Therapeutic Devices for Motor Symptoms in Parkinson's Disease: Current Progress and a Systematic Review of Recent Randomized Controlled Trials.

Background: Pharmacotherapy is the first-line treatment option for Parkinson's disease, and levodopa is considered the most effective drug for managing motor symptoms. However, side effects such as motor fluctuation and dyskinesia have been associated with levodopa treatment. For these conditions, alternative therapies, including invasive and non-invasive medical devices, may be helpful. This review sheds light on current progress in the development of devices to alleviate motor symptoms in Parkinson's disease. Methods: We first conducted a narrative literature review to obtain an overview of current invasive and non-invasive medical devices and thereafter performed a systematic review of recent randomized controlled trials (RCTs) of these devices. Results: Our review revealed different characteristics of each device and their effectiveness for motor symptoms. Although invasive medical devices are usually highly effective, surgical procedures can be burdensome for patients and have serious side effects. In contrast, non-pharmacological/non-surgical devices have fewer complications. RCTs of non-invasive devices, especially non-invasive brain stimulation and mechanical peripheral stimulation devices, have proven effectiveness on motor symptoms. Nearly no non-invasive devices have yet received Food and Drug Administration certification or a CE mark. Conclusion: Invasive and non-invasive medical devices have unique characteristics, and several RCTs have been conducted for each device. Invasive devices are more effective, while non-invasive devices are less effective and have lower hurdles and risks. It is important to understand the characteristics of each device and capitalize on these.

MR spectroscopy and imaging-derived measurements in the supplementary motor area for biomarkers of amyotrophic lateral sclerosis.

The diagnosis of amyotrophic lateral sclerosis (ALS) requires both upper and lower motor neuron signs. However, quite a few patients with ALS lack the upper motor neuron sign during the disease. This study sought to investigate whether metabolites, including glutamate (Glu), N-acetyl aspartate (NAA), and gamma aminobutyric acid (GABA), in the supplementary motor area (SMA) measured by magnetic resonance spectroscopy (MRS), could be a surrogate biomarker for ALS. Twenty-five patients with ALS and 12 controls underwent 3.0-T MR scanning, which measured Glu, NAA, and GABA. Finally, receiver operating characteristic (ROC) curves were created and the area under curve (AUC) was calculated to assess the diagnostic power. Logistic regression analysis revealed the usefulness of both Glu and NAA for the differentiation of ALS from controls (Glu, P = 0.009; NAA, P = 0.033). The ratio of Glu to NAA or GABA was significantly increased in patients with ALS (Glu/NAA, P = 0.027; Glu/GABA, P = 0.003). Both the AUCs were more than 0.7, with high specificity but low sensitivity. The present findings might indicate that both the Glu/NAA and the Glu/GABA ratios in the SMA could be potential biomarkers for the diagnosis of ALS.

[JETALS: The Japanese Early-stage Trial of high dose methylcobalamin for ALS].

High-dose methylcobalamin was found to be a therapeutic candidate for amyotrophic lateral sclerosis (ALS) through clinical experience. Our previous study (E0302-J081-761) has suggested that high-dose methylcobalamin (E0302) prolonged the overall survival and suppressed progression in ALS patients with a disease duration less than 12 months in, exploratory analyses. Therefore, we plan to conduct an investigator-initiated trial "The Japan Early-stage Trial of high dose methylcobalamin for ALS (JETALS)" to evaluate the efficacy and safety of E0302 for ALS patients within 12 months from onset. JETALS is a prospective, multicenter, placebo-controlled, double-blind, randomized Phase III study, conducted at 25 tertiary neurology centers, and is funded by the Japan Agency for Medical Research and Development. A total of 128 patients were randomized at a 1:1 ratio to receive intramuscular injection with E0302 50 mg or placebo, twice a week for 16 weeks. The primary endpoint is changes in the ALS Functional Rating Scale (ALSFRS-R) total score at 16 weeks. The patient enrollment period is from November 2017 to September 2019, and the follow-up is scheduled to end in March 2020. If the results are positive, we intend to apply for E0302 approval for methylcobalamin as a new drug for treating ALS.

The Japanese Early-Stage Trial of High-Dose Methylcobalamin for Amyotrophic Lateral Sclerosis (JETALS): Protocol for a Randomized Controlled Trial.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects the upper and lower motor neurons. Currently, only riluzole and edaravone are approved as drugs to treat ALS and new agents with larger effect sizes are warranted. Exploratory analyses in our previous study (study ID #E0302-J081-761) have suggested that high-dose methylcobalamin (E0302) prolonged the overall survival of ALS patients and suppressed ALS progression in patients with a disease duration of less than 12 months. OBJECTIVE: This clinical trial aims to evaluate the efficacy and safety of E0302 for treatment of ALS patients within one year of onset. METHODS: The Japanese early-stage trial of high-dose methylcobalamin for ALS (JETALS) is a prospective, multicenter, placebo-controlled, double-blind, randomized phase III study conducted at 24 tertiary neurology centers and is funded by the Japan Agency for Medical Research and Development. A total of 128 ALS patients within one year of onset were randomized at a 1:1 ratio to receive intramuscular injection with E0302 50 mg or placebo twice a week for 16 weeks. The primary endpoint is changes in the ALS Functional Rating Scale-Revised (ALSFRS-R) total score at 16 weeks. If patients wish to receive E0302 50 mg after the double-blind administration period, E0302 will be provided to them until March 2020 during the continuous administration period. RESULTS: This study began in October 2017 and is being conducted at 24 participating institutions in Japan. The study is in progress and the patient enrollment period is scheduled to end in August 2019, with follow-up scheduled to end in March 2020. CONCLUSIONS: This study is being performed to revalidate the efficacy and safety of E0302 in patients with early-stage ALS in the first year of symptom onset. If positive results are obtained, the aim is to apply for E0302 approval as a new drug for the treatment of ALS. TRIAL REGISTRATION: ClinicalTrials.gov NCT03548311; https://clinicaltrials.gov/ct2/show/NCT03548311 (Archived by WebCite at http://www.webcitation.org/74Fw3rDzb). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/12046.

iPSC-Based Compound Screening and In Vitro Trials Identify a Synergistic Anti-amyloid ß Combination for Alzheimer's Disease.

In the process of drug development, in vitro studies do not always adequately predict human-specific drug responsiveness in clinical trials. Here, we applied the advantage of human iPSC-derived neurons, which offer human-specific drug responsiveness, to screen and evaluate therapeutic candidates for Alzheimer's disease (AD). Using AD patient neurons with nearly 100% purity from iPSCs, we established a robust and reproducible assay for amyloid ß peptide (Aß), a pathogenic molecule in AD, and screened a pharmaceutical compound library. We acquired 27 Aß-lowering screen hits, prioritized hits by chemical structure-based clustering, and selected 6 leading compounds. Next, to maximize the anti-Aß effect, we selected a synergistic combination of bromocriptine, cromolyn, and topiramate as an anti-Aß cocktail. Finally, using neurons from familial and sporadic AD patients, we found that the cocktail showed a significant and potent anti-Aß effect on patient cells. This human iPSC-based platform promises to be useful for AD drug development.

The ratio of N-acetyl aspartate to glutamate correlates with disease duration of amyotrophic lateral sclerosis.

Glutamate (Glu)-induced excitotoxicity has been implicated in the neuronal loss of amyotrophic lateral sclerosis. To test the hypothesis that Glu in the primary motor cortex contributes to disease severity and/or duration, the Glu level was investigated using MR spectroscopy. Seventeen patients with amyotrophic lateral sclerosis were diagnosed according to the El Escorial criteria for suspected, possible, probable or definite amyotrophic lateral sclerosis, and enrolled in this cross-sectional study. We measured metabolite concentrations, including N-acetyl aspartate (NAA), creatine, choline, inositol, Glu and glutamine, and performed partial correlation between each metabolite concentration or NAA/Glu ratio and disease severity or duration using age as a covariate. Considering our hypothesis that Glu is associated with neuronal cell death in amyotrophic lateral sclerosis, we investigated the ratio of NAA to Glu, and found a significant correlation between NAA/Glu and disease duration (r=-0.574, p=0.02). The "suspected" amyotrophic lateral sclerosis patients showed the same tendency as possible, probable and definite amyotrophic lateral sclerosis patients in regard to correlation of NAA/Glu ratio with disease duration. The other metabolites showed no significant correlation. Our findings suggested that glutamatergic neurons are less vulnerable compared to other neurons and this may be because inhibitory receptors are mainly located presynaptically, which supports the notion of Glu-induced excitotoxicity.

[Effects of Vitamin B12 in Patients with Amyotrophic Lateral Sclerosis and Peripheral Neuropathy].

Vitamin B(12)(vB(12)) deficient is regarded as iatrogenic in some cases. Although the recommended oral intake of vB(12) has been determined, administration of vB(12) exceeding the recommended dose could have multiple pharmacological effects. "Ultra-high dose" vB(12) therapy has been used for peripheral neuropathy and amyotrophic lateral sclerosis, suggesting its promising neuroprotective effects.

Immediate effect of spinal magnetic stimulation on camptocormia in Parkinson's disease.

OBJECTIVES: Spinal cord stimulation is a potential therapeutic option for the treatment of Parkinson's disease (PD)-associated symptoms. Repetitive trans-spinal magnetic stimulation (rTSMS) is a non-invasive and safe alternative for stimulation of spinal pathways that has not been studied for therapeutic efficacy in PD. We assessed the benefits of rTSMS on camptocormia, an often treatment-resistant postural abnormality observed in PD patients. METHODS: We compared rTSMS to sham stimulation in PD patients with camptocormia in a single-centre, randomised, single-blind, crossover, placebo-controlled study. PD patients with camptocormia were administered a single trial of rTSMS (a train of 40 stimuli) or sham treatment followed 1 week later by the alternate treatment. Primary outcome measure was thoracolumbar spine flexion angle in the standing position immediately after the trial. RESULTS: Of 320 PD patients examined, 37 had concomitant camptocormia and were randomly assigned to either the rTSMS first group (n=19) or sham first group (n=18). Flexion angle in the standing position decreased by a mean of 10.9° (95% CI 8.1 to 13.65) after rTSMS but remained unchanged after sham stimulation (mean, -0.1°; 95% CI -0.95 to 0.71). The flexion angle while sitting (secondary outcome) decreased by 8.1° (95% CI 5.89 to 10.25) after rTSMS, whereas sham treatment had no significant effect (mean, -0.8°; 95% CI -1.62 to 0.05). CONCLUSIONS: We found an immediate beneficial effect of rTSMS on camptocormia in PD patients. Although the effect was transient, this successful trial justifies further studies to test if repeated rTSMS treatments can induce longer term improvements in camptocormia associated with PD. CLINICAL TRIAL REGISTRATION: UMIN Clinical Trials Registry: UMIN000011495.

[Clinical trials of ultra-high-dose methylcobalamin in ALS].

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting both upper and lower motor neurons. Weakness may begin in the legs, hands, proximal arms, or pharynx. The course is relentless and progressive without remissions, relapses, or even stable plateaus. There is no effective drug therapy for ALS, although riluzole has been shown to prolong life in sufferers, without tracheostomy. A vitamin B12 analog, methylcobalamin, has a protective effect on cultured cortical neurons against glutamate-induced cytotoxicity. We have shown the ultra-high-dose methylcobalamin (25 mg/day i.m.) slows down the progressive reduction of the CMAP (compound muscle action potential) amplitudes in ALS in the short term (4 weeks). The latencies of SSR (sympathetic skin response) were shorter after treatment (50 mg/day i.v., 2 weeks). In the long-term effect of methylcobalamin (50 mg/day i.m., twice a week), the survival time (or the period to become respirator-bound) was significantly longer in the treated group than in the untreated. Larger-scale randomized double blind trial was started in Japan in order to evaluate the long-term efficacy and the safety of ultra-high-dose methylcobalamin for sporadic or familial cases of ALS.

[Case of methotrexate encephalopathy: findings on diffusion tensor image and correlation with clinical outcome].

Methotrexate (MTX) is a major cause of treatment-related acute neurotoxicity. We report on clinical and imaging findings of reversibly restricted diffusion in a patient with transient encephalopathy after high dose MTX therapy for osteosarcoma. During the chemotherapy, a 19-year-old man was introduced for the evaluation of consciousness disturbance. Neurological examination revealed confusion, inability of speak at the onset On next day, there were still difficulties in swallowing and phonation, and furthermore deep tendon reflexes were hyperactive in bilateral lower limbs with positive Babinski responses bilaterally. By the 6th day, findings at neurological examination were completely normal. Initial imaging on presentation was performed using MRI. Diffusion weighted MRI clearly indicated areas of restricted diffusion within both centrum semiovale. These abnormalities were confirmed by the diffusion tensor (DT) technique (ADC and FA map). The follow-up MRI examinations using same protocol showed resolution of the ADC and FA abnormalities but increasing T2-signal changes. Neither contrast enhancement nor atrophy was encountered. Early detection of MTX white matter injury by DT image has the potential to alert the oncologist and neurologist to this event and provide a technique by which treatment of neurotoxicity can be monitored.