Satoshi Yano

Mutations in MME cause an autosomal-recessive Charcot–Marie–Tooth disease type 2

The objective of this study was to identify new causes of Charcot–Marie–Tooth (CMT) disease in patients with autosomal‐recessive (AR) CMT.

Accumulation of 123I-Ioflupane Is a Useful Marker of the Efficacy of Selegiline Monotherapy in Drug-Naïve Parkinson’s Disease

Background: Selegiline enhances the patient’s endogenous dopamine by inhibiting dopamine metabolism. The efficacy of selegiline monotherapy for drug-naïve Parkinson’s disease (PD) patients may depend on the degree of dopaminergic neuronal degeneration. 123I-Ioflupane single photon emission computed tomography (SPECT) and 123I-meta-iodobenzylguanidine (MIBG) myocardial scintigraphy are diagnostic methods to assess the pharmacological and pathological changes in PD. Objective: We examined the utility of these imaging methods to predict the efficacy of selegiline monotherapy for motor symptoms in drug-naïve PD patients. Methods: We observed the efficacy of selegiline monotherapy in 28 drug-naïve PD patients and compared the improvement in motor function and the imaging findings. These patients received selegiline monotherapy, and the amount was increased to the optimal dose in clinical practice. Motor function was assessed using the Unified Parkinson’s Rating Scale (UPDRS) at baseline and at the stable dose. Imaging was performed before treatment, and the striatal Specific Binding Ratio (SBR) of the 123I-Ioflupane SPECT and the Heart-to-Mediastinum (H/M) ratio of the 123I-MIBG myocardial scintigraphy were calculated. Both ratios were compared with improvements in scores for motor assessment using Pearson’s correlation coefficient. Results: The mean UPDRS part III score significantly improved with at least 5.0 mg/day of selegiline. Further dose escalation did not improve the mean motor score. The percent improvement in the motor score from baseline showed a significant negative correlation with the SBR of average of the right and left striatum, but not with the H/M ratio. Multiple regression analysis using patient’s background factors showed that percent improvement in the UPDRS part III score directly correlate with the SBR (p = 0.04), but not with the age (p = 0.72), disease duration (p = 0.31), baseline UPDRS part III (p = 0.77) and the drug dose (p = 0.26). Conclusion: PD patients with a lower accumulation of 123I-Ioflupane in the striatum can have greater improvement with selegiline monotherapy.

Efficacy of levetiracetam in primary hemifacial spasm

Hemifacial spasm (HFS) is a peripherally-induced movement disorder characterized by the involuntary, unilateral, intermittent, irregular, tonic or clonic contractions of muscles innervated by the ipsilateral facial nerve. Kindling-like hyperactivity of the facial nucleus induced by constant stimulation of compressing artery is considered as the predominant mechanism underlying the pathogenesis of HFS. As a treatment for HFS, microsurgical decompression and botulinum toxin injection have been shown to be highly successful. Anticonvulsant drugs relieve HFS in some patients; however, the use of such drugs is limited owing to their side effects, predominantly in elderly patients. We experienced two elderly HFS patients who exhibited a marked response to levetiracetam (LEV) without side effects. Although the exact underlying pharmacological mechanism remains unknown, we assume anti-kindling effect as one of the important pharmacological mechanism underlying the effect of LEV against HFS. Moreover, LEV is considered to be suitable for use in elderly patients because of its good tolerability. In addition, the lack of hepatic induction or inhibition makes it an easy and safe drug when used in addition to other anticonvulsants. Although the long-term benefit remains unknown, LEV may represent an alternative treatment for elderly HFS patients who are unable to undergo or decline surgical intervention and/or botulinum toxin injections or are intolerant to other anticonvulsants.

Supratherapeutic concentrations of cilostazol inhibits β-amyloid oligomerization in vitro

Alzheimer disease (AD) is the most common type of dementia, and is currently incurable. The efficacy of existing treatments for AD such as acetylcholinesterase inhibitors is limited to symptom improvement. Research on disease-modifying therapies (DMTs) has conventionally focused on amelioration of CNS pathogenesis. Two neuropathological changes correlate strongly with AD, the appearance of neurofibrillary tangles containing the microtubule-associated protein tau and extracellular amyloid deposits containing amyloid β-protein (Aβ). The aggregation of Aβ is believed to be the key pathogenic event in AD, with oligomeric assemblies thought to be the most neurotoxic form. Inhibitors of oligomer formation, therefore, could be valuable therapeutics for AD patients. The clinical phosphodiesterase type-3 inhibitor cilostazol (CSZ) was recently found to suppress the progression of cognitive decline in patients with stable AD receiving acetylcholinesterase inhibitors. Here we examined the effects of CSZ on in vitro aggregations of Aβ1-40 and Aβ1-42 including oligomerization, using the thioflavin T assay, photo-induced cross-linking of unmodified proteins, and electron microscopy. CSZ (25-100 μM) inhibited Aβ aggregation, especially oligomer formation. Considering that CSZ might be a key molecule for DMTs of AD, it cannot be ruled out that the low concentration of CSZ achievable in patient dosing may display some ant-oligomeric activity in synergy with its known therapeutic effects.

Cerebrospinal fluid 5-HIAA concentrations correlate with cardiac uptake of 123 I-MIBG during myocardial scintigraphy in drug naïve Parkinson’s disease

We examined the correlations between cerebrospinal fluid (CSF) concentrations of homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-HIAA) and imaging assessment scores, using 123I-Ioflupane SPECT and 123I-MIBG myocardial scintigraphy in 23 drug naïve PD patients. The CSF 5-HIAA concentration correlated with the H/M ratio of the delayed image (r = 0.458, p < 0.05) and the washout rate (r = − 0.642, p < 0.01) of 123I-MIBG myocardial scintigraphy. These correlations suggest some unclarified pathophysiological links between the central serotonergic and cardiac sympathetic systems.

Effects of dopaminergic drug adjustment on executive function in different clinical stages of Parkinson’s disease

Background Effects of dopaminergic medication on executive function in patients with Parkinson’s disease (PD) are inconsistent. Objective We examined the effect of dopaminergic medication on executive function in 24 drug-naïve PD patients (de novo group) and in 21 PD patients on chronic dopaminergic medication (chronic medication group). Methods PD patients without dementia were included in this study. For the de novo group patients, dopaminergic medication was initiated, and the dose was increased to improve motor symptoms. For the chronic medication group patients, dopaminergic medication was adjusted to relieve clinical problems. All participants were tested prior to and at 4–7 months after the drug initiation/adjustment. Executive function was assessed by using the Behavioral Assessment of the Dysexecutive Syndrome (BADS). Motor function was assessed by using the Unified Parkinson’s Disease Rating Scale (UPDRS; part III). Improvement in executive function was compared with a simultaneous change in levodopa equivalent doses (LED) of dopaminergic medication and with improvement in motor functions. Results The mean standardized BADS scores showed no significant improvement in both the groups. In the de novo group, percent improvement in the standardized BADS scores showed a significant positive correlation with the LED, but not with percent improvement in UPDRS part III. In the chronic medication group, percent improvement in the standardized BADS scores was negatively correlated with change in the LED, but not with percent improvement in UPDRS part III. Multiple regression analysis using improvement in the standardized BADS score as a dependent variable and patient’s background factors (ie, age, education, disease duration, and motor and executive assessments at baseline) as independent variable showed that improvement in the executive assessment is significantly correlated with the LED only in the de novo group. Conclusion Effects of dopaminergic drug adjustment on executive function differ according to the patient’s clinical stage and depend on LED in de novo stage.

Differential Effects of the Factor Structure of the Wechsler Memory Scale-Revised on the Cortical Thickness and Complexity of Patients Aged Over 75 Years in a Memory Clinic Setting

The Wechsler Memory Scale-Revised (WMS-R) is one of the internationally well-known batteries for memory assessment in a general memory clinic setting. Several factor structures of the WMS-R for patients aged under 74 have been proposed. However, little is known about the factor structure of the WMS-R for patients aged over 75 years and its neurological significance. Thus, we conducted exploratory factor analysis to determine the factor structure of the WMS-R for patients aged over 75 years in a memory clinic setting. Regional cerebral blood flow (rCBF) was calculated from single-photon emission computed tomography data. Cortical thickness and cortical fractal dimension, as the marker of cortical complexity, were calculated from high resolution magnetic resonance imaging data. We found that the four factors appeared to be the most appropriate solution to the model, including recognition memory, paired associate memory, visual-and-working memory, and attention as factors. Patients with mild cognitive impairments showed significantly higher factor scores for paired associate memory, visual-and-working memory, and attention than patients with Alzheimers disease. Regarding the neuroimaging data, the factor scores for paired associate memory positively correlated with rCBF in the left pericallosal and hippocampal regions. Moreover, the factor score for paired associate memory showed most robust correlations with the cortical thickness in the limbic system, whereas the factor score for attention correlated with the cortical thickness in the bilateral precuneus. Furthermore, each factor score correlated with the cortical fractal dimension in the bilateral frontotemporal regions. Interestingly, the factor scores for the visual-and-working memory and attention selectively correlated with the cortical fractal dimension in the right posterior cingulate cortex and right precuneus cortex, respectively. These findings demonstrate that recognition memory, paired associate memory, visual-and-working memory, and attention can be crucial factors for interpreting the WMS-R results of elderly patients aged over 75 years in a memory clinic setting. Considering these findings, the results of WMS-R in elderly patients aged over 75 years in a memory clinic setting should be cautiously interpreted.