bluuebunny/crossref_metadata_2025_split huggingface dataset:
RESISTANCE EXERCISE AND BRAIN CONNECTOME IN MILD COGNITIVE IMPAIRMENT
Authors: Ribeiro Isadora Cristina , de Campos Brunno , Teixeira Camila Vieira de Ligo , Uchida Marco Carlos , Aventurato Ítalo Karmann , da SIlva Marjorie Cristina Rocha , Gonçalves Brenda Costa , Rizzi Liara , Rochetti Ana Luiza Gonçalves , Guimaraes Emanuel R. , Magalhães Thamires Naela Cardoso , Fernandes Paula , Balthazar Marcio Luiz Figueredo 
Published: January 2025

AbstractBackgroundIndividuals with Mild Cognitive Impairment (MCI) are at greater risk of developing Alzheimer's disease (AD). Previous studies have shown that physical exercise is a protective factor against the clinical evolution of dementia in MCI. Lower muscle strength levels are associated with a greater risk of AD incidence. Physical exercises can also promote improvements in brain networks' functional connectivity (FC). However, the influence of resistance exercise, which significantly impacts the development of muscular strength and cognition, remains unknown concerning FC in MCI. We aimed to investigate the FC of brain networks after 24 weeks of resistance training.Method37 older adults with MCI were investigated. Nineteen performed the resistance training protocol, and 18 constituted the control group, not performing the exercises. Participants were evaluated before and after the intervention using a magnetic resonance imaging device (3 Tesla) for functional magnetic resonance imaging. FC was assessed in Matlab software using the uf2c program to investigate intra‐network connectivity, considering a p‐value of 0.05 with an FDR‐corrected comparison. We evaluated 12 networks: AnteSalience, PostSalience, Auditory, BasalGanglia, Dorsal Default Mode Network, Ventral Default Mode Network, Language, Left executive control network, Right executive control network, Sensorimotor, Visual and Visuospatial networks.ResultAnteSalience connectivity decreased in the control group (T‐score > 3.1473) and increased in the exercise group in the PostSalience (T‐score > 3.7114). The results suggest that the training intervention also increased the FC of the visuospatial network (uncorrected results T‐score > 2.7195), while the control group showed no changes. None of the other networks shows differences between the pre‐and post‐intervention moments. The intervention time may have influenced the results, as changes in FC tend to occur over extended periods; even so, resistance exercise proved influential.ConclusionFC increased or tended to increase in some networks in the exercise intervention group, while in the control group, it decreased or remained stable, suggesting that exercise may be a beneficial modulator of brain connectivity in specific networks such as AnteSalience, PostSalience, and the Visuospatial network. More studies are suggested, especially those that monitor FC changes over extended periods.
Plasma proteomic changes in carriers of progranulin mutations on the novel NULISA platform
Authors: Simrén Joel , Benedet Andrea L. , Zhang Bingqing , Molfetta Guglielmo Di , Cantoni Valentina , Libri Ilenia , Rivolta Jasmine , Blennow Kaj , Zetterberg Henrik , Borroni Barbara , Ashton Nicholas J. 
Published: January 2025

AbstractBackgroundWith no effective therapy targeting the pathology of genetic frontotemporal lobar degeneration (FTLD), there is a need for easily accessible biomarkers enabling the development of therapeutic agents and for clinical diagnostics. Thus, we aimed to investigate the proteomic changes in plasma of progranulin (GRN) mutation carriers using a novel ultrasensitive antibody‐based platform.MethodsWe cross‐sectionally evaluated carriers of pathogenic GRN mutations (GRN+) and age‐ and sex‐matched cognitively healthy non‐carriers (GRN‐) from the University of Brescia. Participants underwent venipuncture, with blood being collected in EDTA tubes to obtain plasma. In these samples, we quantified the proteins included in the “CNS disease panel” on the novel nucleic acid‐linked immuno‐sandwich assay (NULISA) platform (Alamar Biosciences). Biomarker data were log2‐transformed prior to statistical analysis, including linear models (age and sex as covariates) comparing protein concentrations between GRN+ and GRN‐. P‐values were adjusted for false discovery rate (FDR). Protein log2‐fold changes between GRN+ and GRN‐ were calculated using untransformed data.ResultsWe included twenty (2 presymptomatic and 18 symptomatic with median [range] Global CDR plus NACC FTLD scores of 1 [0.5‐3]) GRN+ and twenty GRN‐ (median [range] age 64 [45‐85] years, 65% women). Fifty‐four of the 116 proteins quantified had an adjusted P<0.05 (Figure 1). Significantly altered proteins included markers of neuronal/synaptic injury (neurofilament light [NfL], α‐synuclein, tau, NPTX2 and SNAP‐25, log2‐fold changes 0.2‐2.7; Figure 2A‐E), glial activation/neuroinflammation (glial fibrillary acidic protein [GFAp], YKL‐40, MDH1, FABP3, and sTREM2, log2‐fold changes 0.5‐1.5; Figure 2F‐J) and blood‐brain barrier dysfunction (PDGFR‐β and VEGFA, log2‐fold changes 0.6 and 0.8; Figure 2K‐L). Notably, TDP‐43 was elevated in GRN+ (log2‐fold change 1.5, P<0.01; Figure 2M). Notable markers that were unaltered included p‐tau217, Aβ42 and NPTX1.ConclusionUsing a biomarker panel simultaneously quantifying >100 relevant proteins on the NULISA platform, clear plasma proteomic alterations were observed in GRN mutation carriers. This new methodology has the potential of improving clinical diagnostics and trials, as well as providing insights into the pathophysiology of FTLD due to GRN mutations. Further data will increase the sample size, including >20 presymptomatic carriers, C9orf72 mutation carriers, and a wider range of disease phenotypes, providing opportunities for more detailed analyses.
Acute treatment with OLX‐07010 reduced tau aggregates and upregulated a marker of autophagy with dose dependence in aged P301L tau JNPL3 mice
Authors: Patel Dhruv R. , Lopez Patricia , Romero Daisy , Davidowitz Eliot J. , Moe James G 
Published: January 2025

AbstractBackgroundOLX‐07010 is an oral small molecule inhibitor of tau self‐association that prevented the accumulation of tau aggregates in the htau mouse model expressing wild type human CNS tau isoforms and in P301L tau JNPL3 mice using chronic treatment by administration in diet (Davidowitz et al., 2020, PMID: 31771053; 2023 PMID:37556474). A therapeutic study of JNPL3 mice with chronic treatment from 7‐12 months of age inhibited the progression of tau aggregation and improved motor coordination. This study evaluated the effect of acute treatment of aged JNPL3 mice using once daily oral dosing of OLX‐07010 for one month.MethodSerum and brain exposure of OLX‐07010 was determined following a single oral dose via gavage to select the optimal doses for the short‐term treatment study. This study was designed with four groups: Baseline (7 months; n = 15), Vehicle (n = 20) and two treatment groups (20 and 40 mg/kg; n = 20 each). Treatment was administered from nine to ten months‐of‐age once daily by oral gavage. Cortical levels of aggregated tau were determined by two independent methods, SDS‐PAGE to resolve aggregates with immunoblot for detection, and high‐speed centrifugation to pellet aggregates with AlphaLISA for detection. Cortical levels of LC3‐II protein were evaluated using immunoblot. Motor behavior was evaluated from 7‐10 months of age using Open Field Test and Rotarod assays. The primary endpoint was reduction of aggregated tau with statistical significance; secondary endpoints included dose‐dependent reduction of tau aggregation and rescue of motor impairment.ResultThis work characterized the exposure of orally dosed OLX‐07010 in the blood and brain and demonstrated a dose‐dependent reduction of tau aggregates to baseline levels in conjunction with a dose‐dependent increase of LC3‐II, a marker for autophagosome levels, in the cortex and amelioration of the motor impairment phenotype in aged JNPL3 mice, all with statistical significance.ConclusionFour weeks of daily oral dosing was sufficient to demonstrate a dose dependent therapeutic effect on tau pathology and motor function supporting clinical development of OLX‐07010. This molecule, selected for inhibiting tau self‐association in vitro, may also improve the clearance of protein aggregates in vivo, further supporting its therapeutic potential.
Analytical Validation of MSD S‐PLEX Neurology Panel 1
Authors: Demos Catherine , Padmanabhan Nikhil , Cohen Rachel , Brown Jermaine , Gorham Taron , McBride Jack , Sesay Sia , Valez Sol M Rivera , Barnes Allan , Yang Jun , Graham David , Everett Allen D , Mathew Anu , Stengelin Martin , Sigal George , Wohlstadter Jacob N 
Published: January 2025

AbstractBackgroundThree blood‐based biomarkers of neurological injury—glial fibrillary acidic protein (GFAP), neurofilament light (Nf‐L), and Tau—have emerged as promising biomarkers of neurological disorders and injuries such as hypoxic‐ischemic encephalopathy (HIE), traumatic brain injury, and Alzheimer’s disease (AD). The low levels of GFAP, Nf‐L, and Tau in serum and plasma require highly sensitive assays to detect them. Here, we report the analytical validation of an ultrasensitive, electrochemiluminescence‐based, multiplexed immunoassay for neurological biomarker assessment.MethodThe MSD S‐PLEX Neurology Panel 1 kit uses ultrasensitive S‐PLEX assay technology to simultaneously measure GFAP, Nf‐L, and Tau (total) in a 96‐well plate format. Analytical validation was performed in a series of studies based in part on Clinical and Laboratory Standards Institute guidelines to evaluate precision, dilution linearity, interference screening, detection capability, stability, spike recovery, and cross reactivity. Reproducibility was performed to assess precision across three different laboratories at MSD, Johns Hopkins University, and All Children’s Hospital using three independent reagent lots and an identical sample set.ResultIn this study, the assay used 5 μL of a sample per replicate. This differs from the commercial protocol for this panel because of the extremely high concentrations observed in HIE samples. The quantifiable range of the assay was 2.4–4,200 pg/mL for GFAP, 7.6–10,000 pg/mL for Nf‐L, and 0.34–740 pg/mL for Tau. A set of 15 common interfering substances was screened, and none showed interference exceeding 18%. Dilution of spiked samples up to 256‐fold recovered at 80‐120% of the expected value for all analytes. Precision error was calculated using identical samples across 3 independent laboratories and 3 production lots of the panel (180 measurements) demonstrating excellent reproducibility. The samples included adult and umbilical cord serum and plasma, samples containing human anti‐mouse antibodies, anti‐nuclear antibodies, and clinical samples, including those from subjects with AD.ConclusionThe MSD S‐PLEX Neurology Panel 1 kit provides a new, analytically validated tool for assessing human GFAP, Nf‐L, and Tau. The kit is sufficiently sensitive to detect these analytes in normal serum and plasma and its dynamic range is capable of quantifying elevated levels found in target neurological disorders.
Understanding Willingness to Share SBEDOH Information: Cultural Sensitivity and Community Engagement in ADRD Research
Authors: Adams Larry D. , Rajabli Farid , Douglas Mary E , Sanchez Jose Javier , Moise Rhoda , Cuccaro Michael L. , Pericak‐Vance Margaret A , Seixas Azizi A 
Published: January 2025

AbstractBackgroundUnderstanding social, behavioral, and environmental determinants of health (SBEDOH) are key in identifying modifiable risk factors for Alzheimer’s Disease and related Dementias (ADRD), particularly the disproportionate burden seen in minorities. However, a lack of standardized SBEDOH methods exists with current methods limited in scope and cultural sensitivity (i.e. can be used across different settings and populations and devoid of stigma). To address these gaps, we created a SBEDOH survey and conducted focus groups in Black American (BA) and Hispanic/Latino (H/L) participants to determine the culturally sensitivity and how best to communicate the survey benefits to diverse groups.MethodFocus groups were conducted, engaging 11 BA and 15 (H/L) individuals, using semi‐structured interviews to elicit in‐depth discussions around the cultural sensitivity of SBEDOH items (56 questions, across 13 SBEDOH domains). Sessions were transcribed verbatim, and thematic analysis performed using NVivo software. Two primary coders analyzed data, with a third coder resolving discrepancies. The semi‐structured nature of the interviews facilitated flexible dialogue, probing deeper to responses, enriching the data collected for cultural nuances.ResultWe identified nine cultural sensitivity themes: initial reactions, participation interest, impact perception of information sharing, survey benefits communication, research engagement, tangible benefits, potential misuse of shared data, emotional reactions, and attitudes towards SBEDOH. BA’s reluctance was linked to historical mistrust (e.g. slavery), while H/L’s were about privacy. Both groups noted the importance of clarity on the survey’s benefits to their communities and research at‐large. Readiness to participate was contingent upon careful consideration of these aspects to ensure cultural sensitivity and trust‐building. Both groups emphasized the expectation that information be relayed by culturally responsible professional and SBEDOH should come with guidance on available social care services, highlighting the importance of a reciprocal relationship for sharing sensitive information.ConclusionThis study affirms that when approached with cultural sensitivity and clear communication, BA and H/L individuals are receptive to sharing SBEDOH information. The significance of culturally attuned methods and articulation of direct community benefits are critical to success, underscoring the need for an environment that fosters connectivity and trust resulting in enhanced participation in ADRD research.
Laugh with Me: A Case Study of Easing a Caregiver’s Burden through Music
Authors: Ray Kendra , Kaiser Marion , Mittelman Mary S 
Published: January 2025

AbstractBackgroundIn the United States, approximately 2 million caregivers of people with Alzheimer’s disease or related dementia (ADRD) are Latin American. As many of these caregivers are family or friends, most are not equipped with the tools necessary to address common behaviors associated with ADRD. Music‐based interventions are an effective and accessible tool to assist caregivers in addressing these persistent behaviors. Here, we provide an example of a Latina caregiver for her mother who used music to help relieve symptoms of ADRD.MethodCarmen (pseudonym) attended a 6‐week music‐based, psychoeducational intervention explicitly created for caregivers of people with ADRD via Zoom for 1 hour. She incorporated music specific to her culture with songs like “Metete Teté” during the six weeks. The Neuropsychiatric Inventory (NPI‐Q) and Short‐Form Zarit Burden Interview were completed at pretest and posttest. A rewrite of “Stand by Me” occurred in week six. A comparison of scores was documented, and then a percentage was calculated to determine changes between the pretest and posttest. Informed by grounded theory, a lyric analysis of the rewrite of “Stand by Me” involved creating codes for each textual idea, which led to developing categories. Themes were then revealed based on the organization of codes and categories.ResultCarmen’s burden decreased by 47% between pretest and posttest. Comparatively, there was a 77% decrease in the severity of persistent behaviors in her mom. Additionally, Carmen’s distress was reduced by 87% following the 6‐week intervention. Carmen reported that agitation remained at posttest, which contributed to mild caregiver distress. In her rewrite of the lyrics, Carmen retitled the song, “Laugh with Me.” Four themes revealed include ‘changes in the environment during sunset’, ‘agitation appears’, ‘no stress, no fear’, ‘laughter, and togetherness as the solution’.ConclusionThis case example demonstrated the use of a music‐based intervention facilitated by a Latina caregiver, resulting in reductions in caregiver burden, caregiver distress, and neuropsychiatric symptoms in her mom. Using a case example allowed a closer analysis of NPI‐Q posttest scores, which revealed ongoing agitation. Comparatively, the lyric analysis described how agitation arises and potential caregiving techniques used to resolve agitation.
Estimating age at Aβ onset in the 1946 British birth cohort: exploring the influence of APOE ɛ4 carriership and sex
Authors: Coath William , Betthauser Tobey J. , Teague Jordan P , Scott Catherine J , Thomas David L , Dickson John , Markiewicz Pawel J , Barkhof Frederik , Schöll Michael , Richards Marcus , Fox Nick C , Cash David M , Schott Jonathan M ,   the Insight 46 team
Published: January 2025

AbstractBackgroundCerebral Aβ accumulates decades before symptom onset in AD. Sampled iterative local approximation (SILA, Betthauser et al. 2022) is a technique for estimating time from Aβ positivity (Aβ+) using Aβ‐PET. Here we explore the influence of APOE‐ɛ4 carriership and sex on estimated age of Aβ+ (EAAβ) in primarily cognitively normal individuals from the longest‐running British birth cohort.MethodParticipants in Insight 46 were drawn from the 1946 British birth cohort and underwent combined PET/MR scanning with [18F]florbetapir at two timepoints. Centiloid (CL) values were calculated using a whole cerebellum reference region and partial volume correction. We used Gaussian mixture modelling (99th percentile of lower distribution) to define an Aβ+ threshold of 12 CL. We constructed a CL vs Aβ time curve with SILA from available longitudinal Aβ‐PET scans (n=324, interval=2.4+/‐0.2yrs), which was applied to the whole sample (n=463) to calculate EAAβ. Some scans were below the CL range that could be modelled, and the estimated EAAβ was truncated to the furthest time before onset on the CL vs time curve. Kaplan‐Meyer plots and Cox regression were used to investigate EAAβ and risk of estimated Aβ+ by APOE‐ɛ4 and sex, right censoring participants where EAAβ was truncated.ResultMean (SD) chronological age was 70.6+/‐0.7yrs at baseline and 73.0+/‐0.6yrs at follow‐up scan and 30.5% were Aβ+ve by follow‐up (n=141, 55.3% APOE‐ɛ4, 51.8% female). SILA results and distribution of EAAβ are shown in Figures 1 and 2. EAAβ were truncated due to low Aβ binding in 35.7% (n=166, 15.7% APOE‐ɛ4, 50% female). APOE ɛ4 carriers reached median EAAβ 8.6 years earlier than non‐carriers (Figure 3A). Median EAAβ for females was marginally earlier than males with overlapping CIs (Figure 3B). APOE‐ɛ4 was strongly associated with risk of estimated Aβ+ (HR[95%CI] = 2.4[1.9,3.0]), adjusted for sex. Female sex (1.1[0.8,1.3]) and the interaction between APOE‐ɛ4 and sex (1.2[0.8,1.9]) were non‐significant.ConclusionEstimated Aβ positivity was reached on average 8.6 years earlier for APOE ɛ4 carriers. Consistent with results from other cohorts, APOE‐ɛ4, not sex, significantly heightened the risk of estimated Aβ positivity. Future research will explore life course and downstream events related to Aβ timing.
MCI Diagnosis and Neighborhood Disadvantage Predict Differences in White Matter Microstructure in a Rural Aging Cohort
Authors: Bender Andrew R. , Giriprakash Pavithran Pattiam , Cordes Dietmar , Zhuang Xiaowei , Caldwell Jessica ZK , Miller Justin B 
Published: January 2025

AbstractBackgroundDiffusion magnetic resonance imaging (dMRI) studies show cerebral white matter alterations are associated with both mild cognitive impairment (MCI) and contextual psychosocial factors. However, these reports are almost exclusively based on older adults residing in metropolitan areas. Individuals living in rural communities face increased risk for Alzheimer’s disease and related dementias, but little is known regarding the sensitivity of dMRI markers to incident MCI or psychosocial stressors in this population. In a rural‐dwelling community cohort of older adults, this study evaluated associations between dMRI measures of white matter microstructure and both clinical MCI diagnosis and neighborhood disadvantage.MethodThe study sample included rural‐dwelling older adults (n=69) from the Nevada Exploratory Alzheimer’s Disease Research Center. Participants were characterized as cognitively unimpaired (CU; n=42) or diagnosed with MCI (n=27) based on clinical expert consensus, and all had dMRI data and Area Deprivation Index (ADI) measures of neighborhood disadvantage. dMRI data processing leveraged the MRtrix3 fixel‐based analysis framework and free water mapping to estimate voxel‐based measures of white matter organization, transformed to a sample template. Data analysis utilized voxel‐based analysis (VBA) to model differences in clinical diagnosis and ADI scores as predictors of fiber density, crossing fiber entropy, and extracellular free water, and free water‐corrected diffusion tensor parameters, accounting for differences in age, sex, and handedness.ResultsThe VBA models showed both MCI diagnosis and elevated neighborhood disadvantage predicted significantly greater (familywise error corrected p<.05) free water and reduced crossing fiber entropy in centrum semiovale and internal capsule (Figure 1). Uncorrected models for both diagnosis and higher ADI level revealed widespread associations with dMRI measures of free water, tensor parameters, and fiber density that were nonsignificant following permutation‐based corrections.ConclusionThese preliminary findings reveal white matter alterations associated with consensus MCI diagnosis and to socioeconomic differences in a clinical cohort of rural‐dwelling older adults. The present results highlight the value of modeling extracellular cerebral spinal fluid or ‘free water’ as a marker of microstructural changes associated with both cognitive impairment and contextual psychosocial factors. Future efforts are needed to compare these effects between rural‐ and metropolitan‐dwelling older adults at risk for dementia.