bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relationships between locus coeruleus microstructural integrity, sleep, and 24‐h rest‐activity rhythm in the context of plasma markers of Alzheimer’s disease: a 7T MRI study of asymptomatic older individuals
Authors: Van Egroo Maxime 
Published: January 2025

AbstractBackgroundThe brainstem locus coeruleus (LC) is among the first sites of Alzheimer’s disease (AD) pathology, accruing hyperphosphorylated tau as early as in young adulthood. Animal studies indicate that the LC is crucially involved in sleep‐wake regulation, a recently established factor contributing to AD‐related pathophysiological processes. However, the associations between LC integrity and sleep‐wake phenotypes in the context of AD pathology remain poorly characterized in humans. Here, we examined the relationships between in vivo 7T MRI‐derived LC microstructural integrity and objective measures of sleep or circadian rest‐activity patterns at different levels of AD pathology.MethodThirty‐eight cognitively unimpaired older adults (mean age = 66.53±9.22y., 18 females, Table 1) underwent dedicated LC imaging combined with whole‐brain neurite orientation dispersion and density imaging (NODDI) at 7T to extract microstructural indices of neurite density (NDI) and orientation dispersion (ODI) within the bilateral LC. In addition, they performed 10 days of actigraphy from which objective measures of sleep (average sleep duration and proportion of wake after sleep onset (WASO%)) and 24‐h rest‐activity rhythm (intradaily variability (IV), interdaily stability (IS)) were computed. Plasma concentrations of GFAP and phosphorylated tau epitopes were derived from blood samples using Single molecule array technology (p‐tau181, p‐tau231) and the Meso Scale Discovery platform (p‐tau217).ResultMultiple linear regression models adjusted for age, sex, BMI, and actigraphic recording duration showed that higher LC ODI was associated with longer sleep duration (t(32) = 3.93, p<.001) and lower WASO% (t(32) = ‐2.33, p = .03, Figure 1). Importantly, interaction models revealed a synergistic deleterious effect of displaying lower LC ODI and elevated levels of p‐tau217 on WASO% as well as cross‐over interactions between LC NDI or ODI and p‐tau181, p‐tau217, or GFAP on IV and IS (Figure 2).ConclusionThese preliminary results suggest that poorer LC microstructural integrity is linked to worse proxy measures of sleep quality and circadian rest‐activity patterns, but only in individuals with elevated levels of AD pathology. Our findings therefore provide novel evidence of the involvement of the LC in sleep‐wake phenotypes in older adults in the context of AD pathophysiological processes, and have implications for the identification of individuals at higher risk for AD‐related sleep‐wake disturbances.
Association of Objective Sleep Measures and White Matter Limbic System Integrity in Community‐Dwelling Cognitively Unimpaired Older Black and White Adults
Authors: Bubu Omonigho Michael , Gills Joshua L , Cesar Oliver , Kovbasyuk Zanetta , Sogade Anamarie , Dominguez Joanna , Browne Laurel Y , Valkanova Elena , Mbah Alfred , Figueredo Luisa F , Kam Korey , Mullins Anna E , Parekh Ankit , Masurkar Arjun V. , Varga Andrew , Osorio Ricardo 
Published: January 2025

AbstractBackgroundWe examined racial differences between measures of limbic white matter tracts and objective sleep parameters in cognitively unimpaired older‐adults.MethodThis cross‐sectional study included 170 community‐dwelling cognitively unimpaired older‐adults (mean±SD: age = 67.2±5.2y) participating in NYU studies of sleep, aging, and memory. Subjects completed polysomnography (NPSG) and brain MRI. Sleep measures of interest included total sleep time (TST), NREM stages 2, 3 and REM sleep duration, sleep latency and fragmentation, slow sleep spindles (SSP), sleep spindle density (SPD), AHI4% and REM AHI4%. Microstructural properties of the cingulum, uncinate fasciculus (UF), and fornix were estimated using diffusional tensor imaging (DTI) metrics including radial kurtosis (RK), radial diffusivity (RD), and fractional anisotropy (FA). Adjusted Linear mixed‐effects regression models examined associations between race, sleep, race*sleep and DTI metrics.ResultParticipants were 44.1% Black with 16.8±2.5y of education. Subjects were relatively matched on AHI4%, age, BMI and educational level. In the cingulum, increased fragmentation was associated with higher RD β[Left] = 0.0026, p = 0.022), decreased RK (β[Right] = ‐0.0069, p = 0.039) in Blacks. Additionally, increased sleep latency was associated with reduced FA (β[Right] = ‐0.0010, p = 0.019), higher RD (β [Right] = 0.0010, p = 0.008) in Blacks. In the UF, increased fragmentation was associated with higher RD(β[Left] = 0.0052, p = 0.019) and lower RK (β[Right] = ‐0.0010, p = 0.039) in Blacks; increased AHI4%REM was associated with reduced FA β[Left] = 0.0007, p = 0.041), higher RD (β[Right] = ‐0.0007, p = 0.027) and lower RK (β[AHI4%, Left] = ‐0.0029, p = 0.001) in Blacks. Furthermore, higher SSP (βRight] = 0.00031, p = 0.045 and SPD (β[Right] = 0.045, p = 0.025) was associated with higher RK in Blacks. In the cingulum of white participants, higher AHI4%REM was associated with reduced FA β[right] = ‐0.0006, p = 0.013), higher RD β[Left] = 0.0005, p = 0.051), and reduced RK β[Right] = ‐0.00198, p = 0.008). Additionally, NREM stage‐2 sleep duration was associated with higher FA β[Right] = 0.0010, p = 0.037) and higher RK β[Right] = 0.0031, p = 0.040). In the UF, increased fragmentation was associated with reduced RK β[Left] = ‐0.017, p = 0.047) in Whites.ConclusionCognitively‐unimpaired Black and White older‐adults showed sleep disruption associations with limbic white matter integrity, with race‐specific associations observed across various microstructural properties of the cingulum, UF, and fornix. Thus, highlighting possible sleep‐related underpinnings of racial differences in Alzheimer disease‐risk.
Sex‐associated differences in brain insulin signaling and energy metabolism uncover early pathological alterations driving Alzheimer’s disease neuropathology
Authors: Lanzillotta Simona , Tramutola Antonella , Paul Bindu D , Domenico Fabio Di , Perluigi Marzia , Barone Eugenio 
Published: January 2025

AbstractBackgroundBiological sex influences Alzheimer’s disease (AD) development, particularly concerning brain insulin resistance (bIR) and early energy metabolism defects. Biliverdin reductase‐A (BVR‐A) plays a crucial role in insulin signaling, and its downregulation leads to bIR. However, the sex‐related differences in AD neuropathology and underlying mechanisms remain unclear. We aimed to identify early changes in brain insulin signaling in males and females, shedding light on pathological signs preceding overt bIR and AD neuropathology.MethodC57BL/6J mice (WT or BVR‐A knock‐out, M and F, n = 10/sex/group) received a chow or a high‐fat diet (HFD, 60% kcal by fat) for 1 or 8 weeks. Peripheral metabolic measurements (fasting glucose, insulin, and OGTT) and cognitive tests (NOR and Y‐maze) were performed. Brain insulin signaling activation (basal and intranasal insulin‐induced), oxidative stress marker levels, mitochondrial activity, and AD neuropathology markers were evaluated in the hippocampus and cortex. Correlations were performed with peripheral metabolic measurements (fasting glucose, insulin, and OGTT) and cognitive tasks (spatial memory).ResultMale mice exhibited more pronounced alterations in brain insulin signaling, mitochondrial activity, oxidative stress, and AD‐related neuropathology compared to female mice after 8 weeks of HFD. These changes initially manifested in the cortex and subsequently in the hippocampus. Intriguingly, despite these molecular alterations, male mice showed better cognitive performances than female mice following 8 weeks of HFD. This evidence suggests that female mice are more susceptible to these metabolic alterations and that subtle changes promote worse outcomes on cognitive tasks. BVR‐A levels were found decreased in both cortex and hippocampus following HFD, and these changes were sex‐dependent. Loss of BVR‐A significantly correlated with the observed molecular alterations, as confirmed in BVR‐A knock‐out mice. Notably, knock‐out mice exhibited similar alterations observed in C57BL/6J mice after just 1 week on HFD, emphasizing the pivotal contribution of BVR‐A.ConclusionThis study highlights the importance of identifying sex‐related differences as well as shared features in the progression of bIR in AD. Loss of BVR‐A is a common event, although temporal‐ and regional‐associated differences in males and females are observed. These observations warrant further investigations to unveil early pathological changes driving AD neuropathology.
Physical exercise upregulates Irisin in extracellular vesicles
Authors: De Felice Fernanda Guarino 
Published: January 2025

AbstractBackgroundPhysical exercise improves overall brain health, cognition, and stimulates the release of extracellular vesicles (EVs) in humans. Exercise upregulates irisin, a myokine derived from fibronectin type III domain‐containing protein 5 (FNDC5) previously shown to mediate the beneficial actions of exercise on memory in mouse models of Alzheimer’s disease (AD). Here, we investigated if physical exercise upregulates EVs. We further studied if EV’s cargo includes irisin and tested whether physical exercise protocols modulate its content in EVs.MethodIndividuals underwent a high intensity interval training exercise program. HIIT sessions were performed 3 times a week, over 6 weeks. Serum was collected before and the day after the last exercise session. Mice were submitted to a daily swimming exercise protocol, 5 times per week, over 5 weeks. Mice were terminated 1 hour after the last bout of exercise and plasma was collected. EVs concentration and number in humans and mice. EVs obtained from the cerebrospinal fluid (CSF) from cynomolgus and Rhesus monkeys at rest obtained by lumbar punctures were also studied. We further investigated if EV’s cargo includes irisin and tested whether physical exercise protocols modulate irisin content in EVs un mice and humans. FNDC5/Irisin in EVs was detected by Western blotting, Mass spectometry and ELISA.ResultOur results indicate that irisin is associated with serum, plasma and CSF EVs from humans, mice and monkeys. Exercise upregulated EV‐associated FNDC5/Irisin in mice and humans, but did not alter circulating EV concentration. EV‐associated FNDC5/Irisin correlated positively with BDNF levels in serum obtained from humans post‐exercise.ConclusionThese findings indicate a potential physiological role of exercise‐induced upregulation of EV‐associated irisin.
Aβ immunotherapy drives immune activation and cerebrovascular damage in a mouse model of Alzheimer’s Disease
Authors: Taylor Xavier , Noristani Harun , Fitzgerald Griffin , Oluoch Herold , Babb Nick , McGathey Tyler , Hole Justin T. , Lacor Pascale , DeMattos Ronald B. , Wang Yaming ,   Neuroscience Discovery, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA
Published: January 2025

AbstractBackgroundAnti‐amyloid‐β (Aβ) immunotherapy trials have shown amyloid‐related imaging abnormalities (ARIA) as the most common and serious adverse events linked to pathological changes in cerebral vasculature. Nevertheless, the mechanisms underlying how amyloid immunotherapy triggers vascular damage, increases vascular permeability, and results in microhemorrhages remains unclear. Notably, activation of perivascular macrophages and infiltration of peripheral immune cells have been implicated in regulating cerebrovascular damage. However, further research is needed to understand the immediate downstream consequences of macrophage activation that exacerbate CAA‐related vascular permeability and microhemorrhages associated with amyloid immunotherapy.MethodsThis study investigates immune responses induced by amyloid‐targeting antibodies and CAA‐induced microhemorrhages using RNA in situ hybridization, histology and digital spatial profiling in an Alzheimer’s disease (AD) mouse model of microhemorrhage.ResultsIn the present study, we demonstrate anti‐Aβ (3D6) immunotherapy induces robust vascular inflammation and profound smooth muscle cell loss, leading to vascular damage and loss of blood‐brain barrier (BBB) integrity. Additionally, digital spatial profiling reveals robust recruitment of peripheral immune cells encompassing T and B‐ lymphocytes encircling vascular amyloid deposits. Finally, RNA in‐situ hybridization coupled with immunohistochemistry identifies 2 distinct subsets of macrophages encompassing tissue‐resident and monocyte‐derived macrophages around vascular amyloid deposits after Aβ immunotherapy demonstrating the multifaceted roles of immune activation and vascular damage in response to Aβ immunotherapy.ConclusionsIn summary, our study establishes a significant link between CAA‐Aβ antibody immune complex formation, macrophage activation, vascular damage leading to impairment of BBB integrity. Nevertheless, the full implications of this phenomenon on the susceptibility to microhemorrhages needs to be explored further. Therefore, additional investigations are needed to determine the potential preferential roles played by tissue‐resident and monocyte‐derived macrophages surrounding vascular amyloid deposits, unraveling the intricate interplay between immune activation, vascular damage and accelerated smooth muscle cell loss in response to Aβ immunotherapy.
Sex differences in locus coeruleus physiology
Authors: Rae Rosaria Josephine , McMahon Lori L 
Published: January 2025

AbstractBackgroundAlzheimer’s disease disproportionately affects women in the U.S., with two‐thirds of individuals diagnosed being female. This gender disparity underscores the crucial role of sex as a significant risk factor for disease development. Recognizing the importance of this, it becomes imperative to investigate how Alzheimer’s disease presents differently between males and females, especially in the early stages when intervention is most potent. The locus coeruleus (LC) is the initial brain region affected by hyper phosphorylated tau in Alzheimer’s disease, preceding the accumulation of other pathological indicators. A deeper understanding of sex differences in this crucial region can provide insights into how Alzheimer’s disease related dysfunction manifests uniquely between the sexesMethodIn vivo electrophysiology under anesthesia was used to measure single unit activity of LC firing patterns in wild‐type Fischer male and female rats. Females have been estrous cycle tracked and stratification between estrus phases may uncover further differences within females. Recordings measured tonic firing and phasic firing in response to footshock. Spike sorting and signal processing differentiated LC principal neurons and interneurons, unique units, physiological features, and bursting patterns that were compared between groups.ResultThis data shows no significant differences in LC principal cell tonic firing between males and females. However during burst firing, females have an increased interspike interval, indicating decreased firing supporting sexually distinct physiology of the LC. Additionally, females have distinct waveform patterns from males including area under the curve and peak/valley energies, suggesting possible differences in intrinsic properties.ConclusionSex influences LC phasic physiology which may contribute to AD disproportionately impacting women.
Comparison of cerebrospinal fluid and plasma oxidative stress biomarkers
Authors: de la Colina Adrian Noriega , Charisis Sokratis , Ntanasi Eva , Mamalaki Eirini , Skaperda Zoi , Kouretas Demetrios , Scarmeas Nikolaos 
Published: January 2025

AbstractBackgroundNumerous studies have highlighted the role of oxidative stress in Alzheimer’s disease (AD) development. Yet, the alignment of systemic and central oxidative stress biomarkers is unclear across diverse populations in the AD continuum. This study aims to assess protein damage levels in plasma and cerebrospinal fluid (CSF) within the AD continuum.MethodsOne hundred forty participants without clinical dementia (47 with Mild Cognitive Impairment [MCI] and 93 cognitively unimpaired) from a memory clinic cohort underwent examination for central (CSF) and systemic (plasma) markers of oxidative stress. We measured Total Antioxidant Capacity (TAC), reduced glutathione (GSH), thiobarbituric acid reactive substances (TBARS), and reducing power (RP) using standard laboratory techniques and absorbance spectrophotometry (Hitachi U‐1500). Pearson’s correlations were employed to determine the congruence between the same biomarkers of oxidative stress in CSF and plasma. Factor analysis was performed to ascertain how many antioxidant dimensions they represent.ResultsTable 1 outlines participants' baseline characteristics. Pearson’s correlation analysis for the entire sample revealed no congruence between CSF and plasma in TAC (r = +.087) and GSH (r = .‐.161), while CSF and plasma RP (r = .+385*) and TBARS (r = ‐.216*) were correlated (Figure 1). Upon analyzing group‐level data, the cognitively unimpaired group showed congruence between CSF and plasma for GSH (r. = ‐.279*) and TBARS (r = ‐.287*) but not for TAC (r = +.191) and RP (r = +.202). In the MCI group, only RP (r. = +.640*) demonstrated congruence between CSF and plasma. Factor analysis with CSF biomarkers identified two components in the whole sample (Figure 2). Dimension 1 = GSH, and Dimension 2 = TAC, TBARS, and RP. Factor analysis with plasma identified as well two components: Dimension 1 = RP and GSH, Dimension 2 = TBARS and TAC. The factor analysis for the MCI group revealed the presence of a single component for CSF biomarkers, while there were two components for plasma: Dimension 1 = RP and TBARS, Dimension 2 = TAC and GSH.ConclusionOxidative stress biomarker patterns differ across the AD continuum. RP demonstrates the most reliability, while TAC is the least. GSH and TBARS plasma and CSF measurements are negatively associated in the cognitively unimpaired, but not in the MCI population. Understanding oxidative biomarker evolution can enhance our comprehension of their role in AD and age‐related disorders.
Spontaneous and iatrogenic ARIA: Mechanistic insights from CAA‐related inflammation
Authors: Piazza Fabrizio , Lucia Davide Donato , Guzzi Francesca , Pascarella Rosario , DeBernardi Elisabetta , Antolini Laura , Basso Gianpaolo , Zedde Marialuisa ,   The CAA‐SINdem Study Group and The iCAB International Network Research Group
Published: January 2025

AbstractARIA‐E/H (amyloid‐related imaging abnormalities‐Edema/Hemorrhage) is an umbrella term that defines the radiographic appearance of MRI images abnormality during treatments with Aβ‐lowering monoclonal antibodies (mAbs) for Alzheimer’s disease immunotherapy.Today, it is well‐recognized that ARIA‐E events can also occur spontaneously in patients with cerebral amyloid angiopathy‐related inflammation (CAA‐ri), a rare autoimmune encephalopathy associated with raised cerebrospinal fluid (CSF) concentrations of spontaneous auto‐antibodies against Aβ (aAbs).In this framework, the last years of research and experience of the iCAB international Network generated an increased consensus that therapy‐induced ARIA is the iatrogenic manifestation of CAA‐ri. Indeed, the natural history of CAA‐ri, the response‐to‐corticosteroid therapy outcomes, the regional and temporal co‐localization of radiographic ARIA‐E with microglial activation (both on neuropathology and in vivo with TSPO‐PET), the downstream negative effects on Aβ‐clearance pathways and the related risks for an ARIA‐H subsequent event, all provide remarkable supportive evidence that ARIA‐E associated with mAbs therapy is iatrogenic CAA‐ri.In this talk, we will present and critically discuss the emerging new data supporting the potential of the assay for anti‐Aβ (auto)antibody CSF testing as a companion diagnostic and early biomarker for CAA‐ri and ARIA in real‐world clinical practice and immunotherapy trials. In this framework, we will also present the recently launched “ARIAisCAAri NET” project; an international, prospective, longitudinal, observational Registry and Biobank of patients with ARIA and CAA‐ri from the real‐world clinical practice aimed at fostering a precision medicine approach and biomarker research collaborations between the AD and CAA community.Funding: Alzheimer’s Association Research Grant: 23AARG‐1030214 ‐ UncoveriNg Immune MechanIsms and Biomarkers of ARIA (UNIMIB‐ARIA Toolkit)References:Piazza F. et al. Association of Microglial Activation With Spontaneous ARIA‐E and CSF Levels of Anti‐Aβ Autoantibodies. Neurology, 2023Kelly L. et al. Clearance of interstitial fluid (ISF) and CSF (CLIC) group‐part of Vascular Professional Interest Area (PIA), updates in 2022‐2023. Cerebrovascular disease and the failure of elimination of Amyloid‐β from the brain and retina with age and Alzheimer’s disease: Opportunities for therapy. Alzheimer’s and Dementia, 2023Zedde ML et al. CAA‐ri and ARIA: Two Faces of the Same Coin? American Journal of Neuroradiology, 2023
Mayo Normative Studies: regression‐based normative data for remote self‐administration of the Stricker Learning Span, Symbols Test and Mayo Test Drive Screening Battery Composite for ages 33‐100 and validation in MCI and dementia
Authors: Stricker Nikki H. , Frank Ryan D. , Boots Elizabeth A. , Fan Winnie Z. , Christianson Teresa J. , Kremers Walter K. , Stricker John L. , Machulda Mary M. , Lucas John A. , Hassenstab Jason J. , Graff‐Radford Jonathan , Vemuri Prashanthi , Jack Clifford R. , Knopman David S. , Petersen Ronald C. 
Published: January 2025

AbstractBackgroundFew normative data for computerized measures administered in unsupervised remote environments are available. We aimed to determine what variables to include in normative models for remote self‐administered assessments, develop normative data for measures administered through Mayo Test Drive (MTD, a multi‐device remote cognitive assessment platform) and evaluate application of norms.Method1240 adults ages 33‐100 (96% White) from the Mayo Clinic Study of Aging and Mayo Alzheimer’s Disease Research Center met normative sample inclusion criteria that included a concordant Cognitively Unimpaired (CU) diagnosis (3 independent raters all diagnosed CU) and CDR = 0 (see Table 1 for sample characteristics). Raw test scores were converted to normalized scaled scores. We derived regression‐based normative data that adjusted for age, age2, sex and education (base model); alternative models are also provided (age+age2+sex; age+ age2). We evaluated whether additional model terms beyond the base model were needed using an a priori cut‐off of 1% variance improvement in adjusted R2 over and above the base model. We examined rates of low test performance defined as performance below ‐1 SD in independent validation samples (n = 167 concordant CU, n = 64 mild cognitive impairment (MCI), n = 14 dementia). Rates are considered significantly different than expected when 95% confidence intervals (CIs) do not include the expected 14.7% base rate frequency.ResultNo additional potential model terms met our a priori cut‐off for inclusion beyond the base model (see Table 2), including other quadratic and cubic terms or interactions, device type, response input type, potential session interference, and national area deprivation index (ADI available in subset; N = 776). Application of norms showed expected rates of low test performance among CU participants (95% CI includes expected base rate) and significantly greater than expected rates of low test performance for all variables in MCI (e.g., 62.5% for composite) and dementia (e.g., 71.4% for composite; see Table 3).ConclusionTypical normative models appear appropriate for remote self‐administered measures and are sensitive to cognitive impairment. Device type and response input did not explain enough variance to warrant inclusion in normative models but are important for individual level interpretation. Future work will improve representation of individuals from under‐represented groups.