Computer-aided discovery of novel AMPK activators through virtual screening and SAR-driven synthesis.

AMPK is a promising target for various chronic illnesses such as diabetes and Alzheimer's disease (AD). We sought to develop a novel small molecule that directly activates AMPK, with the potential to fundamentally modulate the pathogenic mechanisms of the metabolic disorders. To identify a potent novel pharmacophore in an unbiased way, we performed structure-based virtual screening on a commercially available chemical library, and evaluated the actual AMPK activity of 118 compounds selected from 100,000 compounds based on docking scores.

Advancements in Frank's sign Identification using deep learning on 3D brain MRI.

Frank's sign (FS) is a diagnostic marker associated with aging and various health conditions. Despite its clinical significance, there lacks a standardized method for its identification. This study aimed to develop a deep learning model for automated FS detection in 3D facial images derived from MRI scans.

Impact of diabetes on the progression of Alzheimer's disease via trajectories of amyloid-tau-neurodegeneration (ATN) biomarkers.

Background: Alzheimer's disease (AD) is characterized by the accumulation of abnormal proteins, such as β-amyloid and tau, in the brain, which precedes cognitive impairment. Although diabetes mellitus (DM) is a well-established risk factor for AD, few studies have investigated how the presence of DM affects the sequential pathogenesis of AD, specifically within the amyloid-tau-neurodegeneration (ATN) and cognition framework.

Objectives: This study aims to investigate the trajectories of ATN biomarkers in relation to the presence of DM in the preclinical and prodromal stages of AD.

Impact of amyloid and cardiometabolic risk factors on prognostic capacity of plasma neurofilament light chain for neurodegeneration.

Background: Plasma neurofilament light chain (NfL) is a blood biomarker of neurodegeneration, including Alzheimer's disease. However, its usefulness may be influenced by common conditions in older adults, including amyloid-β (Aβ) deposition and cardiometabolic risk factors like hypertension, diabetes mellitus (DM), impaired kidney function, and obesity. This longitudinal observational study using the Alzheimer's Disease Neuroimaging Initiative cohort investigated how these conditions influence the prognostic capacity of plasma NfL.

Developmental origin of oligodendrocytes determines their function in the adult brain.

In the mouse embryonic forebrain, developmentally distinct oligodendrocyte progenitor cell populations and their progeny, oligodendrocytes, emerge from three distinct regions in a spatiotemporal gradient from ventral to dorsal. However, the functional importance of this oligodendrocyte developmental heterogeneity is unknown. Using a genetic strategy to ablate dorsally derived oligodendrocyte lineage cells (OLCs), we show here that the areas in which dorsally derived OLCs normally reside in the adult central nervous system become populated and myelinated by OLCs of ventral origin.

Hyperglycemia enhances brain susceptibility to lipopolysaccharide-induced neuroinflammation via astrocyte reprogramming.

Hyperglycemia has been shown to modulate the immune response of peripheral immune cells and organs, but the impact of hyperglycemia on neuroinflammation within the brain remains elusive. In the present study, we provide evidences that streptozotocin (STZ)-induced hyperglycemic condition in mice drives a phenotypic switch of brain astrocytes to a proinflammatory state, and increases brain vulnerability to mild peripheral inflammation. In particular, we found that hyperglycemia led to a significant increase in the astrocyte proliferation as determined by flow cytometric and immunohistochemical analyses of mouse brain.

Hyperpolarized [1-C]pyruvate Magnetic Resonance Spectroscopy Shows That Agmatine Increased Lactate Production in the Brain of Type 2 Diabetic Mice.

Purpose: Type 2 diabetes mellitus (T2DM) is associated with a 2-fold increased risk of developing Alzheimer's disease. In earlier research, agmatine has been demonstrated to alleviate diabetes symptoms and increase cognitive performance. However, it is unclear whether the improvement of cognitive function is attributable to the reduction of diabetic symptoms or its direct influence on brain metabolism.

The development and evaluation of a self-efficacy enhancement program for older adults with mild cognitive impairment.

Objective: The aims of this study were to develop a self-efficacy enhancement program and to evaluate its effect on cognitive function, dementia knowledge, self-efficacy, depression, and dementia preventive behaviors in older adults (age ≥ 65 years) with mild cognitive impairment (MCI).

Methods: This equivalent control group pretest-posttest study was conducted at a tertiary hospital in Seoul, South Korea. Older adults with MCI were randomly allocated to an experimental (EG, n = 16) or control group (CG, n = 16).

Weight loss and risk of dementia in individuals with versus without obesity.

Introduction: Using nationwide cohort data, we aimed to elucidate whether baseline obesity altered the relationship between loss in body mass index (BMI) or waist circumference (WC) and risk of dementia.

Methods: Among 9689 participants whose BMIs and WCs were repeatedly measured over 1 year, 1:1 propensity score matching was conducted between participants with and without obesity (n = 2976 per group, mean age 70.9).

The effects of long-term cumulative HbA1c exposure on the development and onset time of dementia in the patients with type 2 diabetes mellitus: Hospital based retrospective study (2005-2021).

Aims: We examined cumulative effects of long-term glycemic exposure in patients with type 2 diabetes mellitus (T2DM) on the development of dementia.

Methods: The study involved 20,487 records of patients with T2DM identified in the electronic medical record at Severance Hospital, Korea. Cumulative HbA1c (AUC) and mean HbA1c over time (HbA1c) as measures of long-term glycemic exposure were compared for the development of dementia and the time to dementia.

Restless leg syndrome and risk of all-cause dementia: a nationwide retrospective cohort study.

Background: Restless leg syndrome (RLS) is associated with poor sleep quality, depression or anxiety, poor dietary patterns, microvasculopathy, and hypoxia, all of which are known risk factors for dementia. However, the relationship between RLS and incident dementia remains unclear. This retrospective cohort study aimed to explore the possibility that RLS could be deemed as a non-cognitive prodromal feature of dementia.

Pioglitazone Use and Reduced Risk of Dementia in Patients With Diabetes Mellitus With a History of Ischemic Stroke.

Background And Objectives: Previous studies have reported the protective effect of pioglitazone on dementia in patients with type 2 diabetes mellitus (DM). Recent studies have shown that pioglitazone also lowers the risk of primary and recurrent stroke. Understanding the characteristics of patients particularly associated with the benefits of pioglitazone would facilitate its personalized use by specifying subpopulations during routine clinical care.

Immobilized Amyloid Hexamer Fragments to Map Active Sites of Amyloid-Targeting Chemicals.

As amyloid-β (Aβ) peptide is considered a biomarker and pathological culprit of Alzheimer's disease, Aβ-targeting compounds have been investigated for diagnostics development and drug discovery of the disorder. Unlike amyloid plaque targeting agents, such as clinically available amyloid radiotracers intercalating into the β-sheet structures of the aggregates, monomer and oligomer targeting chemicals are difficult to develop, as the transient and polymorphic nature of these peptides impedes their structural understanding. Here, we report a mapping approach to explore targeting residues of Aβ-imaging probes and Aβ-regulating drug candidates by utilizing a set of fragmented Aβ hexamers immobilized on a 96-well microplate in combination with fluorescent full-length Aβ for on-plate aggregation.

Plasma amyloid-beta oligomer is related to subjective cognitive decline and brain amyloid status.

Background: Subjective cognitive decline (SCD) is a target for Alzheimer's disease prediction. Plasma amyloid-beta oligomer (AβO), the pathogenic form of Aβ in blood, has recently been proposed as a novel blood-based biomarker of AD prediction by representing brain Aβ deposition. The relationship between plasma AβO, brain Aβ deposition, and SCD in individuals with normal objective cognition has not been investigated.

Associations between non-alcoholic fatty liver disease and cognitive impairment and the effect modification of inflammation.

This study aimed to evaluate the association between non-alcoholic fatty liver disease (NAFLD) and cognitive impairment and explore the effect modification by the inflammatory status. A total of 4400 community-based participants aged 50-64 years from the Cardiovascular and Metabolic Disease Etiology Research Center were included in this cross-sectional study. NAFLD was identified as the Fatty Liver Index 30 or higher in the absence of excessive alcohol consumption.

Association of cognitive enhancers and incident seizure risk in dementia: a population-based study.

Background: Although individuals with dementia have a high risk of developing seizures, whether seizures are associated with cholinesterase inhibitors, which are commonly prescribed to treat individuals with dementia, remains unknown. This study investigated the risk of incident seizure following cholinesterase inhibitor use in patients with dementia.

Methods: A nationwide, nested case-control study was conducted using data from the Korean Health Insurance Review and Assessment Service (HIRA) from 2014 through 2018.