The case for regulatory approval of amyloid-lowering immunotherapies in Alzheimer's disease based on clearcut biomarker evidence.

Decades of research have provided evidence that Alzheimer's disease (AD) is caused in part by cerebral accumulation of amyloid beta-protein (Aβ). In 2023, the US Food and Drug Administration gave full regulatory approval to a disease-modifying Aβ antibody for early AD. Secondary prevention trials with Aβ antibodies are underway.

Safety and efficacy of endoscopic submucosal dissection with gel immersion technique for superficial esophageal neoplasms.

Background And Aim: Gel immersion (GI) endoscopy provides a good visual field in endoscopic submucosal dissection (ESD); however, its clinical outcomes are poorly understood. This study aimed to compare the treatment outcomes between esophageal gel immersion endoscopic submucosal dissection (GI-ESD) and conventional ESD (C-ESD) to determine the safety and efficacy of GI-ESD.

Methods: The data of 71 consecutive patients who underwent esophageal ESD between April 2021 and March 2023 at a Japanese tertiary center were retrospectively reviewed.

A case of gastrolithiasis produced by a 5-day diet.

A 55-year-old man with a history of distal gastrectomy was admitted to our hospital due to gastrointestinal bleeding from an anastomotic ulcer. After endoscopic hemostasis, his oral intake resumed after 1 day of fasting; however, he could not ingest food because of early satiety and nausea on the fifth day of oral intake resumption. Esophagogastroduodenoscopy was performed again to investigate the cause of anorexia and revealed a massive gastrolithiasis that was not observed in the previous esophagogastroduodenoscopy, which was diagnosed as the cause of his anorexia.

Chronic Neuronal Hyperexcitation Exacerbates Tau Propagation in a Mouse Model of Tauopathy.

The intracerebral spread of tau is a critical mechanism associated with functional decline in Alzheimer's disease (AD) and other tauopathies. Recently, a hypothesis has emerged suggesting that tau propagation is linked to functional neuronal connections, specifically driven by neuronal hyperactivity. However, experimental validation of this hypothesis remains limited.

-ε4 allele[s]-associated adverse events reported from placebo arm in clinical trials for Alzheimer's disease: implications for anti-amyloid beta therapy.

-ε4 allele[s] is a risk factor for Alzheimer's disease (AD) and Amyloid-Related Imaging Abnormalities (ARIA) in anti-amyloid beta therapy, and is also associated with cerebrovascular risk factors such as hyperlipidemia or atherosclerosis. During AD clinical trials, -ε4 carriers may experience neuropsychiatric adverse events (AEs) related to these risks, complicating the differentiation of ARIA from cerebrovascular events based on symptoms. This study aimed to examine the hypothetical impact of considering the -ε4 allele's risk for non-ARIA AEs during AD clinical trials.

Effect of sarcopenia on short-term outcomes of gastric endoscopic submucosal dissection.

Background: Sarcopenia has been reported to be associated with short-term outcomes after gastric endoscopic submucosal dissection (ESD). The "strength, assistance with walking, rising from a chair, climbing stairs, and falls" (SARC-F) questionnaire has been widely used as a screening tool for sarcopenia; however, SARC-F combined with body mass index and age (SARC-F+EBM) has recently been reported to be more useful than SARC-F alone. This study aimed to investigate the association between sarcopenia, measured using SARC-F+EBM, and short-term outcomes after gastric ESD.

Combining plasma Aβ and p-tau217 improves detection of brain amyloid in non-demented elderly.

Background: Maximizing the efficiency to screen amyloid-positive individuals in asymptomatic and non-demented aged population using blood-based biomarkers is essential for future success of clinical trials in the early stage of Alzheimer's disease (AD). In this study, we elucidate the utility of combination of plasma amyloid-β (Aβ)-related biomarkers and tau phosphorylated at threonine 217 (p-tau217) to predict abnormal Aβ-positron emission tomography (PET) in the preclinical and prodromal AD.

Methods: We designed the cross-sectional study including two ethnically distinct cohorts, the Japanese trial-ready cohort for preclinica and prodromal AD (J-TRC) and the Swedish BioFINDER study.

Widespread use of proton pump inhibitors or potassium-competitive acid blocker has changed the status of gastrointestinal bleeding in patients with ischemic heart disease: real-world data from high volume centers.

Background: Although proton pump inhibitors (PPIs) or potassium-competitive acid blocker (PCAB) are useful in peptic ulcer prevention, their efficacy in preventing other gastrointestinal bleeding remains unclear. This study aimed to identify the status of gastrointestinal bleeding in the modern era when PPIs are widely used.

Methods: This study included patients who underwent percutaneous coronary intervention (PCI) between 2018 and 2019 at two high-volume centers.

Simplifying Alzheimer's Disease Monitoring: A Novel Machine-Learning Approach to Estimate the Clinical Dementia Rating Sum of Box Changes Using the Mini-Mental State Examination and Functional Activities Questionnaire.

Background: Primary outcome measure in the clinical trials of disease modifying therapy (DMT) drugs for Alzheimer's disease (AD) has often been evaluated by Clinical Dementia Rating sum of boxes (CDRSB). However, CDR testing requires specialized training and 30-50 minutes to complete, not being suitable for daily clinical practice.

Objective: Herein, we proposed a machine-learning method to estimate CDRSB changes using simpler cognitive/functional batteries (Mini-Mental State Examination [MMSE] and Functional Activities Questionnaire [FAQ]), to replace CDR testing.

Usability of a Web-Based Registry for Preclinical Alzheimer's Disease: Implications from a Cross-Sectional Online Survey.

Background: We have been conducting a Japanese trial-ready cohort web study since 2019 as a web-based online registry to enroll individuals with preclinical Alzheimer's disease to facilitate trials on Alzheimer's disease prevention. The usability of a website might be an important factor in determining user participation and retention.

Objectives: We conducted a user questionnaire survey to analyze the usability of the Japanese trial-ready cohort website and user characteristics for future website improvement.

Involvement of the glymphatic/meningeal lymphatic system in Alzheimer's disease: insights into proteostasis and future directions.

Background:  Alzheimer's disease (AD) is pathologically characterized by the abnormal accumulation of Aβ and tau proteins. There has long been a keen interest among researchers in understanding how Aβ and tau are ultimately cleared in the brain. The discovery of this glymphatic system introduced a novel perspective on protein clearance and it gained recognition as one of the major brain clearance pathways for clearing these pathogenic proteins in AD.

Inhibitory Roles of Christchurch Astrocytes in Curbing Tau Propagation Using Human Pluripotent Stem Cell-Derived Models.

Genetic variants in the () gene affect the onset and progression of Alzheimer's disease (AD). The Christchurch ( Ch) variant has been identified as the most prominent candidate for preventing the onset and progression of AD. In this study, we generated isogenic Ch/Ch human-induced pluripotent stem cells (iPSCs) from / healthy control female iPSCs and induced them into astrocytes.

CASM mediates LRRK2 recruitment and activation under lysosomal stress.

Conjugation of ATG8 to single membranes (CASM) at endolysosomal compartments has attracted attention as the non-autophagic function of the Atg8-family protein conjugation system, and the V-ATPase-ATG16L1 axis has emerged as a core mechanism. Our recent research has revealed that this mechanism contributes to the lysosomal recruitment and activation of LRRK2, a Parkinson disease-associated kinase that phosphorylates a subset of RAB GTPases. The activated LRRK2 under CASM-causing lysosomal stress acts to regulate lysosomal morphology and stimulate extracellular secretion of lysosomal contents, thereby promoting the lysosomal stress response.

Refractory Gastroesophageal Reflux Disease Successfully Treated with Endoscopic Anti-gastroesophageal Reflux Mucosal Resection by the ESD-G Method (with Video).

A 70-year-old man who had undergone treatment for gastroesophageal reflux disease (GERD) by a family doctor presented to our hospital with severe heartburn and dysphagia despite taking vonoprazan (20 mg) for 3 months. A diagnosis of vonoprazan-refractory nonerosive reflux disease was made based on esophagogastroduodenoscopy and esophageal function examinations. The patient elected to undergo endoscopic treatment for GERD.