bluuebunny/crossref_metadata_2025_split huggingface dataset:
Advancing the understanding of Aβ plaques through a systematic comparison of statistical methods applied to hyperspectral Raman data
Authors: Haessler Annika , Jung Nathalie , Windbergs Maike 
Published: December 2023

AbstractBackgroundWhile fluorescence microscopy is widely applied in Alzheimer’s disease (AD) research, spectroscopic imaging methods like Raman imaging have only emerged recently. As a label‐free, chemically selective method, Raman microscopy can complement established imaging approaches by providing data as hyperspectral images, containing information on the molecular structure, composition, and distribution within a sample. However, brain tissue is a challenging tissue to analyze, since spectral variations in the sample are extremely low. Thus, to analyze pathologic hallmarks such as beta‐amyloid (Aβ) plaques, including the surrounding tissue, a systematic approach to accessing hyperspectral images is needed and herein presented.MethodRegions of interest containing Aβ plaques in brain sections of 10 month old APP/PS1 (Amyloid‐Precursor‐Protein / Presenilin‐1) mice were imaged using a confocal Raman microscope (WITec GmbH, Ulm, Germany). The hyperspectral Raman data sets were processed using Project 4 software (WITec GmbH, Ulm, Germany), in‐house written Matlab scripts (The Mathworks, Inc., Natick, USA) and the Matlab‐integrated RamanLight App.ResultBy comparing univariate peak integration analysis and multivariate methods, such as hierarchical cluster analysis, spectral unmixing, and 2D correlation spectroscopy on the same hyperspectral Raman data set of an Aβ plaque and its surrounding tissue, the approaches could be systematically studied. pathological structures in the tissue can only be successfully differentiated, if multivariate methods (cluster analysis, spectral unmixing) are used. Nonetheless, univariate peak integration can provide basic spatial and compositional information on the tissue and the Aβ plaque. By applying 2D correlation spectroscopy, interfaces between the Aβ plaque and the surrounding tissue can be thoroughly analyzed.ConclusionIn this study, a hyperspectral Raman image of an Aβ plaque and the surrounding tissue has successfully been analyzed with diverse explorative statistical methods to access Therefore, this study paves the way for the application of label‐free techniques such as Raman imaging into AD research by serving as a guide for the systematic analysis of hyperspectral images of pathological structures.
Genes and Cognition, a recallable cohort to study Dementia/Alzheimer’s disease
Authors: Rahman Md Shafiqur , Hill Steven M , Tom Brian D M , Chinnery Patrick F , BioResource NIHR 
Published: December 2023

AbstractBackgroundDecades of research have not resulted in a cure for dementia/Alzheimer’s disease (AD). Most treatments have failed to benefit patients in clinical trials, potentially due to treatment being provided too late when brain damage is irreversible. There is an urgent need to understand the disease mechanism at the preclinical and prodromal stages of AD, which requires early identification of participants at risk of AD.MethodWe attempt to address this need by establishing an open cohort named Genes and Cognition (GC), nested within NIHR Bioresource (https://bioresource.nihr.ac.uk/) and comprising 21,051 healthy people aged 17‐85 who consented to be recalled for follow‐up studies. Participants took 11 cognitive tests (CTs) covering various domains of cognition. We examined the association between CT scores and demographic characteristics, explored phenotypic and genotypic correlations between CTs, and estimated SNP‐based heritability. In addition, AD polygenic risk (high vs low) was determined in 10,038 participants using 20 single nucleotide polymorphisms (SNPs) from Lambert et al. (PMID:24162737) to identify the earliest age with a noticeable score difference in CTs.ResultCT scores (higher score indicates poorer performance) were associated with age and gender differences were significant for each CT score. Significant linear trends were observed between CTs and educational attainment. Genetic correlations between tests were stronger than the phenotypic correlations. SNP‐heritability for CTs and general cognitive ability ranged from 8‐28%. We observed that three CTs (Reaction Time, Stroop Box, Stroop Ink) began deviating around age 55 between high (≥ 96th percentile) and low (≤ 95th percentile) AD polygenic risk groups, although not significant. Similar deviations in some CTs were observed among APOE E4 allele carriers compared to E3/E3 carriers. However, AD risk groups determined without including the APOE region indicated such deviation after age 65.ConclusionWe presented preliminary findings for the GC study cohort. Our results suggest that AD polygenic risk measured with or without APOE region may be less beneficial than the two APOE SNPs (rs429358 and rs7412) alone for the early identification of AD. Repeated CT measures would shed more light on this observation; therefore, we aim to investigate this with CTs repeated at two years intervals.
Psychometric analysis of validity, generalizability, and extrapolation inferences of Modified Mini Mental Status Examination (3MSE) scores in American Indian adults
Authors: Suchy‐Dicey Astrid M , Vo Thao , Oziel Kyra , King Roxanna , Buchwald Dedra , French Brian 
Published: December 2023

AbstractBackgroundThe Modified Mini‐Mental State Examination (3MSE) is a cognitive assessment tool covering multiple domains often used to screen for dementia. Psychometric studies have demonstrated consistent 3MSE test performance across multiple racial/ethnic populations, but American Indians have been underrepresented in clinical validity studies. Population‐based cohort data suggests relatively low score distributions in American Indians, emphasizing a critical need for formal psychometric assessments.MethodThe Strong Heart Study recruited 818 American Indians aged 65‐95 years from 3 states for cognitive examinations in 2010‐13; 403 survivors repeated exams in 2017‐19. Participants self‐reported age, sex, education, and bilingual ability; trained personnel administered the 3MSE. We conducted psychometric analyses to support validity inferences, including scoring using confirmatory factor analysis, generalizability with internal consistency‐reliability estimates, and extrapolation via multiple indicator multiple cause models for differential item functioning.ResultParticipants were mean 73 years (SD 5.9), 67.5% female, mean 12.6 years education, mean 3MSE score 88.4 (SD 9.7); at repeat examination (mean 6.7 years later) mean 3MSE score was 87.1 (9.5). For a scoring inference, factor analysis supported a 4‐factor/second‐order model (comparative fit index: 0.91). The four factors included verbal‐episodic memory (short, long recall; λ: 0.81‐0.82), language‐executive function (animal, command, naming, obey, repetition, similarities; λ: 0.40‐0.58), psychomotor‐working memory (reversal, writing; λ: 0.49‐0.65), and orientation‐visuoconstruction (orientation, pentagons, registration, spatial, temporal; λ: 0.11‐0.69). For generalizability, we detected acceptable internal consistency (>0.90 total score) and strong test‐retest reliability (Pearson’s r: 0.47‐0.78, all p<0.05). For extrapolation and group differences, overall test performance was strongly associated with age and education, but not sex; language use (bilingual) was significant and strongly associated with psychomotor‐working memory factor (β: 0.12‐0.40, p<0.05), but not with the language‐executive function factor (β: 0.01‐0.10).ConclusionOverall, these patterns of evidence support clinical interpretation of 3MSE scores among American Indian elders, with consideration of age and education and possibly also bilingual status or usual language use. Furthermore, these findings suggest that previously‐observed population differences in 3MSE score may result from unaddressed social determinants. Future research should address possible influence of socioeconomic, cultural, historical, or behavioral factors not currently addressed in neuropsychological practice.
Spatiotemporal characterization of tau pathology and dendritic atrophy in the human locus coeruleus
Authors: Adori Csaba 
Published: December 2023

AbstractBackgroundTau pathology of the noradrenergic locus coeruleus (LC) is a hallmark of several age‐related neurodegenerative disorders, including Alzheimer’s disease. However, comprehensive neuropathological examination of the LC is difficult due to its small size and rod‐like shape.MethodTo investigate the LC cytoarchitecture and tau cytoskeletal pathology in relation to possible propagation patterns of disease‐associated tau in a large‐scale and high resolution three‐dimensional view, we applied the state‐of‐the‐art volume immunostaining and optical clearing technology iDISCO+, combined with light sheet fluorescence microscopy. We examined AT8+ pathological tau in the LC/pericoerulear region of 20 brains from Braak neurofibrillary tangle (NFT) stage 0 to 6.ResultWe demonstrate a high morphological complexity of AT8+ cellular structures in the LC, representing various intracellular stages of NFT maturation and their diverse transition forms. We describe novel morphologies of neuronal tau pathology such as AT8+ cells with fine filamentous somatic protrusions or with disintegrating soma. We show that gradual dendritic atrophy is the first morphological sign of the degeneration of tangle‐bearing neurons. Irrespective of the Braak NFT stage, tau pathology is more advanced in the dorsal LC that preferentially projects to vulnerable forebrain regions in Alzheimer’s disease, like the hippocampus or neocortical areas. Moreover, already in the precortical Braak 0 stage, 3D analysis reveals clustering tendency and dendro‐dendritic close appositions of AT8+ LC neurons, AT8+ long axons of NFT‐bearing cells that join the ascending dorsal noradrenergic bundle after leaving the LC, as well as AT8+ processes of NFT‐bearing LC neurons that target the 4th ventricle wall.ConclusionOur study suggests that the unique cytoarchitecture, comprised of a densely packed and dendritically extensively interconnected neuronal network with long projections, makes the human LC to be an ideal anatomical template for early accumulation and trans‐neuronal spreading of hyperphosphorylated tau.
A new strategy for Alzheimer’s disease: low‐dose combination of radiotherapy and pharmacological epigenetic perturbation
Authors: Volmar Claude‐Henry , Ricciardi Natalie R , Modarresi Farzaneh , Lohse Ines , Andrade Nadja S , Newman Ian R , Brown Jonathan M , Borja Caroline , Marples Brian , Wahlestedt Claes 
Published: December 2023

AbstractBackgroundMost Alzheimer’s disease (AD) drug discovery studies focus exclusively on one specific target. This approach has to date shown limited success in AD, mainly because this complex disease is multifactorial and involves numerous pathways. In light of the large number of disappointing clinical trials, the National Institute on Aging (NIA) and the Alzheimer’s Association (AA) published, in 2018, new guidelines recommending focusing on biomarkers of the AD continuum. These guidelines advise targeting Amyloid‐β (A), neurofibrillary tangles (T) and neurodegeneration markers (N), designated “ATN”, to advance AD research. Using 2 different approaches, we have been able to both reverse and prevent ATN burden in mouse models of AD. Indeed, our group has previously demonstrated that histone deacetylase inhibition (HDACi) and cranial radiotherapy (RT) independently improve (AD)‐like pathogenesis in cell and animal models. In the present study, we investigate the synergistic potential of using both RT and HDACi as a low‐dose combination therapy (LDCT) to further improve molecular and behavioral AD‐like phenotypes in AD models.MethodLDCT consisted of daily administration of the HDAC3 inhibitor RGFP‐966 and/or bi‐weekly cranial x‐irradiation. Behavioral analyses, real‐time qPCR, NanoString technology, ELISAs and Western blots were used to assess the effects of RT, RGFP‐966 and LDCT on AD‐like pathogenesis in AD models. Additionally, innate immune response to LDCT was also assessed in vitro and in vivo using human and murine cell models and 3xTg‐AD mice.ResultLDCT induced a tolerant, anti‐inflammatory innate immune response in microglia and increased non‐amyloidogenic APP processing. Both RT and LDCT improved spatial learning and memory in the Barnes maze test. No sensorimotor deficits were observed. LDCT induced a unique anti‐AD gene expression profile in the brain, that included upregulation of neurotrophic genes and downregulation of inflammation‐related genes. Brain region specific observations included lowered Aβ42/40 ratio, decreased Bace1, and reduced p‐tau181 levels.ConclusionThis work shows that it is possible to attenuate AD‐related pathologies through the synergy of low doses of RT and HDACi treatment. This project supports a paradigm shift to a multipronged approach to AD therapeutics.
Dementia needs assessment in Latine communities: strengths, challenges and policy opportunities in Wisconsin, USA
Authors: Pinzon Maria C Mora , de Cordova Susie C Fernandez 
Published: December 2023

AbstractBackgroundLatinx populations are 1.5 times more likely to develop ADRD than non‐Latinx whites. Despite their heightened risk, they are more likely to be undiagnosed, under‐diagnosed and misdiagnosed. This is exacerbated by the lack of culturally appropriate information addressing ADRD to combat culturally specific stigma and misconceptions, as well as a dearth of culturally suitable resources. Infrastructure development that engages the community and community organizations can assist in overcoming these challenges by addressing community needs, capitalizing on existing resources, fostering sustainability, and promoting health equity.MethodUsing a modified version of the instruments included in the ACT on Alzheimer’s® Dementia Friendly Communities Toolkit, we evaluated the ADRD related needs and other social needs (e.g. transportation) that Latine communities experience in Madison, Wisconsin (USA). The instrument was distributed via email to community organizations and individuals serving Latine individuals in the area. Additionally, a community advisory group contributed to the identification of existing assets/priorities and strategic planning.ResultThe strengths identified for the community were: a sense of community that leads to individuals caring for one another and wanting to provide for one another’s needs, and the availability of a variety of community organizations and individuals who play a role in serving people living with dementia and their care partners. The absence of bilingual/bicultural resources to serve individuals was cited as the most significant challenge, followed by the lack of information regarding dementia, and the paucity of care options for those who are not eligible for Medicare or Social Security benefits. Table 1 reflects the most important services needed in the community. Reimbursement/Service fees (e.g., organizations use Medicare/Medicaid funding and do not have additional revenue sources to serve individuals without insurance), educational requirements for employees without a comparable requirement on language proficiency, and limited funding for multi‐language services were identified as pertinent policies.ConclusionCommunity members viewed dementia education and awareness of care services as crucial. Collaboration with current organizations to provide additional resources that enable them to implement culturally and linguistically appropriate processes for all is key to ensure the sustainability of future endeavors.
Exploring Culturally‐safe Dementia Care Policy in First Nation Community of the James and Hudson Bay Region in Northern Ontario, Canada
Authors: Shrestha Hom Lal , Shrestha Lucy 
Published: December 2023

AbstractBackgroundCulturally‐safe dementia care (CSDC) is new dynamic concept that empowers clinical and traditional health care practitioners to provide culturally respectful care for older adults with dementia. The World Health Organization’s (WHO) recognized diverse Indigenous local community partners, members and leaders as critical community stakeholders for dementia care and prevention worldwide in 2018. However, there is a critical lack of policy framework and evidence‐based research on CSDC globally. As dementia spreads as a global epidemic, the dementia prevalence among First Nations people over the age of 60 is expected to quadruple by 2031, compared to a 2.3‐fold increase among non‐First Nations people in Canada. The Mamow Ahyamowen Partners (2019) study found a higher dementia mortality rate of 7% in the James and Hudson Bay region of Northern Ontario between 1992 and 2014, compared to 23% in Ontario overall.MethodA qualitative research design is employed in conjunction with a community‐based participatory rural dementia action research approach to conduct four participatory Focus‐Group Discussions with physicians, nurses, caregivers, and community partners with 24 to 32 participants to explore the knowledge, experience, barriers and challenges to develop knowledge of CSDC policy. Thematic analysis and the Total Quality Framework will be used for quality rigour, and a two‐eyed seeing framework and explanatory dementia models will be applied in the perspectives and worldviews of the physician‐patient‐community to honour cultural care, diet, language, ethical and spiritual pathways.ResultThis research will lay foundation for policymakers to develop knowledge of CSDC policy, care plan and guidelines. This will guide the development of educational interventions and curricula and community support systems that are aimed at building and sustaining the capacity of healthcare professionals and community partners to begin integrated biomedical and Indigenous traditional dementia care practices.ConclusionThis research endeavours to equip physicians, nurses, allied health care workers, community partners (Elders, knowledge‐holders and traditional healers) and the community support systems to initiate CSDC on a global scale to implement the WHO Global Action Plan on the Public Health Response to Dementia (2017‐2025). Inclusion of Indigenous community partners as community stakeholder are underpinning to bridge the dementia equity gap.
Rat Model of Aerodigestive Dysfunction in Alzheimer’s Disease
Authors: Rowe Linda M , Russell John A , Connor Nadine P 
Published: December 2023

AbstractBackgroundOral nutrition and aspiration pneumonia are significant factors impacting survival in patients with Alzheimer’s disease and related dementias (ADRD). Patients with ADRD demonstrate impairments to critical aerodigestive functions, including: prolonged oral phase durations, impaired masticatory performance, and prolonged swallow apnea durations. However, the pathophysiology underlying these functional changes is poorly understood. Establishing a translational model of swallowing dysfunction in ADRD will be critical for identifying underlying mechanisms of aerodigestive dysfunction and optimizing clinical treatments.MethodsAdult male TgF344‐AD rats (n = 6) and wild type rats (WT; n = 6) underwent videofluoroscopy (60 fps) to assess swallowing kinematics at 12 months of age. Jaw movement, bolus position, and diaphragm movement (proxy for respiration) were analyzed off‐line. All rats underwent a hypoglossal nerve electrical stimulation protocol, with the protruded tongue attached via small suture to a force transducer. All rats were stimulated maximally at a range of frequencies from 1 Hz – 140 Hz.ResultsThe AD group had significantly slower mastication rates (p = .037) and prolonged swallow apnea durations (p = .017) compared to WT. The AD group produced significantly lower forces at 60 Hz (p<.001) and 80 Hz (p<.001), indicating a higher frequency of nerve stimulation was required to elicit a given force of isometric tongue muscle contraction.ConclusionThe TgF344‐AD rat demonstrates functional mastication and swallowing decline consistent with clinical findings in patients with ADRD, with concomitant alterations in tongue muscle contractile properties and can serve as a valuable tool for interrogating biological and physiological mechanisms of aerodigestive dysfunction.
Factors influencing choice and ability to age in place: A qualitative study with patients, caregivers, and clinicians
Authors: Auriemma Catherine L , Silvestri Jasmine , Butt Maayra , McMillan Julia , Turner Dania , Klaiman Tamar , Harkins Kristin , Karlawish Jason , Halpern Scott D 
Published: December 2023

AbstractBackground“Aging in place” (AIP), the ability to remain in one’s home with age, has broad appeal to policy makers and professionals providing services to adults with serious illness. AIP is viewed as both an intervention for people with dementia (PWD) and as a desirable outcome. However, it’s not clear that AIP is always associated with sustained quality of life, and in some circumstances, may hinder it. As clinical and policy efforts increase to promote AIP for PWD, it is imperative to understand how AIP aligns with patient and family values and what factors influence choice and ability to remain in one’s home.MethodIn this qualitative study, we explored stakeholders’ perspectives on what makes a “good day” for a PWD and their family caregivers and decision making around AIP. We conducted semi‐structured interviews among PWD or cognitive impairment, family caregivers of PWD or cognitive impairment, and clinicians who care for PWD. Participants were purposively sampled to enroll individuals with a range of dementia severity, professional expertise, and demographic characteristics. All interviews were audio‐recorded and transcribed. De‐identified transcripts were reviewed by the research team independently and during weekly consensus meetings to identify relevant themes. Sample size was determined by reaching thematic saturation within each stakeholder sub‐group.ResultWe conducted 70 interviews among 13 patients, 33 caregivers, and 24 clinicians (Table 1). Caregiver burden, caregiver guilt, patient independence, patient safety, perceptions of care facilities, and financial consideration were all themes that influence whether a person can and will AIP (Table 2). Among patient‐caregiver dyads who wished to prioritize AIP, a change in the patient’s living situation was only pursued if and when a “breaking point” was reached by the caregiver. Themes were organized in a conceptual model as patient, caregiver, or systems factors (Figure).ConclusionNumerous factors influence the ability and choice of PWD and their family caregivers to AIP and likely impact the quality of life of patient and family caregivers as dementia progresses. Any program seeking to enhance AIP must take these factors into account. Furthermore, measuring success of AIP will need outcome measures that better capture these dimensions.