bluuebunny/crossref_metadata_2025_split huggingface dataset:
Financial toxicity in dementia caregiving
Authors: Hart Danielle M , Leggins Brandon , Sanches Clara , Chiong Winston 
Published: December 2023

AbstractBackgroundDementia caregiving is associated with significant financial costs. The term “financial toxicity” has been used in many care settings to describe the negative effects of medical expenses on both financial security and health‐related quality of life. Here, we utilize the validated COmprehensive Score for financial Toxicity (COST) to examine the experience of financial toxicity in American dementia caregiving.MethodWe conducted a nationally representative survey of 317 US dementia caregivers, oversampling non‐Hispanic Black (n = 75) and Hispanic (n = 61) caregivers, with the COST questionnaire. Financial toxicity was defined as COST <26 and further categorized as mild (COST ≥14 & <26), moderate (COST >0 & <14), or severe (COST = 0) according to the measure’s predetermined cut points. COST was treated categorically to generate descriptive statistics and continuously for linear regression. We built nested multivariable models to use in our regression‐based analysis. The base model included key caregiver demographics (age, gender, race/ethnicity, rurality), to which the fully adjusted model added supplementary caregiver demographics, care recipient clinical characteristics, and caregiver‐recipient relational characteristics.ResultSurvey‐weighted categorical analysis revealed 52.7% of American caregivers experience some degree of financial toxicity. Of those who experience financial toxicity, 73.1% are classified as mild, 25.7% as moderate, and 1.2% as severe. Financial toxicity was identified in 69.5% of non‐Hispanic Black, 54.1% of Hispanic, and 42.3% of non‐Hispanic White caregivers, with non‐Hispanic Black caregivers significantly more likely to experience financial toxicity compared to non‐Hispanic White caregivers (p = 0.017). In our base linear regression model, older caregiver age was protective against financial toxicity (p = 0.024). Caregiver employment status mediated this effect in the fully adjusted model, with retirement protective against financial toxicity (p <0.001). In contrast, unemployment predisposed caregivers to financial toxicity (p <0.001).ConclusionMost dementia caregivers in the US experience financial toxicity, with Non‐Hispanic Black caregivers bearing the highest risk. Older caregiver age protects against financial toxicity, likely due to the relationship between age and retirement.
The association between cognitive reserve and cognitive trajectories among older adults in Europe
Authors: Khalaila Rabia , Dintica Christina S. , Yaffe Kristine 
Published: December 2023

AbstractBackgroundThe literature on cognitive reserve (CR) and cognitive trajectories is limited in in the using of individual CR measures rather than composite CR measure. Moreover, to date, the findings about the association between CR and cognitive trajectories are conflicting and inconsistent.AimsTo examine the longitudinal association of a composite CR measure and each individual indicator of CR on cognitive decline, both combined and on individual domains, over 6‐years follow up, adjusting for age, gender, number of chronic diseases, functional disability and physical activityMethodsWe conducted a longitudinal analysis using a cohort study on 55,340 participants from 16 European countries, aged 50 and more taken from the survey of health, Aging, and Retirement in Europe (SHARE). We used cognitive performance assessments (including immediate memory, delayed memory, verbal fluency and numeracy) and information on CR factors (encompassing education, occupation and cognitive activities) collected in four waves conducted at 2‐years interval from 2011 to 2017. First, structural equation modeling was used to construct the composite CR score, and then was analyzed by tertile. Finally, linear mixed‐effect models were used to examine the study aims.ResultsAt baseline, compared with highest CR, middle and lowest CR showed large differences in combined cognition and in all individual domains. At the longitudinal results revealed that compared with the highest CR, the lowest CR was related to a faster decline in composite cognition score over time, despite the small difference, it remains significant (β: ‐0.02, 95% confidence interval [CI]: ‐0.03 to ‐0.01), as well as in all specific cognitive domains. However, no association was found for the middle CR trajectory. Among the individual CR measures, education was associated with better cognitive performance over time (β: 0.01, 95%CI: 0.01 to 0.01) and occupation complexity was associated with less decline over time (β: ‐0.01, 95%CI: ‐0.01 to ‐0.00), but cognitive activities were not associated with cognition.ConclusionsThe composite CR provides a comprehensive measure in preserve cognitive functions and in avoiding cognition decline, more than using individual CR indicator.
Exosomal IL‐12p70 is increased in Minority Participants at Risk for Alzheimer’s Disease
Authors: Winston Charisse N. , Rissman Robert A 
Published: December 2023

AbstractBackgroundDetecting toxic proteins, including Aβ and p‐tau species within neuronal (NEVs) and astrocyte extracellular vesicles (AEVs) has initiated an ongoing effort to assess the clinical utility of EVs as potential biomarkers for Alzheimer’s Disease (AD) and other AD‐related dementias (ADRDs). African Americans (AAs) and Hispanics are approximately 1.5 to 2 times more likely to develop AD and ADRD as compared to non‐Hispanic Whites (NHW). Specifically, AAs are more likely to have higher levels of chronic stress, inflammation, and vascular related co‐morbidities. Here, we assess the proinflammatory phenotype of EV cargo loads of different cellular origins for novel biomarker assessment amongst Hispanic and AA subjects with AD.MethodPlasma EVs derived from normal controls and AD subjects (NHW, Hispanics, AAs, n = 20/group) were extracted, precipitated using a polymer‐based isolation method (ExoQuick), and enriched against neuronal (L1CAM), astrocyte (GLAST), and microglial (TMEM119) sources using magnetic immunocapture and fluorescence‐activated cell sorting (FACS). ONI Nanoimager was used to characterize EVs by size and EV marker profiling was done via ELISA. Concentrations of proinflammatory cargo proteins were quantified using MSD immunoassay (V‐PLEX Proinflammatory Panel 1). Patients were stratified based on race, cognitive status, sex, and APOE genotype.ResultNeuronal and glial EVs were similar in size and distribution. Plasma concentrations of EV marker CD81 were not statistically different between the three EV preparations. Plasma concentrations of IL‐12p70 were significantly increased in NEVs derived from demented NHW and Hispanics as compared to AAs. Increased plasma NEV and AEV concentrations of IL‐12p70 were positively correlated with APOE4 carrier status. No difference was observed based on sex. No significant difference was observed in MEV concentrations of IL‐12p70 based on race, cognitive status, sex, and APOE genotypeConclusionDifferential pro‐inflammatory phenotypes of EV cargo exist amongst Hispanics and AAs as compared to NHW. Plasma NEV concentrations of IL‐12p70 may serve as a novel biomarker for identifying AD amongst AAs subjects. The biomarker capabilities of additional proinflammatory‐related EV cargo proteins will be investigated in a larger sample cohort of normal controls and AD subjects.
Strategies for managing patients with moderate to severe Alzheimer’s disease: high‐dose donepezil vs. memantine combination
Authors: Shim YongSoo , Jung San 
Published: December 2023

AbstractBackgroundsWhen dementia patients who took already a maintenance dose of 10mg donepezil get worse to advanced stage, clinicians would consider and select which one is better between higher‐dose donepezil (23 mg/day) and memantine combination.ObjectivesTo compare the clinical benefits between high‐dose donepezil and memantine (20 mg/day) combination in moderate to severe Alzheimer’s diseaseMethodsA single center, retrospective, observational study was conducted. Patients with moderate to severe AD who were treated with a stable dose of donepezil were included. They started further treatments such as higher‐dose donepezil or memantine combination because they showed poor or waning response to a maintenance dose. After 6 months follow‐up, clinical efficacy and safety were compared between two groups, higher‐dose donepezil and memantine combination.ResultsA total of 108 patients, 35 with higher‐dose donepezil and 75 with memantine combination, were included. Baseline characteristics such as age, sex, education, MMSE, and CDR were similar between groups. After follow‐up, changes of MMSE and CDR were not different. Treatment responses measured as CGI‐C were as follows: 41.3% (improved 31, not changed 25, and worse 9) of patients improved after memantine combination and 22.9% (improved 8, not changed 12, and worse 15) improved after higher‐dose donepezil (p = 0.069). Adverse events were not different. Among patients with memantine combination, those who had no benefits to the initial donepezil showed better responses (27 vs. 48). Patients who had benefits to lower dose of donepezil showed better responses (24 vs. 11) after higher‐dose.ConclusionBoth of higher‐dose donepezil and memantine combination, which are approved as effective in moderate to severe AD, were not different in clinical benefits and safety. Although not statistically significant, treatment responses showed some differences. Patients who had shown good response at the time of the initial therapy of donepezil preferred higher‐dose donepezil over memantine combination, whereas those who did not respond to the initial donepezil had more effective after memantine was added. Further studies including randomized blind trials could strengthen these findings.
The influence of baseline sleep on exercise‐induced cognitive change in older adults: A randomised clinical trial
Authors: Sewell Kelsey R , Rainey‐Smith Stephanie R , Peiffer Jeremiah J , Sohrabi Hamid R , Frost Natalie , Markovic Shaun J , Erickson Kirk I. , Brown Belinda M 
Published: December 2023

AbstractBackgroundObservational studies consistently demonstrate that physical activity is associated with enhanced cognitive function and reduced risk for dementia. However, there remains significant heterogeneity in study findings regarding the effect of exercise interventions on cognitive function. Individual variation in sleep behaviours are hypothesized to be a source of this variability in the effectiveness of exercise to influence cognition, however this has not yet been investigated. Thus, the current study aimed to 1) investigate the influence of a 6‐month exercise intervention on sleep pre‐ and post‐intervention and 2) investigate whether baseline sleep measures moderate exercise‐induced cognitive changes.MethodWe utilised data from the Intense Physical Activity and Cognition (IPAC) study (n = 89), a 6‐month moderate intensity and high intensity exercise intervention, in cognitively normal community‐dwelling older adults aged 60‐80 years (68.76 ± 5.32). Exercise was supervised and completed on a stationary exercise bicycle, and cognitive function was measured using a comprehensive neuropsychological battery administered pre‐ and post‐intervention. Sleep was measured using the Pittsburgh sleep quality index (PSQI) to yield measures of sleep duration, efficiency, and sleep latency.ResultThere was no effect of the exercise intervention on any sleep outcomes from pre‐ to post‐intervention. There was a significant moderating effect of baseline sleep efficiency on both episodic memory and global cognition within the moderate intensity exercise group (β = ‐0.024, SE = 0.008, p = .004; β = ‐0.011, SE = 0.005, p = .036), such that those with poorer sleep efficiency at baseline showed greater exercise‐induced cognitive improvements.ConclusionThese results indicate that those with poorer sleep may have the greatest exercise‐induced cognitive benefits and that baseline sleep behaviours may be an important source of heterogeneity in previous exercise interventions targeting cognitive outcomes.
Extremes of baseline cognitive function determine the severity and outcomes of delirium: findings from a prospective longitudinal cohort study
Authors: Tsui Alex 
Published: December 2023

AbstractBackgroundEpidemiological studies have shown the bidirectional relationship between dementia and delirium to be complex and non‐linear. This has implications for mechanistic studies investigating the extent to which any pathophysiology might be specific to delirium, or shared with dementia. While delirium is associated with long‐term dementia risk and cognitive decline, this association may be independent of classical Alzheimer’s pathology in oldest‐old patients.MethodThe Delirium and Population Health informatics (DELPHIC) study prospectively followed a population‐representative sample of 1510 individuals aged ≥70 years living in London, UK. We performed cognitive assessments at baseline, two years, and ascertained delirium symptoms during incident hospitalisation in 209 participants across 371 episodes.ResultBetter baseline cognitive function was generally associated with a lower likelihood of delirium. However, during delirium episodes, there was a U‐shaped relationship between baseline cognition and delirium symptom severity; participants with the lowest and highest baseline cognition experienced the most severe delirium and arousal deficits (baseline z‐score ‐2: mean MDAS 15; baseline z‐score +2: mean MDAS 11). At follow‐up, we observed the largest cognitive decline in participants with better baseline cognition experiencing delirium (2.2SD decline vs 0.8SD without delirium).ConclusionThese findings imply that delirium pathophysiology research should take into account differences in baseline cognition, for example by defining pre‐existing subclinical dementia pathology. We suggest the need for prospective, serial pathophysiological studies to consider the temporal sequence of delirium‐related neural damage. In this way, we could differentiate which mechanisms are unique to delirium, and which might interact with pre‐existing dementia pathophysiology to result in long‐term cognitive deficits.
Association between poor periodontal health and 15‐year risk of incident dementia
Authors: Asher Sam , Suominen Anna Liisa , Stephen Ruth , Ngandu Tiia , Koskinen Seppo , Solomon Alina 
Published: December 2023

AbstractBackgroundPoor oral health, particularly tooth loss, has been highlighted as a potential modifiable risk factor for dementia. However, longitudinal evidence concerning the association of poor periodontal health with dementia is limited. This study examines the impact of poor periodontal health on 15‐year risk of incident dementia.MethodThis study included 4596 dementia‐free and dentate (i.e., having ≥1 teeth remaining) participants, aged 30‐93 years, from population‐based Finnish Health 2000 Survey. Periodontal health at baseline was evaluated through bleeding on probing (BOP), periodontal pocket depths (PPD), and alveolar bone loss (ABL). BOP for each sextant and PPD for each tooth (excluding third molars and residual roots) were recorded clinically during oral examination. Based on BOP, participants were dichotomized into having ≥1 sextant with BOP versus no BOP.Tooth with PPD of ≥4mm was considered as having deepened periodontal pocket. Based on PPD, participants were dichotomized into having ≥1 teeth with deepened PPD versus no PPD. ABL for each tooth was examined through orthopantomographs and defined as vertical bone loss extending apically to at least the middle third of tooth root. Based on ABL, participants were dichotomized into having ≥1 teeth with ABL versus no ABL. Dementia diagnosis until 2015 was retrieved from national health registers.Cox proportional regression was conducted and adjusted for age, gender, education, cardiovascular risk, socioeconomic status, depression, alcohol consumption, c‐reactive protein, and overall tooth count. Sensitivity analysis accounting for potential reverse causality bias was conducted by excluding incident dementia during the first five years of follow‐up.Result183 participants developed dementia over 15 years. Fully adjusted hazard ratio among participants with ≥1 sextant with BOP was 1.15 (CI:0.80‐1.65), with ≥1 teeth having deepened PPD was 0.94 (CI:0.67–1.31), and with ≥1 teeth having ABL was 0.97 (CI:0.64–1.49). Findings from sensitivity analysis for potential reverse causality bias corroborated with results for main analyses.ConclusionPreliminary findings indicate no association of BOP, PPD, or ABL with 15‐year dementia risk. However, further well‐designed longitudinal studies with more comprehensive periodontal assessment (e.g., clinically diagnosed periodontitis and severity of periodontitis) are warranted to conclusively assess its impact on dementia risk.
Time of the day at sampling affects amyloid‐beta levels in CSF and plasma
Authors: Orduña Dolado Anna , Stomrud Erik , Ashton Nicholas J. , Nilsson Johanna , Brinkmalm Ann , Zetterberg Henrik , Blennow Kaj , Janelidze Shorena , Hansson Oskar 
Published: December 2023

AbstractBackgroundStudies suggest that cerebrospinal fluid (CSF) levels of Alzheimer’s disease (AD) biomarkers, amyloid‐β (Aβ) and tau, follow a circadian rhythm. However sustained sampling of CSF with indwelling intrathecal catheter used in most of these studies might have affected the observed fluctuations in the biomarker levels.MethodsWe included 38 individuals with either normal (N = 18) or abnormal (N = 20) CSF Aβ42/40 status. CSF and plasma were collected, at the same occasion, at two different visits separated by an average of 53 days with lumbar punctures and venepunctures performed either in the morning or evening. At the first visit, collection was performed in the morning for 17 participants and the order was reversed (evening collection first) for the remaining 21 participants. CSF and plasma samples were analyzed for Aβ42, Aβ40, GFAP, NfL, p‐tau181, p‐tau217 and p‐tau231. CSF samples were also tested for a battery of synaptic and lysosomal proteins.ResultsCSF Aβ42 (mean difference [MD] = 0.208ng/ml; p = 0.043), CSF Aβ40 (MD = 1.85ng/ml; p<0.001), plasma Aβ42 (MD = 1.65pg/ml; p = 0.002) and plasma Aβ40 (MD, 0.011ng/ml, p = 0.003) levels were increased in the evening samples compared with morning samples by 4.2%‐17.0% (Figures 1‐2). However, changes between morning and evening samples were not significant for either CSF or plasma Aβ42/40. Additional proteins in CSF, APP, STX1B, NPTXR and NPTX1, were also found increased in the evening samples (MDrange, 0.087–0.243; p<0.048) by 4.7%‐12.15% (Figure 3). No significant differences were found between morning and evening levels for any of the other biomarkers, including p‐tau’s, NfL and GFAP. There were no significant interactions between time of day at sample collection and either Aβ status or order in which samples were obtained.ConclusionOur findings provide further evidence for diurnal fluctuations in Aβ peptides, which is observed in both CSF and plasma. Additionally, CSF levels of some synaptic proteins followed circadian rhythm. Importantly, CSF and plasma Aβ42/40 ratios remained unaltered, suggesting that increased production or decreased clearance of Aβ peptides during daytime similarly affect the CSF and plasma levels of both Aβ42 and Aβ40. Thus, these ratios are more suitable for implementation as biomarkers of AD as they are not influenced by diurnal fluctuations.
Liver X receptor α suppresses SNAI2 ensuring blood‐brain barrier function
Authors: Vacondio Davide , Coenen Loet , Mulder Inge , Fontijn Ruud , Hof Bert , Fung Wing Ka , Kooij Gijs , Rozemuller Annemieke J.M. , Zelcer Noam , Vries Helga E , Wit Nienke M 
Published: December 2023

AbstractBackgroundMore than 48% of Alzheimer’s disease (AD) patients display amyloid beta (Aβ) accumulation around small brain vessels: capillary cerebral amyloid‐angiopathy (capCAA). The accumulation triggers reduction in the cerebral blood‐flow and localized hypoxia, possibly inducing dysfunction of the neuroprotective blood‐brain barrier (BBB). However, the molecular mechanism driving vascular changes and BBB impairment is largely unknown. Recently, a unique role for Liver x receptor α (LXRα) in securing BBB stability has been discovered. Nonetheless, the role of LXRα in BBB dysfunction remains elusive. This study investigates the activity of LXRα in the promotion of BBB functions evaluating how this is compromised in AD and capCAA.MethodWe use shRNA based gene‐editing to ablate LXRα in human brain endothelial cells (BECs) followed by RNA‐sequencing to identify differentially expressed genes. In addition, BECs are grown in hypoxia to mimic capCAA and study the role of LXRα. We further evaluate the angiogenic ability of LXRα KD cells and hypoxic cells. Finally, post‐mortem human brain tissue is used to validate promising candidates and recapitulate the molecular mechanism in pathological condition.ResultThe gene set enrichment analysis performed on LXRα knockdown (LXRα KD) cells revealed a downregulation of BEC markers including ABC transporters and tight junctions. The significantly upregulated genes suggested SNAI2 as the major player in the BECs dedifferentiation. In depth molecular studies revealed the indirect inhibitory role of LXRα on SNAI2 expression. We further implicate hypoxia as LXRα regulatory condition and substantiate the importance of LXRα in BECs identity. SNAI2 upregulation in LXRα KD and hypoxic BECs represses DLL4‐Notch1 signaling, thereby promoting aberrant angiogenesis. Ultimately, we provide evidence of SNAI2 upregulation in capillaries of AD and capCAA patients.ConclusionOur data suggests that LXRα helps preserving BECs identity and function via the constitutive inhibition of SNAI2. This mechanism is compromised in capCAA patients where Aβ deposition creates an hypoxic environment responsible for LXRα suppression. The resulting SNAI2 increase leads to BBB impairment and abnormal angiogenesis. These findings contribute to understand the microvascular dysfunction taking place in AD and capCAA, providing new insights on their pathophysiology.