iPSC-Based Compound Screening and In Vitro Trials Identify a Synergistic Anti-amyloid β 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 β peptide (Aβ), a pathogenic molecule in AD, and screened a pharmaceutical compound library. We acquired 27 Aβ-lowering screen hits, prioritized hits by chemical structure-based clustering, and selected 6 leading compounds. Next, to maximize the anti-Aβ effect, we selected a synergistic combination of bromocriptine, cromolyn, and topiramate as an anti-Aβ cocktail. Finally, using neurons from familial and sporadic AD patients, we found that the cocktail showed a significant and potent anti-Aβ effect on patient cells. This human iPSC-based platform promises to be useful for AD drug development

Repurposing bromocriptine for Aβ metabolism in Alzheimer’s disease (REBRAnD) study : randomised placebo-controlled double-blind comparative trial and open-label extension trial to investigate the safety and efficacy of bromocriptine in Alzheimer’s disease with presenilin 1 (PSEN1) mutations

Introduction Alzheimer’s disease (AD) is one of the most common causes of dementia. Pathogenic variants in the presenilin 1 (PSEN1) gene are the most frequent cause of early-onset AD. Medications for patients with AD bearing PSEN1 mutation (PSEN1-AD) are limited to symptomatic therapies and no established radical treatments are available. Induced pluripotent stem cell (iPSC)-based drug repurposing identified bromocriptine as a therapeutic candidate for PSEN1-AD. In this study, we used an enrichment strategy with iPSCs to select the study population, and we will investigate the safety and efficacy of an orally administered dose of bromocriptine in patients with PSEN1-AD. Methods and analysis This is a multicentre, randomised, placebo-controlled trial. AD patients with PSEN1 mutations and a Mini Mental State Examination-Japanese score of ≤25 will be randomly assigned, at a 2:1 ratio, to the trial drug or placebo group (≥4 patients in TW-012R and ≥2 patients in placebo). This clinical trial consists of a screening period, double-blind phase (9 months) and extension phase (3 months). The double-blind phase for evaluating the efficacy and safety is composed of the low-dose maintenance period (10 mg/day), high-dose maintenance period (22.5 mg/day) and tapering period of the trial drug. Additionally, there is an open-labelled active drug extension period for evaluating long-term safety. Primary outcomes are safety and efficacy in cognitive and psychological function. Also, exploratory investigations for the efficacy of bromocriptine by neurological scores and biomarkers will be conducted. Ethics and dissemination The proposed trial is conducted according to the Declaration of Helsinki, and was approved by the Institutional Review Board (K070). The study results are expected to be disseminated at international or national conferences and published in international journals following the peer-review process

[18F]THK-5351 PET imaging in early-stage semantic variant primary progressive aphasia: a report of two cases and a literature review

Abstract Background Semantic variant primary progressive aphasia (svPPA) is a subtype of primary progressive aphasia characterized by two-way anomia and disturbance in word comprehension, with focal atrophy in the left temporal lobe. [18F]THK-5351 was originally developed to trace tau protein. However, it has recently been suggested that [18F]THK-5351 binds to monoamine oxidase B in astrocytes, which reflects gliosis. Herein, the authors present two cases involving patients with early-stage svPPA who underwent [18F]THK-5351 positron emission tomography (PET) imaging, and examined whether [18F]THK-5351 PET imaging is more sensitive to neurodegenerative lesions than conventional imaging modalities such as magnetic resonance imaging (MRI) and cerebral blood flow (CBF)-single photon emission computed tomography (SPECT). Case presentation Two patients, 64- and 79-year-old men, without notable medical or family history, exhibited disturbances in word comprehension and mild anomia with fluent speech and spared repetition. In both cases, surface dyslexia was observed but prosopagnosia was absent. Although mild depression was detected in 1 of the 2 patients, no behavioral disorders were present in either case. In both cases, MRI revealed atrophy in the anterior and inferior portions of the left temporal lobe. Technetium-99-ethyl cysteinate dimer ([99mTc]ECD) SPECT revealed hypoperfusion in the left temporal lobe. Alzheimer’s disease was ruled out by [11C]Pittsburgh Compound-B (PiB) PET scan. Both patients fulfilled the diagnostic criteria for svPPA. Because of mild language deficits and lack of right temporal atrophy, they were considered to be at an early stage of the disease. In both cases, [18F]THK-5351 retention was observed in bilateral temporal lobes, predominantly on the left side. Comparison of different imaging modalities suggested that [18F]THK-5351 was more sensitive in detecting neurodegenerative change in the right temporal lobe than MRI and [99mTc]ECD SPECT. Conclusions [18F]THK-5351 retention was clearly demonstrated at an early stage of svPPA. Results of the present study suggest that [18F]THK-5351 PET imaging may facilitate very early diagnosis of the disease

Simple and Objective Evaluation Items for the Prognosis and Mortality of Delirium in Real‐World Clinical Practice: A Preliminary Retrospective Study

Objective Identifying factors associated with poor outcomes in patients with delirium is important for predicting prognosis. This retrospective study developed an easy and objective cognitive function measurement scale that can predict the prognosis and mortality related to delirium. Methods Fifty‐five patients aged ≥65 years and diagnosed with delirium were included. Objective data regarding attention and orientation related to time and place were extracted from their medical records during the first consultation, and in total, six points were evaluated. The patients were categorized into high and low cognitive function (LCF) groups. The severity at the first visit and 1‐week post‐treatment was evaluated using the Clinical Global Impressions‐Severity scale. Outcomes (survival or death) at 6 months from the initial visit were evaluated by reviewing medical records. Results Although the Clinical Global Impressions‐Severity score at the first visit was not significantly different between the two groups, 1 week after treatment, it was significantly lower in the high cognitive function (HCF) group than in the LCF group. Regarding the outcome (survival or death) after 6 months, the LCF group had significantly higher mortality than the HCF group. A multivariate logistic regression analysis revealed the same result (OR = 17.049, 95% CI = 2.415–120.373, p = 0.004). Conclusion A simple cognitive assessment of attention and orientation may help predict unfavorable outcomes, including mortality, in patients with delirium

Highly aligned 2D NV ensemble fabrication from nitrogen-terminated (111) surface

The nitrogen vacancy (NV) center in diamond is fascinating and has a long spin coherence time. It is applied to magnetic sensors with high sensitivity (∼fT). To achieve a high sensitivity, an aligned NV ensemble is required. This paper presents a new methodology for the fabrication of two-dimensional (2D) aligned NV ensembles by using nitrogen-terminated (111) surface. To realize this, pure diamond growth and high nitrogen coverage on (111) surface were performed. As a result, we have succeeded in producing 2D NV ensembles, with 1 × 109 cm−2. Coherence time T2 was 2.45 μs. Also, Using dynamical decoupling, the decoherence sources were revealed. The alignment ratio along [111] axis was archived 60%. Thermal annealing of the nitrogen termination was introduced to improve the alignment ratio. After that, the alignment rate was up to 73%. This report shows that the aligned 2D NV ensemble has possibility to be applied for multiple quantum devices

Fabrication of 2D NV Ensemble and its Spin Property Improvement

2次元NVアンサンブルの作製とスピン特性向上に関する研究14th International Conference on New Diamond and Nano Carbons 2020/202

Additional file 1: of [18F]THK-5351 PET imaging in early-stage semantic variant primary progressive aphasia: a report of two cases and a literature review

Figure S1. THK-5351 PET images in a healthy control (81-year-old female), Alzheimer’s disease (80-year-old male), and the current cases. All participants signed a written consent. (TIF 4617 kb