bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epigenetic age from peripheral blood predicts progression to Alzheimer’s disease, white matter disease burden, and cortical atrophy
Authors: Bonham Luke W. , Sirkis Daniel W. , Pang Alina PS , Sugrue Leo P , Santamaría‐García Hernando A , Ibanez Agustin , Miller Bruce L , Yokoyama Jennifer S. , Corley Michael J ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

AbstractBackgroundCross‐sectional studies suggest a limited but promising relationship between epigenetic clocks, estimated using DNA methylation patterns, and Alzheimer’s disease (AD) pathophysiology and risk. However, prior analyses did not utilize longitudinal analyses or neuroimaging biomarkers of AD. Herein, we employed survival and structural neuroimaging analyses to test the hypothesis that DNA methylation age predicts AD progression.MethodUsing data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we calculated two established epigenetic ages, ‘DNAmPhenoAge’ and ‘DNAmGrimAge’ which proxy biologic age and mortality risk, respectively. Using Cox proportional hazard regression analysis in normal controls (NC), we tested whether DNAmPhenoAge/DNAmGrimAge associated with progression to mild cognitive impairment (MCI) or AD. Structural magnetic resonance (MR) images were segmented using Freesurfer 5.1 and a previously described white matter hyperintensity (WMH) quantification pipeline. Multiple regression analysis was used to test whether DNAmPhenoAge/DNAmGrimAge predicted WMH volumes and cortical atrophy.ResultReplicating prior work, we found no significant differences in DNAmPhenoAge and DNAmGrimAge between NC (n = 128), MCI (n = 251), and AD (n = 50) diagnoses. Strikingly, however, in NC participants, both DNAmPhenoAge (p = 0.004) and DNAmGrimAge (p = 0.05) associated with progression to MCI or AD (Figure 1). Even after correction for chronologic age, DNAmPhenoAge remained significantly associated with progression to MCI or AD (p = 0.01). Utilizing samples from across the spectrum of normal aging to AD, DNAmPhenoAge and DNAmGrimAge strongly associated with WMH in all diagnoses (Table 1). Moreover, DNAmPhenoAge remained significantly associated with WMH in select groups after correction for chronologic age (Table 1). Finally, both DNAmPhenoAge and DNAmGrimAge predicted cortical thickness in multiple AD‐relevant regions (Figure 2).ConclusionIn contrast to earlier work suggesting limited applicability of blood‐based DNA methylation scores in the context of AD, our novel survival and neuroimaging analyses have revealed the broad utility of second‐generation epigenetic clocks not only in predicting progression to MCI and AD but also via their association with neuroimaging biomarkers of AD, including white matter disease burden and cortical atrophy in AD‐relevant regions. Easily accessible, blood‐based measures of biologic age therefore represent promising predictors of AD risk and pathophysiology.
Novel mouse models of late‐onset Alzheimer’s disease
Authors: Sasner Michael , Oblak Adrian L , Pandey Ravi S , Uyar Asli , Garceau Dylan , Kotredes Kevin P , Soni Disha , Lin Peter Bor‐Chian , Ingraham Cynthia , Lamb Bruce T , Howell Gareth R , Carter Gregory W ,   MODEL‐AD
Published: December 2023

AbstractBackgroundThe Model Organism Development and Evaluation for Late‐onset AD (MODEL‐AD) Consortium was established to generate and characterize more translatable animal models for late‐onset Alzheimer’s disease (LOAD) based on human genetic risk variants. While numerous genetic risk loci for LOAD have been identified, few have been experimentally verified in vivo and in many cases the risk variants have not been validated. The development of new models incorporating LOAD genetic risk should improve our understanding of disease mechanisms and improve preclinical testing of potential therapeutics.MethodCoding and non‐coding LOAD risk variants were prioritized based on human data sets, with the goal of targeting diverse pathways (e.g., neuroinflammation, vascular risk, metabolic function, lipid homeostasis). Risk variants in Abca7, Adamts4, Bin1, Erc2, Mthfr, Mtmr4, Plcg2, Ptk2b, Slc6a17, Snx1, Sorl1 and other loci were engineered into mouse models expressing humanized APOE4 and the Trem2*R47H risk variant; in more recent models, a humanized Abeta allele was also included. A novel transcriptomic panel, based on clinical LOAD samples (Preuss et al, 2020) was used to evaluate how well each model replicated clinical transcriptomic changes with disease. Models were aligned to ROSMAP clinical subtypes.ResultWe have identified specific human AD‐related pathways disrupted in an age‐dependent manner in these novel mouse models. Specifically, mouse models carrying human AD risk variants Abca7*A1527G, Mthfr*C677T, and Plcg2*M28L exhibited transcriptomics changes similar to those seen in LOAD patients. Most models could be readily matched to either the inflammatory or non‐inflammatory subtype.ConclusionWe have prioritized mouse models expressing LOAD risk variants in Abca7, Mthfr, and Plcg2 for comprehensive phenotyping using clinically relevant measures including transcriptomics and proteomics, biomarkers, neuropathology and in vivo imaging at advanced ages (24 months). Ongoing projects will use human data to guide how to combine alleles to create models that match multi‐omic signatures of AD subtypes and test the effects of environmental risk factors such as high‐fat diet. Through this effort we aim to develop improved models for testing targeted therapeutics.
Usefulness of R2 maps to detect GM changes in AD continuum: a pilot study
Authors: Martin‐Echave Marta , Montesinos Paula , Grau‐Rivera Oriol , Suarez‐Calvet Marc , Puig‐Pijoan Albert , Minguillon Carolina , Cascales‐Lahoz Diego , Contador José , Fernández‐Lebrero Aida , Navalpotro Irene , Sanchez‐Gonzalez Javier , Gispert Juan Domingo , Falcon Carles 
Published: December 2023

AbstractBackgroundMRI multi‐echo sequences can be used to compute quantitative R2 maps (1/T2). This pilot study aimed to determine whether R2 maps might offer relevant information on GM changes in AD continuum.MethodThe sample consisted of 60 subjects: 20 healthy controls (HC), 20 cognitively unimpaired individuals with CSF Aβ42/40<0.071 (preAD) and 20 subjects with clinical diagnosis of Alzheimer disease (AD) validated by biomarkers (Ab42/p‐Tau181 ratio <10.25; Lumipulse‐Fujirebio). The MRI protocol included 3D T1W (voxel size: 1.2×1.2×1.2mm3, TR = 9.8ms, TE = 3ms, TI = 900ms) and multi‐echo (GRASE, voxel size: 2×2.2×2 mm3, TR = 2000ms, 32 echoes, TE: successive multiples of 9.3ms). R2 maps were obtained through linear regression of the logarithm of multi‐echo images. GM and R2 maps were spatially normalized to the MNI and smoothed (8mm FWHM). Voxel‐wise one‐way 3‐group ANOVA and post‐hoc paired t‐tests were performed on modulated GM (GMv) and R2 maps using age and sex as confounders and applying a common GM mask (SPM12, statistical threshold: p<0.001 uncorrected; k>100 voxels (∼0.33cm3) in all analyses).ResultTable 1 displays the descriptive statistics of the sample. Figure 1 shows the results from post‐hoc two‐sample t‐tests between HC and AD for GMv and R2 maps. GMv decrements were mostly located in temporal and parietal regions, as expected. Differences in R2 maps covered those regions but also others such anterior cingulate. No differences were found between HC and preAD neither in R2 maps nor in GMv.ConclusionResults might indicate that changes in R2 are not only reflecting atrophy but other undetermined tissular changes. Further research is warranted to further determine the mechanisms underlying R2 maps changes and the potential usefulness of R2 maps in AD characterization and diagnosis.
Association between coronary artery atherosclerosis and Alzheimer’s disease pathology: preliminary results
Authors: Yahagi‐Estevam Maristella , Farias‐Itao Daniela Souza , Grinberg Lea T. , Leite Renata Elaine Paraizo , Rodriguez Roberta Diehl , Paes Vitor Ribeiro , Pasquallucci Carlos Augusto , Nitrini Ricardo , Jacob‐Filho Wilson , Suemoto Claudia Kimie 
Published: December 2023

AbstractBackgroundCoronary heart disease (CHD) is the leading cause of mortality worldwide. Dementia is also among the ten most common causes of mortality, and it is one of the main causes of disability in older people. However, the association of direct morphometric percentage of obstruction in coronary arteries with Alzheimer’s disease (AD) type‐pathology remains unclear. We investigated the association of the percentage of obstruction of coronary arteries with AD type‐pathology.MethodThe heart and brain of participants 50 years or older, who underwent full‐body autopsy were collected. The main coronary arteries were dissected and the region with the largest luminal narrowing or with unstable plaques were sampled. The percentage of obstruction was calculated using the lumen and internal elastic lamina areas. The dependent variable was defined by the presence of at least moderate AD‐type pathology (Braak≥3 and CERAD≥B), according to the Braak staging for neurofibrillary tangles, and CERAD for neuritic plaques. Regression models were adjusted for sociodemographic and clinical factors, with robust standard error to account for repeated measures in the same individual.ResultThe sample included 193 participants (mean age = 75±12 years old, 56% men, and 70% white). The percentage of obstruction of coronary arteries was not associated with the neuropathological diagnosis of AD (OR = 1.00, 95% CI = 0.99; 1.01, p = 0.52), Braak staging (β = ‐0.002, 95% CI = ‐0.009;0.003, p = 0.36) or CERAD (β = ‐0.0002; 95% CI = ‐0.005;0.004, p = 0.93).ConclusionThere is no association between coronary artery obstruction and AD type‐pathology in this autopsy study with morphometric measurements of atherosclerosis.
The association of neighborhood socioeconomic status, cognition, cardiovascular risk factors, and vascular risk biomarkers in the HABS‐HD study
Authors: Vintimilla Raul 
Published: December 2023

AbstractBackgroundNeighborhood socioeconomic status (NSES) is linked to poorer cognition and physical health, influencing the risk of cardiovascular disease and mortality. Adverse neighborhood conditions have been also associated with higher cardiovascular biomarker levels. This study goal is to examine whether NSES is associated with cognitive function and whether this relationship is explained by associations between NSES and cardiovascular risk and biomarker factors in a sample of non‐Hispanic Whites (NHW) and Mexican American (MA) elders.MethodWe studied 1391 subjects from the Health and Aging Brain Study (HABS‐HD) with signed consent, fasting blood samples, 3T MRI, clinical evaluation, and cognitive testing. Area deprivation index (ADI) was used as a measure NSES. Cardiovascular risk factors (CVRF) were ascertained by self‐ report and medical history, and biomarkers were assayed via a multiple‐plex biomarker assay platform using electrochemiluminescence. Three linear regression models examined the association of ADI with cognitive performance, adjusting for age, sex, and education, CVRF, and vascular risk biomarkers.ResultSixty percent of the sample were female. MA were significantly younger, less educated, and had higher ADI scores than NHW. They also had lower scores in global cognition and executive function measures. MA had a higher prevalence of hypertension, diabetes and obesity (p = <0.0001). After controlling for demographic variables, ADI was associated with SEVLT [NHW (B = ‐0.003, t = ‐2.18, p = 0.02); MA (B = ‐0.005, t = ‐2.96, p = 0.003)] and Trails B [NHW (B = ‐0.006, t = ‐2.55, p = 0.01); MA (B = ‐0.01, t = ‐3.76, p = <0.001)] scores in both ethnic groups. Dyslipidemia influenced the association of ADI with SEVLT in MA, while obesity influenced the association of ADI and trails B in NHW. The association of ADI and trails B was partially influenced by IL6 in MA, and this association was partially influenced by TNF, CRP, and VCAM values in NHW.ConclusionNSES may influence cognitive functioning. This relationship is only partially explained by CVRF and vascular blood biomarkers. Future research is needed on the longitudinal relationships of NSES, cognitive impairment, and vascular factors.
Entorhinal Cortex Circuit Dysfunction in Mouse Models of APOE4 and Chemotherapy‐Induced Cognitive Impairment
Authors: Luo Nancy , Vicini Stefano , Rebeck Bill 
Published: December 2023

AbstractBackground
APOE4 has broad effects, one of which is worsened cognitive outcomes in cancer survivors following chemotherapy treatment compared to APOE3.Method1‐2 month old female APOE3 and APOE4‐Targeted Replacement (TR) mice were used for whole cell patch‐clamp experiments in the entorhinal cortex. Chemotherapy was introduced via a single injection of doxorubicin (10 mg/kg) or saline (control) and treated APOE‐TR mice were euthanized 1 week post‐injection. 0.5% biocytin internal solution was used to visualize cell morphology post hoc under a confocal microscope.ResultsPyramidal cells in the entorhinal cortex of APOE4‐TR mice (4 mice, n = 26 cells) exhibit significantly decreased spontaneous excitatory and inhibitory postsynaptic current frequencies, thereby contributing to an elevated excitatory‐inhibitory balance compared to APOE3‐TR mice (4 mice, n = 23 cells). Doxorubicin‐treated APOE3‐TR mice (4 mice, n = 33 cells) show a significant increase in spontaneous excitatory and inhibitory postsynaptic current amplitudes compared to controls (2 mice, n = 16 cells), while doxorubicin‐treated APOE4‐TR mice (5 mice, n = 20 cells) display no such synaptic changes compared to controls (4 mice, n = 19 cells).Conclusion
APOE4 has baseline effects on entorhinal cortex circuit inhibition and the lack of response to chemotherapy may reflect reduced resilience to stressors.
Biofluid markers of Alzheimer’s disease‐associated CNS inflammation in adults with Down syndrome
Authors: Belbin Olivia , Iulita Maria Florencia , Serrano‐Requena Sara , Videla Laura , Barroeta Isabel , Benejam Bessy , Altuna Miren , Tamayo Natalia Valle , Cervantes‐Gonz Alba , Gil Laia Lidón , Dols‐Icardo Oriol , Bejanin Alexandre , Alcolea Daniel , Lleó Alberto , Fortea Juan , Carmona‐Iragui Maria 
Published: December 2023

AbstractBackgroundDown syndrome (DS) is a genetically determined form of Alzheimer’s disease (AD), and a priority population to study early AD changes. This study explores inflammatory markers in biofluids over the course of the AD continuum in adults with DS.MethodThis is a cross‐sectional study of the Olink Target 96 Inflammation (v.3022) panel in paired plasma and CSF from adults with DS from the DABNI cohort across the AD continuum (83 asymptomatic and 109 symptomatic), 60 cognitively unimpaired controls and 130 sporadic AD (sAD) patients. See Table for demographics. We used linear regression to compare group differences, including age and sex as covariates. Age was excluded and intellectual disability was added as a covariate when comparing across AD stages in DS. We controlled the false discovery rate using the Bonferonni‐Hochberg method and considered only statistically and biologically relevant changes (fold‐change+/‐10%, adj.p<0.05).ResultWe detected 59/96 inflammatory markers on the panel in CSF and 81/96 in plasma. In asymptomatic DS vs CN, 12 inflammatory markers were decreased (<0.84‐fold, adj.p<0.02) and 3 were increased (>1.27‐fold, adj.p<0.03) in CSF. In the same comparison in plasma, 2 were decreased (<0.84‐fold, adj.p<0.03) and 26 were increased (>1.13‐fold, adj.p<0.04). Over the AD continuum in DS, 29 inflammatory markers were increased (>1.1‐fold, adj.p<0.04) and 1 was decreased (0.78‐fold, adj.p = 0.003) in CSF. We did not see the same profile in sAD vs CN CSF (1 marker; 1.59‐fold, adj.p<0.0001). To focus on CNS inflammation, we restricted plasma analyses to the 11 inflammatory markers that showed AD‐associated changes in CSF and correlated between both biofluids (r2 = 0.03‐0.43; p<0.04). CCL23, CCL3, CXCL9 and CXCL10 were increased over AD stages in plasma (>1.15‐fold, adj.p<0.03) with similar effect sizes to those in CSF (>1.17‐fold, adj.p<0.02). We observed no change in those inflammatory markers in sAD vs CN plasma (all adj.p>0.14).ConclusionTrisomy 21 is associated with a distinct inflammatory profile in CSF and plasma. However, certain markers showed similar changes in both biofluids across the AD continuum in DS. CCL23, CCL3, CXCL9 and CXCL10 represent promising novel plasma biomarkers of AD‐related inflammation in DS.
Table. Demographics (%/mean+sd) for the participants used in this study.
Developing video content for New Zealand’s online iSupport
Authors: Sani Tara P , Cheung Gary , Peri Kathy , Yates Susan , Stuckey Adrian , Kaa Beryl , Nepia Bobby , Whaanga Hēmi , Cullum Sarah J 
Published: December 2023

AbstractBackgroundThe Empowering Dementia Carers in an iSupport Virtual Assistant (e‐DIVA) project aims to develop a website based on the World Health Organisation’s iSupport to support carers in Aotearoa New Zealand (NZ), Australia, Indonesia, and Vietnam. The website will be supplemented with culturally‐appropriate videos showing different scenarios in caring. As NZ had limited funding for the adaptation process, we decided to utilise the videos already developed by the Australian team and modify them to be locally‐relevant to NZ culture. There are some similarities in the culture and ethnic populations of the two countries, but also considerable differences. Here we aim to understand the need of cultural adaptation and describe the process of developing locally‐relevant videos for self‐paced dementia training to support carers in NZ.MethodWe worked with carers and social and health care practitioners to adapt the iSupport manual for use in NZ. We conducted separate focus groups with carers and care practitioners to agree on adapted videos for use in different modules in iSupport website. We reviewed the scripts and visuals and discussed how to ensure the content (scenario, dialogue) and delivery (music, visuals) were acceptable and relatable for NZ carers from different backgrounds.To adapt for Māori carers, we took the manual and videos that had been adapted for non‐Māori, and conducted focus groups with Māori carers and care practitioners to produce content that was culturally‐appropriate and Māori‐friendly.ResultUsing co‐design and consultation with carers and care professionals from specific cultures, we made changes to the backgrounds and visual representation of the characters to better reflect NZ culture, and ensuring inclusion and representation of Māori and Pasifika in the videos. We will present the adapted videos in AAIC 2023 next to the poster.ConclusionAdapting existing videos can be a low‐cost approach to provide supporting media for an online training tool such as iSupport.
A cloud‐based application for cognitive stimulus therapy for the Togolese elderly population
Authors: Mawuli Lawson Laté Jean Paul 
Published: December 2023

AbstractThe diagnosis, management, and prevention of Alzheimer’s disease and vascular dementia are still in their early stage in Togo, a small West African country with a population of 8,966,632 and a percentage of the population over 65 years old of 3.57%. With a steadily growing elderly population, Togo has an old‐age dependency ratio of 94.5%. As clinical psychologists, practicing neuropsychological assessments, we receive more and more patients referred by medical doctors for symptoms affecting memory and reasoning. In our desire to contribute to the prevention of Alzheimer’s disease and to fight against the early onset of symptoms in our population, we propose a cloud‐based therapeutic and preventive tool called “Susu” (which is the name of memory in our local language). Susu is a cloud‐based application that allows people at risk of developing dementia to save content from their daily lives, in pictures or videos, with precise descriptions and annotations. This includes, for example, photos or videos of family members, places visited, and content specific to the person’s culture of origin. These pieces of information are stored in the cloud and will later be used in cognitive stimulation therapy based on the data stored in the cloud when the first symptoms of memory loss appear. The whole eSusu platform is a digital mental health marketplace dedicated to the prevention and care of dementia, where professionals and patients with their families can meet, exchange, and go through the process together, from assessment to therapy. As we say in our culture, the person who has lost his memory has simply forgotten the path leading to the memory hut: this memory hut is always preserved. Our commitment is simply to re‐draw the path to that memory house.
Increased regional brain inflammation predicts longitudinal brain atrophy in individuals in the Alzheimer’s disease continuum
Authors: Povala Guilherme , Bellaver Bruna , Ferreira Pamela C.L. , Lussier Firoza Z , Ferrari‐Souza João Pedro , Leffa Douglas Teixeira , Tissot Cécile , Therriault Joseph , Bezgin Gleb , Servaes Stijn , Benedet Andrea Lessa , Stevenson Jenna , Rahmouni Nesrine , Cohen Ann D. , Lopez Oscar L. , Tudorascu Dana , Klunk William E , Villemagne Victor L , Karikari Thomas K , Zimmer Eduardo R , Rosa‐Neto Pedro , Pascoal Tharick Ali 
Published: December 2023

AbstractBackgroundNeuroinflammation typically involves the activation of microglial cells in the brain and has been linked to Alzheimer’s disease (AD) pathology. However, how microglial activation influences brain neurodegeneration in individuals across the AD continuum is still poorly understood. Here, we aimed to investigate the influence of microglial activation in longitudinal brain atrophy in individuals across the AD continuum. We hypothesize that high levels of regional brain inflammation predict widespread brain atrophy.MethodWe assessed 95 individuals from the TRIAD cohort (60 cognitively unimpaired and 35 cognitively impaired) with available [11C]PBR28‐PET, a measure of microglial activation, and a 2‐year longitudinal MRI (mean = 2.07 years). We generated grey matter voxel‐based morphometry (VBM) images using SPM12 and DARTEL, smoothed with a Gaussian kernel of full‐width half maximum of 8mm. We built the uncorrected (p < 0.05) association matrix between the [11C]PBR28‐PET SUVR and longitudinal VBM ROIs (z‐score) with the β‐estimates from linear regressions accounting for age, sex, and diagnosis. We divided the [11C]PBR28‐PET levels into terciles (low, intermediate, and high) to generate the averages of longitudinal VBM changes.ResultBaseline ROI‐based [11C]PBR28‐PET levels associate with longitudinal brain atrophy not only locally but also in distinct brain regions (Fig 1a). After FDR‐correction, the inferior temporal cortex was the region where [11C]PBR28‐PET levels were better associated with widespread longitudinal brain atrophy (Fig. 1b). Brain atrophy was observed in AD‐related regions, including the amygdala, insula, and the superior temporal cortex, independently of global amyloid load and tau (Fig. 1b). Accordingly, individuals with higher [11C]PBR28‐PET levels in the inferior temporal cortex presented increased longitudinal brain atrophy compared to individuals with lower [11C]PBR28‐PET (Fig. 1c).ConclusionWe identified increased baseline [11C]PBR28‐PET levels in the inferior temporal cortex that were highly associated with longitudinal brain atrophy in individuals across the AD continuum. Our results demonstrated that higher levels of inflammation in key brain regions could predict widespread longitudinal brain atrophy, suggesting that microglial activation has a detrimental impact on AD‐related neurodegeneration progression.