bluuebunny/crossref_metadata_2025_split huggingface dataset:
Omics‐Imaging Data Integration via Mediation Analysis with High‐Dimensional Exposures and Mediators
Authors: Zhao Yi , Li Lexin 
Published: December 2023

AbstractBackgroundMultimodal technologies have transformed AD research in recent years, by collecting different types of data from the same group of subjects and enabling the investigation of complex interrelated mechanisms underlying AD development.MethodIn this article, a mediation analysis approach with high‐dimensional exposures and high‐dimensional mediators is proposed to integrate data collected from multiple platforms. The proposed method combines principal component analysis with penalized least squares estimation for a set of linear structural equation models. The former reduces the dimensionality and produces uncorrelated linear combinations of the exposure variables, whereas the latter achieves simultaneous path selection and effect estimation while allowing the mediators to be correlated.ResultApplying the method to the AD data, it identifies numerous interesting protein peptides, brain regions, and protein‐structure‐memory paths, which are in accordance with and also supplement existing findings of AD research.ConclusionThe proposed approach is designed to integrate multiview data via a mediation framework. Under biological mechanistic assumptions, it articulates the underlying mechanisms and interrelations between data modalities and further infers disease pathology.
Altered BOLD Signal Fluctuations in precuneus relate to inflammatory markers and vascular risk in the AD spectrum
Authors: Maass Anne , Behrenbruch Niklas , Incesoy Enise I , Brosseron Frederic , Menze Inga , Bernal Jose , Hayek Dayana , Kleineidam Luca , Bürger Katharina , Fliessbach Klaus , Laske Christoph , Perneczky Robert , Peters Oliver , Priller Josef , Schneider Anja , Spottke Annika , Teipel Stefan , Wiltfang Jens , Wolfsgruber Steffen , Yakupov Renat , Wagner Michael , Jessen Frank , Duzel Emrah , Schreiber Stefanie , Heneka Michael T. , Ziegler Gabriel 
Published: December 2023

AbstractBackgroundInflammation, vascular disease and Alzheimer’s Disease (AD) appear to be closely linked. We recently showed that increased vascular risk relates to certain inflammatory profiles in CSF in the DELCODE cohort (Hayek et al, AAIC 2022). Moreover, we found cerebrovascular alterations in posterior‐midline regions including precuneus in subjects at risk for AD and with cognitive impairment relative to controls (Behrenbruch et al). Here, we examined the contributions of vascular risk and related inflammatory markers to alterations in resting‐state fMRI BOLD fluctuations that are sensitive to cerebrovascular reactivity (CVR)—a proposed marker of cerebrovascular dysfunction.MethodLeveraging resting‐state fMRI BOLD signal, we mapped voxel‐wise relative CVR (rCVR), using mean global signal as regressor, and the relative coefficient of variation (rCV). See Figure 1 for methodological details. We derived average rCV/rCVR from the precuneus as region of interest. Inflammation‐related CSF markers and AD markers (ptau181 and Aβ42/40) from CSF were available in 205 subjects with rCVR/rCV maps. A Principal component (PC) analysis on 16 inflammation‐related CSF markers previously revealed 4 PCs. PC2 and PC3 were related to higher vascular risk scores (covering hypertension, diabetes and abnormal fat metabolism based on medical reports). We used linear regression models to assess how inflammation PC scores and AD biomarkers related to precuneus rCVR or rCV (controlling for age, sex, site, education and mean framewise displacement). We also tested if rCVR/rCV was related to vascular risk or memory.ResultLower precuneus rCVR was predicted by higher values of the inflammatory component PC2 (mainly driven by markers CRP, C1q and FactorB), with no additional effect of other PCs or AD markers. Lower precuneus rCV was predicted by higher values of the inflammatory component PC3 (mainly driven by IP10, MCP1, MIF, CRP, C4) and by higher ptau. Lower precuneus rCVR was also related to higher vascular risk. Lower rCVR and rCV related to worse memory. Figure 2 shows supplementary correlations of individual inflammation markers.ConclusionLower rCVR and rCV in the precuneus that are thought to reflect vascular dysfunction, relate to higher vascular‐risk related inflammatory markers beyond AD pathology. Their concurrent dynamics requires further investigation to understand their unique contributions to microvascular pathology.
Diagnostic accuracy of a new case‐finding tool for dementia in primary care: The Brief Assessment of Impaired Cognition Questionnaire (BASIC‐Q)
Authors: Oxbøll Anne‐Britt 
Published: December 2023

AbstractBackgroundThe aim of the project was to examine the diagnostic accuracy of BASIC‐Q (Brief Assessment of Impaired Cognition Questionnaire), a questionnaire‐based tool for detection of dementia in a community setting. Community health care professionals often see citizens who are older and therefore in risk of developing dementia or having undetected dementia. BASIC‐Q is an easy and quick (≤5 min) conversation‐based tool to be used to support community health care professionals when observing signs of dementia.MethodThe project has been carried out in collaboration with 14 general practices in Denmark in the period October 2021‐October 2022. Patients ≥ 70 years with appointment in the clinic for any given reason, were invited to participate in the study. The general practitioner or the nurse at the clinic administered BASIC‐Q ‐ consisting of four questions about orientation and three questions regarding the participants memory for both the participant and a close relative. Subsequently the participant participated in a structured telephone interview and an extended cognitive testing. Among other, the extended testing consisted of RBANS (Repeatable Battery for the Assessment of Neuropsychological Status) that together with an IADL‐evaluation (instrumental activities of daily living) and GDS‐15 (15‐item geriatric depression scale) was used as gold standard for classification of cognitive status when analyzing the sensitivity, specificity, and diagnostic accuracy of BASIC‐Q.ResultThe mean age of the total of 275 participants was 77.7 years, of which 148 were women (52.9%) and 127 were men (46.1%). Of the participants 142 (51.6%) showed no evidence of cognitive impairment, 33 (12%) showed evidence of affective disorder, and 82 (29.8%) showed indications of cognitive impairment. 18 participants (6.5%) could not be classified and were not included in the analyses.ConclusionBASIC‐Q is a quantifiable indicator of cognitive function. BASIC‐Q can be used as an assistive tool when health care professionals observe signs of dementia and need to decide whether to intervene.Preliminary analyses indicate that BASIC‐Q is a reliable tool for the detection of possible dementia in primary health care. The analyses of results are still ongoing and more results regarding the BASIC‐Q’s diagnostic accuracy will follow.
Promises and Challenges of Blood Based Biomarkers of Alzheimer’s Disease and Neurodegeneration in Mild Cognitive Impairment: Importance of Non‐Alzheimer’s Aetiologies
Authors: Hamilton Calum Alexander , O'Brien John T , Heslegrave Amanda , Laban Rhiannon , Donaghy Paul C , Durcan Rory , Lawley Sarah , Barnett Nicola , Roberts Gemma , Firbank Michael J , Taylor John‐Paul , Zetterberg Henrik , Thomas Alan J 
Published: December 2023

AbstractBackgroundBlood‐based biomarkers of Alzheimer’s disease (AD) may help to rule AD in, with particular promise at the mild cognitive impairment (MCI) stage when potential disease‐modifying treatments may be most effective. However, AD is not the only common cause of cognitive impairment: Lewy body disease and other non‐AD pathologies are common and under‐recognised. Reliance on AD‐specific biomarkers alone may therefore contribute to missed diagnosis of non‐AD aetiologies. We aimed to examine the utility of emerging AD plasma biomarkers in identifying disease‐specific MCI due to AD (MCI‐AD), MCI with Lewy bodies (MCI‐LB) and in disease‐general MCI. We also aimed to compare these with alternative disease‐general biomarkers of neurodegeneration, and examined any change over time.MethodIn a longitudinal study, plasma samples were collected for 172 participants (31 healthy controls, 48 MCI‐AD, 28 possible MCI‐LB and 65 probable MCI‐LB) at baseline, and a subset (n = 55) who provided repeated samples after ≥1 year. Samples were analysed with Simoa assays for Alzheimer’s disease (Aβ42, Aβ40, ptau‐181) and neurodegeneration (GFAP and NfL) biomarkers.MCI cases were differentially classified as MCI‐AD or MCI‐LB by an expert panel of old age psychiatrists, based on current consensus diagnostic criteria, and including Lewy body disease‐specific imaging biomarkers.Age‐adjusted mixed effects models assessed any longitudinal changes over time in each biomarker, and associations with severity of cognitive impairment as assessed by the Addenbrooke’s Cognitive Examination – Revised.ResultGFAP performed comparably to AD‐specific biomarkers in identifying any‐cause MCI (GFAP AUC = 0.75; ptau‐181 = 0.73), while maintaining good accuracy in identifying MCI‐AD specifically. AD biomarkers did not reliably distinguish MCI‐AD from MCI‐LB. Severity of cognitive impairment in any‐cause MCI and MCI‐AD was most strongly correlated with the disease‐nonspecific neurodegenerative biomarker NfL (r = 0.48, p = 0.005; cf. GFAP r = 0.23, p = 0.121), which progressively increased over time.ConclusionGiven the high prevalence of unrecognised non‐AD pathologies at autopsy (>1/3 cases in UK brain banks), blood biomarkers of neurodegeneration may be a useful alternative to AD‐specific biomarkers in screening for neurodegenerative disease in MCI. As AD biomarkers do not reliably differentiate MCI‐AD from MCI‐LB, there is a need for disease‐specific biomarkers of synucleinopathies.
Taking care of family dementia caregivers: A qualitative examination of patient perspectives and perceived health outcomes after receiving usual care and after a digitally supported care management programme
Authors: Klein Olga A. , Karras Antonia , Hoffmann Wolfgang , Teipel Stefan , Kilimann Ingo 
Published: December 2023

AbstractBackgroundAlmost two‐thirds of people with dementia (PwD) living at home receive care from a family or other informal caregiver. Evidence shows that family caregivers experience increased physical, psychological, emotional, and social stress which, in the long term, results in adverse health outcomes. The development of effective healthcare and support management for family caregivers is vital. Therefore, our aim was to examine and compare the perceptions of participants who received a digitally supported care management programme with those who received usual care.MethodThis study was embedded within a multi‐centre, cluster randomized controlled trial (GAIN study) examining the effectiveness of a care management programme for family caregivers of people with dementia. The trial is registered at ClinicalTrials.gov (NCT04037501). Data collected through semi‐structured interviews with participants of the GAIN trial were audio recorded, transcribed and analysed using framework analysis. We developed two semi‐structured interview schedules, each tailored to the content of the group (control or intervention).ResultWe interviewed 36 dementia caregivers (30 women, six men) of whom 20 were in the intervention and 16 in the control group. The mean age was 68 years (SD 11,28, range 50‐82). The majority was the caregiver for their spouse, six were the caregiver for their parent and one was the caregiver for their aunt. The lengths of interviews varied between 15‐82 minutes with most interviews being 35 minutes long. Six themes were identified: (1) Health and well‐being before participating in GAIN (2) Use of services and support (3) Perceived health changes (4) Additional services discussed & received in the intervention group (5) Impact of study nurse support and (6) Possible improvements. Each theme had further sub‐themes and categories, which will be presented.ConclusionOverall, participants in the care management programme reported benefits and additional services they used as a result of being in the intervention group (e.g., rehabilitation, home adaptations, care services) compared to the control group. Having someone professional by their side was reported to be helpful and motivating. Participants of both groups also reported that they preferred house visits rather than telephone contacts. The results can be used to further improve the care management programme.
A3 receptor as a target for the treatment of Alzheimer’s disease
Authors: Farr Susan A. , Doyle Timothy M , Jacobson Kennth A. , Salvemini Daniela 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disease with clinical features including memory loss, cognitive impairment and dementia that affects over six million Americans. Current treatments for AD have limited efficacy due, in part, to the poorly understood multifactorial nature of the mechanisms driving AD. Our data suggests that alteration of adenosine kinase‐dependent adenosine metabolism and inadequate A3 adenosine receptor (A3AR) signaling in the central nervous system (CNS) are key to these processes. The SAMP8 mouse are a mouse model of sporadic AD exhibiting many key characteristics of AD including age‐associated impairment in learning and memory, which corresponds to age‐related increase in beta amyloid, phosphorylated tau, oxidative stress, neuroinflammation, impaired efflux across the blood‐brain barrier and increased regulatory T‐cells in the brain.MethodWe first measured expressions of ADK and A3AR in the hippocampus of 12 month old. SAMP8 mice. We then treated 11 month old SAMP8 mice with MRS5980 an A3AR receptor agonist MLN5980 every other day for 6 weeks. At the end of the 4th week of treatment, behavior tests were conducted for two weeks. Mice were tested in T‐maze, Novel Object Recognition (NORPT), elevated plus maze and open field.Result12 month old SAMP8 mice treated with the A3AR agonist MRS5980 had improved learning and memory in the T‐maze and NORPT compared to the vehicle treated control mice. There was no difference between the young vehicle treated SAMP8 mice and the MRS5980 treated mice. MRS5980 did not affect activity or anxiety in the open field or elevated plus mazes indicating these factors did nor contribute to improvement in learning and memory.ConclusionHere we identify A3AR in key cognitive centers of the brain and its expression increases with cognitive impairment in the SAMP8 AD mouse model. Moreover, adenosine kinase, an enzyme that reduces extracellular adenosine, also increased. We discovered that supplemental A3AR signaling with highly selective, orally bioavailable, CNS‐penetrant A3AR agonists reversed cognitive impairment without any confounding influence on locomotor activity or anxiety. Our results indicate that A3AR is a useful pathway to give additional insight into changes in the brain with AD potential novel therapies.
Social health and subsequent cognitive capability: examining the potential mediating roles of depression symptoms and inflammatory biomarkers
Authors: Stafford Jean , Dekhtyar Serhiy , Ning Ke , Welmer Anna‐Karin , Vetrano Davide Liborio , Grande Giulia , Marseglia Anna , Moulton Vanessa G , Mansfield Rosie , Liu Yiwen , Ploubidis George B , Gessa Giorgio Di , Richards Marcus , Davis Daniel , Patalay Praveetha , Maddock Jane 
Published: December 2023

AbstractBackgroundSocial health (SH) markers, including marital status, contact frequency, network size, and social support, have been linked with increased cognitive capability. However, the underlying mechanisms remain poorly understood. We aim to investigate whether depression symptoms and inflammatory biomarkers mediate associations between SH and cognitive outcomes.MethodWe used data from waves 1‐9 of the English Longitudinal Study of Ageing, involving 7,136 participants aged 50 or older at baseline. First, we examined associations between SH (wave 1) and depression and inflammatory biomarkers (C‐reactive protein (CRP) and fibrinogen) (wave 2) using linear regression models. Second, we tested associations between a) SH and b) depression and inflammation with subsequent standardised verbal fluency and memory in wave 3 and change between waves 3‐9, indexed using slopes derived from multilevel models. We adjusted for age, sex, socio‐economic position, cardiovascular disease, basic and instrumental activities of daily living, health behaviours, and baseline depression symptoms and cognition. We will also conduct causal mediation analysis.ResultAll SH markers, except contact frequency, were associated with lower subsequent depression, but not inflammatory biomarkers. Greater contact frequency (e.g. once‐twice a week vs <once per year: β = 0.18 [0.01, 0.36]) and less negative support (β = 0.02 [0.00, 0.03]) were associated with higher verbal fluency. Larger network size (>6 people vs none: β = 0.007SD/year [0.001, 0.012]), less negative (β = 0.001SD/year [0.001, 0.002]) and more positive support (β = 0.001SD/year [0.000, 0.001]) were linked with slower memory decline, and more positive support predicted slower verbal fluency decline (β = 0.001SD/year [0.000, 0.001]). Depression symptoms were associated with lower memory and verbal fluency, and faster memory decline (β = ‐0.001SD/year [‐0.001, ‐0.000]) and verbal fluency (β = ‐0.001SD/year [‐0.001, ‐0.000]). CRP was associated with lower verbal fluency (β = ‐0.02 [‐0.04, 0.00]), whereas fibrinogen was linked with faster memory decline (β = ‐0.001SD/year [‐0.003, ‐0.000]).ConclusionDepression symptoms and SH showed associations with subsequent cognitive capability and change. SH was linked with lower depression, but not inflammatory biomarkers. Findings highlight the potential for depression to underpin associations between SH and cognition, a pathway which we will test using causal mediation analysis. We will also examine whether findings replicate in the Swedish National Study of Aging and Care in Kungsholmen.
Association between Mild Behavioral Impairment trajectories and AD biomarkers in adults with Mild Cognitive Impairment. Results from the CompAS study
Authors: Mallo Sabela Carme , Fernández Miguel Ángel Rivas , Vázquez‐Vázquez Laura , Galdo‐Álvarez Santiago , Lindín Mónica , Nieto‐Vieites Ana , Juncos‐Rabadán Onésimo , Aldrey Jose M. , Díaz Fernando , Ismail Zahinoor , Pereiro Arturo X 
Published: December 2023

AbstractBackgroundOur aim was to investigate the association of the NPS trajectories in time measured by MBI‐C for MCI patients with the CSF biomarkers and temporal lobe atrophy detected at baseline.MethodCSF biomarkers at baseline were obtained from 71 patients with MCI belonging to Compostela Aging Study (CompAS) (Spain). Positivity for A (β‐amyloid), T (p‐Tau), and N (t‐Tau) was defined by cut‐off levels. Structural MRI was employed to evaluate cortical thickness and volume. Mild behavioral impairment was assessed using the validated Spanish‐language MBI‐C (Mallo et al., 2018) at baseline, 24 months, and 60 months follow‐up. Spearman correlations were performed to evaluate the relationships between CSF biomarkers at baseline and MBI‐C scores for the three evaluations. Logistic regressions were used to test the predictive value of the MBI‐C scores at each evaluation on the biomarkers’ positivity at baseline, and linear regression analyses to test the relationships between cortical thickness and volume at baseline and the three MBI‐C scorings.ResultsSpearman correlations showed no significant relations between MBI‐C and β‐amyloid, pTau, tTau and tTau/β‐amyloid ratio at baseline. However, significant positive correlations appeared between MBI‐C at 24‐month follow‐up and pTau (rho = .371), tTau (rho = .282) and tTau/β‐amyloid ratio at baseline but not with β‐amyloid. MBI‐C scores at the 60‐month follow‐up only significantly correlated with tTau/β‐amyloid ratio (rho = ‐.418). MBI‐C at 24 months and at 60 months were respectively predicted by pTau and tTau (Table 1). Linear regression analyses showed that MBI‐C at 24 months was predicted by cortical thickness of entorhinal, fusiform, inferior temporal, inferior parietal, middle and supramarginal gyri. MBI‐C at 24 and 60 months were predicted by Volume of entorhinal, inferior temporal, precuneus and whole hippocampus (Table 2).ConclusionThe markers of atrophy in structures of the medial temporal lobe and the lateral and parietal temporal lobe, and pTau+ or tTau+ in MCI patients at baseline were associated with worsening of neuropsychiatric symptoms at 24 and/or 60 months.
Integrating population neuroscience and syndemics frameworks to better understand global sex and gender‐based risk in Alzheimer’s disease and related dementias
Authors: Shaaban C. Elizabeth , Trani Jean‐Francois , Babulal Ganesh M. ,   the Sex and Gender Special Interest Group of the ISTAART Diversity and Disparities Professional Interest Area
Published: December 2023

AbstractAging populations in low‐ and middle‐income countries (LMICs) are growing more rapidly than those in high income countries (HICs). Thus, globally, the burden of Alzheimer’s disease and related dementias (ADRD) profoundly impacts LMICs, with greater burden and risk for late‐life women than men. LMICs are unable to meet diagnostic challenges with underfunded healthcare infrastructure, low numbers of clinicians with training and expertise in ADRD, and a lack of culturally and linguistically sensitive screening assessments. Emerging social and societal factors that are important risk and protective factors for later life ADRD and are differentially experienced by gender/sex are relatively understudied, yet essential in LMICs. Typical samples in neuroscience studies have been small and highly selected. They have been biased toward Western, Educated, Industrialized, Rich, and Democratic (WEIRD) samples and do not apply well to target populations in LMICs. In addition, levels‐of‐analysis across social/societal and biological determinants of disease are not typically integrated, and social/societal factors such as sociocultural (e.g., culture, religion, gender norms, access to education, discrimination, social aspects of pandemics, disability), political (e.g., governments and policies; migrants and displaced persons; war and conflict; reproductive health, justice, and agency), environmental (e.g., climate change and pollution), and economic factors (e.g., poverty), and their co‐occurrence, have been minimally considered for their role and impact on ADRD. To better understand gender/sex differences in ADRD in LMICs, we review how these social and societal factors may be important to ADRD using an integrated Population Neuroscience and Syndemics framework. Population neuroscience considers the brain in context using multiple levels of analyses, a life course perspective, and tools to enhance internal and external validity, while Syndemics suggest that diseases and social conditions may cluster and interact in populations with syndemic risk factors—sociocultural, political, economic, and environmental factors which promote stress pathways. We lay out a model in which syndemic risk and protective factors contribute to or protect from stress and biological aging and ultimately ADRD risk, both directly and indirectly through physical and mental health conditions. We close with recommendations for future aging and ADRD research based on this integrated Population Neuroscience‐Syndemics of ADRD framework.