with atypical PKAN. The age of onset may influence the presentation of extrapyramidal symptoms.

Kinematic Analysis in Patients with Parkinson's Disease and SWEDD

BACKGROUND AND OBJECTIVES The differential diagnosis between mild Parkinsons disease (PD) and Scan Without Evidence of Dopaminergic Deficit(SWEDD) is challenging. Progressive reduction in amplitude and speed of finger tapping (sequence effect) has been considered as the most useful sign for discriminating PD from SWEDD. However, a video analysis reported that sequence effect is a major confounding factor for the misdiagnosis of PD. Our objective was to perform a kinematic analysis of finger tapping to explore parameters for distinguishing between patients with PD and SWEDD. METHODS We enrolled 14 patients with PD, 17 patients with SWEDD and 18 age- and sex-matched healthy controls. Amplitude, speed and frequency of finger tapping were measured using gyroscopes, and the means, decrement and variability in kinematic parameters for specific tapping duration were calculated. RESULTS Compared to SWEDD group, PD group showed more decrement in amplitude and speed of the first 20 taps, more decrement in frequency after 20 taps and more variability in speed of 15 seconds of taps. However, none of parameters was a practically useful indicator distinguishing individual patients with PD from those with SWEDD. CONCLUSIONS Analysis of finger tapping, even using an apparatus, is not useful for distinguishing mild PD and SWEDD.

Impact of regional striatal dopaminergic function on kinematic parameters of Parkinson’s disease

Among the cardinal parkinsonian motor deficits, the severity of bradykinesia correlates with striatal dopamine loss. However, the impact of regional striatal dopamine loss on specific components of bradykinesia remains unknown. Using gyroscopes, we measured the amplitude, speed, and frequency of finger tapping in 24 untreated patients with Parkinson’s disease (PD) and 28 healthy controls. Using positron emission tomography (PET) studies and [18F]-N-3-fluoropropyl-2-beta-carboxymethoxy-3-beta-(4-iodophenyl) nortropane (FP-CIT) in PD patients, we investigated the relationship between the mean values, variability and decrements of various kinematic parameters of finger tapping on one side (e.g. the mean, variability and decrement) and contralateral striatal FP-CIT binding. Compared with controls, PD patients had reduced amplitudes and speeds of tapping and showed greater decrement in those parameters. PD patients also exhibited greater irregularity in amplitude, speed, and frequency. Putaminal FP-CIT uptake levels correlated with the mean speed and amplitude, and caudate uptake levels correlated with mean amplitude. The variability of amplitude and speed correlated only with the caudate uptake levels. Neither caudate nor putaminal uptake correlated with frequency-related parameters or decrement in amplitude or speed. Reduced amplitude and speed of repetitive movement may be related to striatal dopaminergic deficit. Dopaminergic action in the caudate nucleus is required to maintain consistency of amplitude and speed. Although decrement of amplitude and speed is known to be specific for PD, we found that it did not mirror the degree of striatal dopamine depletion.

Abnormal somatosensory temporal discrimination in Parkinson’s disease: Pathophysiological correlates and role in motor control deficits

OBJECTIVE The somatosensory temporal discrimination threshold (STDT), defined as the shortest time interval required for two tactile stimuli to be perceived as separate, is longer in patients with Parkinsons disease (PD). In this review, we discuss STDT findings in healthy subjects and in PD patients and the relationship between altered STDT and motor disturbances. METHODS A search was conducted on PubMed for papers dealing with PD and temporal discrimination published from January 1990 to July 2017. RESULTS Abnormal STDT in PD correlates with disease duration, disease severity and degree of nigrostriatal dopamine loss, and responds to dopaminergic medication. In PD, a prolonged STDT does not correlate, or only marginally correlates, with clinically assessed bradykinesia of finger tapping. By contrast, a prolonged STDT correlates with the variability in amplitude and speed of finger tapping as assessed by means of neurophysiological techniques and may contribute to impaired finger dexterity in PD. CONCLUSIONS We suggest that abnormal temporal processing of sensory information in PD generates incorrect signals for the execution and control of voluntary movements. SIGNIFICANCE This review sheds light on unsolved questions regarding the relationship between STDT alterations and motor disturbances in PD and proposes directions for future research on this topic.

An autopsy confirmed case of progressive supranuclear palsy with predominant cerebellar ataxia

Progressive supranuclear palsy (PSP) is characterized by early appearance of postural instability and supranuclear gaze palsy [1]. However, considerable clinical variability has been reported, such as Richardson’s syndrome, PSPparkinsonism, PSP-pure akinesia with gait freezing, behavioral variant frontotemporal dementia, and non-fluent/agrammatic variant primary progressive aphasia [1]. Kanazawa et al. recently defined a new clinical subtype of PSP with cerebellar ataxia as the initial and prominent symptom, called PSP with predominant cerebellar ataxia (PSP-C) [2]. Here, we present our observation of a pathologically confirmed PSP-C patient, who was initially diagnosed with multiple system atrophy-cerebellar type (MSA-C). A 64-year-old man had been referred to our hospital for frequent falls and disequilibrium. His symptoms started with orthostatic dizziness and gait unsteadiness at the age of 59. Dysarthria, hitting and kicking his wife during sleep, severe snoring, dysphagia, and urinary frequency had developed over the last 4 years. He had also become emotionally labile at approximately the same time. At the age of 64, his postural instability had become more apparent and he had frequently fallen backward when standing without assistance. He had been treated for Gi Yeong Huh, Eun-Joo Kim contribute equally.

Weight loss is associated with rapid striatal dopaminergic degeneration in Parkinson's disease

INTRODUCTION Weight loss in Parkinsons disease (PD) is associated with poorer clinical outcomes and rapid disease progression. However, it is unclear whether a longitudinal association between weight loss and striatal dopaminergic degeneration exists. METHODS Using data from 171 PD patients in the Parkinsons Progression Markers Initiative (PPMI) cohort, we investigated longitudinal associations of change in body mass index (BMI) with striatal dopaminergic activity on 123I-N-3-fluoropropyl-2-beta-carboxymethoxy-3beta-(4-iodophenyl) nortropane (123I-FP-CIT) single positron emission computed tomography (SPECT). We defined BMI loss as a reduction in BMI value > 5% of baseline, and categorized the PD patients into 2 subgroups (patients with and without BMI loss). Linear mixed model (LMM) analysis was employed to compare the progression of striatal dopaminergic degeneration. RESULTS In LMM analyses, BMI values in PD patients were not correlated with clinical severities of parkinsonian motor deficits, cognitive impairment and depressive mood. However, BMI values were positively associated with changes in striatal 123I-FP-CIT binding over 24 months (caudate nucleus, estimate = 9.37 × 10-3, p = 0.009; putamen, estimate = 7.04 × 10-3, p = 0.031). Patients with BMI loss exhibited greater deterioration of striatal dopaminergic activity than those without (caudate nucleus, estimate = 3.35 × 10-3, p = 0.008; putamen, estimate = 2.34 × 10-3, p = 0.025). CONCLUSION Our findings suggest a potential association between striatal dopaminergic activity with body weight or impairment in energy homeostasis. Body weight and its change may be a clinical biomarker reflecting striatal dopaminergic dysfunction in PD.