Astrocytes colocalize with fibrillar amyloid-β (Aβ) plaques in postmortem Alzheimer’s disease (AD) brain tissue; however, their spatiotemporal dynamics in vivo remain poorly understood. This multicenter study aimed to investigate the progression of astrocyte reactivity across the AD continuum, including healthy controls (HC), mild cognitive impairment (MCI), and AD, using the novel monoamine oxidase B (MAO-B)-specific PET tracer [18F]SMBT-1, while exploring its association with cognitive performance and amyloid burden. A total of 91 participants (35 HC, 44 MCI, 12 AD) underwent [18F]SMBT-1 PET, amyloid PET, T1-weighted MRI, and standardized neuropsychological assessments. Standardized uptake value ratios (SUVRs) were calculated based on [18F]SMBT-1 PET data using four reference regions for subgroup comparisons stratified by Aβ status. [18F]SMBT-1 uptake was significantly elevated in amyloid-positive MCI (MCI+) and AD groups compared with amyloid-negative HC (HC−) in the frontal, temporal, and posterior cingulate regions. Notably, astrogliosis patterns distinguished MCI subtypes: MCI+ individuals exhibited a widespread AD-like pattern, whereas the MCI− group showed a distinct profile. Furthermore, the uptake in symptomatic MCI+ individuals was significantly higher than that in asymptomatic HC+ individuals. Regional SMBT-1 uptake also strongly correlated with greater Aβ burden and worse cognitive scores. This study demonstrates that [18F]SMBT-1 is a promising tool for characterizing the spatial pattern and magnitude of reactive astrogliosis across the Aβ-defined AD continuum. Our findings further suggest that astrogliosis may represent an important mechanistic link between amyloid pathology and cognitive impairment, supporting its potential relevance in therapeutic development. Japan Registry of Clinical Trials (jRCT) jRCTs031210602, registered Feb. 07, 2022. https://jrct.mhlw.go.jp/en-latest-detail/jRCTs031210602 .
To develop a simple admission risk stratification rule to identify older inpatients at risk of hospital-associated disability (HAD). A four-item rule (age ≥ 80, CFS ≥ 5, MMSE ≤ 23, emergency admission) stratified HAD risk effectively (AUC 0.80). Low scores identified patients with very low risk, whereas high scores identified those at markedly increased risk. This bedside rule supports targeted use of comprehensive geriatric assessment and tailored management while avoiding unnecessary intervention in low-risk patients. Hospital-associated disability (HAD) is a frequent complication in hospitalized older adults and is associated with unfavorable outcomes. Because preventive interventions require substantial resources, efficient identification of high-risk patients at admission is required. We developed a simple admission-based clinical decision rule for early risk stratification using routinely available admission information. In a multicenter retrospective cohort study, adults aged ≥ 65 years admitted to acute care hospitals between October 2019 and March 2025 were included. HAD was defined as a ≥ 5-point decline in the Barthel Index from admission to discharge. Candidate predictors included age, admission type, Clinical Frailty Scale (CFS), and Mini-Mental State Examination (MMSE). A multivariable logistic regression model derived a simplified point-based score; discrimination was assessed by AUC, calibration by bootstrap-corrected calibration, and clinical utility by decision curve analysis with 2,000 bootstrap resamples. Among 1,292 patients (mean age 82.9 ± 6.7 years, 58.2
To examine the association between oral frailty and laboratory-based Frailty Index (FI-lab) in older adults attending a frailty outpatient clinic. Oral frailty was significantly associated with FI-lab-defined frailty after adjusting for age, sex, and comorbidities. This finding suggests that oral frailty is linked to physiological vulnerability captured by the FI-lab. Assessment of oral frailty may help identify older adults with latent physiological vulnerability before overt clinical frailty becomes apparent. To examine the association between oral frailty and laboratory-based Frailty Index (FI-lab) in older adults. This cross-sectional study included patients aged ≥ 65 years who attended a frailty outpatient clinic. Oral frailty was assessed using the Oral Frailty five-item checklist. The FI-lab was constructed from 31 laboratory parameters, with frailty defined as an FI-lab value > 0.21. The association between oral frailty and FI-lab–defined frailty was examined using multivariable logistic regression analysis. Among the 486 patients, the mean age was 77.9 ± 6.3 years, and 63.6
The 2024 National Institute on Aging–Alzheimer’s Association (NIA-AA) criteria establish a biological definition of Alzheimer’s disease (AD), marking a pivotal step toward linking research biomarkers with clinical practice. This review traces the evolution of AD diagnostic frameworks from the 1984 NINCDS-ADRDA clinical criteria, through biomarker-informed updates in 2011, to the 2024 biology-based criteria that bridge research and clinical care. The 2024 framework defines AD by its underlying pathology rather than clinical symptoms, recognizing that biomarker evidence alone can establish diagnosis. It expands the traditional AT (N) model into a multimodal profile (AT1T2NISV), in which Core-1 biomarkers (A and T1) are diagnostic, while Core-2 biomarkers (T2) support biological staging. Non-specific but mechanistically important processes (N, neurodegeneration; I, inflammation) and common co-pathologies (S, α-synuclein; V, vascular injury) are also incorporated to better capture the complexity of late-life dementia. Recent advances in plasma and PET biomarkers, including p-tau217, mid-region p-tau, and α-synuclein imaging, are redefining biological diagnosis and expanding its reach. Moreover, co-pathologies involving TDP-43, glial dysfunction, and vascular factors contribute to disease heterogeneity and variable therapeutic response. While the 2024 criteria represent a major conceptual step forward, they should be regarded as a dynamic framework open to future integration of emerging biomarkers. Bridging molecular pathology, neuroimaging, and clinical presentation will be essential to realize the goal of patient-centered precision medicine in AD. In this review, we synthesize recent advances in biomarker-based frameworks for AD and discuss co-pathologies, resilience-related modifiers, and emerging evidence challenging traditional interpretations of structural neurodegeneration markers. We also address implications for clinical implementation, including PET standardization and disease-modifying therapies.
Frailty, a syndrome that decreases healthspan in older individuals, lacks effective therapies. We conducted a randomized, dose-finding clinical trial to test whether human bone marrow-derived allogeneic mesenchymal stem cells (MSCs; laromestrocel) improve physical functioning and patient self-reported outcomes in ambulatory individuals with frailty (ClinicalTrials.gov #NCT03169231; N = 148). Laromestrocel infusion results in clinically meaningful, dose- and time-dependent increases in the 6-min walk test (6MWT; primary endpoint) compared with placebo: 63.4 m (95% confidence interval [CI]: 17.1-109.6 m; p = 0.0077) at month 9 and 41.3 m (95% CI: -2.4-84.9 m; p = 0.0635) at month 6. Increased 6MWT distance correlates with PROMIS Physical Function score, and increasing doses of laromestrocel are associated with decreases in soluble (degraded) tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (TIE2), the cognate receptor for the angiopoietins, identifying a potential biomarker of laromestrocel responsiveness. These findings identify a stem cell therapy approach for the management of patients with hypomobility and other features of aging frailty.
