Kenichiro Murate

Neurotropin promotes NGF signaling through interaction of GM1 ganglioside with Trk neurotrophin receptor in PC12 cells

Activation of the high-affinity nerve growth factor (NGF) receptor Trk occurs through multiple processes consisted of translocation and clustering within the plasma membrane lipid rafts, dimerization and autophosphorylation. Here we found that a nonprotein extract of inflamed rabbit skin inoculated with vaccinia virus (Neurotropin(®)) enhanced efficiency of NGF signaling. In rat pheochromocytoma PC12 cells overexpressing Trk (PCtrk cells), Neurotropin augmented insufficient neurite outgrowth observed at suboptimal concentration of NGF (2ng/mL) in a manner depending on Trk kinase activity. Cellular exposure to Neurotropin resulted in an accumulation of Trk-GM1 complexes without affecting dimerization or phosphorylation states of Trk. Following NGF stimulation, Neurotropin significantly facilitated the time course of NGF-induced Trk autophosphorylation. These observations provide a unique mechanism controlling efficiency of NGF signaling, and raise the therapeutic potential of Neurotropin for various neurological conditions associated with neurotrophin dysfunction.

MR neurography for the evaluation of CIDP.

Introduction: To visualize peripheral nerves in patients with chronic inflammatory demyelinating polyneuropathy (CIDP), we used MR imaging. We also quantified the volumes of the brachial and lumbar plexus and their nerve roots. Methods: Thirteen patients with CIDP and 12 healthy volunteers were enrolled. Whole‐body MR neurography based on diffusion‐weighted whole‐body imaging with background body signal suppression (DWIBS) was performed. Peripheral nerve volumes were calculated from serial axial MR images. Results: The peripheral nervous system was visualized with 3‐dimensional reconstruction. Volumes ranged from 8.7 to 49.5 cm3/m2 in the brachial plexus and nerve roots and from 10.2 to 53.5 cm3/m2 in the lumbar plexus and nerve roots. Patients with CIDP had significantly larger volumes than controls (P < 0.05), and volume was positively correlated with disease duration. Conclusions: MR neurography and the measurement of peripheral nerve volume are useful for diagnosing and assessing CIDP. Muscle Nerve 55: 483–489, 2017

Magnetic resonance neurography for the evaluation of CIDP.

Introduction: To visualize peripheral nerves in patients with chronic inflammatory demyelinating polyneuropathy (CIDP), we used MR imaging. We also quantified the volumes of the brachial and lumbar plexus and their nerve roots. Methods: Thirteen patients with CIDP and 12 healthy volunteers were enrolled. Whole‐body MR neurography based on diffusion‐weighted whole‐body imaging with background body signal suppression (DWIBS) was performed. Peripheral nerve volumes were calculated from serial axial MR images. Results: The peripheral nervous system was visualized with 3‐dimensional reconstruction. Volumes ranged from 8.7 to 49.5 cm3/m2 in the brachial plexus and nerve roots and from 10.2 to 53.5 cm3/m2 in the lumbar plexus and nerve roots. Patients with CIDP had significantly larger volumes than controls (P < 0.05), and volume was positively correlated with disease duration. Conclusions: MR neurography and the measurement of peripheral nerve volume are useful for diagnosing and assessing CIDP. Muscle Nerve 55: 483–489, 2017

Retrospective analysis of parkinsonian patients exhibiting normal 123I-MIBG cardiac uptake

BACKGROUND Although most patients with Parkinsons disease (PD) show decreased cardiac (123)I-metaiodobenzylguanidine (MIBG) uptake, some exhibit normal uptake. We evaluated the clinical characteristics of such patients. METHODS We enrolled 154 non-demented patients showing parkinsonism with normal cardiac MIBG uptake and had been clinically followed up during 29.9 ± 27.6 months. We defined the patients who did not fit the exclusion criteria for PD and demonstrated ≥ 30% reduction in the Unified Parkinsons Disease Rating Scale (UPDRS) motor score after anti-Parkinson agent administration as probable PD. We compared clinical characteristics and the cardiac MIBG heart-to-mediastinum (H/M) ratio between the probable PD group (N=37) and other groups (N=117). RESULTS The probable PD group showed significantly higher UPDRS motor scores and greater incidence of tremor/rigidity than those of other groups. In addition, they showed a significantly lower cardiac MIBG H/M ratio in the delayed phase (delayed, p<0.0001). Washout-rate (WR) was significantly higher in probable PD cases (p<0.0001). Among 16 probable PD patients undergoing serial cardiac MIBG scintigraphy, the delayed phase cardiac MIBG H/M ratio showed a significant decrease and WR significantly increased during follow-up periods. CONCLUSIONS An increase in WR and lower delayed phase cardiac MIBG uptake were found to be characteristics of such patients.

Differentiation of cancer from atrial fibrillation in patients with acute multifocal stroke

OBJECTIVE Acute multifocal embolic infarction (AMEI) is conventionally caused by etiologies such as cardioembolism due to atrial fibrillation (Af), but can also be caused by serious underlying diseases such as cancer. We characterized cancer-related AMEI and identified useful indicators for cancer-associated strokes. METHODS A retrospective analysis was performed on 35 patients with Af-related AMEI and 35 patients with cancer-related AMEI selected from 1235 consecutive patients with acute infarcts. All patients received diffusion-weighted magnetic resonance (MR) imaging. Cerebral MR angiography, carotid and cardiac ultrasonography, electrocardiogram-monitoring and whole body computed tomography were also performed on these patients. D-dimer levels were evaluated on admission, and were measured during the sub-acute phase in 19 of the patients with Af and 27 of the patients with cancer. RESULTS Acute phase D-dimer levels were significantly higher in patients with cancer than in patients with Af alone. The cut-off D-dimer value to identify cancer-associated infarcts was 2.0μg/mL. D-dimer levels during the sub-acute phase remained elevated in the cancer patients. CONCLUSIONS We may differentiate cancer-associated AMEI from Af using a D-dimer level≥2.0μg/mL, which does not decrease during the sub-acute phase.

Usefulness of combining 123I-FP-CIT-SPECT striatal asymmetry index and cardiac 123I-metaiodobenzylguanidine scintigraphy examinations for diagnosis of parkinsonisms

BACKGROUND Although single-photon emission computerized tomography of the dopamine transporter (DAT-SPECT) is useful for diagnosing parkinsonian syndrome, its applicability toward the early phase of Parkinsons disease remains unknown. METHODS We enrolled 32 patients showing parkinsonism with normal cardiac 123I-metaiodobenzylguanidine (MIBG) uptake and abnormal DAT-SPECT findings among 84 consecutive patients with parkinsonism. We divided these patients into two groups (group 1: Parkinsons disease, group 2: corticobasal degeneration, progressive supranuclear palsy, multiple system atrophy), and compared their clinical characteristics, specific binding ratios, and striatal asymmetry indexes on DAT-SPECT examinations. RESULTS The striatal asymmetry indexes were significantly lower in group 1 than in group 2 (p<0.05), but there were no differences in the specific binding ratios between the two groups. CONCLUSION The combined use of striatal asymmetry index on DAT-SPECT and cardiac MIBG scintigraphy might offer useful clues for the differential diagnosis of the early phase Parkinsons disease from other parkinsonian syndromes.

Histone deacetylase inhibitor attenuates neurotoxicity of clioquinol in PC12 cells

Clioquinol is considered to be a causative agent of subacute myelo-optico neuropathy (SMON), although the pathogenesis of SMON is yet to be elucidated. We have previously shown that clioquinol inhibits nerve growth factor (NGF)-induced Trk autophosphorylation in PC12 cells transformed with human Trk cDNA. To explore the further mechanism of neuronal damage by clioquinol, we evaluated the acetylation status of histones in PC12 cells. Clioquinol reduced the level of histone acetylation, and the histone deacetylase (HDAC) inhibitor Trichostatin A upregulated acetylated histones and prevented the neuronal cell damage caused by clioquinol. In addition, treatment with HDAC inhibitor decreased neurite retraction and restored the inhibition of NGF-induced Trk autophosphorylation by clioquinol. Thus, clioquinol induced neuronal cell death via deacetylation of histones, and HDAC inhibitor alleviates the neurotoxicity of clioquinol. Clioquinol is now used as a potential medicine for malignancies and neurodegenerative diseases. Therefore, HDAC inhibitors can be used as a candidate medicine for the prevention of its side effects on neuronal cells.

Changes in Serial D-Dimer Levels Predict the Prognoses of Trousseau's Syndrome Patients

Background: The development of acute multiple embolic infarctions (AMEI) resulting from cancer is known as Trousseaus syndrome (TS). At present, however, there is no good marker for predicting the prognosis of TS patients. In the present study, we evaluated the use of serial D-dimer levels as a prognostic marker for TS. Methods: This retrospective cohort study included 1,409 consecutive acute ischemic stroke patients. We selected a group of patients with TS showing AMEI (n = 38; TS group) and a group of patients with atrial fibrillation (Af) and AMEI (n = 35; Af group) as controls. Serial D-dimer levels were measured between days 7 and 28 after stroke (sub-acute phase) in 21 patients of the TS group and 24 patients of the Af group. Results: D-dimer levels at onset (acute phase) were significantly higher in the TS group (8.45 ± 1.79 μg/mL, n = 38) compared with the Af group (1.14 ± 0.14 μg/mL, n = 35) (p < 0.0001). In patients for whom serial D-dimer measurements were made, D-dimer levels measured at the sub-acute phase decreased to 0.48 ± 0.12 μg/mL (n = 24) in the Af group, but remained elevated in the TS group during the sub-acute phase (11.20 ± 2.77 μg/mL, n = 21) (p < 0.0001). In all TS patients in whom serial D-dimer measurements were made, D-dimer levels in 17 patients who died within 500 days (13.31 ± 3.23 μg/mL) were significantly higher than those of the four surviving patients (2.23 ± 0.38 μg/mL) (cut-off D-dimer level = 3.0 μg/mL) during this period. Moreover, serial D-dimer levels of 10 patients who died within 90 days (17.78 ± 4.60 μg/mL) were significantly higher than those of the 11 patients who survived up to 90 days (5.21 ± 2.12 μg/mL) (p < 0.05). Conclusions: Serial D-dimer levels may be a good biomarker for TS as well as a useful predictor of the prognosis of TS patients.

Combinatory use of 123I-FP-CIT-SPECT and cardiac 123 I-metaiodobenzylguanidine scintigraphy for the diagnosis of parkinsonisms

• Parkinson’s disease (PD) is the second most common neurodegenerative disorder in an aging population1. • Early intervention is beneficial but early diagnosis is still difficult 2. • Single-photon emission computerized tomography of the dopamine transporter (DAT-SPECT) is useful for differentiating parkinsonian syndromes from other movement disorders, Cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphy is useful for differentiating PD from other parkinsonian syndromes 3. • Recent studies indiated a possible usefulness of the striatal asymmetry index (SAI) of DAT-SPECT for differentiating parkinsonian syndromes.

The serial D-dimer measurements predicts the prognoses of Trousseau’s syndrome patients

The acute multiple embolic infarction (AMEI) due to cancer-associated hypercoagulation is known as Trousseau’s syndrome (TS). Heretofore, the diagnosis of TS has been based on multifocal simultaneous high-intensity lesion on diffusionweighted imaging (DWI) of MRI, and hypercoagulability indicated by elevation of D-dimer value in the acute phase. We recently disclosed that D-dimer level ≥2.0 μg/mL was found to be useful diagnostic marker of TS. Furthermore, we also revealed that in case of patients with TS, the D-dimer levels during subacute phase were further elevated despite the anticoagulation therapy than at onset (Ito S et al. J Neurol Sci. 2016;368:344-48). This latter information suggested that serial D-dimer levels in TS patients can be used as an important clue for predicting the prognosis of patients.