bluuebunny/crossref_metadata_2025_split huggingface dataset:
Developing the 4R model for care delivery, coordination, and patient and their care partners self‐management for suspected or diagnosed Alzheimer’s disease and related dementias
Authors: Weldon Christine B , Zwerling Jessica , Martin Joanna , Wolf Michael S , Rapkin Bruce , Nair Kavita V , Phillips Kathryn A , Epperly Mikele , Yagnik Supriya Kumar , Trosman Julia R 
Published: December 2023

AbstractThe incidence of Alzheimer’s disease and related dementias (ADRD) is on the rise, but diagnoses are frequently delayed, and treatment options are limited. Nevertheless, systematic care protocols and plans of action for patients and their care partners (partners) are widely thought to enhance patient outcomes, facilitate patients/partners' sense of control and optimize patients’ quality of life. However, in ADRD, these approaches are lacking or limited in their ability to facilitate care or enable patient/partner self‐management. We explored whether the 4R model, previously tested in oncology, could address these gaps in ADRD (4R = Right Information/Care/Patient/Time).The 4R model is a novel approach and set of clinician‐ and patient‐facing tools for care planning and delivery, which addresses challenges to appropriate timing and sequencing of complex care and patient self‐management. 4R demonstrated significant improvement in patient self‐management and timing/sequence of care delivery in cancer (Trosman, JCOOP 2021). Under 4R, patients/partners and care teams use a novel plan of action called Care Sequence® that systematically guides them through care.Herein, we developed the scope of comprehensive ADRD care based on guidelines, literature and expert input (Figure‐1); compared relevant aspects of ADRD and advanced cancer to understand whether and how previous 4R work may apply (Table‐1); and conducted interviewed experts in ADRD to identify relevant gaps and implications to a potential use of the 4R model in ADRD (Table‐2).Our findings indicate that adapted to ADRD, the 4R model has the potential to improve the timeliness of diagnosis, care initiation and subsequent care, as well as care coordination and patient/partner self‐management. The 4R model may give providers a concrete template‐based care plan for communicating with other specialties and with patients/partners. A concrete plan of action may remove the barrier of providers’ hesitancy to engage in screening and diagnosis of ADRD with their patients. 4R may also help patients/partners to seek help with potential cognitive issues through a concrete plan of action, restoring the sense of control and improving their ability to self‐manage aspects of the care process. Our next step is a U.S.‐based project to design and evaluate the 4R model ADRD, starting with Alzheimer’s.
Examining sex differences in Alzheimer Disease neuropathology in Down Syndrome
Authors: Head Elizabeth 
Published: December 2023

AbstractBackgroundPeople with Down syndrome (DS) have a higher risk of developing Alzheimer disease (AD), due to an extra copy of the amyloid precursor protein (APP) gene on chromosome 21. Overexpression of APP is associated with increased production of amyloid beta (Aβ) in DS, and contributes to early onset of AD. Some studies suggest women with DS are at a higher risk for AD, while others find the opposite. Sex differences may be mediated by estrogen, which is critically involved in neuronal survival and modulation. We hypothesized that lower levels of ERα protein would correlate with increasing AD pathology in DS.MethodWe examined 35 brains (frontal and occipital cortices) of people with DS and DS with AD. Serial sections were immunostained for phosphorylated tau (pTau ‐AT8) and Aβ (6E10) along with ERα and quantified using QuPath. Spearman rank correlations using log transformed % load data were calculated, Kruskal‐Wallis was used to compare men and women.ResultNo significant differences in protein levels of ERα, Aβ, or tau were observed when comparing men and women with DS. However, we found higher levels of ERα protein were associated with higher levels of Aβ in the gray matter of the occipital cortex (R = 0.7078; p = 0.0005) in all cases. This positive correlation was driven primarily by women. Females with DS showed a significant positive association with Aβ and ERα (R = 0.93; p = 0.00012) whereas men showed a weaker trend (R = 0.62; p = 0.057). In contrast, no significant associations between ERα, Aβ or pTau were observed in the frontal cortex. PTau measures in the occipital cortex in women with DS were positively associated with ERα (R = 0.61; p = 0.055), whereas men with DS showed a slight negative, though not significant association (R = ‐0.29; p = 0.41). There was no such trend in the frontal cortex.ConclusionThese results suggest ERα, in contrast to our original hypothesis, may be increasing in response to AD pathology to preserve neuronal health in the occipital cortex. Lack of similar positive associations in the frontal cortex may be related to AD progression, with the occipital cortex being affected later in disease, giving us the opportunity to observe increased ERα.
Female TgF344‐AD hippocampal plasticity after estrogen deprivation
Authors: Rae Rosaria Josephine , Smith Lindsey , Goodman Anthoni , McMahon Lori L 
Published: December 2023

AbstractBackgroundAlzheimer’s Disease (AD) is the seventh leading cause of death worldwide, disproportionately affecting women, with two‐thirds of individuals with AD being female. A decrease in circulating ovarian estrogen during menopause is believed to be a contributing factor to this discrepancy in disease prevalence. AD pathology is known to impact synaptic transmission in the hippocampus, resulting in memory deficits, a hallmark symptom of AD. This study investigates the effect of estrogen deprivation in the dentate gyrus (DG) and CA1 region, areas affected early on in the disease and crucial for memory. As the disease progresses, deficits are seen in the dentate gyrus prior to CA1 region supporting the anatomical spread of the pathology.MethodSynaptic signaling was assessed in DG and CA1 hippocampal subregions of 9 month old TgF344‐AD female rats who underwent long‐term (from ages 3 to 9 months) ovarian hormone deprivation. Extracellular dendritic field potential recordings were conducted in the DG by stimulating the medial perforant path onto dentate granule cells, and in the CA1 region by stimulating Schaffer collateral axons. Input/output relationship, paired pulse ratio, and long term potentiation were assessed, analyzed, and statistically compared between TgF344‐AD rats and non‐transgenic hormone deprived littermates.ResultIt was found that AD females were able to maintain synaptic transmission as there were no significant differences found in the input/output relationship, paired pulse ratio, or long term potentiation between AD animals and their controls.ConclusionThese results show that at this early stage in the disease, ovarian estrogen deprivation does not accelerate synaptic impairment. These results also suggest the possibility that a compensatory mechanism exists at these synapses to maintain function.
A Pragmatic Pilot Phase Preliminary Results of Daily Engagement in Meaningful Activity Professional Program for home care patients with subjective cognitive decline
Authors: Lu Yvonne YF 
Published: December 2023

AbstractBackgroundA substantial number of home health older patients with subjective cognitive decline (SCD) require more time, structure, and guidance to complete tasks and adjust to new skills and environments, thereby presenting complex demands on home health services and caregivers. Without support, patients with SCD often lose their sense of control, have fewer personal choices, disengage from meaningful activities, and have less confidence in their ability to manage daily challenges and other chronic illness issues. Our multi‐component intervention titled, Daily Engagement in Meaningful Activities Professional (DEMA‐Pro) intervention was developed based on five preliminary studies shown to improve health outcomes and promote confidence in managing daily challenges in patients with SCD. The objectives of pragmatic pilot phase study were to 1) evaluate the feasibility and benefits of a DEMA‐Pro for patients with SCD; 2) explore nurses’ experience of DEMA‐Pro implementation.MethodWe used a one‐group, pre‐ and post‐intervention design and recruited 49 patients with SCD, aged 50+, from the four home healthcare sites to receive six weekly DEMA‐Pro telephone sessions. The Outcome and Assessment Information Set D (OASIS‐D) were collected at starting date (pre‐intervention) and discharge date (post‐intervention). Quantitative surveys and qualitative focus group methods were used to explore the DEMA‐Pro nurses (n = 3) experiences of implementation.ResultThe consent rate was 67.1%, the completed intervention rate 36.7%, and the partial completed intervention rate 25.5%. For 36 subjects with discharge data available, both IADLs and self‐care scores improved (d = 3.11 and d = 2.66, respectively). Specifically, those that completed all 6 DEMA‐Pro sessions (n = 14), partial completers (n = 12), and non‐completers (n = 10), had improved scores on IADLs (d = 4.0, 4.2, and 2.5, respectively) and Self‐Care (d = 3.7, 3.1 and 2.0, respectively). Completers had greater improvement than non‐Completers for both outcomes and greater improvement on IADLs than partial completers (all p‐values < 0.03). Nurses reported high satisfaction with their training, and high confidence that the implementation of the intervention met patient and caregiver needs.ConclusionThe DEMA‐Pro has shown benefits and feasibility that will need further testing in a large pragmatic trial in homecare settings.
Immunomodulating mechanisms of human neural stem cell transplantation in a transgenic Alzheimer’s disease mouse model
Authors: Chen Kevin S , McGinley Lisa M , Noureldein Mohamed , Hayes John M , Rigan Diana M , Kwentus Jacquelin F , Mason Shayna N , Mendelson Faye E , Savelieff Masha G , Feldman Eva L 
Published: December 2023

AbstractBackgroundMany pathways are implicated in pathogenesis of Alzheimer’s disease (AD). Stem cells are a promising strategy to simultaneously correct multiple pathways; however, therapeutic mechanisms of stem cells are not well described. Here, we used spatial transcriptomics to quantitate gene expression following intracranial transplantation of human neural stem cells (hNSCs) in a mouse model of AD.MethodThe 5XFAD mouse model was utilized. An hNSC cell line (HK532‐IGF1, Palisade Bio) was transplanted into fimbria fornix of the hippocampus (6 total injections, 180,000‐600,000 total cells). Spatial memory was assessed by Morris water maze. Amyloid plaques were assessed by immunofluorescence and ELISA. Hemibrains were submitted for spatial transcriptomics (Visium 10X, 10X Genomics) and significant differentially expressed genes (DEGs) were identified (p < 0.05). Pathway enrichment was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG), and CellChat network analysis examined communication between cell populations.ResulthNSC transplantation restored learning curves of 5XFAD mice in Morris water maze, mimicking wild‐type performance (Fig 1A). However, there were no changes in amyloid‐beta burden (Fig 1B‐C). Spatial transcriptomics elucidated non‐amyloid hNSC therapeutic mechanisms. In hippocampal subregions, we discovered 1061 normalized DEGs. KEGG pathway analysis revealed significant impact on protein processing (“ubiquitin mediated proteolysis”, “protein export”, and “proteosome”), “long‐term potentiation,” and “metabolic pathways” (Fig 2). Plaque induced genes were normalized upon hNSC transplantation, particularly in microglia (Fig 3A). A reduction in stage 1 and stage 2 disease associated microglia (DAM) was seen, without affecting homeostatic microglia (Fig 3B). CellChat analysis showed hNSCs interacted with stage 1 and stage 2 DAM along many pathways (Fig 3C). Pathologic signaling between hippocampus and DAM upregulated in the 5XFAD model was again normalized upon hNSC transplantation.ConclusionTransplantation of hNSCs rescued memory in 5XFAD mice. No change in amyloid plaque burden was noted, but spatial transcriptomics revealed many genes dysregulated in 5XFAD that were normalized with hNSC transplantation. hNSCs interacted with and normalized populations of stage 1 and stage 2 DAM. Our results suggest that hNSCs exert beneficial effects in part by modulating microglia‐mediated neuroinflammation in AD.
Longitudinal sleep instability predicts cognitive decline and is associated with increased MRI‐visible perivascular space burden
Authors: Keil Samantha A , Schindler Abigail G , Piantino Juan , Lim Miranda , Willis Sherry L , Iliff Jeffrey J 
Published: December 2023

AbstractBackgroundAlthough emerging data suggest a direct link between sleep duration, aging, and cognitive performance, the impact of longitudinal sleep patterns have on Alzheimer’s disease‐associated pathology and cognitive decline remains unclear.MethodUtilizing longitudinal data on self‐reported sleep duration collected within the Seattle Longitudinal Study, we used a Cox proportional hazard (CPH) regression to evaluate the relationship between longitudinal sleep factors on the development of cognitive decline. Additional analysis in a sub‐cohort utilized multivariate linear regression prediction analyses to evaluate the predictive value of these longitudinal sleep factors on the incidence of developing cognitive impairment over an interval of 10 years.A cohort within the study received MRI and FLAIR neuroimaging, enabling the assessment of the impact these longitudinal sleep factors have on subcortical white matter MRI‐visible perivascular space burden (PVS). A semi‐automated segmentation algorithm accounted for PVS total burden and volume, as well as average PVS width, length, and median volume across participants, blinded by group.ResultCPH analysis found years of education (HR 1.12, 95% CI 1.02, 1.22), APOE4 status (HR 2.18, 95% CI 1.37, 3.49), higher depression scores (HR 1.08, 95% CI 1.04, 1.13), short sleep phenotype (HR 1.78, 95% CI 1.03, 3.08) and increased sleep variability (HR 3.10, 95% CI 1.66, 5.80) were significantly associated with cognitive impairment. Further, when including these factors into our linear regression prediction analyses, age (p<0.0001), depression (p = 0.01) and sleep variability (p = 0.042) were significant predictors of cognitive impairment over a 10‐year period.Preliminary analysis showed significant association between high sleep variability and increased whole‐brain PVS volume (p = 0.04) and length (p = 0.03), with a significant correlation between sleep variability and median PVS volume (p = 0.04). Follow‐up analysis evaluated PVS features within the wider cohort.ConclusionThese findings suggest that variability in longitudinal self‐reported sleep duration exerts a previously unappreciated influence on downstream cognitive performance and pathological processes, potentially including glymphatic dysfunction. These findings elaborate the link between sleep instability, aging, cognitive decline and neuropathologic disease state. Future studies should evaluate these findings on an independent cohort to assess whether sleep variability of different time scales (weeks, years, decades) exerts similar effects on these outcomes.
A comparative study of Amyloid positive and negative individuals with “Alzheimer Syndrome”
Authors: Lahiri Durjoy , Roncero Carlos Tyler , Lima Bruna Seixas , Verhoeff Nicolaas Paul L.G. , Freedman Morris , Al‐Shamaa Sarmad , Chertkow Howard 
Published: December 2023

AbstractBackgroundOutside academic centres, the diagnosis of probable Alzheimer’s Disease remains a clinical diagnosis supported by basic blood work and structural brain imaging. It has already been documented, approximately 1/3rd of individuals meeting clinical criteria for probable AD, do not show underlying amyloidopathy on PET or cerebrospinal fluid. Thus, the clinical “Alzheimer Syndrome” encompasses individuals with abnormal amyloid (Amyloid positive: A+), as well as “amyloid negative” individuals lacking amyloidopathy. Finding ways to distinguish these subgroups clinically will become increasingly important as anti‐amyloid therapies become more available. It is not yet clear if these two groups have any clinical or imaging features that might distinguish them. Our objective was to find out if there are any clinical or imaging pointers towards amyloid biomarker status.MethodsA retrospective chart review of 23 patients screened for anti‐amyloid clinical trials was performed, of whom 13 were (A+) and 10 were (A‐). The following information was collected from the chart review‐ demography, medical history, clinical presentation, course of disease and rate of progression, neuropsychological test scores, blood work, brain scans, and any other relevant investigations. Relevant data were subjected to appropriate statistical analysis.ResultsThis is an ongoing study and the results are derived from interim analysis. Comparison of the (A+) and (A‐) groups revealed no statistically significant difference in terms of age, sex, amnestic presentation and cognitive decline rate. We did not find evidence (in this small group) that (A‐) subjects had a greater vascular load ‐ no difference in Hachinski score or Fazekas score. The only statistically significant difference between the groups was found in their NPI scores, with the A+ group showing a higher score (2.92 versus 0.80, p = 0.008).ConclusionAmyloid positive individuals are more likely to have neuropsychiatric manifestations during the course of their cognitive decline than their Amyloid negative counterpart. Work is ongoing to delineate biological and biomarker differences that account for the cortical dementia (Alzheimer Syndrome) in Amyloid negative subjects. Delineating differences in clinical presentation may prove useful in specifying which of these individuals are actually Amyloid positive. Confirmation in a larger group of subjects will be necessary.
Mitochondria in Memory Retrieval in Wild‐Type Mice and in the Impairment of Memory Retrieval in Amyloid Precursor Protein Transgenic Mice
Authors: Beglopoulos Vassilios 
Published: December 2023

AbstractBackgroundTreatment of Alzheimer’s disease (AD) would benefit from earlier diagnosis and a better understanding of the biochemical and cellular events underlying memory loss. This study, which follows our previous work identifying early deficits in long‐term memory retrieval and memory‐associated glucose uptake in amyloid precursor protein transgenic (APPtg) mice, aims to a) test our hypothesis of stimulus‐dependent synaptic mitochondrial activity as a mechanism underlying memory retrieval, and b) investigate any mitochondrial abnormalities possibly associated with the impairment of memory retrieval in APPtg mice (and possibly in presymptomatic AD).MethodThe J20 APPtg mouse line has been used. Two genotypes (APPtg and wild‐type) and two behavioral groups have been analysed, a) a group subject to criterion‐based watermaze training, sacrificed 20 sec following a probe trial seven days after learning the task (the memory retrieval group), and b) a group with no behavioral training (the basal levels group). Synaptosome forebrain samples (enriched in synapses) from 16 mice (four mice from each of the genotype/behavioral combinations) have been subjected to proteomics, Western blot and electron microscopy analyses. Oxygen consumption and enzymatic activity assay analyses are ongoing.ResultOur previous behavioral result of significantly impaired 7‐day memory retrieval has been reproduced. Our proteomics analysis has suggested higher synaptic levels of mitochondrial proteins during memory retrieval, compared to basal levels in wild‐type mice, a phenotype also present but less evident in APPtg mice. Western analysis has indicated lower synaptic levels of proteins involved in mitochondrial fusion and fission during memory retrieval, compared to basal levels. No difference was identified by electron microscopy in a) numbers of synaptic mitochondria or b) synaptic mitochondrial area. Our oxygen consumption and enzymatic activity assay results are planned to be collected on time for this presentation.ConclusionOur data provide evidence supporting our hypothesis of mitochondrial involvement a) in memory retrieval and b) in the impairment of memory retrieval in APPtg mice and possibly in early AD. They also provide some clues on the exact mitochondrial mechanisms, which is the focus of our current research.
Novel metabolic biomarkers for diagnosis of Alzheimer’s disease
Authors: Zhao Yingxin , Villasante‐Tezanos Alejandro , Miranda Ernesto , Pappolla Miguel A , Fang Xiang 
Published: December 2023

AbstractBackgroundThe need for biomarkers for the etiological identification of dementia syndromes can not be overemphasized. Blood metabolites are attractive targets for identifying biomarkers with predictive values for AD diagnosis and progression. This study aims to identify novel AD blood metabolic biomarkers and develop a high‐sensitivity and specificity blood‐based test for AD.MethodIn the discovery phase, the serum metabolome of AD patients (n = 10) and age, sex‐matched healthy controls (n = 10) were analyzed with a mass spectrometry (MS)‐based approach. Supervised machine learning was used to identify the biomarker candidates and develop a computational model for AD diagnosis. Finally, the computational model and biomarker candidates were verified with a second AD cohort in the verification phase, where the serum metabolome of AD patients (n = 27) and age, sex‐matched healthy controls (n = 30) were analyzed.ResultIn this discovery study, 7075 metabolic features were quantified. Among them, the abundance of 750 unique features significantly differed between AD and Controls (t‐test p‐value <0.05). Support vector machine (SVM) with radial basis function (RBF) kernel was used for features optimization and identified a panel of 14 metabolic features which predicted AD with 0.0% classification error rate (4‐fold cross‐validation). In the verification study, 10595 metabolic features were quantified. Among them, 908 unique features significantly differed between AD and Controls (t‐test with Permutation q‐value <0.05). Then, the computational model and biomarker panel identified in the discovery phase were tested with the verification dataset and confirmed that they could predict AD with high accuracy (0.0% classification error rate, 4‐fold cross‐validation).ConclusionThis study comprehensively profiled the AD serum metabolome and identified a panel of metabolic biomarkers and a computational model for AD diagnosis, which will serve as a foundation for a high‐performance, blood‐based test for clinical AD screening and diagnosis.