Eungseok Oh

Safety and efficacy of recombinant human erythropoietin treatment of non-motor symptoms in Parkinson's disease.

BACKGROUND Numerous animal studies and clinical trials have demonstrated that erythropoietin (EPO) has therapeutic effects in ischemic and degenerative diseases. However, few clinical trials have investigated the effect of EPO in Parkinsons disease (PD) patients. This study was an exploratory pilot study to investigate the effects of recombinant human EPO (rhEPO) on motor and non-motor symptoms (NMS) in PD patients. METHODS A total of 26 PD patients at the Hanyang University Hospital were enrolled in the study. The participants were randomly assigned to rhEPO and placebo groups. The rhEPO group was infused intravenously (40,000 IU each) twice a week for 5 weeks. Clinical improvement was estimated using the Unified Parkinsons Disease Rating Scale-III (UPDRS-III), the NMS Scale (NMSS) and the 39-Item Parkinsons Disease Questionnaire (PDQ-39). [(18)F] N-(3-fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) nortropane (FP-CIT) photon emission tomography (PET) scanning was performed on each participant at baseline and again after 12 months. RESULTS The rhEPO administration significantly improved the NMSS and PDQ-39 scores at 12 months. The UPDRS-III, which reflects motor function, did not change significantly after the rhEPO treatment. With the NMSS, the domains of cardiovascular autonomic function, sleep/fatigue, mood/cognition and attention/memory showed significant changes. None of the participants experienced any serious adverse effects. DISCUSSION We found that rhEPO had beneficial effects on NMS but not on motor function. Dopaminergic refractory NMS, such as cardiovascular autonomic dysfunction and cognition, showed improvement after the administration of rhEPO. Our results suggest that rhEPO might be a good candidate for the treatment of NMS in PD patients.

Treatment of Alzheimer's Disease with Repetitive Transcranial Magnetic Stimulation Combined with Cognitive Training: A Prospective, Randomized, Double-Blind, Placebo-Controlled Study

Background and Purpose Repetitive transcranial magnetic stimulation (rTMS) has been examined as a potential treatment for many neurological disorders. High-frequency rTMS in particular improves cognitive functions such as verbal fluency and memory. This study explored the effect of rTMS combined with cognitive training (rTMS-COG) on patients with Alzheimers disease (AD). Methods A prospective, randomized, double-blind, placebo-controlled study was performed with 27 AD patients (18 and 8 in the treatment and sham groups, respectively, and 1 drop-out). The participants were categorized into mild [Mini-Mental State Examination (MMSE) score=21-26] and moderate (MMSE score=18-20) AD groups. The rTMS protocols were configured for six cortical areas (both dorsolateral prefrontal and parietal somatosensory associated cortices and Brocas and Wernickes areas; 10 Hz, 90-110% intensity, and 5 days/week for 6 weeks). Neuropsychological assessments were performed using the AD Assessment Scale-cognitive subscale (ADAS-cog), Clinical Global Impression of Change (CGIC), and MMSE before, immediately after, and 6 weeks after the end of rTMS-COG treatment. Results Data from 26 AD patients were analyzed in this study. There was no significant interactive effect of time between the groups. The ADAS-cog score in the treatment group was significantly improved compared to the sham group (4.28 and 5.39 in the treatment group vs. 1.75 and 2.88 in the sham group at immediately and 6 weeks after treatment, respectively). The MMSE and CGIC scores were also improved in the treatment group. Based on subgroup analysis, the effect of rTMS-COG was superior for the mild group compared to the total patients, especially in the domains of memory and language. Conclusions The present results suggest that rTMS-COG represents a useful adjuvant therapy with cholinesterase inhibitors, particularly during the mild stage of AD. The effect of rTMS-COG was remarkable in the memory and language domains, which are severely affected by AD.

Dysport and Botox at a ratio of 2.5:1 units in cervical dystonia: A double‐blind, randomized study

We aimed to compare Dysport (abobotulinumtoxinA, Ipsen Biopharm, Slough, UK) and Botox (onabotulinumtoxinA, Allergan, Irvine, CA, USA) at a 2.5:1 ratio in the treatment of cervical dystonia (CD). A Dysport/Botox ratio of lower than 3:1 was suggested as a more appropriate conversion ratio, considering its higher efficacy and more frequent incidence of adverse effects not only in the treatment of CD but also in other focal movement disorders. A randomized, double‐blind, multicenter, non‐inferiority, two‐period crossover study was done in CD, with a duration of at least 18 months. Patients were randomly assigned to treatment for the first period with Dysport or Botox, and they were followed up for 16 weeks after the injection. After a 4‐week washout period, they were switched to the other formulation and then followed up for 16 weeks. The primary outcome was the changes in the Tsui scale between the baseline value and that at 1 month after each injection. A total of 103 patients were enrolled, and 94 completed the study. Mean changes in the Tsui scale between baseline and 4 weeks after each injection tended to favor Botox; however, this was not statistically significant (4.0 ± 3.9 points for the Dysport treatment vs. 4.8 ± 4.1 points for Botox; 95% confidence interval, −0.1‐1.7; P = 0.091). The mean change of the Toronto western spasmodic torticollis rating scale score, the proportion of improvement in clinical global impression and patient global impression, and the incidences of adverse events were not significantly different between the two treatments. With regard to safety and efficacy, Dysport was not inferior to Botox in patients with CD at a conversion factor of 2.5:1. [clinicaltrial.gov: NCT00950664]

Vitamin D deficiency in Parkinson's disease patients with orthostatic hypotension

The purpose of our study was to investigate the associations between serum vitamin D3 levels and orthostatic hypotension (OH) in patients with Parkinsons disease (PD).

Olfactory dysfunction in early Parkinson’s disease is associated with short latency afferent inhibition reflecting central cholinergic dysfunction

OBJECTIVE Our study aimed to determine whether the short latency afferent inhibition (SAI) response could be associated with the severity of olfactory dysfunction in PD patients. METHODS A total of 71 PD patients and 20 controls were enrolled. All PD patients were classified into 3 groups by the severity of the olfactory deficit. Single-pulse transmagnetic stimulation (TMS) parameters and SAI were assessed. RESULTS The integrated SAI in the PD with anosmia and PD with hyposomia groups was significantly less inhibited than that in the PD with normosmia and control groups [64.79 {Interquartile range (IQR): 59.96, 71.33}, 84.79 {IQR: 75.03, 90.63} versus 36.72 {IQR: 32.28, 48.33}, 42.15 {IQR: 34.60, 44.96}, respectively]. In PD subjects, the severity of olfactory dysfunction also showed a significant negative correlation with the SAI response (r=-0.829, p<0.001). CONCLUSIONS Considering that the SAI response partly reflects central cholinergic dysfunction and that our study shows a relationship between the SAI response and the severity of olfactory dysfunction in PD, our findings indicate that cholinergic dysfunction could possibly contribute to the pathogenesis of olfactory dysfunction in early PD. SIGNIFICANCE SAI could be a useful marker to detect severe olfactory dysfunction in PD.

Activation of the HMGB1-RAGE axis upregulates TH expression in dopaminergic neurons via JNK phosphorylation

The derangement of tyrosine hydroxylase (TH) activity reduces dopamine synthesis and is implicated in the pathogenesis of Parkinsons disease. However, the extracellular modulator and intracellular regulatory mechanisms of TH have yet to be identified. Recently, high-mobility group box 1 (HMGB1) was reported to be actively secreted from glial cells and is regarded as a mediator of dopaminergic neuronal loss. However, the mechanism for how HMGB1 affects TH expression, particularly through the receptor for advanced glycation endproducts (RAGE), has not yet been investigated. We found that recombinant HMGB1 (rHMGB1) upregulates TH mRNA expression via simultaneous activation of JNK phosphorylation, and this induction of TH expression is blocked by inhibitors of RAGE and JNK. To investigate how TH expression levels change through the HMGB1-RAGE axis as a result of MPP+ toxicity, we co-treated SN4741 dopaminergic cells with MPP+ and rHMGB1. rHMGB1 blocked the reduction of TH mRNA following MPP+ treatment without altering cell survival rates. Our results suggest that HMGB1 upregulates TH expression to maintain dopaminergic neuronal function via activating RAGE, which is dependent on JNK phosphorylation.

Vitamin D receptor polymorphisms and Parkinson's disease in a Korean population: Revisited.

Recently, the effect of genetic variants in the Vitamin D receptor (VDR) gene on Parkinsons disease (PD) has gained interest. However, the precise relationship between VDR polymorphisms and PD remains unclear. In Korea, one study reported an association between VDR gene polymorphisms and PD. However, this study was conducted with a small sample size, and only the Bsml locus was evaluated. Therefore, further investigations about the relationship between VDR polymorphisms and PD are necessary in a Korean population. A total of 300 subjects were included in this study. One hundred and forty-six PD patients were diagnosed according to the United Kingdom Parkinsons Disease Society Brain Bank (UKPDBB) criteria with abnormal dopamine transporter imaging, and 154 healthy control subjects were also enrolled. We used a TaqMan genotyping assay to identify four SNPs of the VDR gene, including BsmI, FokI, ApaI, and TaqI (rs731236, rs2228570, rs7976091, and rs731236). A significant association was not noted between the risk of PD and genetic polymorphisms in the four loci in a Korean population. However, when the genetic variants of the VDR gene were analyzed after adjusting for the serum 25-OH vitamin D3 level, the TaqI and BsmI minor allele increased the risk of PD. Our data suggest no correlation between PD and the VDR polymorphisms, including BsmI, FokI, ApaI, and TaqI, in a Korean population; however, the results should be interpreted carefully because gene-environment interactions may exist. Further investigations of the VDR and its relationship with PD are required to identify the role of vitamin D in the pathogenesis of PD.

Clinicians’ Tendencies to Under-Rate Parkinsonian Tremors in the Less Affected Hand

The standard assessment method for tremor severity in Parkinson’s disease is visual observation by neurologists using clinical rating scales. This is, therefore, a subjective rating that is dependent on clinical expertise. The objective of this study was to report clinicians’ tendencies to under-rate Parkinsonian tremors in the less affected hand. This was observed through objective tremor measurement with accelerometers. Tremor amplitudes were measured objectively using tri-axis-accelerometers for both hands simultaneously in 53 patients with Parkinson’s disease during resting and postural tremors. The videotaped tremor was rated by neurologists using clinical rating scales. The tremor measured by accelerometer was compared with clinical ratings. Neurologists tended to under-rate the less affected hand in resting tremor when the contralateral hand had severe tremor in Session I. The participating neurologists corrected this tendency in Session II after being informed of it. The under-rating tendency was then repeated by other uninformed neurologists in Session III. Kappa statistics showed high inter-rater agreements and high agreements between estimated scores derived from the accelerometer signals and the mean Clinical Tremor Rating Scale evaluated in every session. Therefore, clinicians need to be aware of this under-rating tendency in visual inspection of the less affected hand in order to make accurate tremor severity assessments.

Familial Creutzfeldt–Jakob disease with M232R mutation presented with corticobasal syndrome

Dear Editor-in-Chief, Creutzfeldt–Jakob disease (CJD) mimicked various neurodegenerative diseases among them corticobasal syndrome (CBS) is very rare as an initial manifestation of CJD. There are some cases of sporadic CJD (sCJD) presented as CBS, but none of familial CJD (fCJD) case is reported yet. In addition, the only one case of M232R mutation in fCJD was reported in South Korea [1]. We report a case of 73-year-old woman who diagnosed CBS with dystonic posturing of unilateral arm and finally confirmed as fCJD. A 73-year-old right-handed South Korean woman visited with severe gait disturbance, bradykinesia and dystonic posturing of left arm. Three months before the admission, she diagnosed parkinsonism with bradykinesia and gait disturbance at another hospital. Brain magnetic resonance image (MRI) was normal and has been taking levodopa constantly. But levodopa was not effective and her parkinsonism was getting worse rapidly. At the time of admission, she showed gait disturbance, postural instability, stuttering, swallowing difficulty, severe rigidity of axial and limb muscles, and jerky dystonic tremor and posturing of left arm. In addition, bilateral esotropia and vertical gaze palsy were observed. Ideomotor and buccofacial apraxia, alien hand syndrome, right-left disorientation, frontal lobe releasing sign were also observed. Laboratory studies including cerebrospinal fluid (CSF) examination were all Table 1 Results of neuropsychological test

Triple stimulation technique findings in vascular Parkinsonism and Parkinson's disease.

OBJECTIVE One of the predominant clinical features that differentiates vascular Parkinsonism (VP) from Parkinsons disease (PD) is the pyramidal sign. The triple stimulation technique (TST) is one of the most sensitive methods for comparing upper motor neuron involvement in patients with VP and PD. This study aimed to evaluate the usefulness of the TST as a diagnostic tool for VP. METHODS Thirteen VP patients, 18 PD patients and 10 age-matched healthy controls were enrolled in this study. We obtained basic participant demographic information and transcranial magnetic stimulation (TMS) parameters, including the TST amplitude ratio, from all participants. We compared the TMS parameters among the VP, PD and control groups. RESULTS The TST amplitude ratio was significantly lower in the VP group than in the PD and control groups (71.59 ± 11.86 vs. 96.42 ± 5.11 and 97.70 ± 3.82, respectively; p<0.01). The TST amplitude ratio was positively correlated with scores obtained on the United Parkinsons Disease Rating Scale-III, which reflects motor function. CONCLUSIONS The TST is an effective and easy technique that offers improved diagnostic sensitivity in patients with VP by assessing upper motor neuron involvement. The TST may also represent a useful monitoring tool for evaluating disease progression. SIGNIFICANCE This study is the first to assess pyramidal involvement in patients with VP using the collision technique.