bluuebunny/crossref_metadata_2025_split huggingface dataset:
Low and asymmetrical hippocampal glutamate levels in healthy older adults
Authors: Roalf David R , Robinson Heather , Kesselring Irena , Jee Joelle , Mordy Arianna , Ruparel Kosha , Meeks Jacqueline , Wolk David A. , Nanga Ravi Prakash Reddy , Gur Ruben C , Reddy Ravinder 
Published: December 2022

AbstractBackgroundGlutamate (Glu) is a critical molecule in cellular metabolism and the most abundant excitatory neurotransmitter in the brain. Glutamate dysfunction is common in neurodegenerative disorders—patients with Alzheimer’s disease (AD) have lower hippocampal glutamate—and likely contributes to age‐related declines in cognitive functioning. The extant literature on age‐related changes in brain Glu is small and all studies have employed proton spectroscopy. Thus, in this investigation we use a novel 7T magnetic resonanace imaging technique, Glutamate Chemical Exchange Saturation Transfer (GluCEST), to compare bilateral hippocampal brain Glu in between healthy old and young adults.MethodHippocampal GluCEST data were acquired from 14 healthy older adults [HOA; age: 71 (+/‐3)] and 10 young healthy adults [HYA; age: 21 (+/‐3)] using a Siemens 7T Terra. GluCEST data was acquired in axial slice positioned through bilateral hippocampus. Associations between MoCA scores and bilateral hippocampal GluCEST levels were investigated.ResultBilateral glutamate levels were 7% higher HYA as compared to HOA. HOA showed significant asymmetry (Left>Right) within the hippocampus while GluCEST in HYA were equivalent across hemisphere (t(22)=2.37, p<0.03). Within HOA, higher left hippocampal GluCEST levels were associated with higher performance on the MoCA [r(13)=0.55, p<0.04].ConclusionGluCEST appears to be a marker of aging‐related neurological and cognitive change. The present findings are similar to previous findings in AD (Graff‐Radford et al., 2013) Moreover, the left‐right asymmetry in GluCEST aligns with recent translational studies indicating a left‐right dissociation in long‐term memory function, which may be partially mediated by asymmetries in glutamate receptor content (Shipton et al., 2014). This preliminary study is the first to compare GluCEST levels in young and older adults and is the first step towards elucidate age‐related trajectories of glutamatergic alterations and their relationship to clinical and cognitive phenotypes.
Caregiving Experiences during the COVID‐19 Pandemic
Authors: Ta Kevin , Alto Raquel , Nguyen Krystal , Nguyen Rachel , Tran Duyen , Meyer Oanh L. 
Published: December 2022

AbstractBackgroundCaring for a family member with cognitive impairment can be emotionally and physically exhausting. Caregiver challenges have been exacerbated by the COVID‐19 pandemic. This qualitative study examined caregiving experiences during the pandemic, exploring what caregivers perceived as most important in their caregiving experience while navigating through the pandemic.MethodWe enrolled 158 adults (non‐Hispanic White (NHW): 66%; Latino: 16%; Black: 9%; Asian: 8%) caring for a family member with MCI, mild cognitive impairment, (35%) or dementia (65%). Approximately 37% were recruited from an Alzheimer’s Disease Research Center (ADRC) and 63% from the community. Caregivers completed demographic questionnaires and open‐ended questions about their experience during the pandemic. They were asked (1) what was the most important thing to them in terms of providing care; (2) if they felt that they had enough support to help them provide care; (3) how the COVID‐19 pandemic has impacted them and the care they provide; and (4) what strategies have they used to help them provide care. Responses were open‐coded by 2 teams of 2, who met several times with the principal investigator to discuss and refine the themes.ResultSeveral themes emerged from the analyses, including (1) caregivers managing their own physical health and safety, or that of their care recipient; (2) changes in relationship dynamics and familial support; (3) fluctuations in availability of formal support; (4) focus on wellness; and (5) employment/financial concerns brought upon by the pandemic.ConclusionThe pandemic has filled the lives of caregivers with more adversities and struggles, which can exacerbate the stress of caregiving and call attention to the need for more formal support. These findings highlight the urgent need for more online and at‐home caregiving resources that can continue beyond the pandemic.
GWAS of Genetic Resilience to Age‐Related Risk for Alzheimer’s Disease in Admixed African Ancestry Individuals
Authors: Belloy Michael E , Guen Yann Le , Eger Sarah J , Napolioni Valerio , He Zihuai , Mormino Elizabeth C. , Greicius Michael D 
Published: December 2022

AbstractBackgroundWe sought to identify genetic variants that confer resilience to age‐related Alzheimer’s disease (AD) risk in subjects of admixed African ancestry.MethodsParticipants were ages 60+, of African ancestry (> = 25%), and diagnosed as cases or controls. Genetic data were available from SNP arrays imputed to TOPMed, whole genome sequencing (WGS), or whole exome sequencing (WES). Genome‐wide association studies (GWAS) were performed per data type, split by Hispanic/non‐Hispanic participants (Table‐1), followed by meta‐analysis (Plink v2.0; GWAMA v2.2.2). GWAS performed multiple linear regression on an AD‐age score that models resilience to age‐related risk for AD (Le Guen & Belloy et al. 2021; Figure‐1). Models adjusted for sex, APOE*4/APOE*2 dosage, the first five genetic principal components (PC‐AiR; GENESIS; R v3.6), and array/sequencing center. Brain amyloid Positron Emission Tomography (PET) qualitative reads together with SNP array data imputed to TOPMed were also available for African American individuals in A4. These data were independent from the primary GWAS and were used to evaluate significant GWAS variants for their association with binarized amyloid outcome (negative/positive), using a consistent model that additionally adjusted for age‐at‐scan.ResultsWe found a novel protective genome‐wide significant intergenic variant (rs77450754) ∼200kb downstream of ATXN8OS/KLHL1 (Figure‐2‐3). It has a MAF of 13% in African ancestry samples, but is rare (0.1%) in Europeans and (<2%) Latino/Admixed Americans in gnomAD v.3. The latter may explain why effects appeared less pronounced in the considered Hispanic samples (since linkage to potential causal nearby variants may differ) (Figure‐3). The variant also displayed a protective, non‐significant, association with brain amyloid in African ancestry samples (Table‐2). Interestingly, KLHL1, also known as MRP2, is a member of the superfamily of ATP‐binding cassette (ABC) transporters, and has potential functions related to neurite outgrowth and efflux transport at the blood‐brain barrier, supporting its potential relevance to AD pathogenesis.ConclusionsOur results provide new insights into genetic resilience to AD across aging and emphasize the importance of including ancestrally‐diverse populations in genetic studies. Our results also highlight the need for the field to compose ancestrally‐diverse multi‐omics and endophenotype data to support further validation analyses of genetic risk loci prioritized from GWAS.
The Effect of Apolipoprotein e4 on Object Mnemonic Discrimination in Healthy Adulthood.
Authors: Lancaster Claire L , Daly Jessica , Berens Samuel , Tabet Naji , Dowell Nicholas , Bakker Arnold , Bird Chris , Rusted Jennifer M 
Published: December 2022

AbstractBackgroundImpairment in mnemonic discrimination is a hallmark feature of the very early stages of Alzheimer’s Disease (AD) and is associated with aberrant hippocampal function. Carriers of an Apolipoprotein (APOE) e4 gene, the most well‐established risk factor for AD, show differences in hippocampal function from youth. The cognitive consequences of altered brain activation in this group, however, remain poorly understood.MethodsAn online web‐platform has been developed – the APOE Memory Bank, which presents a collection of in‐depth behavioural tasks targeting hippocampal (object and spatial mnemonic discrimination) and non‐hippocampal cognitive processes (prospective memory, working memory and executive control). Cognitively healthy adults (aged 45–65 years) were invited to take part from the NIHR BioResource database. Selection processes have ensured a well‐matched, equivalent sample of e4 carriers and non‐carriers.ResultsFour hundred and twenty‐one participants have provided data to the APOE Memory bank to date. Ongoing, pre‐registered analyses will test if APOE e4 carriers show alterations in their ability to discriminate objects in memory, and if genotype differences in the cognitive processes supporting successful mnemonic discrimination underpin disparities. The sample is enriched with a high proportion of homozygous e4 carriers, providing a novel examination of gene‐dose effects at scale.ConclusionsEstablishing which cognitive processes are sensitive to the detrimental effects of APOE e4 will advance understanding of how genotype differences in brain development confer vulnerability in this high‐risk group. To date, indices of mnemonic discrimination have been used to discriminate preclinical or prodromal AD. This research provides a novel test of whether, in mid‐life, a web‐based object mnemonic discrimination task can differentiate risk for subsequent cognitive impairment. Identifying non‐invasive, easy‐to‐administer risk markers will advance future avenues of prophylactic, personalised intervention
Infections in people with dementia and mortality: A population‐based cohort study
Authors: Mavrodaris Angelique , Mueller Christoph , Perera Gayan , Brayne Carol , Stewart Robert 
Published: December 2022

AbstractBackgroundInfections in older people are a major cause of mortality and morbidity and may be important modifiers of outcomes for people with dementia. There is limited evidence on the role of infections and associated hospital admissions on subsequent outcomes for people living with dementia. We explored mortality in individuals with dementia admitted to hospital for infections from a defined population in comparison to those not admitted and admitted for other reasons.MethodA retrospective cohort analysis was created using secondary care data from one of Europe’s largest mental health and dementia care providers in South London (UK). People with recorded dementia between January 2008 and March 2017 were linked to national hospitalisation and mortality data and classified as either admitted for infections, admitted for other causes or no admissions around first recorded dementia diagnosis and followed to death or a census date on 31st March 2019. Multivariate Cox proportional hazards regression with date of first dementia diagnosis as index date were applied.ResultIn total 14,375 people diagnosed with dementia were included, of whom 3,480 (24%) were admitted for infections, 3604 (25%) admitted for other causes and 7,291 (51%) not admitted to hospital. Individuals with dementia admitted for infections had lower MMSE scores, higher rates of co‐morbidity and ranked significantly higher on deprivation indices compared to those with no admissions. Adjusted multivariate Cox regression models indicated that people with dementia admitted to hospital for infections had significantly higher mortality rates compared to no admissions (Hazard ratio (HR): 2.3; 95% confidence interval (CI): 2.1 ‐ 2.5) and to admissions for other causes (HR: 1.5; 95% CI: 1.4 ‐ 1.6).ConclusionIn people with dementia, admissions for infections are critical events associated with substantial increased mortality risk. Addressing care patterns both before and after admission with a focus on infection could improve outcomes and is a key health research area, with optimisation of care a direct priority.
Social health factors and dementia risk – assessing potential pathways in a population‐based cohort study
Authors: Duffner Lukas , Deckers Kay , Cadar Dorina , Steptoe Andrew , de Vugt Marjolein , Köhler Sebastian 
Published: December 2022

AbstractBackgroundEpidemiological studies suggest an association between social health factors and dementia risk, but potential pathways between these factors remain largely unexplored. Therefore, the current study assesses the relationship between social isolation, social activity engagement, and dementia risk, including potential effect mediation by level of loneliness.MethodWe used data from 7520 participants of the English Longitudinal Study of Ageing (ELSA), assessed from baseline (Wave 2, 2004/2005) until Wave 9 (2018/2019) for incident dementia. Level of social isolation was defined as the frequency of contact with children, other family and friends in addition to the membership in clubs and organizations. Social activities were inferred by the self‐reported frequency of engagement in activities with a strong social component (e.g. volunteering). Both variables were dichotomized, representing low vs. high social isolation or social activity engagement. Level of loneliness was measured using the short form of the UCLA loneliness scale. Depression diagnoses were assessed through self‐report.Separate multivariable Cox proportional hazard regression models were fitted, with social isolation and social activities as predictors while controlling for age, sex, education, wealth, cardiovascular risk factors (model 1) and, subsequently, for depression and level of loneliness (model 2).ResultAfter a median follow‐up period of 11.8 years (IQR = 5.9 years‐13.9 years), 495 people (67.1 cases per 10,000 person‐years; 95% CI 61.5‐73.3) developed dementia. Higher social isolation (HR = 1.30; 95% CI 1.03‐1.64) and more frequent social activity engagement (HR = 0.74; 95% CI 0.60‐0.92) were related to dementia risk in model 1. Social isolation still predicted dementia risk in model 2 (HR = 1.30; 95% CI 1.02‐1.66), while social activity engagement did not (HR = 0.83; 95% CI 0.65‐1.07). Both depression and loneliness significantly predicted dementia risk in the model including social isolation, while, for the model including social activity engagement, only depression was associated with dementia risk. The change in HR between model 1 and 2 for social activity engagement was mainly due to adding level of loneliness rather than depression to the model.ConclusionLower social isolation and more frequent social activity engagement are associated with lower dementia risk. Part of the association might be explained by level of loneliness and depression.
Associations of AD risk factors with cerebrospinal fluid ATN biomarker profiles in 10,662 persons without dementia from the Amyloid Biomarker Study
Authors: Jansen Willemijn J. , Tijms Betty M. , Janssen Olin , Oomens Julie Elisabeth , Vos Stephanie J. B. , Verhey Frans R.J. , Visser Pieter Jelle ,   the Amyloid Biomarker Study Group
Published: December 2022

AbstractBackgroundThe pathophysiology of Alzheimer’s disease (AD) is characterized by amyloid‐β deposition (A), tau tangle formation (T) and neurodegeneration (N). In order to promote the development and implementation of a successful intervention to prevent or delay AD progression, frequency estimates of the evolution of these pathological events across age and its relation with other AD risk factors in the various pre‐dementia stages are essential.MethodsWe selected 4413 participants with normal cognition (NC), 1356 with subjective cognitive decline (SCD) and 4887 with mild cognitive impairment (MCI) from 53 studies that participated in the Amyloid Biomarker Study. We classified participants into 8 ATN biomarker profiles (A‐T‐N‐, A+T‐N‐, A+T‐N+, A+T+N‐, A+T+N+, A‐T+N‐, A‐T‐N+, A‐T+N+) based on CSF amyloid‐β42 (A), phosphorylated tau (T) and total tau (N) abnormality according to data‐driven (A) and center‐specific (TN) cutoffs. Markov‐Chain‐Monte‐Carlo generalized linear mixed models were used to evaluate associations of age, sex, educational level (dichotomized at 14 years) and APOE‐e4 copy number with frequencies of the ATN profiles.ResultsFrequencies of the ATN biomarker profiles strongly depended on age (p<0.001), cognitive status (NC vs. SCD p>0.05; NC/SCD vs. MCI p<0.001) and APOE‐e4 gene dose (p<0.001; Figure 1). In participants with NC and SCD, A+T‐N‐ was most frequent in persons with 2 ε4 alleles, A+T+N+ was most frequent with aging in persons with 1 ε4 allele while A‐T‐N‐ and A‐T+N+ were, depending on age, most frequent in non‐carriers. In MCI, the A+T+N+ biomarker profile was most frequent starting at age 55 for persons with 2 ε4 alleles, at age 60 for persons with 1 ε4 allele and at age 75 for non‐carriers. ATN biomarker profile frequencies were also associated with educational level (p=0.01). Overall, A‐T+N+ was up to 10% more frequent with aging in persons with high educational level, whereas A+T‐N‐ and A+T+N+ were about 5% more frequent across age in persons with low educational level. Sex was unrelated to ATN biomarker profile frequencies.ConclusionsFrequencies of the ATN biomarker profiles in persons without dementia changed substantially with age, cognitive status, APOE‐ε4 copy number and educational level but not sex. These results may enable a more specific approach to AD prevention.
Neuroprotective role of Syzygium aromaticum on SIRT1 and oxidative balance in Alzheimer’s disease
Authors: Yadav Yudhishthir , Dey Sharmistha , Dey Aparajit Ballav 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is a progressive and fatal neurodegenerative disorder manifested by cognitive and memory impairment. The holistic approach can be better option to prevent and treat the pathological consequences of neurodegenerative disorders. Recent studies, suggest that Ayurveda may provide a good holistic care and treatment. The accumulation of Reactive oxygen species (ROS) in the brain increases with ageing ultimately to the oxidative stress. Sirtuin1 (SIRT1) is a potential mediator of oxidative balance. Syzygium aromaticum have antioxidant properties, may help in scavenging free radical generation and prevent the diseases. This study determined the role of Syzygium aromaticum on neuroprotection and oxidative balance in amyloid beta (Aβ) induced neurotoxicity by activating SIRT1 protein.MethodThe anti‐oxidative capacity of Syzygium aromaticum was analyzed in Aβ induced neurotoxicity in differentiated SHSY‐5Y cells. The rescue effect of Syzygium aromaticum was performed by MTT assay in time and dose dependent manner. The expression levels of γ‐secretase and SIRT1 were analyzed by western blotting. The neuroprotective effect of Syzygium aromaticum by activating antioxidant enzymes under Aβ induced neurotoxicity was also observed.ResultSyzygium aromaticum was capable to scavenge ROS and elevated the percentage of anti‐oxidant enzymes. It also activated and elevated the level of SIRT1 and downregulated γ‐secretase level. The cell survival rate of Aβ induced cells was increased by the treatment of Syzygium aromaticum around 60% at 72 h.ConclusionThis study explored the role of Syzygium aromaticum in prevention of AD like pathology by targeting SIRT1 pathway. This product showed capability of neuroprotection and redox balance for management of oxidative stress.
A digital biomarker for remote self‐assessment of Alzheimer’s Diseases: development and validation
Authors: Butler Joe , Watermeyer Tamlyn J , Matterson Ellie , Harper Emily G , Parra‐Rodriguez Mario A 
Published: December 2022

AbstractBackgroundOnline data‐collection provide an opportunity for Alzheimer’s Disease research to collect large datasets crucial for understanding important public health concerns. However, the reliability of online tasks as compared to those administered in the lab is poorly examined. Our goal is to validate an online version of the short‐term memory‐binding task (STMBT), a potential digital biomarker sensitive to Alzheimer’s Disease (Parra et al., 2010), to understand if data collected online in two environments, at‐home and in the lab, is comparable.MethodWe created an online version of the STMBT task using Psytoolkit (Stoet 2010; Stoet 2017). Development involved piloting, group and user discussions to explore how such a novel tool could be best presented for self‐assessment. Useful insights led to refinement of the online tool (i.e., instruction videos, images, and text). The validation stage involves test‐retest reliability assessment of cognitively fit participants (aged >40 years) who complete the two conditions of this paradigm (i.e., shape only and binding). Task Environment (home and in the lab) and conditions (shape and binding) were fully counterbalanced. Measures of general cognitive abilities, anxiety and at‐home environment were also taken.ResultRecruitment is on‐going, but preliminary data (n = 10) has already proved informative. A repeated measures ANOVA looking at task‐accuracy with factors of Environment (home vs. lab) and Condition (shape vs. binding) revealed no significant effects of Environment: F(1, 9) = 0.308, p = .591; Condition: F(1, 9) = 2.202, p = .172); or Interaction: F(1, 9) = 0.308, p = .591). For the shape condition, all participants performed near ceiling regardless of testing environment. In the binding condition, we observed good‐to‐excellent test‐retest reliability between environments using single measures interclass correlation (ICC = 0.954, CI 0.83‐0.99, (F(9, 9) = 39.62, p <.001).ConclusionThese preliminary results indicate the STMBT can provide reliable data when self‐administered using an online version of the task which has important implications for public health researchers. For our fully powered sample, we will provide summary of other measures.
The heterogeneous amyloid‐positive brain: mapping individualised patterns of atrophy in amyloid‐positive Alzheimer’s disease patients using neuroanatomical normative models
Authors: Verdi Serena , Loreto Flavia , Kia Seyed Mostafa , Duvnjak Aleksandar , Hakeem Haneen , Perry Richard J , Win Zarni , Patel Neva , Schott Jonathan M , Marquand Andre F , Malhotra Paresh A , Cole James H 
Published: December 2022

AbstractBackgroundPatterns of atrophy in the brain highly differ between individual Alzheimer’s Disease (AD) patients, however, most clinical research focuses on group‐level differences (Verdi et al., 2021). Here we used a novel technique, neuroanatomical normative modelling, to reveal individual patterns of cortical thickness by quantifying deviations from the normative range. We applied a hierarchical Bayesian regression (HBR) normative model (Kia et al., 2021), to amyloid‐positive AD patients who had clinical amyloid PET imaging at the Imperial Memory Clinic (IMC). Patients had either AD dementia or mild cognitive impairment due to AD. We hypothesised that there would be individual differences in patterns of cortical atrophy in these patients.MethodCortical thickness across 148 regions of interest (ROIs) was generated using FreeSurfer from n=130 (102 AD patients and 28 healthy controls) T1‐weighted MRIs acquired from the IMC. A reference HBR normative model was trained on a separate dataset of n=34,490 healthy individuals to index population variability, which predicted cortical thickness at each ROI using age and sex. This generated cortical thickness z‐scores for each ROI, per patient (z‐score < ‐1.96 = outlier).ResultThe patterns of cortical atrophy outliers were highly varied in amyloid‐positive AD patients. For instance, the largest proportion of outliers in a region was 60% within the superior temporal sulci, if atrophy were homogenous we would expect 100% of outliers to be here (Fig.1). This heterogeneity was also seen when comparing how similar outlier patterns were between patients (Fig.2). We also found that the proportions of outliers differ according to disease severity, e.g. the highest percentage of outliers was 70% within superior temporal sulci within the AD dementia subgroup, and 50% in superior temporal sulci in the mild cognitive impairment due to AD subgroup (Fig.3).ConclusionAmyloid‐positivity results in heterogenous patterns of cortical atrophy. This is more pronounced in AD dementia, though still present in people with mild cognitive impairment due to AD. Neuroanatomical normative maps have the potential to be individualised markers of disease, and with application to longitudinal data could track individual disease progression.