bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vitro antioxidant and anticholinesterase activity of Aegle marmelos fruit: implications for Alzheimer’s disease treatment
Authors: Sood Parul , Shri Richa , Kaur Gagandeep 
Published: December 2023

AbstractBackgroundIncreased antioxidant and anticholinesterase activity are key pathological hallmarks of Alzheimer’s disease (AD). In various Ayurvedic formulations Aegle marmelos (AM) belonging to family Rutaceae have traditionally been used as a brain tonic. However, there was no scientific validate proof of it. Hence, the present study was aimed to identify bioactive extract/fraction/constituent of AM fruit having potential to treat AD.MethodFour different crude extracts of AM fruits by using different solvents on basis of increasing polarity‐such as petroleum ether, chloroform, methanol and distilled water‐by successive Soxhlet extraction were prepared and evaluated for in‐vitro antioxidant and anticholinesterase inhibition assay by using DPPH and Ellman’s assay respectively. Most bioactive extract was further subjected to fractionation by using solvent‐solvent partioning followed by flash chromatography for further sub fractionation of most bioactive fraction. Total phenolic (TPC) and flavonoid content (TFC) was also calculatedResultComparative evaluation of all four prepared extracts for in‐vitro antioxidant and anticholinesterase inhibition assays showed that the methanol extract (ME) was most bioactive. Furthermore, bioactivity‐guided fractionation of this bioactive ME revealed that Dichloromethane (DCM) fraction evinced highest antioxidant and anticholinesterase activity with IC50 value 74.56±1.43 µg/ml and 47.65±2.76 µg/ml due to presence of higher phenolic and flavonoid content. However, further sub‐fractionation of DCM fraction showed significantly higher IC50 values thus decreased activity.ConclusionThis preliminary study clearly suggested that the DCM fraction from the ME of A. marmelos may prove to be potential candidate for the treatment of AD may be due to synergistic effect of phenolic and flavonoid content present in it. However, to validate the neuroprotective effect of DCM fraction of AM fruit against AD further exploration at cellular and molecular level is required to underlying its pharmacological mechanism as well as identification of the active phytoconstituents responsible for anti‐Alzheimer’s effect.
A comparative study of medication profiles from AD, MCI, and non‐demented patients
Authors: Sharoar Md Golam , Koganti Bhavya , Falki Vaibhavkumar , Zaman Zakia , Osentoski Tammy , Graham Stewart F 
Published: December 2023

AbstractBackgroundThe ever‐increasing incidence of Alzheimer’s disease (AD) and the lack of effective therapeutics to treat the disease are leading to a “silver tsunami”. Current FDA‐approved drugs to treat the disease are limited as their benefit is simply momentary relief of the symptoms. Due to the chronic and progressive nature of AD, patients are routinely prescribed multiple non‐AD medications to preserve their ability to perform daily activities and to improve their quality of life. However, how those medications affect AD pathology remains unknown. In the present study, we have compared medication profiles of AD (n = 135), mild cognitive declined (MCI; n = 120), and non‐demented (n = 259) patients, with an aim to determine the effects of top‐ranked drugs on AD pathology.MethodsStudy subjects (≥65 years) were recruited from an academic geriatric practice that is heavily focused on memory disorders. All subjects underwent for the following cognitive assessments: a) Clinical dementia rating scale (CDR), b) Mini‐Mental Status Examination (MMSE), c) logical memory test, d) digit span forward and backward, e) category fluency test, f) ordering test, g) trails A&B, and finally the Geriatric Depression Scale. Individual medication for each subject was listed and they were categorized into major drug classes. Statistical analysis was performed to determine the frequency of each drug in each class.ResultsEight top‐ranked drug classes were categorized from a list of 453 individual medications. Vitamins (30‐40%) and anti‐inflammatory (∼30%) drugs were the major categories for each cohort. Interestingly, 11% of drugs were proton pump inhibitors in non‐demented patients, and this decreased by 8% in MCI, and 5% in AD. We found a reduced (8%) Lipitor prescriptions for AD patients compared MCI (11%) and non‐demented (13%) patients. We are investigating the effects of these highly prescribed drugs on β‐amyloid production/aggregation, cytotoxicity, plaque load, and tau phosphorylation in vitro and in vivo using cell culture and AD mouse models.ConclusionWhile the effects of routinely prescribed drugs on AD pathology are not well known, we found reduced vitamins, proton pump inhibitors, and Lipitor in the medication profiles of AD patients compared to the non‐AD population.
Developing a residual cognitive reserve index in a paediatric cohort with ADHD
Authors: Irani Zubin , Sheridan Andrew , Anderson Vicki , Silk Timothy J , Weinborn Michael , Gavett Brandon E 
Published: December 2023

AbstractBackgroundCognitive reserve (CR) is thought to be protective against late‐life cognitive decline induced by neurodegenerative disease and other forms of neurological insult. Although CR is thought to be influenced by early life experiences, information about its development during childhood and adolescence is lacking. The current study operationalised CR with a residual index approach (Reed et al., 2010) optimised for a diverse paediatric cohort. Criterion and construct validity of the index was also assessed.MethodData collected across 2011‐2019 from N = 115 children (MAge= 10.48, SDAge= 0.61, n = 72 [63%] male, n = 43 [37%] with ADHD) were acquired from the Murdoch Children’s Research Institute. Elastic‐net regularised linear regression was used to generate baseline and longitudinal CR indices that represented residual variance in (change in) fluid intellect (Matrix Reasoning) not explained by demographics (i.e., sex and age) or MRI‐based brain variables (i.e., cortical surface areas and cerebellar/subcortical volumes); brain regions were selected with the aim of partialling maximal variance out of the CR residual index. Outcome variables, including word reading, math computation, and Conners 3 ADHD Index were then regressed onto baseline and longitudinal CR indices.ResultsBaseline CR predicted baseline math computation (p<.001), while change in CR predicted change in word reading ability (p<.001). Further, in individuals with low grey matter volume, higher CR was associated with higher word reading score (p = .019) and lower ADHD Index (p = .047) compared to those with lower CR, at baseline. Higher change in CR also protected word reading trajectory in individuals with higher change in WMH volumes (p = .048).ConclusionThese results suggest that individual differences in CR, as operationalised through a residual index, may be detectable in school‐age children. While findings regarding criterion and construct validity of the CR index are stronger than previous research featuring an unoptimised residual model (Irani, 2022), support for the validity of the index remains incomplete compared to established geriatric models – possibly due in part to a relatively less predictable relationship between brain structure and cognition in children versus adults. Future research would benefit from longer‐term follow‐up in paediatric samples with greater variability in neuropathological indices, cognitive functioning, academic achievement, and functional outcomes.
The influence of genetic predisposition to Alzheimer’s disease in cognitive decline differs among sex in cognitively unimpaired individuals in the Alzheimer’s continuum
Authors: Brugulat‐Serrat Anna , Genius Patricia , Rodríguez‐Fernández Blanca , Sánchez‐Benavides Gonzalo , López‐Martos David , Grau‐Rivera Oriol , Minguillon Carolina , Fauria Karine , Molinuevo Jose Luis , Esteller Manel , Navarro Arcadi , Gispert Juan Domingo , Vilor‐Tejedor Natalia ,   for the ALFA study
Published: December 2023

AbstractBackgroundEvidence shows sex differences in cognitive performance in Alzheimer’s disease (AD). However, studies exploring whether genetic predisposition to AD differs in cognition among sex are scarce. We aimed to evaluate whether the influence of AD genetic liability in cognition differs among sex in cognitively unimpaired (CU) individuals in the AD continuum.MethodWe included 318 CU individuals from the ALFA+ cohort (Table 1). Cognitive change (∼3‐year follow‐up) was measured with a PACC and for individual cognitive domains. Polygenic scores estimating each participant’s genetic predisposition to AD were calculated with (PRS‐AD) and without (PRS‐ADnoAPOE) considering the APOE region (threshold = 5×10‐6). Amyloid positivity (Aβ+) was defined as cerebrospinal fluid (CSF) Aβ42/40<0.0071. Generalized linear models stratified by sex and amyloid status were performed to assess the association between cognitive change and genetic predisposition to AD. Models were corrected by age, years of education, and time between visits. Models were additionally corrected by baseline Jack’s cortical thickness AD signature as a marker of neurodegeneration.ResultIn Aβ+ women (n = 65), a higher genetic predisposition to AD was associated with steeper memory (p
PRS_AD = 0.04; pPRS_ADnoAPOE = 0.01) and executive function (p
PRS_ADnoAPOE = 0.001) decline after correcting by brain AD signature. In Aβ+ men (n = 44), a higher genetic predisposition to AD was associated with worse follow‐up performance on attention (p
PRS_AD = 0.05, pPRS_ADnoAPOE = 0.04), and results did not remain significant after correcting by brain AD signature (Figure 1). In Aβ‐, genetic predisposition to AD was also associated with executive function decline in women (n = 122) (p
PRS_AD = 0.16, p
PRS_ADnoAPOE = 0.02), while Aβ‐ men (n = 87) showed worse follow‐up performance on visual processing (p
PRS_AD = 0.251, pPRS_ADnoAPOE = 0.001). Results remained significant after correcting by brain AD signature (Figure 2).ConclusionOur results showed that genetic predisposition to AD is associated with changes in different cognitive domains in men and women. These findings will contribute to developing precision medicine approaches in AD encompassing sex‐sensitive strategies for prevention.
Investigating the social and environmental contexts of habitual walking ACTIVities in older adult DYADs: A mixed methods protocol for the ActivDyad study
Authors: Ardle Ríona Mc , Ryan Leigh James , McCarthy Louis , Wilson Cameron , Hamilton Calum Alexander , Tangen Gro Gujord , Farina Nicolas , Ireson Neil , Lanfranchi Vita , Hicks Ben , Bayat Sayeh 
Published: December 2023

AbstractBackgroundMobility‐related ambulatory activity (e.g., walking) is essential to healthy cognitive and functional ageing. Wearable technology (e.g., accelerometers/inertial measurement units; IMUs) allows us to objectively and continuously capture digital mobility outcomes (DMOs), e.g. volume, pattern and variability of walking activities. Continuous digital mobility assessment has been shown as feasible and acceptable to older adults with and without dementia. However, interpretation of DMOs is limited as we do not yet understand the impact of different social and environmental contexts on walking activity. For example, DMOs may be influenced by the volume of walking that one’s partner participates in, or by the walkability of their local area. Understanding the impact of social and environmental contexts on DMOs will support development of socio‐ecological strategies to support mobility in ageing. We aim to conduct a feasibility study in older adults with the following objectives: (1). Objectively assess DMOs in older adult dyads using digital mobility tools (i.e., IMUs/GPS); (2). Identify key social and environmental influences on DMOs through mixed‐methods exploration; (3). Develop a novel analytical approach combining DMOs with GPS data to assess independence/interdependence in dyads’ walking activities.MethodWe will recruit 20 older adult dyads in North‐East England for an observational cross‐sectional study. Walking activities will be recorded continuously for seven days using an IMU attached to participants’ lower backs. DMOs include volume (e.g., daily steps), pattern (e.g. mean bout length) and variability (of bout length) of walking activities. Simultaneously, participants will carry a GPS device (i.e., smartphone) to monitor excursions outside the home. Questionnaires will capture information on cognition, function, falls risk, exercise motivation, wellbeing, relationship mutuality, spatial navigation, and walkability of local area. Participants will complete a “mobility diary” for the assessment period (e.g., daily journeys, motivations/perceptions/familiarity of journeys).ResultPreliminary results will be presented regarding associations between social/environmental contexts with DMOs via flexible Bayesian statistical models and thematic qualitative analysis.ConclusionThis study will assess the feasibility of the protocol and analysis strategies, with intentions of developing further research to examine the impact of social and environmental influences on DMOs in people with dementia and their carers.
Performance of the CANTAB ‐ Paired Associates Learning task in an unsupervised online setting: Results from the Brain Health Registry
Authors: Ashford Miriam T. , Aaronson Anna , Kwang Winnie , Eichenbaum Joseph , Gummadi Shilpa L , Jin Chengshi , Cashdollar Nathan , Thorp Emily , Wragg Elizabeth , Zavitz Kenton , Cormack Francesca K , Banh Timothy , Neuhaus John , Ulbricht Aaron , Camacho Monica R , Fockler Juliet , Flenniken Derek , Truran‐Sacrey Diana , Mackin Scott R , Weiner Michael S. W. , Nosheny Rachel L 
Published: December 2023

AbstractBackgroundThe aim of this study was to evaluate the feasibility and usability of collecting data from an unsupervised online version of the Paired Associates Learning (PAL) task from the Cambridge Neuropsychological Test Automated Battery (CANTAB™) in adults enrolled in the Brain Health Registry (BHR).MethodBHR is an online cognitive aging registry for referral and longitudinal unsupervised assessment. The PAL assesses visual associative learning and memory and was administered in BHR between 03/2021‐07/2022. PAL variables included in this analysis were ‘Memory Score’ (patterns correctly identified at first attempt for each difficulty level) and ‘Total Errors’, adjusted for level reached. We analyzed PAL task completion rate and characteristics of PAL completers and used linear regressions to assess whether cross‐sectional PAL Memory Score and PAL Total Errors were associated with participant data (age, gender, education, self‐ and study partner‐reported cognitive complaints (Everyday Cognition scale (ECog)), self‐reported memory concern, and self‐reported depressive symptom severity (PHQ‐9), self‐report of Mild Cognitive Impairment (MCI)).ResultAs of July 2022, 14,520 participants aged 18+ years have completed PAL at least once. Participants were on average 66.3 years old (SD = 11.3), 72.4% female gender, 92.8% self‐identified as White, and had a mean of 16.6 years of education (SD = 2.27). BHR received 374 requests for study support regarding PAL, of which 36% (135) were related to device compatibility. Mean PAL scores were similar to those of previous, supervised studies (Figure 1). Worse PAL performance was significantly associated with being older, female gender, having less education, more self‐ and study partner‐reported ECog, self‐reported memory concern, more depressive symptoms, and self‐report of MCI (Table 1).ConclusionOur findings provide evidence for the feasibility of collecting PAL data in an unsupervised online setting and construct validity of cross‐sectional BHR PAL. In terms of usability, there was a minimal need for support. Future studies will investigate the predictive value of BHR PAL in identifying adults with self‐reported MCI, longitudinal BHR PAL performance and associations with in‐clinic assessments and Alzheimer’s disease biomarkers. Our sample lacked diversity. Therefore, a future direction is to increase accessibility of PAL to ethnoculturally and socioeconomically diverse communities.
Differences in Dementia Caregiver Distress Based on Caregiver Gender and Care Recipient Neuropsychiatric Symptoms
Authors: Bell Sophie A. , Gallagher Virginia , Reilly Shannon , Manning Carol A 
Published: December 2023

AbstractBackgroundOur healthcare system relies on unpaid family caregivers (e.g., spouses) for care of individuals with Alzheimer’s disease and related dementias (ADRD). Several caregiver and care recipient characteristics are known to be associated with caregiver burden and psychological outcomes in dementia caregivers. Research suggests that caregiver emotional distress is higher among women versus men, and that it increases with elevated care recipient neuropsychiatric symptoms (NPS). However, it is unclear whether gender differences in caregiver distress are independent of care recipient characteristics.MethodCaregivers completed the Neuropsychiatric Inventory‐ Questionnaire (NPI‐Q). Presence of NPS in care recipients was summed across 12 NPI‐Q domains. Using one‐way analyses of covariance (ANCOVAs), we assessed how caregiver gender (woman/man) and care recipient NPS are associated with caregiver burden (Zarit Burden Interview), anxiety (Geriatric Anxiety Index), quality of life (WHO‐5 Well‐Being Index), preparedness for caregiving (Preparedness for Caregiving Scale), and self‐efficacy (General Self‐Efficacy Scale) in a sample of 112 unpaid family caregivers. Covariates included caregiver age and co‐living status. Bonferroni corrections were used to adjust for multiple comparisons. The sample was comprised of 73.2% women with a mean age of 64.6 ± 12.2 years. Caregivers were primarily spouses (68.5%) and daughters (20.7%) of care recipients.ResultRelative to men caregivers, women caregivers reported higher levels of burden (F(1,103) = 24.4, p<.005) and anxiety (F(1,103) = 8.60, p<.005) and lower quality of life (F(1,103) = 9.85, p <.005). Caregivers who rated their care recipients as having more NPS also reported greater burden (F(1,103) = 27.2, p<.005), higher anxiety (F(1,103) = 26.0, p<.005), and lower quality of life (F(1,103) = 34.9, p <.005). There were no significant interactions between gender and NPS. Gender and presence of NPS were not associated with caregivers’ preparedness for caregiving or general self‐efficacy.ConclusionWhile women and men caregivers in this sample reported similar levels of preparedness and self‐efficacy, women endorsed greater levels of emotional distress in the form of caregiver burden, anxiety, and decreased quality of life. Across caregiver gender, age, and co‐living status, NPS in care recipients predicted poor psychosocial outcomes in our sample. Our data suggest the need for interventions to support women caregivers, and mitigate the burden associated with neuropsychiatric disturbances.
DNA methylation alterations in Lewy Body Dementia
Authors: Chouliaras Leonidas , Thomas Alan J , Clark Graeme , Donaghy Paul C , Swann Peter , Malpetti Maura , Mak Elijah , Savulich George , Prats‐Sedano Maria A , Low Audrey , Su Li , Rowe James B. , O'Brien John T 
Published: December 2023

AbstractBackgroundThe epigenetic mechanism of DNA methylation has been implicated in the pathophysiology of neurodegenerative disorders such as Lewy body dementia (LBD). DNA methylation profiling may help to identify novel treatment targets and early disease markers. We hypothesized that DNA methylation alterations are detectable in blood due the influence of genetic and environmental factors as well as immune system changes associated with LBD.MethodGenome‐wide DNA methylation profiling was carried out using reduced representation bisulfite sequencing in blood samples from 89 LBD patients and 67 controls. Fifty five LBD patients had amyloid PET imaging. Data processing was performed using FastQC, TrimGalore, Bismark and MethylKit. DNA methylation alterations at specific CpG sites as well as at promoter, CpG island and CpG shore regions were compared between LBD cases and controls. A log odds logistic regression was used to identify differential DNA methylation after adjusting for age, sex and smoking status. The false discovery rate (FDR) was used for correction for multiple testing. We also tested the diagnostic classification performance of the differentially methylated regions using receiver operating characteristic (ROC) curve analysis and examined the potential of DNA methylation as a predictor of amyloid PET positivity in LBD.ResultTwo single CpG sites at TNFRSF1B and EMC6 and three CpG shore regions at ABCG5, ETAA1 and TENM4 reached genome‐wide significance in the differential DNA methylation analysis comparing LBD cases and controls. The combined panel of the top three differentially methylated CpG shores reached an area under the curve (AUC) of 0.91 for the diagnosis of LBD compared to controls (sensitivity 0.89, specificity 0.85). DNA methylation at TENM4 was associated with amyloid PET positivity in LBD with an AUC of 0.84 (sensitivity 0.99, specificity 0.55).ConclusionOur data suggest that DNA methylation alterations in blood are observed in a cohort of LBD patients compared to controls. Our findings need to be replicated in larger cohorts and tested for specificity in LBD in order to explore their future potential as diagnostic markers and/or targets for novel therapeutics.
Investigations of altered neutrophil apoptosis in Alzheimer’s disease
Authors: Aries Michelle , Cook Makayla , Hensley‐McBain Tiffany 
Published: December 2023

AbstractBackgroundThere is strong evidence that neutrophils are dysregulated in Alzheimer’s disease (AD) and exacerbate disease pathogenesis. Under homeostatic conditions, neutrophils are short‐lived, and the least inflammatory mechanism of neutrophil clearance from tissues is caspase‐3 mediated apoptosis followed by engulfment by macrophages. However, in pathological conditions, neutrophil apoptosis is delayed, resulting in cell death mechanisms that exacerbate inflammation, including necrosis, pyroptosis, and the release of neutrophil extracellular traps (NETosis). Here we address the hypothesis that neutrophil apoptosis is delayed in AD, contributing to increased NET release.MethodWe assessed neutrophil apoptosis, frequency, and activation in blood from 4‐5 month old mice with 5 familial mutations for AD (5xFAD; n = 8) compared with C57BL6/J (B6; n = 8) as controls. Active caspase‐3 was stained in neutrophils using a fluorescent probe and distinguished from secondary necrosis via a membrane impermeable viability stain. Activation was assessed as the percentage of neutrophils expressing low levels of CD62L. Neutrophils were assessed fresh and after 4 hours of rest in complete culture medium. In addition, we investigated the ability of the osmolyte ectoine to rescue neutrophil apoptosis by incubating blood with 1mM ectoine for 4 hours. Finally, plasma was assessed for neutrophil elastase (NE) via ELISA as a marker of NET release.ResultIn 5xFAD blood, we found significantly decreased neutrophil apoptosis and increased total neutrophils compared to B6 blood. Upon resting for 4 hours in complete culture media (R10), neutrophil apoptosis nearly normalized in 5xFAD mice compared to controls, suggesting a continual in vivo stimulus is required. We observed significantly increased NE in plasma of the 5xFAD mice compared with controls that correlated with neutrophil apoptosis. Using a level of ectoine previously demonstrated to promote neutrophil apoptosis, we observed increased neutrophil apoptosis and reduced neutrophil frequencies in blood from B6 mice but not 5xFAD mice after 4 hours.ConclusionThese data provide evidence of dysregulated neutrophil apoptosis in AD that associates with increased NET release. These data also suggest that AD neutrophils may be resistant to some apoptosis promoting agents, prompting further research into the mechanisms involved in delayed neutrophil apoptosis in AD.