bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Alzheimer’s Association Revised Criteria for Diagnosis and Staging of Alzheimer’s Disease – Where does Lewy body dementia stand?
Authors: Abdelnour Carla 
Published: January 2025

AbstractDementia patients often received one clinical diagnosis, yet most of these cases present multiple underlying pathologies. Bringing the transition from clinical‐based to biological‐based diagnosis holds promise with the diagnostic criteria proposed by the Alzheimer’s Association (AA) Revised Criteria for Diagnosis and Staging of Alzheimer’s Disease and the Neuronal Synuclein Disease Integrated Staging System (NSD‐ISS). This session aims to explore the practical implications of the AA revised criteria for diagnosing and designing clinical trials in Lewy body disease (LBD).The updated version of the AA criteria proposes 3 biomarker categories: core Alzheimer’s disease (AD) biomarkers, non‐specific biomarkers, and biomarkers for common non‐AD co‐pathologies, including synucleinopathy (asyn). Utilizing the seeding amplification assay (SAA) to detect asyn pathology expands the biomarker toolkit, historically dominated by AD biomarkers. Identifying asyn in vivo in dementia cases enables recognizing underlying LBD, potentially reducing oversight of LBD cases with concurrent AD, which are less likely to present core features (particularly females).The AA criteria emphasize the role of clinical judgment in cases with comorbid pathology, proposing a biomarker profile for characterization. Challenges in evaluating several biomarkers in the clinical setting may be addressed using biofluid biomarkers and a stepwise process guided by clinical judgment.Practical applications of these criteria include their role as inclusion/exclusion criteria and stratification of LBD clinical trials. Similarly, in AD clinical trials, this framework allows excluding patients with comorbid pathologies to achieve a homogeneous study population.The AA revised criteria, along with the NSD‐ISS, serve as starting points for hypothesis testing. Future directions involve updating these frameworks with a patient‐centered approach, engaging patients and caregivers to understand the implications of biological‐based diagnosis. Longitudinal studies analyzing multiple comorbid pathologic changes are essential for determining the timeline of each pathology’s development. Finally, it is envisioned the creation of a comprehensive system to stratify disease progression of neurodegenerative diseases by incorporating biomarkers, demographic, clinical, and genetic data.
Development of the 7‐item ASK‐AD Assess Symptoms and Knowledge of Alzheimer’s Disease tool for multigenerational community dementia awareness: Findings from Old SCHOOL Hip Hop
Authors: Noble James M. , Minchala Sandra G , Hedmann Monique G , Teresi Jeanne , Ocepek‐Welikson Katja , Silver Stephanie A , Eimicke Joseph P , Ramirez Mildred , Harris Adrian , Lloyd Arthur , Chhea Kunsorya , Arango Catalina Alvarez , Lee Yejin , Sawyer Vanessa , Williams Olajide 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) health literacy is low in high‐risk populations and is likely a determinant of timely care seeking behavior. Our group aimed to develop a novel brief questionnaire for use in community outreach and related studies of AD awareness.MethodsWe developed an initial 15‐item AD knowledge questionnaire “ASK‐AD (Assess Symptoms and Knowledge of AD)” following pilot study and cognitive interviews with subject matter experts along with elementary school children. The study took place in 28 elementary schools in the New York City area between 2018‐2023. Psychometric analyses explored data acquired immediately following enrollment but before randomization into either arm of the Old SCHOOL Hip Hop randomized controlled trial.ResultsOverall, 1461 diverse elementary school children including 692 (47%) fourth graders and 752 (52%) fifth graders (typically aged 9‐11 years) enrolled along with 783 of their parents. Among parents, 679 (87%) were female with 441 (56%) self‐reporting Black or African‐American race and 215 (28%) Hispanic ethnicity; 97 (12%) reported White race. Most parents were aged 36‐55 years (521 (67%), 18‐35y: 223 (29%)) with 185 (24%) having completed high school; 226 (29%) completed some college, and 182 (24%) had a bachelor’s degree. Performance metrics of 15‐, 11‐, 8‐, and 7‐ question versions were explored. The 7‐item version of the ASK‐AD evidenced optimal performance in students and parents, testing key AD concepts, including common symptoms and signs (six items) and brain localization (one item). ASK‐AD‐7 corrected item‐total correlations ranged from 0.30‐0.50 for student data and 0.24‐0.53 for parents. Psychometric property estimates were good‐to‐excellent for parent and student versions. The unstandardized Cronbach’s alpha coefficient estimate was 0.668 (standardized = 0.667) for students and 0.699 (0.701) for parents. For parents, the McDonald’s Omega estimate Total (ωt) was 0.857, ordinal alpha was 0.854, and the explained common variance (ECV) was 59.567; for students ωt = 0.801, ordinal alpha = 0.798 and ECV = 49.338. Items of AD prevention, treatment, and action plan were not retained in any reduced version.ConclusionsThe novel 7‐item ASK‐AD multigenerational community dementia awareness tool may be used in diverse, at‐risk groups. ASK‐AD could fill important gaps in ongoing AD community outreach programs.
Correlates of Cognitive SuperAging in the Mexican Health and Aging Study
Authors: Saenz Joseph , Doyle Cassidy , Andel Ross 
Published: January 2025

AbstractBackgroundAging is often accompanied by normative cognitive change, with memory decline typically experienced with advanced age. Some older adults reach their 80s maintaining memory performance of people 20 years younger. Little is known about these “SuperAgers” or correlates of SuperAging, particularly in low‐ and middle‐income settings. We evaluate how demographic, psychosocial, and health factors relate to odds of SuperAging in Mexico, an upper middle‐income country experiencing rapid population aging.MethodData came from the Mexican Health and Aging Study, a nationally representative study of adults age 50+. We defined SuperAging as being 80+ years old, having delayed recall scores at or above the median for those age 50‐64, and not having cognitive impairment or dementia. We then explored associations between demographic, psychosocial, and health factors and odds of SuperAging.ResultOur sample included 334 individuals aged 80+ in the 2012 MHAS with no history of dementia or cognitive impairment, of whom 16% (n = 53) met criteria for SuperAging and 84% (n = 281) experienced normal cognitive aging. Women (OR: 1.90, p<0.05) were more likely to be among the SuperAgers, as were younger study participants (OR: 0.87, p<0.05), but years of education did not relate with SuperAging. Higher life satisfaction related positively with SuperAging (OR: 1.32, p<0.05) whereas other psychosocial factors (depressive symptoms and control beliefs) did not discriminate SuperAgers from their normal aging counterparts. Functional ability, chronic condition count, and self‐rated health were not related with SuperAging.ConclusionSome individuals aged 80 and over maintain superior memory performance, with levels consistent with their peers in their fifties and early sixties. Using data from a study of older Mexican adults, we found that women and those reporting higher life satisfaction are more likely to be SuperAgers.
Intranasal dantrolene nanoparticles abolished depression behavior and memory loss as a disease‐modifying drug in 5XFAD mice
Authors: Bhuiyan Piplu , Zhang Wenjia , Chae Rebecca , Kim Kyelee , St. Louis Lauren , Wang Ying , Liang Ge , Wei Huafeng 
Published: January 2025

AbstractBackgroundThe vicious cycle between depression and dementia increases the risk of Alzheimer’s Disease (AD) pathogenesis and pathology. This study investigates therapeutic effectiveness versus side effects and the underlying mechanisms of intranasal dantrolene nanoparticles (IDNs) to treat depression behavior and memory loss in 5XFAD mice.Method5XFAD and wild‐type B6SJLF1/J mice were treated with IDNs (IDN, 5 mg/kg) in Ryanodex formulation for a duration of 12 weeks. Early treatment groups (ETG) began treatment at 2 months until 5 months of age, and late treatment groups (LTG) began treatment at 9 months until 12 months of age. Behavioral assessments including depression (Tail suspension, open field), cognition (fear conditioning, Y‐ maze), olfaction (buried food test), and motor function (rotarod) were conducted between the ages of 5‐6 months in ETG and 12‐13 months in LTG. Blood and brain samples were obtained at 7 and 13 months in ETG and LTG, respectively. Blood Alanine transaminase measured by ELISA for liver function. The changes of brain proteins on Ca2+ release channels on the ER membrane (RyR‐2 and InsP3R‐1), MDA, pyroptosis regulatory proteins (NLRP3, Caspase‐1, full length or NT of Gasdermin D, cytotoxic (IL‐1β, IL‐18, IL‐6, TNF‐a) and cytoprotective (IL‐10) cytokines and PSD‐95, Synapsin‐1 determined using immunoblotting. Mice weight was measured monthly.ResultCompared to WT mice, there were significant depression behavior and memory loss in both ETG and LTG 5XFAD mice, which were abolished by IDNs. IDNs also significantly inhibited the pathologically increased proteins expression of RyR‐2 and InsP3R‐1, MDA‐modified proteins, pyroptosis regulatory proteins (NLRP3, Caspase‐1, NT‐GSDMD), neurotoxic cytokines (IL‐1β, IL‐18, IL‐6, TNF‐α). IDNs also increased the neuroprotective cytokines (IL‐10) and synaptic proteins (PSD‐95, Synapsin‐1) in the LTG mice. IDNs did not affect blood liver function enzymes, motor or smell function, body weight in both ETG and LTG WT or 5XFAD mice.ConclusionIDNs robustly protect both depression behavior and memory loss in young and aged 5XFAD mice, with no adverse effects with chronic use. This was associated with its potent inhibition of inflammation, pyroptosis, and associated synapse protein loss. IDNs emerge as a promising therapeutic intervention for both depression and dementia, particularly in AD.
Area‐based socioeconomic deprivation is associated with cognitive decline in midlife to early late‐life New Zealanders without cognitive impairment
Authors: Röhr Susanne , Gibson Rosemary , Alpass Fiona 
Published: January 2025

AbstractBackgroundResearch identified individual‐level socioeconomic factors as key determinants of cognitive health. This study investigated the effect of area‐based socioeconomic deprivation on cognitive outcomes in midlife to early late‐life New Zealanders without cognitive impairment. Understanding geographical dimensions of socioeconomic determinants of cognitive health is important from an equity perspective.MethodData stemmed from a subsample of the New Zealand Health, Work and Retirement Study, a cohort study on ageing. In 2010, 1,001 participants aged 49‐84 years completed face‐to‐face interviews and were reassessed two years later. Cognitive functioning was measured using Addenbrooke’s Cognitive Examination–Revised, adapted for culturally acceptable use in New Zealand. Area‐based socioeconomic deprivation was assessed using the New Zealand Deprivation Index (NZDep2006). Linear mixed‐effects models analysed the association between area‐based socioeconomic deprivation and cognitive outcomes, controlling for individual‐level socioeconomic (age, age², gender, education, ethnicity [Māori, Indigenous people of New Zealand, and Non‐Māori, mostly of European descent], marital status, employment, net personal income), lifestyle and health variables (Lifestyle for Brain Health/LIBRA index, social loneliness).ResultThe analysis included 783 participants (54.7% female, mean age 62.7 years, 25.0% Māori). Individuals with cognitive impairment at baseline (n = 69) and older than 75 years were excluded (n = 79). Further attrition was due to missing data. At baseline, 39.7% resided in low deprivation areas, 39.0% in moderate, and 21.3% in high deprivation areas. The unadjusted model indicated a significant association between higher area‐based socioeconomic deprivation and lower cognitive functioning (B = ‐0.16, 95%CI: ‐0.22,‐0.10; p < .001) and cognitive decline (B = ‐0.12, 95%CI: ‐0.21;‐0.03; p = .015). The adjusted model yielded similar results for cognitive functioning (B = ‐0.08, 95%CI: ‐0.15;‐0.01; p = .050) and cognitive decline (B = ‐0.12, 95%CI: ‐0.20;‐0.04, p = .013) (Fig. 1). Influential covariates included gender, education, and lifestyle (LIBRA).ConclusionThis study demonstrated a relationship between higher area‐based socioeconomic deprivation and lower cognitive functioning, along with cognitive decline, in cognitively unimpaired New Zealanders aged 48 to 75 years. These findings emphasize the importance of considering neighbourhood characteristics and broader socioeconomic factors in strategies aimed at mitigating cognitive health disparities and reducing the impact of dementia in disadvantaged communities.
Effects of a 4‐Month Supervised Aerobic‐Strength Training on Cognitive Functions and Clinical State of Patients with Parkinson’s Disease
Authors: Ukropec Jozef , Slobodová Lucia , Malenovská Karin Marček , Amiri Ali , Konečná Michaela , Straka Igor , Klepochová Radka , Košutzká Zuzana , Krššák Martin , Valkovič Peter , Ukropcová Barbara 
Published: January 2025

AbstractBackgroundPhysical exercise improves clinical state of patients with Parkinson’s disease (PD), and evidence from experimental models suggests it has a potential to slow down the disease progression. Improved glucose metabolism as well as exerkines, bioactive molecules released into circulation with each exercise bout, contribute to the synchronized exercise‐induced adaptive response at a systemic level. Our aim was to assess effects of exercise on clinical state and molecular changes in cerebrospinal fluid (CSF) and blood of patients with PD.MethodsPatients with PD (H&Y score I‐III, 9F/17M; age 63.3 ± 8.4yrs; BMI 26.5 ± 5.9kg/m2) underwent supervised 4‐month aerobic‐strength training (3×1h/week). Clinical state (MDS‐UPDRS), body composition (BIA/MRI), cognitive functions (CogState, ACE‐R, TMT‐A&B, DSST, RAVL test), VO2max (Rockport 1 mile walk test), muscle strength (dynamometry), resting metabolic rate, metabolic substrate flexibility (indirect calorimetry), and insulin sensitivity (euglycemic hyperinsulinemic clamp) were assessed and CSF was sampled by atraumatic lumbar puncture (in a subpopulation) before / after 4‐month intervention. Extracellular vesicles (EVs) were isolated from serum and CSF by size exclusion chromatography (SEC). Proteomic analysis (mass spectrometry) of the samples is currently ongoing.ResultsFour‐month aerobic‐strength exercise improved or tended to improve clinical state (MDS‐UPDRS, p<0.05), body composition (reduced: BMI, p = 0.007; body fat, p = 0.08; visceral fat, p = 0.038) and cognitive performance (ACE‐R verbal production subscore, p = 0.029; psychomotor function, p = 0.04; visual learning & short‐term memory, p = 0.009) in patients with PD. Training reduced circulating HbA1C, improved whole‐body metabolic flexibility (substrate preference based on the substrate availability, the hallmark of healthy metabolism) and muscle strength (all p<0,05). Proteomic analysis of the samples obtained before and after training is in progress.ConclusionsA relatively short aerobic‐strength exercise has favorable effects on cognition and clinical state in patients with PD which could be, at least in part, related to the improvements in patients’ physical fitness and metabolism. It is plausible to speculate that the specific training‐induced changes in the proteome of CSF, blood and EVs could be involved in the adaptive response underlying the exercise‐induced health benefits in PD.Funding: APVV‐20‐0466, VEGA‐2/0076/22, ADDIT‐CE Horizon Europe 101087124
Neuroprotective effects of fosgonimeton and amyloid‐β‐targeting monoclonal antibodies against amyloid‐β toxicity in primary neuron culture
Authors: Reda Sherif M , Wu Wei , Setti Sharay E. , Berthiaume Andrée‐Anne , Taylor Robert W , Johnston Jewel L , Church Kevin J. 
Published: January 2025

AbstractBackgroundWe have previously reported the neuroprotective effects of fosgonimeton in amyloid‐β (Aβ)‐driven preclinical models of Alzheimer’s disease (AD). Fosgonimeton is an investigational small‐molecule positive modulator of the neurotrophic hepatocyte growth factor (HGF) system, currently under investigation for mild‐to‐moderate AD (LIFT‐AD; NCT04488419). Given the recent approvals of Aβ‐targeting monoclonal antibodies (Aβ‐mAbs) for the treatment of AD, and growing recognition that combination therapies may improve treatment outcomes, we sought to investigate the preclinical activity of fosgonimeton in the presence of Aβ‐mAbs. Here, we report the neuroprotective effects of fosgonimeton against Aβ toxicity in primary cortical neurons in the presence and absence of lecanemab, an Aβ‐targeting mAb that has received full approval for early AD.MethodPrimary rat cortical neurons were pre‐treated with the active metabolite of fosgonimeton (fosgo‐AM; 100 nM), lecanemab (25 nM), or fosgo‐AM + lecanemab for 15 minutes, and subsequently challenged with Aβ1‐42 (15 µM). In another condition, the drug treatments were co‐applied with Aβ1‐42. Following 24‐ or 48‐hour Aβ exposure, cultures were immunoassayed for microtubule‐associated protein‐2 (neuronal marker) to determine neuronal survival and neurite network length.ResultCortical neurons pre‐treated with fosgo‐AM and/or lecanemab exhibited a significant increase in neuronal survival and neurite network length following 24h or 48h Aβ challenge. In the Aβ1‐42 co‐application conditions, following 24h Aβ exposure, all treatments significantly promoted neuronal survival, but only the combination of fosgo‐AM + lecanemab significantly preserved neurite networks. In the Aβ1‐42 co‐application conditions, following 48h Aβ exposure, only the combination of fosgo‐AM + lecanemab significantly promoted neuronal survival, and none of the treatments had a significant effect on neurite network.ConclusionThis study provides preliminary evidence that, on a cellular level, the neuroprotective ability of fosgonimeton against Aβ‐mediated toxicity in primary neurons is maintained in the presence of lecanemab. Furthermore, in some conditions, only the combination of fosgo‐AM and lecanemab demonstrated a significant increase in neuronal survival. While additional experiments are required to characterize these effects, these initial observations may have important implications regarding the potential of fosgonimeton as a treatment for AD, with or without Aβ‐targeting antibodies.
PET imaging utility of a novel Aβ‐tracking PET radiotracer, [18F]FC119S in aged vervet monkeys
Authors: Bhoopal Bhuvanachandra , Frye Brett M. , Bansode Avinash , Miller Mack , Damuka Naresh , Gollepalli Krishna Kumar , Barcus Richard A. , Lockhart Samuel N. , Sutphen Courtney L. , Jorgensen Matthew J. , Craft Suzanne , Register Thomas C. , Whitlow Christopher T , Shively Carol A. , Sai Kiran K. Solingapuram 
Published: January 2025

AbstractBackgroundOlder vervet monkeys are an excellent model for studying age‐associated Aβ deposition; however, they have high proportions of low‐affinity Aβ sites compared to human brains. Commonly used Aβ PET radiotracers are most useful in detecting high affinity Aβ fibrils. Measuring real‐time levels of low affinity Aβ fibrils through PET provides critical information of early AD progression. The radiotracer [18F]FC119S has high binding strength for Aβ1–42 protein aggregates (0.16 nM) and AD brain homogenates (13–15 nM). A pilot clinical trial showed significantly higher hippocampal and cortical uptake in AD patients over cognitively normal participants. Here we report the fully‐automated [18F]FC119S radiochemistry and preliminary imaging and fluid biomarker correlation data in aged vervet monkeys.MethodsRadiochemistry followed [18F]¯‐assisted nucleophilic substitution of mesityl precursor and deprotection of Boc group. [18F]FC119S(∼0.37GBq)‐based brain PET (0‐120min) and T1‐weighted whole‐brain MRI scans were conducted in aged vervets (19‐27 y, n=14). CSF and plasma Aβ40, Aβ42, pTau181, and NfL were measured in samples taken close to the time of PET. Standard Uptake Values with cerebellum as reference (SUVr) and time‐activity‐curves (TACs) were calculated from PET/MR (Figure 1). SUVrs of anterior and posterior cingulate, hippocampus, frontal, parietal, temporal, and occipital lobes were correlated with age, MRI outcomes (grey and white matter volumes), and fluid biomarker data.Results[18F]FC119S production was highly reproducible (n>25 runs) in high (>97%) radiochemical purities, and molar activities (∼140 GBq/µmol). TACs showed favorable washout kinetics from all brain regions. SUVrs of hippocampus and cortical parietal lobe positively correlated with age and SUVrs of all the regions analyzed negatively correlated with MRI deep gray and white matter volumes. Among the high SUVr regions, cortical anterior cingulate SUVr was highly positively correlated (Figure 2) with CSF pTau181 (r=0.78, **p=0.002).ConclusionPreliminary [18F]FC119S PET evaluations agrees with human PET data in vervets with high uptake in regions associated with Aβ deposition. Among all fluid biomarkers analyzed, CSF pTau181 was the best correlate of all the brain PET SUVrs. Association of Aβ PET imaging data with synaptic density and microtubule data in the same cohort is being evaluated to explore the potential neurodegeneration pathways in aged vervet monkeys.
Development of NULISA™ CNS Disease Panel 120 for comprehensive proteomic profiling of neurodegenerative diseases
Authors: Ma Xiao‐Jun , Iyengar Shweta , Deshmukh Shalaka , Comandor Roopa , Kim Sean , Xu Xiaomei , Qiu Xioalei , Zhang Bingqing , Luo Yuling 
Published: January 2025

AbstractBackgroundThe development of reliable blood biomarkers for neurodegenerative diseases (NDDs) has been hindered by the lack of tools with sufficient sensitivity to detect low concentrations of brain‐derived proteins in plasma or serum in a highly multiplexed manner. NULISA™ (NUcleic acid‐Linked Immuno‐Sandwich Assay) has emerged as a promising solution, with attomolar sensitivity and capable of high multiplexing in a fully automated system. In this study, we introduce NULISA CNS Disease Panel 120, a 120‐plex NULISAseq assay for profiling key hallmarks of NDDs in both blood and cerebrospinal fluid (CSF).MethodsNULISA CNS Disease Panel 120 includes many established and emerging disease markers such as amyloid beta 38/40/42, phosphorylated Tau (p‐Tau181, p‐Tau217, and p‐Tau231), neurofilament light and alpha synuclein as well as APOE ε4 for APOE status. NULISA single‐plex assays for each target were developed and pooled into a 120‐plex assay with signal tuning to optimize detection of both low and high abundance targets simultaneously in both plasma and CSF samples. Performance assessment included target detectability, assay precision, and detection of differential abundance between disease and control groups using plasma (n=38) and CSF (n=29) samples from NDD patients and age‐matched controls.ResultsWe developed a CNS disease panel consisting of 120 targets linked to various pathways and processes characteristic of NDDs. Using just 10 µL of plasma or CSF, NULISA™ CNS Disease Panel 120 detected approximately 95% of targets in plasma and around 85% in CSF. It demonstrated high precision, with a median coefficient of variation (CV) of approximately 6.0%. Through linear regression analysis, we identified both known and novel proteins exhibiting significant differences in abundance between disease and age‐matched controls. Furthermore, the APOE ε4 assay accurately classified donor APOE status into carriers and non‐carriers using both sample types.ConclusionWe developed a comprehensive CNS disease‐targeted panel for the NULISA platform to meet the increasing demand for blood‐based biomarker discovery and validation. NULISA CNS Disease Panel 120 provides a powerful new research tool for the early detection and diagnosis of NDDs and developing novel therapeutic interventions.