Hye Mi Lee

Many Faces of Parkinson’s Disease: Non-Motor Symptoms of Parkinson’s Disease

Parkinson’s disease (PD) is a multi-systemic disorder that is characterized by a combination of motor and non-motor symptoms (NMS). The dopaminergic neurodegeneration of PD is involved in the genesis of NMS, but other conditions and side effects of levodopa are also associated with NMS. NMS can develop at all stage of PD and rapid eyeball movement sleep behavior disorder (RBD), constipation, depression, and olfactory dysfunction are considered prodromal signs of PD. Many NMS related with motor deficits and cognitive dysfunction. Some NMS including olfactory dysfunction, RBD and abnormal stereopsis are associated with presence of other NMS of PD. In addition, several NMS can be helpful to differentiate between idiopathic PD and other parkinsonian disorders. Early recognition and management of NMS in PD patients is important for preserving quality of life.

Effects of polymorphisms of the SLCO2B1 transporter gene on the pharmacokinetics of montelukast in humans

Montelukast, a leukotriene receptor antagonist, is a substrate of organic anion transporting OATP2B1 encoded by the SLCO2B1. We evaluated the effects of six non‐synonymous (c.1175C>T, c.1457C>T, c.43C>T, c.935G>A, c.601G>A, and c.644A>T) polymorphisms and one promoter (g.‐282G>A) polymorphism on the pharmacokinetics of montelukast. A single dose of 10 mg montelukast was administered in 24 healthy subjects. Its levels were measured up to 24 hours and a pharmacokinetic analysis was performed based on the SLCO2B1 polymorphisms. We did not encounter subjects with c.1175C>T, c.43C>T, or c.644A>T polymorphisms. The remaining SLCO2B1 polymorphisms did not affect plasma levels of montelukast, and pharmacokinetic parameters of montelukast did not differ among genotype groups. Oral clearance results were as follows: (1) 3.3 L/h for c.935GG, 3.0 L/h for c.935GA, and 3.5 L/h for c.935AA; (2) 3.4 L/h for c.1457CC, 2.9 L/h for c.1457CT, and 3.2 L/h for c.1457TT; (3) 3.2 L/h for c.601GG, 3.4 L/h for c.601GA, and 3.4 L/h for c.601AA; (4) 3.2 L/h for g.‐282GG, 3.4 L/h for g.‐282GA, and 3.2 L/h for g.‐282AA. The findings suggest that SLCO2B1 polymorphisms do not affect the pharmacokinetics of montelukast and that SLCO2B1 polymorphisms appear to be a minor determinant of inter‐individual variability of montelukast.

Nonmotor Symptoms and Cognitive Decline in de novo Parkinson's Disease.

BACKGROUND Cognitive impairments are common in Parkinsons disease (PD). Despite its clinical importance, the development of dementia is still difficult to predict. In this study, we investigated the possible associations between non-motor symptoms and the risk of developing dementia within a 2-year observation period in PD. METHODS A total of 80 patients with PD participated in this study. Nonmotor symptoms (the Nonmotor Symptoms Questionnaire), PD status (Unified Parkinsons Disease Rating Scale), depression (Geriatric d Depression Scale or Montgomery-Asberg Depression Scale), stereopsis and severity of nonmotor symptoms (Non-motor symptoms scale) were assessed. Global cognitive function (Mini-Mental State Examination) were evaluated at baseline and 2 years later. RESULTS Presence of depression, vivid dreaming, REM sleep behavior disorders, hyposmia, abnormal stereopsis, non-smoking and postural instability/ gait disturbance phenotype were associated with a significantly more rapid decline of Mini-Mental State Examination. Logistic regression analyses demonstrated that depression (odds ratio=13.895), abnormal stereopsis (odds ratio=10.729), vivid dreaming (odds ratio=4.16), REM sleep behavior disorders (odds ratio=5.353) and hyposmia (odds ratio=4.911) were significant independent predictors of dementia risk within 2 years. Postural instability/ gait disturbance phenotype and age >62 years were also independent predictors of dementia risk (odd ratio=38.333, odds ratio=10.625). CONCLUSIONS We suggest that depression, vivid dreaming, REM sleep behavior disorders, hyposmia and abnormal stereopsis are closely associated with cognitive decline, and that presence of these nonmotor symptoms predict the subsequent development of Parkinsons disease dementia.

The combined effect of REM sleep behavior disorder and hyposmia on cognition and motor phenotype in Parkinson's disease

BACKGROUND Olfactory dysfunction and REM sleep behavior disorder (RBD) are recognized as pre-motor symptoms of Parkinsons disease (PD). Cognitive dysfunction is observed at a high rate even in the early stages of PD as an important non-motor symptom. PD has been classified in different subtypes and it is unknown if olfactory dysfunction and RBD occur more often in one particular subtype. We investigated the relationship between olfactory impairment, RBD, initial cognitive performance and motor phenotype in PD. METHOD Nighty-eight patients with drug-naïve idiopathic PD who visited the Movement Disorders Unit of Korea University Guro Hospital, Seoul, Korea from March 2012 to February 2014 were retrospectively included. Patients were divided into tremor-dominant-type and akinetic-rigid-type PD subgroups using part III of the Unified Parkinsons Disease Rating Scale. Olfaction was assessed by the Cross Cultural Smell Identification Test. RBD was screened using screening questionnaires. Initial cognitive function was assessed with Mini-Mental State Examination. RESULT The PD-normosmia group had higher MMSE scores (p=0.008). PD patients who have both RBD and olfactory dysfunction had lower MMSE scores (p=0.013). Presence of both RBD and hyposmia in PD patients was more strongly correlated with poor cognitive dysfunction. PD patients with RBD and/or hyposmia primarily exhibited the akinetic-rigidity phenotype. CONCLUSION Olfactory dysfunction and RBD differed according to the motor phenotypes of PD. This suggests that olfactory dysfunction and RBD might relate to prognosis in patients with PD. Patients who have both hyposmia and RBD were more likely to exhibit cognitive dysfunction.

Nonmotor symptoms in essential tremor: Comparison with Parkinson's disease and normal control.

BACKGROUND Recently, the definition of essential tremor (ET) has evolved to have two different meanings. One refers to classic ET, a benign mono-symptomatic disorder, and the other refers to a heterogeneous neurodegenerative disorder. The aim of this study was to categorize nonmotor symptoms according to ET phenotype, and compare them, along with autonomic function, in people with Parkinsons disease (PD) and normal controls. METHODS We divided patients with ET into 3 subtypes according to their motor features: 23 Pure-ET, 25 Cerebellar-ET, and 12 Parkinsonism-ET. Comparisons were made between 30 PD subjects and 22 normal controls, and 60 subjects with ET. The following assessments were conducted: the Nonmotor Symptoms Scale, the Mini-Mental State Exam, Montreal Cognitive Assessment, the Montgomery-Asberg Depression Rating Scale, Neuropsychiatric Inventory Questionnaire, Beck Anxiety Inventory, the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and the Scales for Outcomes in Parkinsons Disease-Autonomic. RESULTS There were significant differences in the Nonmotor Symptoms Scale total scores of the ET, PD, and control groups (ET: 25.500 ± 2.346; PD: 27.960 ± 3.267; CONTROL 3.328 ± 3.796.). There were no significant differences in terms of each ET phenotype. ET patients had significant cognitive dysfunction, neuropsychiatric problems including depression and have complained about significant autonomic dysfunction and excessive daytime somnolence compared to normal controls. CONCLUSIONS Patients with ET have several nonmotor symptoms similar to those of patients with PD, which have a similar impact on their quality of life. Therefore, nonmotor symptoms should be considered in the clinical evaluation and management of ET.

The interrelationship between non-motor symptoms in Atypical Parkinsonism

BACKGROUND Atypical Parkinsonism is less common and has more severe symptoms than Parkinsons disease (PD). Little is known about the non-motor symptom (NMS) characteristics of multiple systemic atrophy (MSA) or progressive supranuclear palsy (PSP). We report the interrelationship of NMS in MSA, PSP, and PD. METHODS We studied 117 cases of PD and 57 of Atypical Parkinsonism. Out of the 57 patients, 31 had multiple systemic atrophy parkinsonian subtype (MSA-P), 14 had multiple systemic atrophy cerebellar dysfunction subtype (MSA-C), and 12 had PSP. We assessed the condition of the patients using the United Parkinsons Disease Rating Scale part III (UPDRS-III), the modified Hoehn & Yahr scale (H&Y), the non-motor symptom scale (NMSS), and the Parkinsons Disease Questionnaire (PDQ-39). RESULTS In Atypical Parkinsonism, the NMSS scores significantly correlated with PDQ-39 scores, but not with UPDRS-III. In the MSA-P group, the mood/cognitive domain significantly correlated with both the urinary and sleep/fatigue domains. In the MSA-C group, the sleep/fatigue domain correlated with the mood/cognition and cardiovascular domains. Finally, in the PSP and PD groups, the attention/memory domain significantly correlated with the sleep/fatigue and mood/cognition domains. DISCUSSION These results suggest that, with respect to cognitive function, dysautonomia and sleep/fatigue are detrimental factors in MSA and PSP, respectively.

Microbial Production of Ethanol from Acetate by Engineered Ralstonia eutropha

This study was performed to produce ethanol from acetate using a genetically engineered Ralstonia eutropha. In order to genetically modify R. eutropha H16, phaCAB operon encoding metabolic pathway genes from acetyl-CoA to polyhydroxybutyrate (PHB) was deleted and adhE encoding an alcohol dehydrogenase from Escherichia coli was overexpressed for conversion of acetyl-CoA to ethanol. The resulting strain produced ethanol up to 170 mg/L when cultivated in minimal media supplemented with 5 g/L of acetate as a sole carbon source. Growth and ethanol production were optimized by adjusting nitrogen source (NH4Cl) content and repetitive feeding of acetate into the bacterial culture, by which the ethanol production was reached to approximately 350 mg/L for 84 h.

Is reduced arm and leg swing in Parkinson's disease associated with rigidity or bradykinesia?

BACKGROUND AND PURPOSE Arm and leg swings during gait are reduced and asymmetric in Parkinsons disease (PD). Although rigidity and bradykinesia are interconnected with each other, and related with gait hypokinesia including arm and leg swing alteration, it remains uncertain which factor is more responsible for the decrease of arm and leg swings. The study aimed to uncover which factor between rigidity and bradykinesia is more associated with the reduction of arm and leg swings during gait. METHODS Patients with PD were selected and divided into a concordance group (21 patients) representing a match of both symptoms and a discordance group (nineteen patients) exhibiting a mismatch of pronounced rigidity and bradykinesia. Visual inspections of video clips for asymmetric features of gait and posture including arm swing, leg swing, shoulder position, external foot rotation were analyzed and accessed by two independent neurologists blindly. RESULTS The side of more pronounced rigidity was significantly and moderately related with the side of more decreased arm and leg swings (p<0.001, κ=0.592 in arm swing; p=0.011, κ=0.432 in leg swing, respectively), but the side of more dominant bradykinesia was associated with neither arm nor leg swing asymmetry (p=1, κ=0.014 in arm swing; p=1, κ=-0.036 in leg swing). In addition, asymmetric posturing including shoulder position and a laterally rotated foot showed no relationship with rigidity or bradykinesia. CONCLUSION The reduction of arm and leg swings during gait in PD was associated with rigidity, but not with bradykinesia.

Effect of P2Y1 and P2Y12 genetic polymorphisms on the ADP-induced platelet aggregation in a Korean population

BACKGROUND P2Y1 and P2Y12 receptors are expressed in platelet membranes and are involved in ADP-induced platelet aggregation. Genetic polymorphisms of P2Y1 and P2Y12 play a major role in the variation of ADP-induced platelet aggregation and in response in antiplatelet therapy. OBJECTIVE To evaluate the allele frequencies of P2Y1 and P2Y12 genetic polymorphisms in a Korean population and to assess their role in ADP (5 μmol/L)-induced maximal platelet aggregation. METHODS P2Y1 (c.1622A>G) and P2Y12 (i-139C>T, i-744T>C, i-ins801, c.52G>T, c.34C>T) polymorphisms were analyzed in 158 Korean healthy participants using pyrosequencing methods. Their ADP-induced maximal platelet aggregation was assessed by the turbidometric method. RESULTS The observed allele frequencies of P2Y1 and P2Y12 were as follows: 0.3101 for P2Y1 c.1622A>G; 0.1804 for P2Y12 i-139C>T, 0.1804 for i-744T>C, 0.1804 for i-801insA, 0.1266 for P2Y12 c.52G>T, and 0.2658 for P2Y12 c.34C>T. ADP-induced maximal platelet aggregation was not influenced by the P2Y1 c.1622A>G polymorphism and was also not affected by three intronic P2Y12 polymorphisms and the P2Y12 c.34C>T polymorphism. However, the P2Y12 c.52G>T polymorphism caused a substantial difference in ADP-induced maximal platelet aggregation (62.75% for c.52GG, 66.27% for c.52GT, and 80.60% for c.52TT; P=0.0092). CONCLUSIONS The P2Y1 and P2Y12 genes were very polymorphic in a Korean population. Three intronic P2Y12 polymorphisms (i-139C>T, i-744T>C, i-801insA) were in complete linkage disequilibrium but not with the c.52C>T polymorphism in this population. Maximal platelet aggregation in response to ADP is associated with the c.52C>T polymorphism but not with the three intronic polymorphisms or the P2Y1 c.1622A>T polymorphism.

Comparison of motor and non-motor features between essential tremor and tremor dominant Parkinson's disease.

BACKGROUND Differential diagnosis of tremor disorders, including essential tremor (ET) and Parkinsons disease-tremor dominant type (PD-TDT), requires further investigation. Therefore, the current study aimed to compare non-motor and tremor features in order to differentiate between ET and PD-TDT. METHODS Twenty-eight patients with classic ET and 24 patients with typical PD-TDT were retrospectively enrolled in a multi-stage investigation process. Tremor features including surface electromyogram (EMG) were analyzed in detail. For non-motor symptom analyses, the global cognition test, frontal function test, and non-motor symptoms scale (NMSS) were administered, in addition to collecting patient history data. RESULTS Patients with PD-TDT presented with more asymmetric tremor, whereas patients with ET presented with more symmetric tremor. Leg tremor was observed only in patients with PD-TDT. Surface EMG analyses of arm tremor demonstrated considerable overlaps in tremor type, tremor frequency, and contractive patterns. However, patients with PD-TDT were significantly more likely to exhibit resting tremor, and experienced alternative contraction patterns only for kinetic tremor, which was in contrast to patients with ET. For non-motor symptom analyses, patients with PD-TDT had more non-motor symptoms compared to patients with ET (mean=5.0 vs. 2.6; P=0.002). Specifically, patients with PD-TDT exhibited higher frequencies of hyposmia, REM sleep behavior disorder (RBD)-like symptom, urinary frequency, and memory disturbance. Age- and gender- matched analyses for the severity of NMSS scores did not indicate significant differences. However, patients with PD-TDT displayed slightly lower scores of frontal function test compared to patients with ET. CONCLUSIONS Careful and detailed evaluations of both tremor features and non-motor symptoms are required in order to distinguish between ET and PD-TDT.