bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protective mechanism of APOE3‐Christchurch in Alzheimer’s disease
Authors: Raulin Ana‐Caroline , Linares Cynthia , Alnobani Alla , Roy Bhaskar , Crow Ailsa , Doss Sydney V. , Kuchenbecker Lindsey A , Dacquel Maxwell V , Karch Celeste M. , Martens Yuka A , Liu Chia‐Chen , Bu Guojun , Kanekiyo Takahisa 
Published: January 2025

AbstractBackgroundHomozygosity for the rare APOE3‐Christchurch (APOE3Ch) variant, encoding for apoE3‐R136S (apoE3‐Ch), was linked to resistance against an aggressive form of familial Alzheimer’s disease (AD). Carrying two copies of APOE3Ch was sufficient to delay autosomal AD onset by 30 years. This remarkable protective effect makes it a strong candidate for uncovering new therapies against AD. Thus, we aim to explore the protective mechanisms of APOE3Ch against AD onset, to inform therapy.MethodsWe used both amyloid mouse models and human induced‐pluripotent stem cells (iPSC) models to address this aim. We examined whether astrocytic expression of apoE3‐Ch through an AAV‐mediated approach can mitigate AD‐related pathology and toxicity in early (3.5 months old) and late (8 months old) amyloid pathology in 5xFAD mice. We also used isogenic iPSC lines carrying the APOE3Ch variant that were generated from APOE3 parental lines using CRISPR/Cas9 technology. Biochemical and biophysical properties of both recombinant and native apoE3‐Ch lipoprotein particles secreted by iPSC‐derived astrocytes have been investigated using different techniques including heparin affinity chromatography and size‐exclusion chromatography.ResultsWe investigated the impact of astrocytic apoE3‐Ch on amyloid pathology and toxicity in 3.5‐month‐old and 8‐month‐old 5xFAD mice. We confirmed successful AAV‐mediated overexpression of apoE3 and apoE3‐Ch in astrocytes. We found apoE3‐Ch specific changes in protein levels and solubility. Astrocytic expression of apoE3‐Ch reduced soluble Aβ oligomer levels and ameliorated ER stress response compared to apoE3 in the 8‐month‐old 5xFAD mice. Furthermore, our findings showed altered biochemical properties of HEK cell‐derived apoE3‐Ch protein, including decreased heparin binding, altered receptor binding, and enhanced lipid accepting capacity. We also characterized APOE3Ch iPSC‐derived cell models, including iPSC‐derived astrocytes, neurons, and cerebral organoids, and found differences between APOE3 and APOE3Ch at the functional level in these iPSC models.ConclusionsThe proposed work and the developed methods to study apoE3‐Ch promises to provide new insights into the possible roles of this rare, mutated protein in protecting against AD, offering new therapeutic avenues for AD treatment.
Lower brain‐derived neurotrophic factor levels and hippocampal subfield volumes are associated with high diabetes risk in later life
Authors: Al‐Shaikh Jennifer Hanna , Ghosh‐Swaby Olivia R , Khan Ali R. , Thornton Jane , Bussey Timothy J , Saksida Lisa M , Liu‐Ambrose Teresa , Nagamatsu Lindsay S 
Published: January 2025

AbstractBackgroundOlder adults with type 2 diabetes (T2D) are more likely to develop Alzheimer’s disease (AD) due to impaired brain metabolism. Although the underlying mechanisms of this relationship are largely unknown, lower levels of brain‐derived neurotrophic factor (BDNF) –which promotes hippocampal neurogenesis in adulthood– and atrophy of the hippocampus are evident in patients with T2D and dementia, possibly linking the two conditions. The hippocampus is comprised of multiple subfields, each with their respective functions, cellular composition, and age‐related sensitivity. In particular, the dentate gyrus, known for its key role in memory processing, is one of the only regions in the brain capable of producing new neurons through BDNF. At the onset of dementia, the rapid loss of hippocampal tissue results in functional disconnection with other areas of the brain involved in cognition, making hippocampal atrophy a biomarker for cognitive decline. Understanding region‐specific hippocampal atrophy during the early stages of diabetes may provide insight into the link between T2D and brain atrophy that is characteristic of AD. Therefore, our study investigates the relationship between BDNF levels and hippocampal subfield volumes in older adults at risk for T2D.MethodSixty older adults (aged 60‐80 years, mean = 68.64, 72.34% female) at risk for diabetes completed demographic and medical history questionnaires. Diabetes risk was assessed using HbA1c, BMI, and a diabetes questionnaire. BDNF serum levels were analyzed from blood samples using an enzyme‐linked immunoassay test (ELISA). Anatomical T1 and T2 weighted brain images were collected via 3T MRI and analyzed using HippUnfold – a novel segmentation tool that accounts for individual variability in the folding patterns of hippocampal subregions.ResultPreliminary results show that higher diabetes risk was associated with lower BDNF levels and reduced hippocampal subfield volumes. In addition, BDNF serum levels were predictive of hippocampal subfield volumes, specifically in the dentate gyrus.ConclusionFindings demonstrate a relationship between diabetes risk factors, BDNF, and hippocampal subfield volumes (i.e., dentate gyrus) in regions where neurogenesis continues throughout adulthood. As life expectancy and diabetes incidence increases, our study urges the development and application of interventions aimed at preventing the progression of diabetes‐related neurodegeneration.
Implementation analysis of community‐based centers for people with dementia and their family caregivers in Chile
Authors: Gajardo Jean , Aubert Josefina , Moreno Ximena , Aravena Jose M , Carcamo Felipe , Abusleme Maria T , Barrientos Carolina , Mascayano Franco 
Published: January 2025

AbstractBackgroundCommunity‐based centers for people living with dementia (PLWD) have been implemented as part of the National Plan of dementia in Chile, delivering a multicomponent intervention to support PLWD and their families. There is limited knowledge on their implementation, and we had previously informed with respect to the implementation outcomes of the first center, called Kintun. This work offers an update on findings describing implementation outcomes of three more centers, with different implementation times and geographic locations in Chile.MethodWe conducted a realistic evaluation using multiple qualitative data collection strategies and diverse informants to analyze complex interventions considering 4 centers. For every center, key informants were identified at different levels (macro‐level of centralized policy, meso‐level of center coordinators and health service supervisors, and micro‐level of intervention deliverers and family caregivers) who participated in individual interviews or focus groups. Table 1 summarizes informants, data collection strategies, and implementation outcomes. Rapid qualitative analysis was used with predetermined codes describing implementation outcomes according to the Active Implementation Frameworks (Blanchard et al, 2017) and implementation outcomes by Proctor et al (2011).ResultAt a macro‐level of implementation, the centers have not experienced relevant transformations, but the lack of updated centralized technical orientations menace fidelity. At a meso and micro level, the centers have been adapted to improve sustainability and appropriateness, supporting their scalability. Differences in core components characterize a transition from adult day services to a multicomponent intervention, following a progressive interprofessional approach. Examples of implementation drivers were engagement with the local health network and and tailoring the intervention according to geographical and cultural context. Relevant implementation aspects of agreement and disagreement among actors were the appropriateness of the program and the program components, respectively.ConclusionMost relevant implementation drivers and adaptations to community centers for PLWD in Chile are identified at micro and meso levels, which stresses the need to define intervention components for standardization and monitoring, providing an implementation frame for new centers. Points of agreement and disagreement among the three levels are key for understanding priorities for improvement
Association of pulsatility of lenticulostriate arteries with cognitive decline in elderly adults: a 7T dual‐VENC PC‐MRI study
Authors: Tang Jianing , Zhao Tianrui , Joe Elizabeth B , Chui Helena C , Yan Lirong 
Published: January 2025

AbstractBackgroundCerebral small vessel disease (cSVD) is a major cause of vascular dementia. Mounting evidence suggests that cSVD pathology is closely linked to vascular dysfunction of lenticulostriate arteries (LSAs). Arterial pulsatility, quantified by pulsatility index (PI), has been used as an indicator of vascular dysfunction. With the advent of ultra‐high field 7T, the velocity and pulsatility of LSAs can be reliably measured. Directly assessing pulsatility of LSAs may offer valuable insight into pathophysiology of cSVD and cognitive impairment. This study aims to investigate relationship between LSA pulsatility and cognitive performance within an aged cohort.MethodTwenty‐five elderly participants (13 female: 71 ± 9.2 years) were enrolled in the study with written informed consent. Cognitive assessments were conducted including 19 participants undergoing the Mini‐Mental State Exam (MMSE) and 23 taking Montreal Cognitive Assessment (MoCA). High‐resolution phase‐contrast MRI (PC‐MRI) with dual‐VENC (Venc=20cm/s and 40cm/s) was performed on a Siemens 7T MRI scanner to image velocities of LSAs. PI was calculated by the difference between the peak systolic flow velocity and minimum diastolic flow velocity divided by the mean velocity throughout a cardiac cycle. Pearson correlation was used to evaluate the associations between LSA PI and age, education level, and cognitive measurements. A linear mixed‐effects model was used to test the association between LSA PI and cognitive measurements while correcting for the effects of age, gender, and education.ResultFlow velocity curves and PI values of LSAs were successfully extracted and calculated from all 25 participants. Figure 1 shows an example of LSA imaging using PC‐MRI and the acquired velocity curve of LSAs. LSA PI significantly increased with age and lower education levels (p=0.002, 0.03, respectively) (Figure 2). Increased PI was strongly associated with lower MMSE scores with and without corrections for age, gender, and educational level (p=0.048, 0.028) (Figure 3). A similar trend was observed between PI and MOCA scores, although there was no significance (p=0.31).ConclusionThis study has demonstrated that LSA pulsatility assessed by 7T high‐resolution PC‐MRI is strongly associated with aging, education, and cognitive performance. These findings suggest the dysfunction of LSA could contribute to the cSVD pathology and result in cognitive impairment.
Occipital amyloid‐β burden and clinical correlates in Lewy body disease
Authors: Vossler Hillary , Abdelnour Carla , Young Christina B. , Winer Joseph R. , Smith Alena , Smith Viktorija , Shahid Marian , Wilson Edward N. , Davidzon Guido A. , Mormino Elizabeth , Poston Kathleen L. 
Published: January 2025

AbstractBackgroundAccurate assessment of amyloid‐β burden in Lewy body disease (LBD) is crucial due to the frequent co‐occurrence of amyloidosis. Current amyloid‐β PET imaging protocols often overlook the occipital lobe, a relevant area in Lewy body disease (LBD). We aimed to determine whether regional amyloid‐β in LBD is associated with global cognition, daily functioning, and neuropsychological performance.MethodWe included 193 Stanford research participants: 78 Cognitively Normal (CN), 42 Alzheimer’s disease (AD), 38 LBD‐Cognitively Normal (LBD‐CN), and 35 LBD‐Cognitively Impaired (LBD‐CI) who underwent 18F‐Florbetaben PET imaging (Table). We calculated SUVRs for the frontal, cingulate, parietal, temporal, and occipital regions using the cerebellum as the reference region. We then used linear regression models adjusted for age, sex, and education to examine the association between regional amyloid‐β burden and global cognition (measured with MoCA), daily functioning (measured with CDR‐SB), and performance in memory, executive function, visuospatial function, and attention/working memory/processing speed (measured with composite scores).ResultIn the LBD‐CI group, amyloid‐β burden in all regions, except the cingulate, was associated with worse MoCA (β = ‐14.31 (SE = 3.59), p < 0.0001) (Figure) and CDR‐SB scores (β = 5.05 (SE = 1.71), p < 0.004). Similarly, amyloid‐β burden in the frontal (β = ‐1.27 (SE = 0.60), p < 0.05), cingulate (β = ‐1.24 (SE = 0.59), p < 0.05), parietal (β = ‐1.42 (SE = 0.62), p < 0.05), and temporal (β = ‐1.68 (SE = 0.70), p < 0.05) regions was associated with worse memory performance, whereas amyloid‐β burden in the occipital region (β = ‐1.76 (SE = 0.88), p < 0.05) was associated with worse executive function. However, only the association between occipital amyloid‐β burden and MoCA scores survived multiple comparison correction. In the LBD‐CN group, regional amyloid‐β burden showed no associations with clinical outcomes.ConclusionOur study suggests the potential significance of the occipital region in assessing amyloid‐β burden among individuals with cognitive impairment due to LBD, as it is associated with worse global cognition. Further validation studies should include the occipital region when calculating SUVRs should be considered in people with LBD.
Autoradiographic comparison of [11C]PiB and [18F]NAV4694 in post‐mortem human brain tissue
Authors: Aliaga Antonio , Therriault Joseph , Aliaga Arturo Aliaga , Socualaya Kely Monica Quispialaya , Soucy Jean‐Paul , Macedo Arthur C. , Carello‐Collar Giovanna , Bastiani Marco De , Rahmouni Nesrine , Pascoal Tharick A. , Zimmer Eduardo R. , Rosa‐Neto Pedro 
Published: January 2025

AbstractBackgroundTo evaluate the in vitro binding properties of [11C]PiB and [18F]NAV4694 head‐to‐head in post‐mortem human brain tissue.MethodAutoradiography was used to assess uptake of [11C]PiB and [18F]NAV4694 in control (CN) and Alzheimer’s disease (AD) autopsy‐confirmed brain tissues. The study focuses on the analysis of the prefrontal cortex, inferior parietal cortex, posterior cingulate cortex and hippocampus sections in 11 CN and 11 AD cases. The binding values of [11C]PIB and [18F]NAV4694 were calculated from regions of interest (ROIs) drawn manually in the mentioned sections. In addition, a histopathology study (CERAD) was performed in the posterior cingulate cortex section of 10 CN and 10 AD cases.ResultFor both radiotracers investigated, we observed significant differences between CN and AD tissues uptakes in the prefrontal cortex, inferior parietal cortex, posterior cingulate cortex and hippocampus. Higher binding was detected for [18]NAV4694 compared to [11C]PIB in AD prefrontal, inferior parietal, and posterior cingulate cortices, while binding in the hippocampus was comparable for both radioligands. A strong correlation between [18]NAV4694 and [11C]PIB was found in the prefrontal cortex (R=0.934, p<0.0001) and inferior parietal cortex (R=0.833, p<0.0001), and lower values were obtained in the posterior cingulate cortex (R=0.699, p=0.0003) and hippocampus (R=0.72, p=0.0002). The analysis of correlation between the binding of [11C]PIB and [18F]NAV4694 in the posterior cingulate cortex section and the CERAD histopathology scores revealed a higher concordance for [18F]NAV4694 (R=0.796) compared to [11C]PIB (R=0.485).ConclusionThis study reports the first head‐to‐head comparison of [11C]PIB and [18F]NAV4694 in postmortem human brain tissue. [11C]PIB and [18F]NAV4694 showed high binding to amyloid beta aggregates in post‐mortem human brain tissues by autoradiography. Our results suggest that NAV4694 may have a higher effect size when differentiating between individuals with and without AD.
Association of Epigenetic Aging with Plasma Biomarkers of Amyloid, Tau, Neurodegeneration and Neuroinflammation in Diverse Hispanic/Latino Adults
Authors: González Hector , Tarraf Wassim , Gonzalez Kevin A , Kuwayama Sayaka , Parada Humberto , Ramos Alberto R , Rundek Tatjana , Perreira Krista M , Levin Bonnie , Decarli Charles , Fornage Myriam 
Published: January 2025

AbstractBackgroundEpigenetic clocks are biomarkers of biological age based on DNA methylation (DNAm) patterns and are widely used as predictors of health and aging outcomes. Multiple epigenetic clocks have been developed and reflect different aspects of the multidimensional aging process, above and beyond chronological age. To date, no study has examined the relationship of epigenetic aging with circulating biomarkers of Alzheimer’s Disease (AD). We investigated the association of 6 epigenetic clocks with plasma glial fibrillary acidic protein (GFAP), amyloid beta 40 and 42, phosphorylated tau 181 (p‐tau181), and neurofilament light chain (NfL) in diverse Hispanic/Latino adults.MethodWe estimated PC‐based epigenetic age acceleration from 6 epigenetic clocks in 2662 Hispanic and Latino adults (mean age 64.1 years; 56% women) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) who had available blood DNAm and plasma biomarker data at visit 2. These included first generation clocks, Horvath1, Horvath2 (“skin‐blood”) and Hannum clocks; second generation PhenoAge and GrimAge; and third generation DunedinPACE. We used survey linear regression weighted least squares to estimate the association of each of these measures with each of the plasma biomarkers.ResultThere were varying strengths of association between the clocks and the plasma biomarkers. There were significant associations of faster acceleration in all epigenetic clocks with higher plasma levels of NfL. There were significant associations of faster acceleration in all epigenetic clocks except DunedinPACE with higher plasma levels of Abeta40 and Abeta42. Faster PhenoAge acceleration was associated with higher levels of all circulating biomarkers (Table).ConclusionEpigenetic age acceleration is associated with circulating biomarkers of amyloid, tau, neurodegeneration and neuroinflammation in diverse Hispanics/Latinos. The second‐generation clock PhenoAge, trained on nine clinical biomarkers and chronological age, showed consistent and strongest associations across all biomarkers, suggesting that it may be particularly relevant to predicting AD.
Serum Alpha‐Synuclein and Inflammatory Markers profile in an Egyptian Alzheimer’s and Parkinson’s Diseases patients: A Pilot Study
Authors: Heikal Shimaa Adel 
Published: January 2025

AbstractBackgroundAlzheimer’s and Parkinson's disease are the most common neurodegenerative diseases. In the current study, we explored the potential of blood‐based markers to differentiate Alzheimer's disease (AD) and Parkinson's disease (PD) from healthy controls using ELISA assays via measuring the serum level of α‐Syn and panels of inflammatory cytokines in the small pilot cohort of Egyptian volunteers. With the ongoing genetic studies, upcoming data suggest that it is not trivial to revisit the findings reported in specific populations to be tested in each ancestor of different genetic and environmental backgrounds.MethodA total of 42 participants were recruited from the Neurology department, Suhag University Hospital, including 18 AD cases, 9 PD cases, and 15 healthy controls. Clinical and demographic characteristics were well‐matched among the three groups.ResultThe current data is the first to provide evidence in an Egyptian cohort that aligns with earlier reports that serum level of α‐synuclein can be a specific marker for distinguishing PD patients from healthy individuals but not AD patients. Both AD and PD, however, exhibited shared neuroinflammatory profiles with elevated IL‐6 and decreased IL‐10, hinting at a common inflammatory component despite their distinct etiologies. While trends toward increased IL‐1β and TNF‐α were observed in AD, the lack of statistical significance suggests a more limited role in its pathogenesis or the need to expand the sample size.ConclusionThese findings, although promising and the first of a kind to be conducted in Egyptian patients, necessitate further investigation with larger sample sizes to solidify these markers' potential for diagnosis and fully unravel the specific roles of individual cytokines in each disease.
“I Find that the Music Really Do Help Them Calm Down”: Qualitative Interviews to Support the Development of a Music‐based Application to Improve Sleep Disturbances in Persons Living with Dementia
Authors: Petrovsky Darina , Sefcik Justine S. , Mobarki Abeer , Kolte Sharvari , Amponsah Abigail , Hodgson Nancy A , Wu Bei 
Published: January 2025

AbstractBackgroundMost persons living with dementia (PLWD) experience sleep disturbances at some point during their disease. Music interventions are promising to address sleep disturbances because long‐term memory for music remains relatively preserved in PLWD. The purpose of this study was to identify the prototype features of the mobile application, entitled, “Calming Music Personalized for Sleep Enhancement in PeRsons living with Dementia” (CoMPoSER) for use among PLWD and their caregivers by conducting the first round of qualitative interviews to co‐design the content, features, and layout of the application prototype.MethodIn the first step of the study (out of two), we conducted 13 virtual interviews with 20 stakeholders (seven PLWD and thirteen caregivers). Five interviews included dyads (n = 3) or triads (n = 2) of PLWD and their caregivers. We used the mHealth Usability framework for mobile applications (Tajudeen et al. 2022) to guide our directed content analysis. Based on this analysis approach, we present the findings under the framework’s constructs.ResultThe average participant age was 66.7 years old (SD: 17.2). Most were women (n = 14). Twelve identified themselves as White/Caucasian, six as Black/African American, and two as Asian. The participants shared with us that it was important to design a mobile application that is simplistic and easy to navigate. For example, too many song options may confuse PLWD. Participants also talked about what their preferences for soothing colors. We captured preferred styles of music that PLWD and caregivers enjoy listening to and the high potential usefulness of the mobile application. Moreover, individuals conveyed their varying levels of comfort with technology. Some expressed high comfort levels, while others outlined the specific assistance and help information needed to feel at ease using the application.ConclusionWe used information gathered in the first step of the study to inform the second‐round interview questions. PLWD and caregivers in this study were committed to the process of developing a music‐based application to improve sleep. Their insights on simplistic features, navigation, and colors of the potential application will inform the next round of interviews, after which the prototype of the mobile application will be developed.