bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recruitment and retention of US Latinos in biomedical research and clinical trials
Authors: Portacolone Elena 
Published: December 2023

AbstractLatinos/Hispanics are underrepresented in clinical trials for Alzheimer’s disease and related dementias (ADRD).This underrepresentation reduces the generalizability of research findings, widening health disparities. These are significant public health concerns, because Latinos have a higher risk than non‐Latino Whites to develop ADRD and represent 19% of the US population.Taking lessons from the micro‐meso‐macro framework of Maria Aranda et al., in this session the Recruitment and Clinical Trials Special Interest Group (SIG) of the US Consortium of Aging, Dementia & Latino Studies (CADLAS) will discuss opportunities, challenges and future directions across multiple lenses of analysis. We argue that to increase Latino representation it is essential a far‐reaching perspective sensitive to the interplay among subjective/community (i.e., micro) factors, meso factors pertaining to the domain of clinical trials and researchers, as well as macro factors such as policies of funders and regulatory agencies such as the Food and Drug Administration (FDA).The SIG aims to promote collaborations among investigators working to improve participation and retention of US Latino/Hispanic populations into clinical research. Building on the expertise of SIG members, key opportunities range from fostering career advancements while offering job opportunities to Latino outreach specialists, to playing Loteria to engage Latino audiences. Opportunities also include new ways of designing participants’ incentives moving beyond financial compensations to include ad‐hoc medical services, and caregiving and transportation supports. Challenges range from funders not requiring comprehensive and culturally‐relevant recruitment plans (and related budgets), to limited awareness of clinical trials in Latino communities. Promising directions include emerging partnerships between national organizations trusted by Latino communities and the Alzheimer’s Clinical Trial Consortium, and the recent plan of the FDA to recommend diversity plans. The session will end with a set of recommendations leveraging on opportunities and promising directions.
Soluble Abeta produces an increase in cytosolic and mitochondrial calcium in astrocytes in vivo, in part by direct effect in astroglial cells
Authors: Sanchez‐Mico Maria V. , Calvo‐Rodriguez Maria , Kelly Patricia H. , Whiteman Sara , Kharitonova Elizabeth K. , Hou Steven S. , Bacskai Brian J. 
Published: December 2023

AbstractBackgroundBy using in vivo multiphoton microscopy, we have previously reported that astrocytic cytosolic resting calcium (Ca2+) is globally elevated in a transgenic mouse model of cerebral β‐amyloidosis (APPswe/PS1dE9) (PMID:19251629). However, this phenomenon is independent of the proximity of astrocytes to amyloid β (Aβ) plaques. In addition, soluble Aβ oligomers (Aβo) are thought to mediate neuronal toxicity by increasing neuronal calcium and causing synapse loss. For those reasons, we hypothesized that Aβo, rather than Aβ plaques, contribute to the Ca2+ insult in astroglial cytosol and mitochondria in vivo.MethodTo test this hypothesis, we topically applied naturally secreted soluble Aβo (conditioned medium from cultured transgenic primary neurons) onto the brain surface of 4‐6‐month old wild‐type mice. We investigated changes on astrocyte and mitochondrial Ca2+ levels relative to baseline via intravital multiphoton imaging, by using a ratiometric genetically‐encoded FRET‐based Ca2+ indicator (Yellow Cameleon 3.6) targeted to astroglial cytosol or mitochondria.ResultWe observed that Ca2+ levels dramatically increased upon topical soluble Aβo application, in all cytosolic astrocyte compartments (soma, branches and end feet), but also in astrocyte mitochondria. Aβ‐immunodepleted transgenic conditioned media and wild‐type conditioned media did not alter astrocyte cytosolic or mitochondrial Ca2+, supporting the specificity of the observed effects. Furthermore, we have also seen this effect in cultured astrocytes, suggesting that Aβo is directly interacting with astroglial cells, and not through an effect on other cell types, such as neurons or microglia. In addition, we previously reported that upon blocking the mitochondrial calcium uniporter (MCU) with Ru360, calcium levels in neuronal mitochondria were restored (PMID:32358564). However, there was still an increase of mitochondrial calcium in astrocytes in presence of soluble Aβo and Ru360 in vivo. Thus, soluble Aβo is disrupting calcium levels in astrocytes through a different mechanism.ConclusionUltimately, these results together support a detrimental role of Aβo which leads to astrocyte Ca2+ dyshomeostasis in vivo, implying that Aβo are involved in the astrocytic dysfunction observed in AD. Future studies will continue to explore the source of soluble Aβo‐induced Ca2+ increase, including intracellular Ca2+ stores and channels involved, which could have therapeutic value.
Major changes in AD brain gene expression caused by the T9861C mtDNA mutation
Authors: Castora Frank J , Pflanzer Haley K , Alvarez Nehemiah S 
Published: December 2023

AbstractBackgroundEvidence of mitochondrial dysfunction in Alzheimer’s Disease (AD) has accumulated over the years. We have previously identified a mutation in mitochondrial DNA (mtDNA) that is strongly associated with AD. This T9861C mutation changes a phenylalanine into a leucine at amino acid position 219 of cytochrome c oxidase subunit 3, resulting in a significant reduction of cytochrome oxidase activity. We report the effect of this mutation on the expression of genes involved in mitochondrial function in AD brains.MethodTotal RNA sequencing with ribosome depletion was performed on frozen archival tissue from parietal cortex of three control and eight sporadic AD (four AD, and four AD+ (AD patients possessing the T9861C mtDNA mutation)) brains. Reads were aligned to a transcriptome reference (Ensemble, GCRh38) containing all annotated mRNA and noncoding RNA using kallisto bus (v0.48). Read counts were calculated for genes using bustools (v0.41). Count data were analyzed using RNAfuzzyApp. Read count normalization was performed using TMM and differential gene expression was determined using edgeR. Pathway enrichment was performed using Gene Ontology (GO).ResultThe heatmap shown identifies a total of 472 deferentially expressed genes (DEGs, p value <0.05, FDR <0.05) in the comparison of control vs AD vs AD+ samples. Principal component analysis shows that gene expression in AD samples is significantly different from that in controls and that a more striking difference exists between the AD+ samples and both control and AD samples. The 472 DEGs can be grouped into five clusters. These clusters impact a variety of mitochondrial functions related to synaptic signaling, cell junctions, neuron projections, the HIF‐1 signaling pathway, voltage‐gated channel activity and carbohydrate metabolism.ConclusionThe presence of the T9861C mutation in the brains of AD patients has a significant effect on expression of the brain transcriptome in the parietal cortex. There is a general and robust decrease in expression of the majority of DEGs relative to control and non‐mutation containing AD brains. There is also a smaller number of DEGs that are upregluated compared to control and non‐mutation containing AD brains. These gene expression changes impact mitochondrial function resulting in neuronal failure and neurodegeneration.
Relationship between a novel virtual reality test of mild functional difficulties and cerebrovascular disease
Authors: Holmqvist Sophia L. , Jobson Katie , DeSalme Dennis , Simone Stephanie M. , Tassoni Molly , Mckniff Moira , Yamaguchi Takehiko , Olson Ingrid , Martin Nadine , Giovannetti Tania 
Published: December 2023

AbstractBackgroundIt is well known that mild cognitive impairment (MCI) is associated with subtle functional decline. However, standardized and cost‐effective methods for the objective quantification of mild functional difficulties are lacking. Here we report preliminary validity data for a novel, non‐immersive virtual‐reality task (Virtual Kitchen Challenge [VKC]) against brain markers of cerebrovascular disease and in contrast to a conventional, self‐report measure of function.MethodTwenty (n = 14 healthy control, n = 6 MCI) community‐dwelling older adults aged 60+ completed neuropsychological testing, including the Functional Activities Questionnaire (FAQ), and the VKC, which requires completion of simulated breakfast and lunch tasks on a touch‐screen computer. White matter hyperintensity (WMH) volumes from Fluid Attenuation Inversion Recovery (FLAIR) MRI sequences were derived using the UBO detector, a cluster‐based WMH extraction pipeline based on k‐nearest neighbors (k‐NN) algorithm. WMH volumes were calculated in SPM’s DARTEL space, precluding the need to adjust for intracranial volume (ICV).ResultMCI participants reported significantly more functional difficulties than healthy controls (FAQ U = 76.50 p = .002) and obtained marginally slower completion times on the VKC (U = 60.00, p = .138). VKC completion time was moderately associated with age (r = .441, p = .059) but relations with sex, race, and IQ were weak and not significant (all rs<.195). VKC completion time significantly and strongly correlated with all WMH measures, even after controlling for age, sex, race, and IQ (total WMH r = .649, p = .031; deep WMH r = .615, p = .044; periventricular WMH r = .623, p = .041). By contrast, FAQ was not associated with WMH (rs<.2, p>.05 for all) or VKC completion time (r<.1, p>05) after controlling for age, sex, race, and IQ.ConclusionOur naturalistic, performance‐based measure of function (VKC) was not associated with race, sex, or premorbid IQ, but was strongly associated with neuroimaging markers of cerebrovascular disease (WMH). By contrast, a conventional self‐report measure of everyday functioning (FAQ) was not associated with neuroimaging measures (WMH). These results offer preliminary support for the VKC as a valid measure of early, subtle functional difficulties associated with cerebrovascular pathology that is not vulnerable to bias associated with race, sex, or premorbid IQ.
Neuropathology in the LifeAfter90 Study: 2023 update on an Ethnically Diverse Cohort Study of Oldest‐Old
Authors: Dugger Brittany N , Jin Lee‐Way , Ortega Krystle , Decarli Charles , Gilsanz Paola , Mungas Dan M. , Kawas Claudia H. , Corrada María M. M. , Whitmer Rachel A. 
Published: December 2023

AbstractBackgroundNeuropathology studies of the oldest‐old have significantly advanced our understanding of the multiple etiologies late in very late life. Most studies, however, have limited ethnoracial diversity with almost exclusively White decedents. Our goal was to characterize neuropathology in a cohort of ethnically and racially diverse oldest‐old decedents.MethodThe LifeAfter90 study is an ongoing cohort study of Kaiser Permanente Northern California members, aged 90+ with targeted recruitment of individuals across different racial/ethnic groups with no prior diagnosis of dementia in their medical record. Interviews and cognitive assessments occur approximately every 6 months. Brain donation was available to all interested consenting participants. Neuropathology was assessed using the National Alzheimer’s Coordinating Center Neuropathology form v.10 and used NIA‐AA guidelines for Alzheimer’s diagnoses. As of January 2023, 304 participants (40%) were enrolled in autopsy (20% Asian, 18% African American, 17% Latino, 9% Multiracial/Other, and 36% White).ResultOf the 304 participants, 59 had died and neuropathological evaluations were completed. The median age of death was 93 years (range 90‐105), 33 (56%) were female, 8 Asian, 5 Black, 10 Latino, 31 White, and 5 Multiracial/Other. At final clinical exam, 17 participants had dementia (29%), 25 questionable/mild cognitive impairment (42%), and 16 were cognitively normal (27%). Alzheimer disease (AD) and vascular pathologies were the most frequent findings (Figure). Twenty two percent of participants did not have AD, one lacked neurofibrillary tangles (NFT). The most severe distributions/densities of NFTs and plaques were infrequent, with high likelihood of AD in two participants. For vascular pathologies, 98% had some level of arteriolosclerosis, 97% had atherosclerosis, 70% had amyloid angiopathy, and 26% had at least one old microinfarct. Other pathologies were less common: 27% had Lewy bodies, 18% had TDP‐43 deposits, and only one had Hippocampal sclerosis. Although data is sparse to test for associations, the proportion of individuals with dementia tended to increase with increasing pathology severity especially for AD pathologies.ConclusionThis diverse cohort of oldest‐old individuals reveal numerous brain pathologies are present with advanced age, with AD and select vascular pathologies being the most common. Future analyses will investigate their role with cognitive impairment.
SLEEP MICROARCHITECTURE IN MILD COGNITIVE IMPAIRMENT: A HIGH‐DENSITY EEG STUDY
Authors: D’Rozario Angela L , Kao Chien‐Hui , Haroutonian Carla , Grunstein Ronald R , Naismith Sharon L 
Published: December 2023

AbstractBackgroundSleep disturbance and sleep disorders are potential risk factors for dementia. Adults with mild cognitive impairment (MCI) are at increased risk of developing dementia and many report disturbed sleep. Altered sleep neurophysiology including deficits in sleep spindles and slow wave activity (SWA) during NREM sleep have been reported in MCI, though studies are sparse. These NREM EEG oscillations are crucial for overnight memory consolidation and optimal daytime functioning. Abnormal EEG activity during sleep in MCI may adversely impact sleep‐dependent memory processes and cognitive trajectory. This study is the first to examine sleep microarchitecture using high‐density EEG technology in MCI.MethodOlder adults with multi‐domain MCI (n = 19, mean age 68.5 years) and cognitively‐intact controls (n = 22, 69 years) had 256‐channel high‐density EEG recordings during overnight polysomnography and resting wakefulness. Declarative (word paired associates) and procedural (finger tapping) memory tasks were administered before and after sleep. Neuropsychological testing and brain MRI scans were also performed. After artefact processing, spectral analysis was performed for high‐density EEG recordings. Topographical power maps were calculated for standard frequency ranges for NREM sleep (N2 and N3 (slow wave sleep)). Maps were compared between groups using normalized power (z‐scores computed for each subject).ResultThe MCI group had worse declarative (% retention, MCI vs Controls: 84.2 ± 16.6 vs. 94.5 ± 7.8, p = 0.024) and procedural (% early improvement: 92.9 ± 11.0 vs. 103.0 ± 12.0%, p = 0.017) overnight memory consolidation than the controls. Topographic analysis of high‐density EEG data revealed a regional increase in SWA (1‐4.5Hz) EEG power during N3 in a cluster of 18 electrodes overlying the centroparietal cortex in the MCI group (cluster mean t‐value = 3.11, p = 0.0036, uncorrected) and a regional reduction in SWA in the left frontal (5 channels, t = ‐3.75, p<0.001) and right temporal areas (5 channels, t = ‐3.46, p = 0.001), Figure 1.ConclusionOvernight memory consolidation was impaired in this MCI population. Regional differences in SWA during deep sleep were present in distinct brain regions and may indicate pathology. Future analysis exploring associations between EEG abnormalities with underlying brain structures may provide mechanistic insights into the impact of altered sleep neurophysiology on cognitive outcomes in MCI.
Fear and avoidance of memory loss: associations with cognitive, psychological and lifestyle factors in mid‐ and later life
Authors: Farina Francesca R , Wells Katie , Marquez Melissa , An Hosanna , Koychev Ivan , Malhotra Paresh A , O'Brien John T , Ritchie Craig W , Naci Lorina , Griffith James W , Lawlor Brian 
Published: December 2023

AbstractBackgroundAlzheimer’s disease and related dementias (ADRD) are among the most feared conditions. Some level of fear can motivate healthy behaviors. However, intense fears can have the opposite effect, leading to avoidance behaviors such as withdrawal from cognitively or socially demanding activities. In this way, fears and avoidance behaviors have potential to influence modifiable ADRD risk. Here, we investigated if fear and avoidance are associated with cognitive, psychological and lifestyle factors in mid‐ and later life.MethodsParticipants were middle‐aged (n = 188, 40‐59 years, mean = 51.4 ± 5, 52.7% female) and older adults (n = 746, 60‐90 years, mean = 65 ± 7.2, 61.5% female). Fears and avoidance behaviors were measured using Fear and Avoidance of Memory Loss scale. Linear regression examined the contribution of fear and avoidance to cognitive, psychological and lifestyle factors. Mid‐life factors included cognition (COGNITO), stress (Perceived Stress Scale), depressive symptoms (Center for Epidemiologic Studies Depression Scale), loneliness (UCLA Loneliness Scale) and lifestyle activities (Lifetime of Experiences Questionnaire). Later life factors included cognition (MoCA) and depression (Geriatric Depression Scale). Models were adjusted for age, gender, education, ADRD family history and anxiety.ResultsMiddle‐aged and older women reported higher fear compared to men (ps < .028). Older individuals with a family history of ADRD also reported higher fear (p < .001). Avoidance behaviors were significantly associated with worse cognitive performance in later life (β = ‐0.10, p = .020), but not in mid‐life. Greater avoidance in mid‐life was associated with higher stress (β = .83, p = .001), loneliness (β = 1.22, p < .001) and depressive symptoms (β = 1.09, p < .001), and lower engagement in lifestyle activities (β = ‐0.19, p = .02). Avoidance was also associated with depressive symptoms in later life (β = .28, p < .001).ConclusionsAvoidance behaviors were associated with lower engagement in healthy lifestyle activities in mid‐life, worse cognitive performance in later life, and reduced psychological well‐being in both mid‐ and later life. While causation cannot be determined, it is likely that these factors interact recursively over time. Thus, targeting avoidance early on may be beneficial for ADRD risk reduction.
“I am the only one I know of who participates in research”: Promoting Equitable Research Methods for Underserved Communities in Dementia Risk Reduction Research
Authors: Booi Laura , Surr Claire , Greene Leanne , Souray Rowan , Naci Lorina , Wells Katie , Keady John , Ritchie Craig W , Lawlor Brian 
Published: December 2023

AbstractBackgroundIt is widely understood that dementia researchers need to do more to foster diversity and equitable access to research participation for underserved groups (e.g. members of racialised communities, those living in low socioeconomic status, and members of the LGBTQIA+ community). Currently, the vast majority of large‐scale dementia risk reduction research participants represent white, upper middle‐class individuals from urban areas. This project identifies the motives, facilitators, and barriers to participation in dementia risk‐reduction research in healthy middle‐aged adults who are traditionally under‐represented in research.MethodsThis is a qualitative study which worked in conjunction with the PREVENT Programme, a large‐scale, multi‐centre programme which aims to establish early biomarkers of Alzheimer’s disease. Participants for this study were healthy middle‐aged adults currently participating in the PREVENT Programme, who also identified as belonging to an underserved population. The method for data collection was semi‐structured interviews using video conference technology (N = 19). Thematic analyses was used by the research team.ResultsFindings from this study highlight motivators for participating falling in three camps: altruistic, individual health curiosity and interest in research. Facilitators to inclusion in research include strong rapport with the research team, clear understanding of the study protocol, flexible scheduling of participation (e.g., evening and weekends), monetary support to facilitate on site attendance and to support time away from paid employment, and innovative use of remote digital methods of data collection. Barriers to participation encompass a lack of awareness of opportunities to participate, and research illiteracy and stigma associated with both dementia and research participation.ConclusionFindings highlight individuals from under‐served communities are less likely to take part in research for a variety of reasons. The onus is on the research community to ensure equitable access to research participation amongst diverse populations. The outcome of this study is the development of guidelines for large‐scale epidemiological studies to encourage diverse, equitable, inclusive and supportive recruitment and engagement of participants from underserved from populations. This will further support the inclusion and diversity of both our research ventures and the solutions developed from them.
Which common MRI research sequences need de‐facing before research data sharing?
Authors: Schwarz Christopher G. , Kremers Walter K. , Arani Arvin , Reid Robert I. , Gunter Jeffrey L. , Senjem Matthew L. , Cogswell Petrice M , Vemuri Prashanthi , Kantarci Kejal , Petersen Ronald C. , Knopman David S. , Jack Clifford R. 
Published: December 2023

AbstractBackgroundWe have previously shown that 3D T1‐weighted and 3D T2‐FLAIR brain MRI can potentially be re‐identified using face recognition, but this has not been tested for other MRI sequences commonly used in imaging studies of aging and dementia. Here we compare match rates of automated face recognition to re‐identify 3D T1‐weighted, 3D T2‐FLAIR, 3D T2‐weighted, 2D Axial T2‐FLAIR, multi‐echo GRE (T2*), diffusion MRI, functional MRI, ASL, and T2* GRE images.MethodWe used a dataset of 182 Mayo Clinic participants each with MRI and face photographs. MRIs used Siemens and GE vendor‐product sequences similar to ADNI3 and ADNI4 protocols. We created face reconstructions (“basic”, with minimal preprocessing, and “advanced” that automatically filled missing face regions using a template) from each MRI sequence, and we trained a Microsoft Azure PersonGroup face recognition classifier to recognize these MRI‐based faces. We then queried the classifier with five face photographs for each participant, and we recorded how often the classifier chose the correct MRI as the top‐ranked match. For image types with match rates > = 10%, we then repeated the experiment after de‐facing each MRI with mri_reface, our leading software that replaces faces in each image (“re‐faces”) with an average face.ResultResults are presented in Table 1. 3D T2‐FLAIR, 3D T1‐weighted, and 3D T2‐weighted images were matched at 96‐98%, and mri_reface reduced all to 8%. Axial T2‐FLAIR and ME‐GRE were matched at 32‐45%, and mri_reface reduced both to 1%. T2*‐GRE matched at 10%, and mri_reface reduced this to 1%. ASL matched at 8%, while dMRI and fMRI matched at only 0‐2%.ConclusionAmong current‐generation vendor‐product sequences, we recommend that de‐facing be applied before research data sharing of T1‐weighted, T2‐weighted, T2‐FLAIR, T2*, and ME‐GRE images. Minimal match rates for current‐generation product fMRI, ASL, and fMRI images suggest that they present low risk of re‐identification and can be shared without de‐facing, but this conclusion should be re‐evaluated if they are acquired without fat‐suppression, with a larger field of view, or if newer developments reduce the current levels of artifacts and distortion around the face.