bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluating the causal association between resting state intrinsic functional networks and the risk for neurodegeneration
Authors: Nassan Malik , Daghlas Iyas , Diamond Bram R , Martersteck Adam , Rogalski Emily J 
Published: January 2025

AbstractBackgroundAlterations of resting state intrinsic functional networks have been associated with neurodegenerative diseases even before the onset of cognitive symptoms. Emerging hypotheses propose a role of intrinsic functional networks alterations in the risk or vulnerability to neurodegeneration. It is unknown whether intrinsic functional network alterations can be causal for neurodegenerative diseases. We sought to answer this question using two‐sample Mendelian randomization, a method able to assess causal relationships.MethodsUsing the largest genome‐wide association study of resting state intrinsic functional connectivity (n = 47,276), we generated genetic instruments (at the significance level 2.8 × 10−11) to proxy resting state intrinsic functional network features. From these, we selected 26 genetically proxied resting state intrinsic functional features from brain regions implicated in neurodegenerative diseases. We tested their association with the paired neurodegenerative outcomes: Alzheimer dementia (111,326 cases, 677,663 controls), frontotemporal dementia (2,154 cases, 4,308 controls), semantic dementia (308 cases, 616 controls), and Lewy body dementia (2,591 cases, 4,027 controls). Major depressive disorder outcome (170,756 cases, 329,443 controls) was included as a positive control. Power and sensitivity analyses were completed to assess the robustness of the results.ResultsNone of the genetically proxied resting state intrinsic functional network features were significantly associated with neurodegenerative disease outcomes (adjusted P value >0.05), despite sufficient power. However, two resting state exposures in the visual cortex showed a nominal level of association with Lewy body dementia (P = 0.01), a finding that was supported using a separate visual cortex connectivity exposure (P = 0.03). For our confirmatory positive control, the global connectivity pattern in the default mode network was associated with risk of major depressive disorder (P = 0.024), supporting the validity of the selected genetic instruments. Sensitivity analyses were supportive of the main results.ConclusionThis is the first study to comprehensively assess the potential causal effect of resting state intrinsic functional network features on risk of neurodegenerative diseases. Overall, the results do not support a causal role for intrinsic functional network connectivity in the pathogenesis of neurodegenerative disorders. However, the suggestive association between visual network connectivity and risk of Lewy body dementia requires further evaluation.
Single‐nuclei RNA‐Sequencing of Postmortem Choroid Plexus Uncovers Dysfunction Alzheimer’s disease
Authors: Philippe Tristan J , Kearns Nicola , Avey Denis R. , Saunders Devin M. , Vyas Himanshu , De Tissera Sashini L , Xu Jishu , Bennett David A. , Wang Yanling 
Published: January 2025

AbstractBackgroundThe choroid plexus (ChP) is formed by epithelial cells and stromal fibroblasts which act as a blood‐cerebrospinal fluid (CSF) barrier, play a key role in maintaining brain homeostasis, and provide a niche for immune cells. ChP dysfunction has been implicated in Alzheimer’s Disease (AD), including changes in CSF secretion, increased apoptosis, and dysregulated immune, mitochondrial, and transporter functions.MethodHere, we performed single‐nuclei RNA‐Sequencing (snRNA‐Seq) on 965,647 ChP nuclei from 68 ROSMAP participants with no cognitive impairment (NCI), mild cognitive impairment (MCI) or Alzheimer’s Dementia (ADem).ResultWe identified 14 major cell types, including two types of epithelial cells, four types of fibroblasts, five types of border associated macrophages (BAMs), one type of T cells, and two types of vascular cells. In ciliated epithelial cells, we observed a decreased expression of genes essential for cilia formation and movement (e.g., DNAH12, CFAP100, ARL13B) in participants with ADem, but not MCI. In ADem and MCI fibroblasts and epithelial cells, we observed changes in cell adhesion (e.g., ITGA8, CEMIP, CEACAM1, ADMTS4), ion transport (e.g., SLC12A2, SLC4A5, STAEP4, SLC1A1), and metabolism (e.g., ALDH4A1, ENO4, AKR1C2, PDE10A) in addition to increased expression of pro‐inflammatory genes (e.g., IL6, CXCL8, IL12RB2). Compared to the NCI group, we also observed increased expression of lipid metabolism genes (e.g., ALOX15B, ACSL1) in phagocytic BAMs and a higher proportion of pro‐inflammatory BAMs in the ADem, but not MCI groups. Proteomics on ex‐vivo CSF and tissue, immunostaining, and RNAscope support the major cell types described herein and validate differential gene expression.ConclusionWe show that multiple cellular and molecular functions are dysregulated in ADem, to suggest ChP dysfunction is a key contributor to AD pathogenesis. Changes to the cilia of ChP epithelial cells and ChP BAM function could contribute to differences in the degree of cognitive impairment across participants.
Experiences of Participant Burden in an Alzheimer’s Disease Research Center Longitudinal Cohort
Authors: Gierzynski Theresa F. , Reader Jonathan M , Flores Bernardo , Gadwa Renee , Bhaumik Arijit K , Rahman‐Filipiak Annalise , Heidebrink Judith L , Giordani Bruno , Hampstead Benjamin M. , Bakulski Kelly M. , Paulson Henry L , Roberts J. Scott 
Published: January 2025

AbstractBackgroundLongitudinal studies of Alzheimer’s and related dementias (ADRD) are crucial to understanding disease progression. Retention among study participants is vital to successful longitudinal research, as dropout can skew the subject population in ways that significantly compromise study outcomes (e.g., limited generalizability). Prior research suggests that higher perceptions of burden among research volunteers are associated with an increased likelihood of attrition and missed visits. Additionally, underrepresented groups (e.g., racial minorities) may be uniquely impacted by barriers that hinder participation and sustained engagement in ADRD research. The current study aimed to measure participants’ perceived burden in a cohort of longitudinal ADRD research participants and assess for potential differences in perceived burden by race.MethodsParticipants enrolled in a study of memory and aging at the Michigan Alzheimer’s Disease Research Center (MADRC) were administered a modified, 22‐item version of the Perceived Research Burden Assessment (PeRBA) survey instrument (Keleman et al., 2023) either in‐person or via telephone. The PeRBA is a validated measure assessing overall, logistical, psychological, and physical burdens of participating in research. A series of Wilcoxon Rank Sum Tests were performed to assess for possible racial differences in the mean scores of overall burden, as well as in each subscale.ResultA total of 76 participants completed the PeRBA; the sample was 18.8% Black/African American, 67.1% female, and 55.3% cognitively unimpaired. Overall burden ranged from 21 to 55 (110 possible) (Overall Mean (SD) = 36.23 (8.25); Black/African American Mean (SD) = 43.86 (2.07); White Mean (SD) = 34.61 (8.17)). Results indicated that Black/African American participants experienced significantly more overall burden than their White counterparts (all ps < 0.05) as well as across all subscales.ConclusionFurther research is needed to better understand the ostensibly higher appraisals of research burden in our Black/African American participants. Future investigations should consider the role of geographic/site‐specific factors as well as structural (e.g., socioeconomic status, transportation) and psychosocial influences and their role in participant retention and recruitment. Moreover, the identification of deterrents and barriers to engagement can inform tailored strategies that support the specific needs of diverse older adult populations in ADRD studies.
Astrocyte selective insulin receptor knockout in the 5xFAD model of amyloidosis
Authors: Wright Nicholas A , Galopin Leopoldine B , Sims Sophiya L , Lin Ruei‐Lung , Rucker Edmund B , Rogers Colin B , Kraner Susan D , Norris Christopher M. , Thibault Olivier 
Published: January 2025

AbstractBackgroundWe have recently published that overexpressing a constitutively active form of the insulin receptor beta subunit (IR‐β) in hippocampal neurons ameliorates spatial memory performance in the F344 rat model of aging (Frazier et al., 2020). Because astrocytes express IRs and are central to cellular energy and information transfer in the brain, here we focus on the knockdown of IR in astrocytes of the primary somatosensory cortex (S1) in the 5xFAD animal model. Using Cre‐lox recombination, we tested the cellular expression of AAV‐Cre recombinases and serotypes to selectively excise the IR, including 1. AAV5.GFAP.Cre.WPRE.hGH (AddGene), 2. AAV5.Gfa104.C1.Cre.WPRE.SV40 (UPenn), 3. AAV5.GFAP.GFP.Cre (UNC), 4. AAV8.GFAP.GFP.Cre (UNC; gift from Dr. Weikang Cai) and 5. AAV5.Gfa104‐Cre‐4×6T (Addgene/UPenn).MethodThe 5xFAD and the IRfl/fl were used to generate unique genotypes IRfl/fl; 5xFAD−/− (WT) and IRfl/fl; 5xFAD+/− (5XFAD). Mice were injected unilaterally in S1 with five different AAVs, followed with 3‐4 week recovery prior to the extraction and processing of the brain for immunohistochemical (IHC) and immunofluorescence (IF) analyses. Coronal sections of S1 were exposed to anti‐Cre recombinase primary antibodies labeled with secondary AlexaFluor antibodies. Counter stains used included DAPI and an anti‐GFAP or anti‐NeuN primary antibodies to address selectivity. In a second set of experiments conducted in older WT and 5xFAD mice injected unilaterally with AAV#2 and AAV#3 above, we used Western blotting techniques on two separate fractions (astrocyte‐depleted [AD] and astrocyte‐enriched [AE]). Samples were separated using the magnetic cell separation techniques followed by anti‐NeuN and anti‐GFAP antibodies to monitor selectivity.ResultInitial IHC indicates that the expression of the Cre recombinase under the GFAP promoter was surprisingly, mostly neuronal with very little expression in astrocytes. AAVs with the smaller Gfa104 promoter show improved specificity toward astrocytes (∼50%), with some expression in neurons. Our modified AAV shows higher cell‐type selectivity toward astrocytes.ConclusionOverall, our attempt to target astrocyte IR knockdown has proven to be difficult and current efforts using molecular remodeling and targeting to astrocytes using an miRNA‐based AAV to degrade transcription in neurons, thus, enriching expression of Cre in astrocytes, is proving to be a very valuable strategy.
A Systematic Review on the Process of Translation and Cross‐Cultural Adaptation of Functional Activity Tests for Dementia
Authors: O'Donald Freddie , Calia Clara 
Published: January 2025

AbstractBackgroundThis systematic review aims to investigate the methodologies employed in the translation and cross‐cultural adaptation of functional activity measures for dementia on a global scale. The Consensus‐based Standards for the Selection of Health Measurement Instruments (COSMIN) initiative is used as a framework, offering established criteria for assessing psychometric properties across diverse domains.MethodA systematic search of five electronic databases (CINAHL Plus, EMBASE, PubMed, MEDLINE, PsycINFO) was conducted from inception until September 2023. Quality assessment criteria were then utilised to evaluate the process of cross‐cultural adaptation and psychometric properties of identified functional activity measures.ResultFifteen studies relating to adapted functional activity measures in eleven languages were identified. It was found that less than half of these studies fully adhered to established guidelines for the translation and cross‐cultural adaptation of instruments. Regarding psychometric properties, while the internal consistency and reliability of included measures were generally strong, there was variability in evaluating other psychometric properties, notably structural validity, measurement error, and cross‐cultural validity.ConclusionThis review underscores the need for researchers and clinicians to follow standardised guidelines for translating and cross‐culturally adapting functional activity measures for dementia and ensuring the comprehensive evaluation of psychometric properties in cross‐cultural settings. Researchers and clinicians should consider whether the psychometric properties and characteristics of an adapted functional activity measure are suitable for use in their population of interest.
Increasing primary and specialty healthcare access for rural older adults: Facilitators, barriers, and opportunities of telehealth in rural community centers
Authors: Fischer Ben , Jackson Yolanda , Roberts Celeste , Robinson Celeste , Early Robert , Sprang Robert , Rhodus Elizabeth K. 
Published: January 2025

AbstractBackgroundShortcomings in primary and specialty healthcare access in rural communities create substantial health disparities among older adults, especially in areas of modifiable risk factors for Alzheimer’s disease and related dementias (ADRD). Telehealth stations in community centers increase healthcare access to patients thereby improving modifiable risk factors for ADRD. The objective of this project was to assess facilitators, barriers, and opportunities of telehealth use for older adults within rural community centers.MethodsFollowing an implementation‐based clinical trial (NCT05552638), this study conducted in‐depth interviews with multi‐level stakeholders, including rural, community‐residing seniors, senior center administrators, and medical partners to assess use of telehealth in rural community centers. Data were analyzed using descriptive thematic analysis. Coding was conducted using HyperResearch Software.ResultsInterviews were completed with nine multi‐level stakeholders who represented of a combine population of >2000 older adults residing in rural communities. Emergent themes reveal facilitators of involvement of community centers as a strategy to promote telehealth usage, as well as involving local providers; both offering familiarity to local residents. Identified barriers include a need for increased acceptance of telehealth services possibly through education and exposure to the technology, patients’ concerns regarding costs, quality of care delivered, and patients’ need for assistance to manage scheduling. Overall, increasing acceptance and fostering positive experiences with technology provide opportunities of improving primary and specialty care via telehealth usage in rural community centers.ConclusionFacilitators, barriers, and opportunities for primary and specialty healthcare via telehealth among older adults in rural communities provides key considerations when developing approaches to address health disparities. Findings of this study provide future implementation strategies to improve acceptance and utilization of telehealth services. Continued research is needed to explore health beliefs of healthcare access mechanisms, as well as innovations to address critical health disparities in rural communities.
Plasma Aβ42/40, APOE4, and Ethnicity in Aβ‐PET Prediction
Authors: Taylor Steven W , Weber Darren M , Lagier Robert J , Stroh Matthew A , Clarke Nigel J , Vaillancourt David , Duara Ranjan , Racke Michael K 
Published: January 2025

AbstractBackgroundAddition of apolipoprotein E4 (ApoE4) proteotype (as a surrogate for high‐risk APOE ɛ4 genotype) has significantly improved models that use the plasma Aβ42/40 ratio to predict Aβ PET‐positivity, but studies suggest different ethnicities may be less affected by the addition. Our objective was to assess the influence ApoE4 proteotype in a predominantly Hispanic cohort of participants.MethodParticipants in this study (n = 250) underwent neurological and neuropsychological evaluations and amyloid PET brain scans (SUVR data and visual reads) at the 1Florida ADRC; they also underwent blood draws for ApoE4 proteotyping and Aβ42/40 ratio determination by LC‐MS/MS performed at Quest Diagnostics. Ethnicity was self‐reported as Hispanic or non‐Hispanic. Using logistic regression analysis and Delong’s test, we examined the effect of incorporating ApoE4 proteotype as a categorical variable on AUCs for the overall population and for participants stratified by ethnicity: Hispanic vs non‐Hispanic. Statistical analyses were conducted using R statistical software version 4.3.3. Two‐tailed P‐values <0.05 were considered statistically significant.ResultThe ADRC cohort had roughly 3‐times the percentage of Hispanic participants (about 60% of both the Aβ PET‐positive and Aβ PET‐negative participants) compared with a previous Aβ42/40 LC‐MS/MS study that incorporated ApoE4 proteotype. Based on ApoE4 proteotype, incorporating APOE4 allele count modestly but significantly increased the AUC (95% CI) from 0.84 (0.79‐0.89) to 0.86 (0.82‐0.91), P = 0.038, Figure A. Subsetting the ADRC cohort participants into Hispanic vs non‐Hispanic ethnicity provided a contrasting effect for ApoE4 proteotype on model improvement. For Hispanic participants, the AUC (95% CI) for the ratio plus ApoE4 proteotype, 0.86 (0.80 to 0.92) and the Aβ42/40 ratio alone, 0.85 (0.78‐0.91) were not significantly different (P = 0.306), Figure B. For non‐Hispanic participants, the AUC (95% CI) for the ratio plus ApoE4 proteotype, 0.87 (0.81‐0.94) was significantly higher (P = .048) than the Aβ42/40 ratio alone, 0.83 (0.75‐ 0.91), Figure C.ConclusionApoE4 proteotype did not improve prediction of PET positivity by plasma Aβ42/40 in the Hispanic subcohort, suggesting that adding APOE4 to Aβ42/40 in algorithms used in Alzheimer’s disease risk assessment may not improve PET‐prediction for all races and ethnicities.
Microglia density measured by TSPO PET across amyloid positivity and clinical variants
Authors: Houlihan Hannah M. , Johnson Aubrey S. , Smith Anna C. , Guzmán Diana S. , Okafor Amarachukwu , Heuer Lauren B. , Talmasov Daniel , Chikwem Ndubisi , Dass Dina S. , Noble James M. , Kreisl William C. , Small Scott A. , Lao Patrick J. 
Published: January 2025

AbstractBackgroundWe hypothesized that TSPO PET, which measures microglia density, would be elevated in the presence of amyloid and impairment across different clinical variants in a pattern that follows their characteristic tau distribution.MethodParticipants (n = 17 amyloid‐negative control, 3 amyloid‐positive AD, 2 amyloid‐positive PCA, 6 amyloid‐negative with impairment (1 aMCI, 1 MCI, 3 AD, 1 LATE); age = 69±7, 43% women) from the Longitudinal Imaging of Microglial Activation in Different Clinical Variants of Alzheimer’s Disease study underwent amyloid PET (Florbetaben), tau PET (MK6240), and TSPO PET (ER176). Amyloid positivity was determined by visual read. Clinical groups were determined at ADRC consensus. Partial volume corrected TSPO and tau SUVR was compared across amyloid positivity and clinical variants (amyloid‐negative controls as reference group).ResultThe amyloid‐positive AD group had elevated TSPO in amygdala (0.34, p = 0.01), prefrontal cortex (0.31, p = 0.0004), middle inferior temporal gyrus (0.29, p = 0.0003), inferior parietal lobe (0.28, p = 0.001), superior temporal lobe (0.23, p = 0.001), cingulate gyrus (0.19, p = 0.01), superior parietal lobe (0.19, 0.04), insula (0.14, p = 0.02), and lingual gyrus (0.13, p = 0.02), while the amyloid‐positive PCA group had elevated TSPO in amygdala (0.50, p = 0.001), superior parietal lobe (0.38, p = 0.04), inferior parietal lobe (0.29, p = 0.001), middle inferior temporal gyrus (0.20, p = 0.0003), prefrontal cortex (0.15, p = 0.0004), superior temporal lobe (0.14, p = 0.001), cingulate gyrus (0.13, p = 0.01), and insula (0.06, p = 0.02). The impaired amyloid‐negative group had elevated TPSO in the amygdala (0.31, p = 0.04), fusiform gyrus (0.15, p = 0.05), cingulate gyrus (0.14, p = 0.02), middle inferior temporal gyrus (0.12, p = 0.02), superior temporal lobe (0.12, p = 0.02), prefrontal cortex (0.12, p = 0.02), and inferior parietal lobe (0.11, p = 0.02). These elevations in TSPO spatially coincide with elevations in tau burden (Figure 1).ConclusionMicroglia may respond to amyloid pathology and follow a spatial pattern similar to that of tau pathology for a given clinical variant. Interestingly, microglia were elevated to the greatest extent in key limbic regions for amyloid‐negative impaired participants. Non‐AD pathologies may be driving this limbic neuroinflammation or limbic neuroinflammation itself may be sufficient for clinical impairment in the context of low amyloid and tau burden.
SmartSocks: a new data collection paradigm for dementia and other neurological disorders
Authors: Steer Zeke , Venkatesh Prabha Thirthahalli , Mejia‐Mejia Elisa , Dennis William Wu , Ogundele Patrick Ademola , Brooking Annie , Eimontaite Iveta 
Published: January 2025

AbstractBackgroundDistress and agitation are predictors of entry into long‐term care and health inequalities (Schulz et al., 2004, Weir et al., 2022). Physiological data has been shown to reliably predict distress (Goodwin et al., 2019), yet wearable devices have low acceptance rates (Koumpouros & Kafazis, 2019). The current study discusses findings from a multifaceted approach investigating the detection of early signs of distress via physiological sensors in a foot‐worn device.MethodFirstly, the acceptance and concern ratings for a foot‐worn device, SmartSocks, wrist‐worn devices, Empatica E4 and Shimmer GSR+, and chest‐worn device, Equivital within a healthy population (N = 10) were assessed with a self‐report questionnaire. Secondly, data accuracy between Shimmer ECG and Polar OH1+ was compared within a healthy population (N = 12) in a standing, sitting and supine position. Finally, an ongoing ecologically valid feasibility trial (N = 2) involving participants with dementia or a learning disability is assessing the reliability of physiological data and AI‐detected stress from SmartSocks relative to subjective ratings of distress, the Abbey Pain Scale (APS), and the Neuropsychiatric Inventory (NPI).ResultFirstly, the SmartSocks received lowest concern ratings compared to wrist‐ and chest‐worn devices (1.64 vs <1.71). Secondly, the accuracy of SmartSocks pulse rate (PR) estimates obtained using photoplethysmography (PPG) in combination with the delineator algorithm was determined by comparing estimates to a Shimmer 1‐lead ECG, recording Mean Absolute Error (MAE)<5bpm at 64HZ for participants in a supine position (Fig. 1). This led to the development of new features for classifying PPG signal quality using neural networks, achieving approximately 95% accuracy. Finally, the initial stage of the feasibility trial indicated APS and NPI scores were lower after the participant with dementia wore SmartSocks for two weeks. Physiological data collected from the participant with a learning disability using SmartSocks showed moderate correlation (χ2
= 0.45) between the reported and AI‐detected stress over the day (Fig. 2 & 3).ConclusionEarly findings suggest SmartSocks are more comfortable than comparable wrist‐ and chest‐worn devices, and validity of the data is comparable to other devices. Preliminary data obtained from people with dementia and learning disabilities suggest SmartSocks are capable of detecting distress to alleviate user discomfort.