bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relational, Community Dementia Care for All: Observations and Lessons from On‐Reservation Providers, Administrators, and Formal Caregivers in the US and Canada
Authors: Ketcher Dana , Jacklin Kristen , Warry Wayne , Lewis Jordan P. , Blind Melissa J , Dertinger Melinda , Arredondo Brandylyn , Pederson Collette , Johnson January , Trudeau Rhonda , Pitawanakwat Karen , Strong Lois , Summers Marlene , Martin Wesley , Lambrou Nickolas H. , Zuelsdorff Megan , Gleason Carey E. 
Published: December 2023

AbstractBackgroundResearch with Indigenous populations in North America has consistently demonstrated divergent views on caregiving for people living with dementia (PLWD) compared to Western biomedical approaches. Few studies to date have applied strengths‐based approaches and, as a result, an Indigenous caregiving framework appropriate for on‐reserve/reservation populations has yet to be created. In this paper we share research findings that can be used to initiate strategies for culturally appropriate, sustainable, and supported care strategies for Indigenous PLWD.MethodWe used a community‐based participatory approach to conduct ethnographic research in a culturally safe way among four Indigenous communities in the US and Canada. Community‐based researchers conducted key informant interviews with dementia administrators and providers (n = 35), and sequential focus groups with local health care staff/formal caregivers that work with Indigenous older adults (14 sessions, n = 17). Data were coded in QSR NVivo and analyzed using a phenomenological framework.ResultParticipants described numerous assets available to Indigenous communities that can help PLWD age in place, based in a wholistic orientation. Main qualitative themes emerging from the analysis include: the need for wholistic models of care; the value and importance of family caregiving; the role of social/community support; the value of caring for the PLWD in the home for as long as possible; and the need for community services to support caregivers. Indigenous values, past experiences with health systems/colonization, and lived experiences of dementia were important underlying factors informing an Indigenous caregiving framework appropriate for on‐reserve/reservation populations.ConclusionWestern models of caregiving for PLWD, especially the eventual placement of PLWD in care facilities, do not fit with Indigenous value systems and teachings. Relational, family, and community‐based care is a culturally appropriate form of care for most elders in Indigenous communities. This model will be most effective when culturally appropriate community support services such as personal support and home care nursing services, as well as adequate respite, are included. Further research with family caregivers and PLWD will be necessary to further our understanding of this Indigenous care model and together with this study will form the basis for a community‐based caregiving intervention.
Screening tyrosine kinases for their involvement in synaptotoxicity induced by tau microtubule‐binding region fibrils
Authors: Hodonou Kelly , Siedlecki‐Wullich Dolores , Vreulx Anais‐Camille , Lambert Jean‐Charles , Kilinc Devrim 
Published: December 2023

AbstractBackgroundSynapse loss is an early event in Alzheimer’s disease (AD); yet, mechanisms of synaptotoxicity induced by amyloid‐β and tau –hallmarks of AD pathology– remain unclear. We have recently developed a lab‐on‐a‐chip device that fluidically isolates synapses of primary neurons from their cell bodies, thereby enabling us to exclusively access synaptic, as well as pre‐ and postsynaptic compartments. Our aim is to identify molecular mechanisms of synaptotoxicity related to AD.MethodUsing the said in vitro model, we assessed the impact of exogenously applied monomeric and fibrillar forms of tau microtubule‐binding region (tau‐MTBR), as well as of full‐length tau isoforms, on synaptic connectivity, quantified through distance‐based assignment of postsynaptic puncta to presynaptic puncta. After confirming that the fibrillar form of tau‐MTBR induces a detrimental effect on mature synapses, we conducted a medium‐throughput compound screening, in which we tested small molecule inhibitors of 25 tyrosine kinases for their capacity to block tau‐MTBR‐induced synaptotoxicity.ResultFive compounds that protected synapses from the detrimental effect of tau‐MTBR were considered potentially protective. Dose‐response analysis conducted on these five compounds highlighted FIIN‐2, a highly specific inhibitor of FGF receptor (FGFR) family. We are currently validating this finding with an alternative compound against FGFR and assessing whether tau interacts with cell surface FGFR. In parallel, we are functionally validating the observed toxic and protective effects using electrophysiological recordings in microfluidic devices integrated with microelectrode arrays.ConclusionDeciphering downstream signaling mechanisms in tau‐induced synaptotoxicity will improve our understanding of AD pathophysiology and allow us to identify potential therapeutic targets.
Clinical Trial Targets Miss the Mark for Endophenotypes Associated with Elevated Disease Risk Metrics
Authors: Cary Gregory A. , Wiley Jesse C , Greenwood Anna K , Carter Gregory W , Center The Emory‐Sage‐SGC TREAT‐AD 
Published: December 2023

AbstractBackgroundMost of the candidate disease modifying agents in clinical trials for Alzheimer’s Disease (AD) have been unsuccessful in providing significant relief to patients. While there are myriad possible reasons for the poor success rate of these trials, one potential explanation is that the targeted proteins and pathways are not the causal mechanisms of disease. The TREAT‐AD Consortium has recently developed tools to score the entire genome across several dimensions of disease risk, as well as organize genes into AD relevant biological domains of gene function. In this work we examine the historical data of AD clinical trials through the lens of AD risk and biological domains.MethodClinical trial data was obtained from the OpenTargets and clinicaltrials.gov platforms. For the target(s) identified for each trialed agent, we obtained the TREAT‐AD Target Risk Scores (TRS) and AD biological domain annotations. The results of gene ontology (GO) term over‐representation tests for the 253 genes targeted by agents in clinical trials were compared to the results from the top scoring genes ranked by the TRS.ResultWe find that genes targeted by agents that have entered phase IV trials tend to have a higher genetics risk score compared with genes targeted by therapeutic agents that are earlier in the clinical trial pipeline (i.e. phase I‐III). There is a mismatch between the biological domain annotations of genes targeted by clinical trials and those with the top TRS. Genes targeted by clinical trials tend to have a relatively higher fraction of annotations and are strongly enriched for terms in the Synapse, Vasculature, and APP Metabolism biological domains. Genes with elevated measures of disease risk tend to have relatively higher fraction of annotations and term enrichments in the Mitochondrial Metabolism, Proteostasis, and Endolysosome biological domains.ConclusionWe find evidence of mismatches between the biological domains that are elevated for AD risk and those that are targeted by therapeutic agents in clinical trials. Our unbiased, genome‐scale analysis suggests that therapeutic development efforts should increase focus on the intersections of Mitochondrial Metabolism and Proteostasis, and Endolysosomal function.
Health‐related quality of life in full spectrum of Alzheimer’s disease: a longitudinal analysis
Authors: Aye Sandar , Bouteloup Vincent , Jean Delphine , Jönsson Linus 
Published: December 2023

AbstractBackgroundUnderstanding the health‐related quality of life (HR‐QoL) in subjective cognitive decline (SCD), mild cognitive impairment (MCI) and demented patients is essential from the health economic perspective for evaluating new disease‐modifying treatments and preventive interventions. This study aims to assess HR‐QoL and the factors associated with longitudinal change in HR‐QoL in the full spectrum of Alzheimer’s disease.MethodLongitudinal data from 918 SCD and 1,346 MCI patients from the MEMENTO cohort were included in the study. MCI was defined as performing one standard deviation (SD) worse than the age, sex and education‐level thresholds in one or more cognitive domains identified within six months of the study enrollment. SCD was defined as having isolated subjective cognitive complaints but without any objective cognitive deficit and aged 60 years or older. HR‐QoL was measured by EuroQol EQ‐5D‐3L patient‐reported version. Linear mixed‐effect models with disease stage as a time‐varying covariate were used to (1) assess the utility changes over time across the dementia spectrum and (2) compare the utility changes between amyloid positive and negative SCD and MCI patients.ResultAt baseline, mean utilities were 0.84 ± 0.16 and 0.81 ± 0.18 in SCD and MCI patients. Linear mixed effect models estimated that the utilities were ‐0.016 (SE 0.003), ‐0.07 (SE 0.009), ‐0.18 (SE 0.014) and ‐0.36 (SE 0.034) lower than SCD in patients with MCI, mild, moderate and severe dementia over the study period. Time is associated with a significant decrease in utility with ‐0.008 (SE 0.001) per year. Baseline age, BMI, female, diabetes, cardiovascular history, neuropsychiatric symptoms and inability to perform Instrumental activity of daily living (IADL) were negatively associated with utilities. Amyloid‐positive SCD patients showed a faster decline in utility than amyloid‐negative SCD patients (p < 0.05). The decrease was not statistically significant in amyloid‐positive MCI patients compared to amyloid‐negative MCI.ConclusionHealth utilities decrease over time in all stages of dementia, and the decline is steeper in moderate and severe stages. Positive amyloid accelerates health utility decline in SCD but not MCI individuals. The ability to perform IADL is the major factor affecting HR‐QoL in all phases of dementia.
Chronic nSMase2 Inhibition Suppresses Neuronal Exosome Spreading In Vivo & Induces Sex‐Specific Attenuation of AD Pathology in APPNL‐F/NL‐F Knock‐In Mice
Authors: Mowry Francesca , Jin Shijie , Quadri Zainuddin , Bieberich Erhard , Yang Yongjie , Yang Yongjie 
Published: December 2023

AbstractBackgroundAltered ceramide metabolism is implicated in Alzheimer’s disease (AD) progression. Although prior work shows that inhibition of neutral sphingomyelinase (nSMase) 2, a key enzyme responsible for hydrolysis of sphingomyelin to ceramide, reduces exosome secretion, attenuates Aβ pathology, and improves cognitive function, these studies have been limited to in vitro application or short‐term treatments in fast‐progressing models.MethodWe employed the slow‐progressing APPNL‐F/NL‐F knock‐in (APP KI) AD mouse model and cell type‐specific exosome reporter CD63‐GFPf/f mice to investigate the impact of chronic long‐term nSmase2 inhibition on in vivo neuron‐derived exosome dynamics, region‐specific Aβ plaque load, and cognitive function. Male and female APPNL‐F/NL‐F‐CD63‐GFPf/+ (APP KI‐CD63) mice were treated daily with the nSmase2 inhibitor, GW4869 (GW; 1.25mg/kg BW; i.p.), or vehicle (VEH, DMSO in saline), from 8 months old (mo.) to 13mo. and from 10 mo. to 18mo. We also analyzed ceramide levels in both APP KI and WT mice. Brain‐derived exosomes of 14mo. APP KI females versus males and age‐ and sex‐matched WT mice were also isolated and quantified.ResultWe found significant elevations in multiple ceramide species from somatosensory cortex (SC) samples of 14mo. APP KI mice compared to age‐ and sex‐matched WT controls. We also found a sex‐specific increase in total exosomes in 14mo. APP KI females versus males that was absent in WT mice. Chronic inhibition of nSMase2 by GW4869 leads to significantly suppression of neuronal exosome spreading. Non‐linear regression analyses of size distribution curves showed consistent shifts to smaller plaque sizes in GW‐treated APP KI females, which were accompanied by decreased plaque numbers in each region examined. Conversely, plaque load was largely unaffected by GW treatment in APP KI males. T maze trials to examine spatial working memory revealed a female‐specific reduction in spontaneous alternation rate in APP KI vs. WT mice, which was significantly reversed with GW treatment.ConclusionOur results demonstrate that chronic nSMase2 inhibition suppresses neuronal exosome spreading in APPNL‐F/NL‐F knock‐in mice and preferentially attenuates Aβ pathology and cognitive dysfunction in females, pointing to a strong contribution of sex‐specific alterations in ceramide metabolism and exosome dynamics to the progression of AD‐like pathology in this model.
Impact of Low‐value Medications in Dementia on Patient‐reported Health‐related Quality of Life, Hospitalizations, and Direct Health Care Costs
Authors: Platen Moritz , Flessa Steffen , Teipel Stefan , Raedke Anika , Scharf Annelie , Mohr Wiebke , Buchholz Maresa , Hoffmann Wolfgang , Michalowsky Bernhard 
Published: December 2023

AbstractBackgroundPersons living with dementia (PwD) are commonly affected by low‐value medications (Lvm), i.e., medications unlikely to benefit patients but to cause harm. Lvm in PwD have been associated with negative physical, psychological, and financial outcomes. However, longitudinal effects have not yet been evaluated. Therefore, we aimed to analyze the impact of Lvm on patient‐centered outcomes among PwD over 24 months.MethodThis longitudinal analysis was based on 352 community‐dwelling PwD. Data were assessed at baseline and after 12 and 24 months. Medications that were explicitly not recommended were used to identify Lvm dichotomously (yes/no) and cumulatively (once, over one or two years). The 12‐Item Short‐Form Health Survey assessed patients' health‐related quality of life (HRQoL). Hospitalizations were assessed retrospectively for 12 months. Health care costs were monetarized by standardized unit costs. Multiple panel‐specific regression models were applied to analyze the impact of Lvm on HRQoL, hospitalizations and costs.ResultOver 24 months, 182 PwD (52%) received Lvm at least once and 56 (16%) continuously. The Lvm prevalence decreased from 36% (CI95% 30.8% – 40.8%) at baseline to 29% (CI95% 24.2% – 33.7%) two years later. Treating PwD with Lvm significantly increased the risk of hospitalization by 58% (CI95% 1.14 OR – 2.19 OR; p = 0.006), increased health care costs by €5,359 (CI95% ‐790€ – 11,508€; p = 0.088), and reduced patients' HRQoL (b = ‐1.81; CI95% ‐3.00 – ‐0.63; p = 0.003). HRQoL declined more strongly the longer that Lvm was received, whereas hospitalizations and health care costs were substantially affected by short‐term Lvm use, indicated by an increased hospitalization risk due to receiving Lvm over one year of 178% (CI95% 1.32 OR – 5.86 OR; p = 0.007) and costs for receiving Lvm once of €8,939 (CI95% €‐590€ – €18,469; p = 0.066).ConclusionMore than every second PwD received Lvm once, up to 12 months or continuously over 24 months, negatively impacting patient‐reported HRQoL, hospitalizations, and costs. While continuous Lvm intake decreased patients' HRQoL, receiving Lvm in the short term was relevant regarding further increases in hospitalizations and costs. Innovative approaches are needed to encourage prescribers to avoid and replace Lvm in dementia care.
Perceptions about Dementia Clinical Trials
Authors: Leggins Brandon , Jackson Ashley , Hart Danielle M , Windon Charles , Levenson Robert W , Merrilees Jennifer , Chiong Winston 
Published: December 2023

AbstractBackgroundThe research community has historically failed to enroll diverse populations in dementia clinical trials. A unique aspect of dementia care research is the requirement of a study partner, who can attest to the care recipient’s clinical and functional capacity. The aim of this study is to assess racial and ethnic differences and the importance of various trial considerations, among dementia caregivers, in their decision to participate in clinical research as study partners.MethodWe embedded a vignette about a hypothetical dementia clinical trial in a nationally representative survey of dementia caregivers, oversampling Black non‐Hispanic and Hispanic caregivers. They were asked about their willingness to participate in the trial with their care recipient, and rated the importance of nine considerations in hypothetical decisions to participate. Caregiver demographic characteristics, care recipient characteristics, and relational characteristics were analyzed as predictors of trial participation in a demographic model. In a second model, caregiver demographic characteristics and the rated importance of the nine considerations were separately analyzed as predictors; both models used survey‐weighted logistic regression.ResultThe sample consisted of 610 caregivers, including 156 Black non‐Hispanic and 122 Hispanic participants. In the demographic model, hypothetical trial participation was negatively associated with caregiver age [OR (odds ratio) = 0.46, P = <0.001], and with care recipient male gender [OR = 0.34, P = 0.007]. In the second model, responsibility to help others by participating in research was significantly associated with participation [OR = 1.56, P = 0.049], while the possibility of the care recipient experiencing serious side effects was negatively associated with participation [OR = 0.51, P = 0.003]. In both models there was no significant difference in hypothetical participation between non‐Hispanic Black and non‐Hispanic White caregivers, or between Hispanic and non‐Hispanic White caregivers.ConclusionHispanic and non‐Hispanic Black dementia caregivers were not less likely than non‐Hispanic White dementia caregivers to participate in a hypothetical dementia clinical trial. Our study suggests that failures to recruit diverse populations in dementia clinical research are not attributable to less willingness among members of underrepresented groups, but may instead reflect structural barriers and historic exclusion from trial participation.
PROGNOSTIC VALUE OF AT(N) CLASSIFICATION IN CSF USING CLUSTERING ANALYSIS
Authors: Gil‐Moreno María José , Hernández‐Lorenzo Laura , Ortega‐Madueño Isabel , Cruz Cárdenas‐Fernández María , Díez‐Cirarda María , Delgado‐Álvarez Alfonso , Palacios‐Sarmiento Marta , Matias‐Guiu Jorge , Corrochano‐Sánchez Silvia , Ayala José Luis , Matias‐Guiu Jordi 
Published: December 2023

AbstractBackgroundThe biological definition of Alzheimer’s disease (AD) and the use of biomarkers according to the AT(N) system may improve the clinical characterization of patients and the sequence of events during the clinical course. However, some studies have raised challenges in the clinical application of AT(N) system. Unbiased, data‐driven techniques such as unsupervised machine learning may help optimize it. We aimed to optimize the classification using unsupervised machine learning algorithms (clustering analysis).MethodWe included 421 patients from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort and 165 from our centre. We included subjective memory complaints (SMC), early mild cognitive impairment due to AD (EMCI), late MCI due to AD (LMCI) and MCI without evidence of neurodegeneration (MCI‐NN) patients according to clinical manifestations, neuropsychological test and CSF biomarkers from our center and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. We clustered the biomarkers separately and all together using the KMeans algorithm for each cohort and compared them in terms of diagnosis, AT(N) system, biomarker values distribution, and risk of progression to dementia.ResultThe optimal number of clusters for all the biomarkers together was three. These clusters differed significantly in both cohorts according to diagnosis, AT(N) categories, biomarker values distribution, and progression to dementia. We found amyloid biomarkers to be more dichotomic, while Tau biomarkers were more continuous. Intergroup comparisons revealed the following groups: 1) non‐defined or unrelated to AD subjects, with no risk of progression to dementia; 2) early stages and/or more delayed risk of conversion to dementia subjects, and 3) more severe cognitive impairment subjects within the early stages of AD and with faster progression to dementia. Findings were largely similar between the two cohorts.ConclusionThis new 3‐group classification, developed with a data‐driven approach, represents a novel perspective to assess the risk of conversion to dementia in a much more simplified way and is complementary to the AT(N) system classification
Alzheimer’s polygenic risk score is associated with Dementia and memory phenotypes in Down syndrome
Authors: Gorijala Priyanka , Aslam Muhammad Muaaz , Dang Lam‐Ha , Fernandez Victoria , Sung Yun Ju , Fan Kang‐Hsien , Feingold Eleanor , Kamboh M. Ilyas , Lee Joseph H. , Cruchaga Carlos 
Published: December 2023

AbstractBackgroundDown syndrome (DS) is a complex neurological disorder manifested by triplication of chromosome 21, which includes the amyloid precursor protein (APP) gene. Triplication of APP which is known for the buildup of Amyloid Beta plaques, a hallmark of Alzheimer’s disease (AD) pathology. Although researchers have studied genetic factors of AD risk in DS, the overall genetic contribution of AD in DS is still not clear. While the polygenic risk score (PRS) explains the overall genetic architecture and overlap between complex traits, no study has used PRS to understand the relative burden of AD risk variants in DS.MethodsWe constructed PRS using Bellenguez et al (2022) summary statistics for five different cohorts: DS (n = 282), sporadic early‐onset (sEOAD, n = 395), sporadic late‐onset (sLOAD, n = 2259), familiar early‐onset (fEOAD, n = 196), familial late‐onset (fLOAD, n = 1413). Unrelated European ancestry samples were selected for analysis (4,545 cases, 2,890 controls). To understand AD risk beyond APOE, PRS including and excluding APOE region was calculated using PRSiceV2.3. Chromosome 21 was excluded from the analysis. We tested the association of PRS with clinical status in each cohort and compared it between cohorts. We further tested association of neuropsychological batteries for cognition/memory, and cerebrospinal fluid (CSF) biomarkers with the AD PRS for DS individuals.ResultsThe PRS of AD was associated with sEOAD, fLOAD and sLOAD, but not with fEOAD. DS status was significantly associated with the AD PRS including APOE (OR = 0.62, P = 1.86×10−3). Down Syndrome Mental Status Examination (DSMSE) memory score was associated with AD PRS regardless of APOE inclusion (P = 8.61×10−4 with APOE, and P = 4.94×10−2 without APOE). In addition, DSMSE total score (P = 4.53×10−3), Dementia Questionnaire for People with Learning Disabilities (DLD) cognitive score (P = 1.46×10−2), CSF Aβ40 (P = 1.28×10−2), and Aβ42 (P = 4.21×10−2) were associated with the AD PRS including APOE.ConclusionsOur study suggests that even if DS individuals were depleted with AD risk variants, the overall genetic architecture for AD is still associated with cognitive and memory phenotypes, as well as AD biomarkers. This suggests that AD risk modulates APP metabolism/Aβ formation and tau protein binding, thus playing a role in the onset and progression of dementia in DS.