bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biological Factors Influencing [18F]MK6240 and [18F]FTP Correlation in Target Regions
Authors: Tissot Cécile , Tsai Hsin‐Yeh , Therriault Joseph , Tudorascu Dana , Rahmouni Nesrine , Servaes Stijn , Stevenson Jenna , Lussier Firoza Z , Pezzoli Stefania , Ziontz Jacob , Gordon Brian A. , Pascual Belen , Lowe Val J. , Soleimani‐Meigooni David N. , Oh Hwamee , Klunk William E , Rosa‐Neto Pedro , Jagust William J. , Pascoal Tharick Ali , Baker Suzanne L. 
Published: January 2025

AbstractBackgroundThe association between [18F]Flortaucipir (FTP) and [18F]MK6240, two commonly used tau‐PET tracers in Alzheimer’s disease (AD), varies due to distinct binding properties and off‐target signal regions. Our study aims to elucidate the biological factors influencing this association and evaluate the applicability of a common equation across different on‐target regions.Method113 individuals from the HEAD dataset (11 young, 58 cognitively unimpaired elderly, and 44 cognitively impaired) underwent [18F]MK6240, [18F]FTP and Aß‐PET scans. Images were processed using the inferior cerebellar grey (CG) as the reference region, with subjects categorized by Aß status. Stepwise linear fitting identified off‐target (OFF) regions impacting tracer associations within the whole cortex, Braak and temporal‐meta regions of interest (ROIs). OFF regions included were a composite mask (pallidum, putamen, caudate ‐ PPC) to address collinearity in subcortical nuclei, as well as the region with the greatest partial volume effects (PVE) on the ROI (meninges, choroid plexus, and the hotspot medial to entorhinal cortices (EC)). Akaike information criteria (AIC) analyses tested linear models with various off‐target regions.ResultPPC and PVE regions influenced tracer association in on‐target regions. PPC binding is associated with age. PPC and meninges retention, along with Aß status interaction, demonstrated the best model fit for the whole cortex (Figure 1). Weighting factors derived from the whole cortex model were applied to Braak regions and temporal meta‐ROI. Braak III‐VI and temporal‐meta ROI showed optimal models including OFF regions and Aß status interaction (Figure 2). Forcing the whole equation gave optimal results. For Braak I (EC), adding the OFF covariates only was the best model. For Braak II (hippocampus), the best model included OFF regions and the interaction with Aß status (Figure 2). Forcing the whole cortex equation onto Braak I and Braak II yielded suboptimal fits.ConclusionHarmonizing tau‐PET tracers involves considering significant covariates. Integrating meningeal and age‐related off‐target regions enhances [18F]MK6240 and [18F]FTP association in on‐target regions, further improved by Aß status inclusion. While the whole cortex model may not suit early ROI, it proves effective for Braak III and beyond. Creating an equation for tracer translation necessitates incorporating meningeal and subnuclei off‐target retention.
Imaging the impact of early and late life risk factors on the brain: a comparison
Authors: Gordon Brian A. 
Published: January 2025

AbstractBackgroundAlzheimer disease (AD) is a chronic progressive neurodegenerative disorder that presents with cognitive dysfunction, memory loss, language difficulties, emotion dysregulation, and the eventual loss of motor function and death. Magnetic resonance imaging (MRI) shows early atrophy in the medial temporal lobes, which then spreads to the posterior temporal lobe, parietal lobe, and finally the frontal lobe with relative sparing of the sensorimotor cortex. Social disadvantage has been shown to have potentially additive impacts on aging trajectories. Over the first years of life the brain undergoes rapid expansion and maturation. Whereas sensory regions are relatively stable from birth, there is tremendous change in the temporal, parietal, and frontal regions which are responsible for higher order cognitive function. This change is paralleled by the development of motor, language, emotion regulation, and executive function. Early life events such as low birth weight, poverty, and adversity can impact neurodevelopment, including cortical expansion and connectivity. Given this mirroring between regional brain development and degeneration, researchers have hypothesized a “last in first out” mechanism underlying progressive neurodegeneration, but minimum direct comparisons have been performed. longitudinally studies older adults.MethodsThis work brings together unique cohorts spanning the two ends of the lifespan. The Early Life Adversity, Biological Embedding (eLABE) study scans infants scanned longitudinally between birth and age three years of age. The Charles F. and Joann Knight ADRC and ADNI longitudinal follow middle and older‐aged individuals. Structural change is estimated a unique multimodal surface matching (MSM) pipeline that estimates the deformation of pairwise cortical surfaces to estimate cortical expansion or atrophy over time. Analyses will include all children with longitudinal MRI data as well as longitudinal MRI data to characterize healthy aging, individuals who convert to AD, as well as longitudinal change in within individuals with an AD diagnosis.ResultsPreliminary results in each cohort (Figure 1) demonstrate highly similar spatial patterns between early life development and AD related cortical thinning.ConclusionsAlthough there has long been speculation that there is a reciprocity between regions that develop in childhood and those vulnerable to age and disease related decline, this work test this theory.
Increasing Amerindian diversity in AD genetics research, A Peruvian perspective
Authors: Cornejo‐Olivas Mario , Illanes‐Manrique Maryenela Z. 
Published: January 2025

AbstractAmerindian (AI) populations are substantially underrepresented in AD genetic studies. The Alzheimer’s Disease Sequencing Project (ADSP), a global genetic initiative established by the National Institute of Aging (NIA) is supporting regional initiatives in Latin America and its admixed population. Latin America is the largest recently admixed population, with variable Native American, European, and African ancestry proportions, as result of successive settlements and new massive migrations. The Native American population from Latin America are descendants of ancestral Asians who entered America through Beringia 15 000 years ago. By the 14‐15 th century the Native American population was about tens of millions with uneven distribution across the Americas. However, about 90% of the NA populated collapsed due to violence, famine, and infectious diseases. Consequently, the NA from Latin America exhibit lower genetic diversity with higher differences among countries. Peru is the fifth largest country of South America with a complex geography that comprise the Andes mountains, the Amazon jungle, and the Pacific coast. Peru is an emergent economy dealing with governance disparities, centralism in Lima, the capital city, with notable inequities in income distribution. The “modern mestizo “population in Peru concentrates a high proportion (˜70%) of NA ancestry, mostly derived from the ancient pre‐Inca and Inca civilizations. Over the past decade, both local and collaborative efforts, have been contributing to the AD genetic research in the Peruvian populations. A combination of regional research teams and multisource ascertainment approaches allowed the recruitment of 250 AD patients and 400 cognitively unimpaired controls from five different regions across Peru (source: PeADI initiative). The studies performed in the Peruvian cohort have been demonstrating the important role of the Amerindian ancestry in the genetic architecture of AD, including the estimation of APOE4 risk higher than non‐Hispanic Whites and Africans, and the recent identification a novel SORL1 variant in a Peruvian AD family. Despite these significant contributions, performing research in Latin American regions requires strong local brain health programs with community engaged approaches to prevent disparities and contributing to long‐term local capacity building.
Metabolic syndrome and risk of incident dementia in EPIC‐Norfolk: the role of age and exposure duration
Authors: Qureshi Danial , Luben Robert , Hayat Shabina , Talarico Robert , Allen Naomi , Kuzma Elzbieta , Littlejohns Thomas J 
Published: January 2025

AbstractBackgroundMetabolic syndrome (MetS) might be a modifiable risk factor for dementia. However, the impact of mid‐life versus late‐life MetS and the duration living with MetS on dementia risk remains underexplored. This study investigated whether the association between MetS and risk of dementia differs across mid‐life versus late‐life, and to explore how duration of MetS influences this risk.MethodWe conducted a prospective study using data from the European Prospective Investigation into Cancer—Norfolk (EPIC‐Norfolk). In full cohort analyses, we studied 20,150 dementia‐free adults aged ≥50 years who attended baseline assessments. Group‐based trajectory analysis was performed on 12,756 participants who attended ≥2 health assessments over 20 years. MetS was defined as the presence of ≥3 of the following: elevated waist‐circumference, triglycerides, blood‐pressure, HbA1c, or reduced HDL‐cholesterol. Incident all‐cause dementia was ascertained using hospital inpatient, death, and mental healthcare records.ResultThe mean (standard deviation [SD]) age of participants was 62.6 (7.5) years, and 54% were female. Over 25 years of follow‐up (mean 18.8 [SD 6.3]), 2,653 participants developed dementia. In the overall cohort (all ages: 50‐79 years), MetS was associated with an increased risk of dementia (Hazard‐Ratio [HR], 1.11, 95% Confidence‐Interval [CI]: 1.01‐1.21). Age‐specific analyses revealed that this risk only remained in those with late mid‐life MetS (age 60‐69: HR, 1.21, 95%CI: 1.05‐1.39) but not in early mid‐life (age 50‐59: HR, 1.12, 95%CI: 0.87‐1.43) or late‐life (age 70‐79: HR, 0.96, 95%CI: 0.81‐1.14). An increasing number of MetS components was also associated with heightened dementia risk, specifically in late mid‐life (P trend = 0.004). Those with a prolonged duration of MetS had a 26% increased risk of developing dementia (HR 1.26, 95%CI: 1.13‐1.40) when compared to those with consistently low MetS. No association was found for increasing MetS (HR, 1.01, 95%CI: 0.88‐1.17).ConclusionLate mid‐life MetS was associated with a significantly increased risk of developing dementia. A prolonged duration of living with MetS also elevated dementia risk. These findings provide insights regarding critical periods of dementia risk in the context of MetS, and highlight the importance of not only considering the presence/absence of MetS, but also exposure duration when devising dementia prevention strategies.
Late onset Alzheimer’s Disease mouse model with altered synaptic and behavior phenotypes
Authors: Seth Ankit , Miller Jacob Bradford , Rafiq Ashiq M. , Deak Ferenc 
Published: January 2025

AbstractBackgroundGenetically modified mouse models have provided a vital understanding of the Alzheimer’s disease (AD) mechanisms, but these models were generally focused on familial AD and do not recapitulate the late‐onset human AD pathophysiology. To circumvent the complications of existing AD mice models, we are investigating a novel non‐mutant humanized amyloid beta (Aβ) expressing mouse line that expresses the humanized mouse App gene within the Aβ peptide sequenceMethodThis study aims to investigate the learning and memory function in this novel human Aβ knock‐in (h‐Aβ KI) mice of different age and sex groups using behavioral tests, neuronal circuitry, and long‐term potentiation experiments.ResultBehavioral studies revealed age and sex specific phenotype: 12 and 18 months old female h‐Aβ KI mice demonstrated reduced locomotor and exploration activities along with pronounced deficits in the preference for social novelty. h‐Aβ KI mice also showed impaired spatial learning and memory in behavior tests as well as reduced synaptic plasticity in hippocampal CA1 and DG regions. Cultured h‐Aβ KI hippocampal neurons had significantly slower rate of synaptic vesicle release but no difference in average recycling pool sizes compared to wild‐type control neurons in fluorescent FM1‐43 assays. Live imaging of neurons loaded with FM2‐10 dye revealed differences in synaptic release dynamics of readily‐releasable pool between female and male h‐Aβ KI mice with sucrose stimulation. Immunohistology revealed no amyloid deposit at these age and needs further investigation at older ages of this animal model.ConclusionOur data demonstrate that expression of wild‐type human Aβ in mice is sufficient to drive synaptic and cognitive changes during aging without plaque deposition.
The Effects of Action Observation Training Combined With Occupation‐Based Intervention through Home Visits on Occupational Performance and Hand Function in Community‐Dwelling Patients with Stroke
Authors: Kim Jong‐Hyeon , Park Jin‐Hyuck 
Published: January 2025

AbstractBackgroundSince January 2023, South Korea has launched a pilot program of home‐based rehabilitation services for patients with acute and chronic conditions. However, research on the effectiveness of occupational therapy for homebound stroke patients, aimed at promoting independence and activity participation, is limited. Additionally, previous action observation training studies in home settings often overlooked clients' occupational priorities and meanings. Therefore, this study investigates the effect of combining action observation training with occupational therapy through home visits on occupational performance and hand function in community‐dwelling stroke patients.MethodIn this study, which employed a mixed methods research design, the quantitative component utilized a single‐subject ABA' design, complemented by qualitative narrative interviews. The intervention involved two stroke outpatients, who participated in ten sessions conducted five times a week over two weeks. Each session began with the participants watching edited videos on the researcher’s laptop for 10 minutes in a quiet room, followed by 50 minutes of self‐training using selected equipment and tools, while imitating the actions from the videos. Assessment tools included the Purdue Pegboard Test and Pinch Gauge for evaluating hand function, while occupational performance was measured using the COPM pre‐ and post‐intervention.ResultFirst, twol participants showed clinically significant improvements with a score increase of two or more points in occupational performance and satisfaction. Second, twol participants demonstrated an improvement in the assembly task of the Purdue pegboard test during the intervention phase compared to the baseline phase, but this improvement was not maintained during the follow‐up baseline phase. Third, in the Pinch gauge, two participants showed an improvement in the affected side from the baseline to the intervention phase, and this improvement was maintained until the follow‐up baseline phase. However, there were no significant changes observed in the unaffected side. Fourth, qualitative research findings revealed that the participants exhibited an improvement in occupational performance, occupational motivation, occupatioanl patterns, and self‐efficacy.ConclusionAction observation training combined with home‐based interventions can be easily implemented at home without significant effort from patients post‐discharge. Therefore, it offers an alternative method for occupational therapy services, serving as a preparatory step before engaging in occupational activities.
A Systematic Review of Interventions Targeting Social Isolation Among Middle‐Aged Adults
Authors: Shin Jiwon , Yang Hyun , Yun Sohyeon , Kim Inhye , An Hyunseo , Park Hae Yean 
Published: January 2025

AbstractBackgroundThis systematic review aims to examine recent interventions targeting social isolation among middle‐aged adults, identifying trends in intervention types and their effectiveness. It highlights the urgent need for establishing a foundation for social isolation research across all ages.MethodA comprehensive literature search was conducted using PubMed, EMBASE, and CINAHL databases from January 1, 2014, to January 1, 2024. The search focused on terms related to social isolation and intervention programs. Eight studies were included, primarily randomized controlled trials.ResultThe majority of interventions employed internet‐based methods, reflecting an adaptation to digital health trends. Interventions significantly reduced social isolation, particularly among female participants, and utilized various formats such as online interactions and group discussions. Notably, the use of the UCLA Loneliness Scale, Version 3 (UCLA‐LS‐3) was prevalent for measuring social isolation.ConclusionThe findings confirm the necessity for ongoing research into diverse and effective social isolation interventions. They serve as crucial evidence supporting the development of future interventions aimed at different age groups to combat social isolation effectively.
Mechanistic Disease Modeling to Inform Potential Strategies for Early Interventions with BACE inhibition
Authors: Stone Julie A , Robey Seth , Kennedy Matthew E. , Duffull Stephen 
Published: January 2025

AbstractBackgroundThe β‐secretase‐1 inhibitors (BACEi), including verubecestat, were extensively studied in prodromal to moderate AD and demonstrated early cognitive decline (negative effect) at doses achieving >50% inhibition of amyloid production. Questions remain as to whether BACEi may still have utility, if used earlier in disease and at lower levels of inhibition. A mechanistic model of the progression of Alzheimer’s disease was used to predict effects of alternative BACEi therapeutic approaches on disease progression.MethodThe mechanistic model could holistically describe the available clinical data including observational trials and interventional trials with BACE inhibitors, anti‐amyloid mAbs, and anti‐tau antisense oligonucleotides. Varying inhibition levels (15‐ 56%) were simulated to predict amyloid PET, CSF Aβ42, CSF and plasma p‐tau, tau PET response. Delay‐times to BRAAK3‐4 region tau PET SUVr of 1.44 (MK‐6240; or 1.2 FTP) were calculated from simulations of intervention relative to untreated. Simulations of Down’s Syndrome populations (represented by increased production rate of amyloid) tested the impact on the dose and timing of the intervention needed to achieve benefits.ResultSporadic AD simulations predicted that NFT progression could be delayed by decade(s) if started very early in disease (amyloid PET of 20‐50 centiloids) with moderate (33‐56%) levels of inhibition maintained for remainder of life. It’s unknown whether these inhibition levels have less cognitive decline than seen previously. Benefits were substantially reduced for later inventions (>60 centiloids), lower levels of inhibition or shorter durations of treatment (<10 years). Predicted biomarker timecourses suggested that separation from placebo within 4‐5 years would be demonstrable for CSF Aβ42 and amyloid PET, but p‐tau and tau PET alterations could take longer, especially for interventions starting at very low plaque loads. Limitations include the limited data from tau‐targeted approaches and on inhibition‐dependencies of the negative cognition effect, which create uncertainties in the predictions.ConclusionMechanistic model‐based simulations suggest that moderate level BACEi interventions very early in the process of amyloid plaque accumulations could lead to substantial delays in progression. The time to differentiation from untreated marker responses was long for tau‐based markers, suggesting that demonstration of effects during a typical trial timeline may be challenging.
Cortical hyperarousal during sleep in mice receiving BACE inhibitors may affect cognitive performance
Authors: Watkins Elyse A , Olker Christopher J , Lin Xuanyi , Song Eun Joo , Kim Sarah , Turek Fred W , Kennedy Matthew E. , Vitaterna Martha H , Vassar Robert J. 
Published: January 2025

AbstractBackgroundBACE inhibitors, while effective in lowering amyloid‐beta production, have been associated with mild cognitive worsening in clinical trials. Additional treatment‐related adverse events reported in multiple clinical trials were sleep disturbances and insomnia. The purpose of this study is to determine if sleep disturbances occur in mice receiving BACE inhibitor, if sleep disturbances correlate with cognitive impairment, and the mechanism by which this may occur.MethodAdult C57BL/6 mice were treated with high dose BACE inhibitor (Merck) or control chow for 12 weeks. At 12 weeks, mice were implanted with a head mount containing electrodes for EEG and EMG monitoring. Sleep was monitored for 48 hours continuously. Cognitive assessments including object location memory, Y‐maze, and Barnes maze were performed. 10 second sleep epochs were manually scored as “wake”, “REM”, and “non‐REM”, based on EEG and EMG, to then train an algorithm to detect and define all remaining epochs. Fast Fourier transforms were performed on all epochs to identify the relative delta, theta, alpha, sigma, beta, and gamma power.ResultMice receiving BACE inhibitor chow had altered sleep patterns. This was marked by fewer, longer REM bouts than control mice. Additionally, mice receiving BACE inhibitor had less slow wave non‐REM sleep, marked by a reduction in delta power. Conversely, mice had an increase in the higher frequency beta and gamma waves during non‐REM sleep, suggestive of cortical hyperarousal.ConclusionMice receiving BACE inhibitors for three months had impaired sleep. Longer REM bouts could point to the vivid dreams and disturbed sleep noted in humans. A reduction in the slow wave sleep indicates reduced restorative sleep, which could impair performance on cognitive tests by leading to lethargy and impaired memory consolidation. Furthermore, cortical hyperarousal during non‐REM sleep is prevalent in a number of disorders in humans, including insomnia, anxiety, and post traumatic stress disorder, which could help elucidate an underlying mechanism. This study has implications for the future of clinical trials, because there are commercially available drugs that could restore normal non‐REM sleep and potentially alleviate cognitive worsening.