Shinji Ito

Stimulated neuronal expression of brain-derived neurotrophic factor by Neurotropin

Expression of brain-derived neurotrophic factor (BDNF) was stimulated in human neuroblastoma SH-SY5Y cells by a nonprotein extract of inflamed rabbit skin inoculated with vaccinia virus (Neurotropin), an analgesic widely used in Japan for treatment of disorders associated with chronic pain, with the optimal dosage at 10mNU/mL. This stimulation was accompanied by activations of p42/44 MAP kinase, CREB and c-Fos expression. Inhibitors of MAP kinases or PI 3-kinase prevented the stimulatory action of Neurotropin, indicating that neuronal TrkB/CREB pathway mediates the action. Repetitive oral administration of Neurotropin (200NU/kg/day, 3months) prevented the age-dependent decline in hippocampal BDNF expression in Ts65Dn mice, a model of Downs syndrome. This effect was associated with the improvement of spatial cognition of the mice. These results open an intriguing new strategy in which Neurotropin may prove beneficial treatment for neurodegenerative disorders.

Potential therapeutic system for Alzheimer’s disease: removal of blood Aβs by hemodialzyers and its effect on the cognitive functions of renal-failure patients

The pathological changes of Alzheimer’s disease include the deposition of amyloid β protein (Aβ) as senile plaques in the brain. We hypothesized that the rapid removal of Aβs from the blood may act as a peripheral Aβ drainage sink from the brain. In this study, the plasma Aβ concentrations and the cognitive functions were investigated for in 57 patients on hemodailysis (69.4xa0±xa03.8xa0years), 26 renal-failure patients without hemodialysis (66.6xa0±xa014.7xa0years), and 17 age-matched healthy controls (66.6xa0±xa04.1xa0years). The concentrations of plasma Aβs increased along with the decline of renal functions. Moreover, the renal-failure patients without hemodialysis and with poorer renal functions showed lower cognitive functions. The plasma concentrations of Aβ1-42 correlated with serum creatinine (Pxa0<xa00.001) and Mini-Mental-State Examination scores (Pxa0=xa00.017). The dialyzers effectively removed Aβs in the blood during hemodialysis sessions. The plasma Aβ concentrations showed steady or slightly decreasing along with duration of hemodialysis. The total amount of Aβs removed during a hemodialysis session was calculated to be comparable to the Aβs dissolved in the blood and the cerebrospinal fluid. The MMSE scores of the hemodialysis patients showed no clear decrease in longer hemodialysis duration. Therefore, the therapeutic approach for Alzheimer’s disease by removing Aβs from the blood is worthy of further investigation, including whether or not Aβs in the brain decrease.

Anti-GM1 antibodies affect the integrity of lipid rafts

Previous studies have shown that patients with the axonal form of Guillain-Barré syndrome (GBS) develop autoantibodies against GM1 ganglioside (GM1). Nerve growth factor (NGF) is essential for neuronal survival in vivo and its functional receptor is Trk-tyrosine kinase. Here, we examined the biological effects of sera from patients with the axonal form of GBS on the morphology and the phosphorylation state of Trk-tyrosine kinase in PC12 cells. Furthermore, we examined the effect of the sera on the integrity of membrane lipid rafts biochemically. The data show that anti-GM1 antibodies found in patients sera but not control sera inhibit NGF-induced Trk autophosphorylation. Most intriguingly, the autoantibodies alter the distribution of Trk in lipid rafts without shifting the distribution of a rafts marker protein. These data strongly suggest that anti-GM1 antibodies directly influence the integrity of the signaling platform, lipid rafts, implicating the importance of lipid rafts in the development of this disorder.

A prospective study on blood Aβ levels and the cognitive function of patients with hemodialysis: a potential therapeutic strategy for Alzheimer’s disease

To obtain the proof of concept of a novel therapy for Alzheimer’s disease (AD), we conducted two prospective studies with hemodialysis patients who had amyloid β protein (Aβ) removed from their blood three times a week. One major pathological change in the brain associated with AD is Aβ deposition, mainly 40 amino acids Aβ1–40 and 42 amino acids Aβ1–42. Impaired Aβ clearance is proposed to be one cause of increased Aβ in the AD brain. Thus, we hypothesized that an extracorporeal removal system of Aβ from the blood may remove brain Aβ and be a useful therapeutic strategy for AD. In the first prospective study, plasma Aβ levels and the cognitive function of 30 hemodialysis patients (65–76xa0years old) were evaluated at baseline as well as 18 or 36xa0months after. Although plasma Aβ1–40 levels either decreased or remained unchanged, levels of Aβ1–42 either remained unchanged or increased at the second time point. Mini-Mental State Examination scores of most subjects increased or were maintained at the second time point. Aβ1–40 influx into the blood correlated with MMSE at the second time point. In the second prospective study, five patients (51–84xa0years old) with renal failure were evaluated before and after the initiation of hemodialysis. Plasma Aβ levels decreased, while cognitive function improved after initiating blood Aβ removal. Therefore, long-term hemodialysis, which effectively removes blood Aβ, might alter Aβ influx and help maintain cognitive function.

Abnormal cross-talk between mutant presenilin 1 (I143T, G384A) and glycosphingolipid biosynthesis

Mutations in the presenilin 1 (PS1) gene are associated with early onset familial Alzheimers disease (FAD). In this study, we found that the expression of mutant‐PS1 in stable transfectants of SH‐SY5Y neuroblastoma cells results in a reduction of the biosynthesis and steady‐state levels of glucosylceramide. As an in vivo corroboration of these data, there was a significant reduction of brain glucosylceramide and gangliosides in an animal model of FAD. In mutant‐PS1‐transfectants (I143T, G384A), immunocytochemistry disclosed a remarkable reduction of glucosylceramide synthase (GlcT‐1)‐like immunoreactivity in the cells when compared with those of mock‐ and wild‐PS1 transfectants. Immunoprecipitation of GlcT‐1 protein from mutant‐PS1 transfectants demonstrated a marked reduction in GlcT‐1 protein, but there was no reduction in the levels of GlcT‐1 mRNA. Both coprecipitation and γ‐secretase inhibition experiments suggest that mutant‐PS1 seems to form a complex with GlcT‐1 protein and to be involved in GlcT‐1 degradation, which was never found in other cell types. Thus, mutations in the PS1 gene result in profound glycosphingolipids abnormalities by abnormal molecular interaction with GlcT‐1.—Mutoh, T., Kawamura, N., Hirabaysshi, Y., Shima, S., Miyashita, T., Ito, S., Asakura, K., Araki, W., Cazzaniga, E., Muto, E., Masserini, M. Abnormal cross‐talk between mutant presenilin 1 (I143T, G384A) and glycosphingolipid biosynthesis. FASEB J. 26, 3065–3074 (2012). www.fasebj.org

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

BACKGROUNDnAlthough 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.nnnMETHODSnWe 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).nnnRESULTSnThe 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.nnnCONCLUSIONSnAn increase in WR and lower delayed phase cardiac MIBG uptake were found to be characteristics of such patients.

Neurotrophin levels in cerebrospinal fluid of adult patients with meningitis and encephalitis.

Background: The data on cerebrospinal fluid (CSF) levels of neurotrophins (NTs) in patients with meningoencephalitis are scarce, especially in adult patients. Methods: We measured CSF levels of NTs such as nerve growth factor (NGF), brain-derived neurotrophic factor, and neurotrophin-3 (NT-3) in adult patients with various meningitis (n = 10) and encephalitis (n = 10) in both acute phase and recovery phase and adult control subjects (n = 21) by the enzyme-linked immunosorbent assay for NTs. Results: Data show that NGF and NT-3 CSF levels were markedly elevated in the patient group in the acute phase compared with non-neurological controls (p < 0.001 and p < 0.05, respectively) and later returned to the levels of controls. Most intriguingly, we only recognized a significant correlation between NGF and NT-3 CSF levels in the patients in the acute phase. Conclusion: Such strong correlation of NGF and NT-3 CSF levels strongly suggests that in adult patients, some common regulatory mechanism(s) might be present among various kinds of NTs to cope with central nervous system infection.

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

OBJECTIVEnAcute 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.nnnMETHODSnA 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.nnnRESULTSnAcute 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.nnnCONCLUSIONSnWe may differentiate cancer-associated AMEI from Af using a D-dimer level≥2.0μg/mL, which does not decrease during the sub-acute phase.