bluuebunny/crossref_metadata_2025_split huggingface dataset:
Racial and Ethnic Differences in Hospice Use and End‐of‐life Hospitalizations among Medicare Beneficiaries with Dementia
Authors: Lin Pei‐Jung , Zhu Yingying , Olchanski Natalia , Cohen Joshua T , Neumann Peter J , Faul Jessica D , Fillit Howard M , Freund Karen M 
Published: December 2022

AbstractBackgroundThe pool of studies examining ethnoracial differences in hospice use and end‐of‐life hospitalizations among patients with dementia is limited and results are conflicting. This study examined how dementia end‐of‐life care utilization and patient treatment preferences differ by race and ethnicity.MethodsUsing U.S. national survey data from the Health and Retirement Study linked with Medicare and Medicaid claims, our sample included 5,058 beneficiaries aged ≥65 years diagnosed with dementia who died in 2000‐2016. We examined the frequency and costs of hospice care, emergency department (ED) visits, and hospitalizations during the last 180 days of life among Medicare decedents with dementia. We analyzed the proportion of dementia decedents with advance care planning and their end‐of‐life care preferences.ResultsLess than half of beneficiaries with dementia in our sample (48%) used hospice in the last 180 days of life; of these, one in three hospice users received the service for seven days or less. In adjusted analysis, non‐Hispanic (NH) Blacks, nursing home residents, and survey respondents represented by a proxy were less likely to use hospice, whereas older age, females, higher education, more severe cognitive impairment, and more IADL limitations were associated with higher hospice enrollment. Among dementia decedents, NH Blacks and Hispanics used more ED and inpatient services and incurred >50% higher inpatient expenditures at the end of life, compared with NH whites. More NH Black and Hispanic beneficiaries with dementia enrolled in hospice were subsequently admitted to the ED or hospital before death. The proportion of dementia beneficiaries completing advance care planning was significantly lower among NH Blacks and Hispanics compared with NH whites (21% and 21% vs. 57%, p<0.01). More NH Black and Hispanic decedents with dementia had written instructions choosing all care possible to prolong life, whereas more NH whites preferred to limit care in certain situations, withhold treatments, and forgo extensive life‐prolonging measures.ConclusionOur results highlighted substantial unmet end‐of‐life care needs among older adults with dementia, especially among NH Blacks and Hispanics. Medicare should consider alternative payment models to promote culturally competent end‐of‐life care and reduce low‐value interventions and costs among the population with dementia.
INSPIRATION: results of a cross‐sectional AD risk‐profiling study
Authors: Zeyen Philip , Sannemann Lena , Escher Claus , Müller Theresa , Bohr Lara , Snijders Katharina Elisabeth , Rostamzadeh Ayda , Jessen Frank 
Published: December 2022

AbstractBackgroundPrevious studies indicate that 30% to 40% of all Alzheimer’s disease (AD) cases are attributable to modifiable risk factors. In addition to cardiovascular risk factors also stress and sleep disturbances have been identified as risk factors (Escher et al. 2019; Sindi et al. 2018). Here, we report results from the cross‐sectional Individual risk profiling for Alzheimer’s disease and dementia prevention (INSPIRATION) study and provide a detailed overview on the frequency and distribution of AD risk factors.MethodThe cross‐sectional assessment of healthy study participants (aged 50 or older) included established and self‐developed questionnaires and physical examination. We inquired about demographics, medical history, family history, physical activity, diet, BMI, hearing loss, presence of depression, anxiety, stress, resilience, and loneliness. In addition, we performed neuropsychological testing (CERAD+) and blood sampling for genetic testing.ResultResults in 162 participants showed a mean age of 64.6 years (50‐86 years), mean education years of 16.3 (10‐20) and a mean MMST score of 29.5 (26‐30). Moreover, 63% were female, 49% were retired, 51% were part‐ or full‐time employed and 70% had at least one relative with dementia.The four most frequent lifestyle risk factors were non‐adherence to Mediterranean diet in 69% of subjects, obesity in 49% with a mean BMI of 25.8 kg/m2 (16.1‐41.6kg/m2sleep disturbances in 52% and reduced resilience in 23% of the subjects. Concerning pre‐existing diagnoses known to increase AD risk, the four most frequent were hypercholesterinemia (50%), a thyroid disease (36%), hypertension (34%) and vitamin deficiency (33%).A preliminary analysis of ApoE ε4 status for n = 123 participants revealed that 32.5% were heterozygotes; the remaining 67.5% were non‐carriers. The full set of assessed risk factors will be presented.ConclusionThe results of the INSPIRATION study aid to understand the prevalence and distribution of a large number of modifiable AD risk factors in a community‐dwelling sample. The data will be used to develop a tool box of interventions for personalized strategies to prevent AD in a population which is particularly interested in dementia prevention.
Estimating the association between parity and mid‐ to later‐life cognitive function in rural South Africa: Evidence from “Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa” (HAALSI)
Authors: Phillips Meredith L , Kobayashi Lindsay C , Chakraborty Rishika , Kabudula Chodziwadziwa , Harezlak Jaroslaw , Ludema Christina , Rosenberg Molly 
Published: December 2022

AbstractBackgroundThe burden of cognitive decline is projected to rise over the next decades, particularly in low‐ and middle‐income countries, contributing to economic hardship, morbidity, and mortality. Reproductive life‐history, including parity, may be associated with later‐life cognitive ability. Using data from the population‐representative “Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa” (HAALSI) cohort, we estimated the association between parity and mid‐ to later‐life global cognitive function.MethodData were from in‐person interviews with 2242 men and 2604 women aged ≥40 in the rural Agincourt sub‐district, Mpumalanga province, South Africa in 2014/15. Cognitive function was assessed as time orientation and immediate and delayed recall of a 10‐word list. Number of living children was self‐reported. We used multivariable linear regression with parity (number of children: 0, 1‐2, 3‐4, 5‐9, 10+) as the categorical predictor and z‐standardized cognitive function as the outcome. Analyses were stratified by sex/gender, controlling for age, education, and literacy.ResultAmong men, there was a U‐shaped relationship between parity and cognitive function (p<0.001), whereby men with 3‐4 children had the highest mean z‐standardized cognitive scores (mean: 0.244, SD: 0.984, Table 1, Figure 1). Women also had a U‐shaped relationship between parity and cognitive function (p = 0.0254), whereby women with 5‐9 children had the highest mean z‐standardized cognitive scores (mean: ‐0.017, SD: 0.935, Table 2, Figure 1). Among men, adjusted regression models showed that parity was associated with higher cognitive function, across all categories compared to no children (Estimates [95% CI]: 1‐2: 0.32 [0.17‐0.48], 3‐4: 0.50 [0.35‐0.65], 5‐9: 0.50 [0.36‐0.74], 10+: 0.55 [0.36‐0.74]; Table 3). Among women, only the 5‐9 children group (Estimate [95% CI]: 0.16 [0.00‐0.31]) had cognitive scores that were significantly different from having no children (Table 3).ConclusionData from this representative sample in rural South Africa indicate that the relationship between parity and later life cognition varies by sex/gender, with having children being associated with greater cognitive performance in men, compared to women. This sex/gender difference may be due to sex and gender differences in biological and social roles involved in childbearing and rearing.
A Methodological Framework for Investigating Diversity in Clinical Research
Authors: Jackson Jonathan D. 
Published: December 2022

AbstractBackgroundMany reports and reviews have been published on best practices in research recruitment, engagement, and retention (RER), yet clinical research broadly lacks identifiable mechanisms to translate these qualitative reports into quantifiable, testable hypotheses on the science of RER. A science of diversity requires precise mechanisms for true efficacy, but before this is possible, we must develop key methodological and ontological frameworks. Thus, we are in dire need a basic sciences approach to identify mechanisms that underpin RER research, and disparities in Alzheimer’s disease and related dementias (ADRD) clinical research more broadly.MethodA science of diversity in clinical trials must ensure research conducted under the umbrella of this discipline is not methodologically confounded. Although researchers studying health inequities have begun to parse health disparitiesfrom health inequities, recruitment into research may still conflate foundational causal concepts, obscuring researchers’ ability to truly determine the nature of group differences. An ordered methodological framework was proposed, formalizing key biases that may confound efforts to diversity clinical research samples, and to determine the nature of health inequities and disparities among marginalized and minoritized populations.ResultIn addition to aspects of biological differences and structural inequities that may inform group differences in both RER and ADRD clinical research, three additional sources of bias were identified: biases of selection and inclusion into research, error and biases of measurement, and biases of implementation of research protocols. Notably, existing tools to measure and mitigate these sources of noise are available, ensuring that detected group differences are not confounded by shortcomings in scientific design.ConclusionI present this novel framework to support a rigorous methodological approach to the study of diversity in ADRD clinical trials, anchoring a formalized science of RER and ensuring that estimates of health disparities and inequities in ADRD research are free of biases introduced by well‐intentioned research teams. Implementing this methodological approach is expected to improve accrual of diverse and representative populations into ADRD research, and to improve the quality and generalizability of ADRD clinical research itself.
Caregiving Experiences and Health of LGBTQ+ Caregivers: Results from the Equality in Caregiving Study
Authors: Kittle Krystal R. , Flatt Jason D. , Anderson Joel G , Verble Danielle D , Likos Kelly D. S. , Wharton Whitney 
Published: December 2022

AbstractBackgroundBetween 27% and 45+% of LGBTQ+ adults care for someone with a chronic illness, with 11% caring for someone living with Alzheimer’s disease and related dementias (ADRD). LGBTQ+ caregivers may experience greater strain than non‐LGBTQ+ caregivers, but differences in characteristics and experiences between LGBTQ+ ADRD and non‐ADRD caregivers are less understood.MethodsAn online survey of demographic characteristics, caregiving experiences, and health‐related questions was administered to LGBTQ+ ADRD (n = 25) and non‐ADRD (n = 24) caregivers recruited from across the U.S. as a part of a larger clinical trial. Descriptive statistics were used to characterize the sample. Non‐parametric tests were used to assess differences between LGBTQ+ ADRD and non‐ADRD caregivers.ResultsCaregivers identified as lesbian (31%), gay (29%), bisexual (18%), queer (8%), heterosexual (6%), and additional identities (8%). Most identified as cisgender female (34%) or male (24%), followed by transgender (16%) and genderqueer, non‐binary, or gender fluid (10%). Respondents were aged 18‐81 (48.42 ± 16.46 years). The majority identified as White (71.4%), had an average of 16.65 years of education (SD = 2.48), and were a child/grandchild (55.1%) or other relative (28.6%) of the person with ADRD. Most had been providing care for 3 to 4 years (37.5%) or 5 to 10 years (25%). ADRD caregivers provided help with slightly more IADLs (7.2 vs. 7.0) and ADLs (6 vs. 5.3) than non‐ADRD caregivers (non‐significant, n.s.). ADRD caregivers reported slightly higher levels of perceived stress (mean: 17.9 vs. 17.6, n.s.) than non‐ADRD caregivers. ADRD caregivers reported a slightly higher score for positive aspects of caregiving (mean: 27.5 vs. 27.0) than non‐ADRD caregivers. ADRD caregivers were more likely to report being asked by a health care provider about needing help with caring for their care recipient than non‐ADRD caregivers (18.0% vs. 10.0%; p = .02).ConclusionLGBTQ+ ADRD and non‐ADRD caregivers were similar across experiences of positive aspects of caregiving and perceived stress. ADRD caregivers were more frequently asked by a health care provider about needing help in providing care compared with non‐ADRD caregivers. More research is needed to understand the experiences and needs of LGBTQ+ ADRD caregivers, particularly in more racially and ethnically diverse communities.
Targeting Substance P Pathway as an Emerging Novel Therapeutic Mechanism for Modulating Amyloid Beta in APP/PS1 Mouse Model
Authors: Yuede Carla M , Cirrito John R , Johns Stefanie , Knie Robb 
Published: December 2022

AbstractBackgroundNeurodegeneration associated with Alzheimer’s disease (AD) is well established to be mediated by amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs) of Tau protein in the brain. However, there are a multitude of underlying processes that individually contribute to the development of these aberrant Aβ aggregations and NFTs over time that are still being elucidated. The substance P/neurokinin‐1 receptor signaling pathways play an important role in regulating neuroinflammation and have recently been demonstrated to also influence mechanisms responsible for Aβ amyloidogenesis and toxicity1,2,3. Accordingly, HT‐ALZ is under development as a novel AD therapeutic to target the SP/NK1R pathway.MethodUsing microdialysis, Aβ levels in the interstitial fluid (ISF) of the hippocampus were measured in male and female APP/PS1 mice (3‐4 months old). ISF samples were collected every hour for 6 hours prior to treatment to establish a baseline, HT‐ALZ or vehicle was administered via oral gavage, and samples were collected continuously for 12‐15 hours following treatment. Aβ levels were measured using ELISA and changes from baseline were calculated for each mouse.ResultWe observed a significant change from baseline in mice treated with HT‐ALZ, but not in vehicle treated mice. Mice treated with HT‐ALZ show a decrease in average ISF Aβ following treatment.ConclusionResults of our microdialysis study indicate targeting the SP/NK1R pathway has a beneficial effect on circulating Aβ levels in the mouse brain, which may lead to lower plaque load with longer term treatment. We are currently investigating the impact of HT‐ALZ on the cognitive and behavioral impairments in APP/PS1 mice; the results of these studies will be provided at the time of presentation.
References:1.	Martinez AN, Philipp MT. Substance P and Antagonists of the Neurokinin‐1 Receptor in Neuroinflammation Associated with Infectious and Neurodegenerative Diseases of the Central Nervous System. J Neurol Neuromedicine. 2016;1(2):29‐36. doi:10.29245/2572.942x/2016/2.10202.	Severini C, Petrella C, Calissano P. Substance P and Alzheimer’s Disease: Emerging Novel Roles. Curr Alzheimer Res. 2016;13(9):964‐72. https://doi.org/10.2174/1567205013666160401114039. PMID: 27033058.3.	Chen XY, Du YF, Chen L. Neuropeptides Exert Neuroprotective Effects in Alzheimer’s Disease. Front Mol Neurosci. 2019;11:493. Published 2019 Jan 11. https://doi.org/10.3389/fnmol.2018.00493
Pathological tau in cognitively normal older adults predicts prospective neurodegeneration and cognitive decline
Authors: Chen Xi , Toueg Tyler N , Harrison Theresa M. , Baker Suzanne L. , Jagust William J. 
Published: December 2022

AbstractBackgroundPathological tau burden has been linked to neurodegeneration in AD patients. Although previous studies have linked brain atrophy in people at the preclinical stage of AD to early tau deposition, most evidence is based on cross‐sectional findings or retrospective changes before the tau measurement. This study examines longitudinal atrophy and cognitive decline following the assessment of tau, and specifically the relationship between whole brain tau measures and prospective changes in brain structure and memory.Methods124 cognitively normal older adults (> 65 yrs old) underwent FTP PET to measure voxel‐wise tau pathology and PiB PET to measure amyloid positivity at baseline. Rates of change in hippocampal volume (N=74) and memory (N=108) following the PET scan were correlated with whole brain (voxel‐wise) FTP‐PET data.ResultsProspective memory decline was related to tau deposition in the left temporal, parietal, and posterior regions, and the right parahippocampal gyrus (Figure 1), driven by Aß+ individuals (Figure 2). Prospective hippocampal atrophy was related to tau in the parahippocampal and entorhinal cortices (Figure 3), regardless of Aß status. The overlapping cluster in the right parahippocampal/entorhinal region suggested tau burden in this area was predictive of both hippocampal atrophy and memory decline (Figure 4). Finally, we explored how tau and hippocampal atrophy contributed to memory decline together. We found that memory decline in Aß‐ people was mediated by hippocampal atrophy (31.9%) and that there was very little direct effect of tau on memory decline. However, no mediation of hippocampal atrophy was found in Aß+ people, suggesting a strong effect of tau on memory decline in Aß+ people above and beyond hippocampal atrophy (Figure 5).ConclusionsOur findings suggest that tau effects on cognitive decline and neurodegeneration are already present in cognitively normal people, and that memory decline may be driven by different factors in normal aging and preclinical AD. Entorhinal tau in Aß‐ adults may be linked to age‐related hippocampal atrophy, which was related to memory decline, whereas degeneration in other regions, or other brain changes (e.g., network integrity, functional activity, etc.), may explain the detrimental effect of tau on memory in Aß+ people.
Premature aging in co‐occurring Alcohol Use Disorder and Post‐Traumatic Stress Disorder from a functional connectome perspective
Authors: Joseph Jane E , Bustos Nicholas , Nowling Duncan , Warner Graham , Barlis Katie L , Mintzer Jacobo E , Dean Brian , Lawson Andrew , Jensen Jens H. , Benitez Andreana , Peterson Alan , Fox Peter T , Flanagan Julianne , Back Sudie 
Published: December 2022

AbstractBackgroundPost‐Traumatic Stress Disorder (PTSD) and Alcohol Use Disorder (AUD) may be associated with premature brain aging which increases the risk for Alzheimer’s Disease and Related Dementias (ADRD). While each disorder alone has been studied as a risk factor for ADRD, few studies have examined premature brain aging in co‐occurring PTSD/AUD. It is important to know whether co‐occurring PTSD/AUD may amplify ADRD risk. Consequently, the present study tested the hypothesis that, relative to healthy controls (HC), PTSD/AUD would show more pronounced premature brain aging than AUD alone.MethodA functional connectome approach was used to develop a model of healthy brain aging. The graph‐theory measure eigenvector centrality was calculated from resting state fMRI scans in 60 mid‐life HC (HC‐mid; mean age=56.9), 69 older adult HC (HC‐older; mean age = 74.1), 36 AUD (mean age=54.4), and 30 PTSD/AUD participants (mean age=55.7). AUD and PTSD/AUD diagnoses were determined by a structured clinical interview. Connectome node features that were most predictive of age in HC‐mid and HC‐older were used in predictive modeling with bootstrap aggregation. These features were from multiple cortical areas and resting state networks. The healthy aging model was transferred to the AUD and PTSD/AUD groups to estimate brain age. Estimated ages in AUD and PTSD/AUD were compared to the predicted age in HC‐mid and HC‐older using generalized linear mixed modeling (GLMM).ResultPredictive modeling in HC yielded an aggregate model with 49.5% accuracy in predicting age (p < .0001), with some network features showing increases in eigenvector centrality with age and others showing decreases. After model transfer and correcting for age estimation bias, the GLMM yielded a main effect of diagnostic group (Wald c23=141.6, p < .0001). Predicted age for PTSD/AUD was significantly higher (M=61.0) than HC‐mid (M=57.2; p=.048) but predicted age for AUD (M=59.9) was not different from HC‐mid (p=.133). HC‐older predicted age (M=74.1) was different from all other groups (p < .0001).ConclusionIn this preliminary analysis, premature brain aging in PTSD/AUD was more pronounced than in AUD alone which may suggest greater vulnerability to AD‐like neurodegenerative processes that are manifest at the level of large‐scale network connectivity.
Targeting mitochondria for healthy brain aging: a case study of non‐psychoactive cannabinoids to rescue mitochondrial dysfunction in Alzheimer’s disease
Authors: Liang Zhibin , Maher Pamela 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) arises from complex and multifaceted pathogenic mechanisms. Although many alterations occur in the aging brain that are likely to contribute to AD, there is growing evidence that mitochondrial inefficiency and dysfunction are one of the pathophysiological changes contributing to neurodegeneration in AD. The oxytosis/ferroptosis regulated cell death pathway recapitulates many features of mitochondrial dysfunction associated with the aging brain and has emerged as a potential key mediator of neurodegeneration. It has thus been proposed that the oxytosis/ferroptosis pathway could be used to identify novel AD drug candidates that act by preserving mitochondrial function.MethodsAiming to identify AD drug candidates from natural products that preserve mitochondrial function, we have focused on phytochemical libraries with medicinal properties. We used a novel preclinical drug‐screening platform based on phenotypic assays that mimic different cellular toxicities and stresses associated with the AD brain that are characterized by mitochondrial dysfunction. To elucidate the molecular mechanisms for mitochondrial regulation, we harnessed an inducible, mitochondrially‐depleted neuronal cell line and employed the combined techniques of live‐cell imaging, super‐resolution microscopy, real‐time mitochondrial metabolic analysis, biochemical assays, immunoblotting, and qPCR.ResultsUsing this combined approach, we discovered that cannabinol (CBN), a non‐psychoactive cannabinoid, is a novel and potent neuroprotector. We demonstrated that not only does CBN protect neurons from oxytosis/ferroptosis in a manner that is dependent on mitochondria, it does so independently of cannabinoid CB1/CB2 receptors. Specifically, CBN alleviates intraneuronal amyloid toxicity, directly targets mitochondria, and preserves key mitochondrial functions including redox regulation, calcium uptake, membrane potential, bioenergetics, biogenesis, and modulation of fusion/fission dynamics that are disrupted following induction of oxytosis/ferroptosis in neuronal cells. These neuroprotective effects of CBN are at least partly mediated by the promotion of endogenous antioxidant defenses and the activation of AMP‐activated protein kinase (AMPK) signaling which help to maintain mitochondrial homeostasis.ConclusionsThis study highlights the potential of mitochondrially‐targeted compounds such as CBN as novel oxytotic/ferroptotic inhibitors to rescue mitochondrial dysfunction for healthy brain aging, as well as opportunities for the discovery and development of future therapeutics for Alzheimer’s disease and other age‐associated neurological disorders.