bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sleep health disparities and its impact on Alzheimer’s disease risk: Examining race specific physiologic mechanisms
Authors: Bubu Omonigho Michael M 
Published: December 2023

AbstractBlacks/African‐Americans (blacks) take longer to fall asleep, have lower sleep efficiency and spend a smaller proportion of time in deep stages of non‐rapid eye movement (NREM) slow wave sleep/activity [SWS]), relative to non‐Hispanic whites (whites). Notably, blacks have a higher burden of severe obstructive sleep apnea [OSA] with excessive daytime sleepiness (EDS). These sleep metrics have been linked to increased vascular risks, inflammation, brain injury, and cognitive impairment, all known risk factors for Alzheimer’s disease (AD). This presentation will provide an update on putative mechanisms that underlie the association between sleep and risk of developing AD, both from a mechanistic (primarily preclinical) as well as a clinical/epidemiological perspective, with a focus on how disturbed sleep might be a race‐dependent physiologic risk conferring increased AD‐risk in blacks. It is vital to examine how sociocultural factors, often through behavioral processes, become physiologically expressed as increased AD‐risk in blacks. Data presented will include cross‐sectional and longitudinal studies. Utilizing data from various cohorts including NYU cohort of older‐adults participating in studies of sleep, aging and memory, and the National Alzheimer’s Coordinating Center, we will describe novel evidence implicating sleep health disparities [SHD] (i.e., shorter sleep duration [SD], smaller proportion of time in deep stages of NREM SWS/SWA and disproportionate burden of symptomatic OSA, that are more prevalent among racial/ethnic minorities, as a risk factor for AD; as a physiologic marker associated with AD pathology/biomarkers (i.e. amyloid and tau), and as a modifier of AD‐risk. We will describe race and sex specific mechanisms underlying SHD‐AD risk, including independent and synergistic effects with Aβ and/or tau, as well as vascular risk. Race‐specific associations of micro and macro‐architectural sleep parameters with novel plasma AD biomarkers will also be presented. Findings will show that social determinants of health factors mediate heterogeneity in sleep and AD outcomes, with Black subjects having worse SHD metrics i.e., shorter SD, reduced NREM SWS/SWA and greater OSA severity, and exhibiting worse race‐specific AD pathology and CVD risk markers (i.e., worse office‐based Framingham Heart Study general CVD [FHS‐CVD] risk scores, & greater WML and abnormal DKI indices) potentially leading to AD disparities.
Impaired mitochondrial dynamics in the blood of patients with Alzheimer’s disease and Lewy body dementia
Authors: Millot Perine , Pujol Claire , Paquet Claire , Mouton‐Liger Francois 
Published: December 2023

AbstractBackgroundMitochondrial dysfunction is an early event in Alzheimer’s disease (AD) physiopathology and may contribute to neuronal loss in several neurodegenerative diseases, such as Lewy body dementia (LBD). The role of mitochondrial dysfunction in AD have been mostly explored in brain post‐mortem tissues. These studies have particularly highlighted abnormal expression levels of mitochondrial fission and fusion protein. The balance between fission and fusion mechanisms is essential to maintain a pool of functional mitochondria inside the cell. Further studies suggest that this dysfunction may also be observed in immune cells, both in the central nervous system as in blood compartment.In this context, we investigate if mitochondrial dysfunction, in particularly, imbalance of mitochondrial fusion and fission could be detected in peripheral blood mononuclear cells (PBMCs) from AD and LBD patients compared to PBMCs from healthy control subjects.MethodOur study is a monocentric retrospective study, using blood derived PBMCs from AD, LBD patients and neurological controls followed at the Cognitive Neurology Center (CNC) in Paris. PBMCs were isolated and stored in Lariboisière hospital’s biobank. Mitochondrial protein level were measured using immunoblot technique.ResultOur results show a significant alteration of fusion (MFN2 and OPA1) and fission proteins level (FIS1) in PBMCs of AD and LBD patients.ConclusionThese new findings pave the way to explore the proteins implicated in mitochondrial homeostasis at peripheral levels, and may provide a new tool to follow the progression of mitochondrial dysfunction in neurodegenerative diseases.
DNA Damage as an Early Marker of Senescence in Tauopathies
Authors: Harris Anner T. 
Published: December 2023

AbstractBackgroundHyperphosphorylated tau accumulation in neurons and astrocytes is a pathological hallmark of a class of neurodegenerative disorders known as “tauopathies”, such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE). Previous research investigating the toxic effects of astrocytic tau pathology identified the DNA damage marker p16 in astrocytes from post‐mortem human cases of AD and FTD. DNA damage is one of many markers of cellular senescence, a state in which cells undergo irreversible cell cycle arrest. Senescence initiation can also be identified via the expression of phosphorylated histone H2AX (gamma‐H2AX) and cyclin‐dependent kinase inhibitor p21. Senescence in astrocytes leads to reduced functional support for neurons. While recognized, the role of senescent astrocytes in tauopathies is not well understood. Here, we sought to determine how expression of other DNA damage markers, such as gamma‐H2AX and p21, and the DAMP protein HMGB1 varies across different tauopathies.MethodImmunohistochemistry (IHC) was performed on postmortem human frontal cortex tissue of CTE (n = 3), AD (N = 3), PSP (n = 3), CBD (n = 3), Healthy (n = 1) and glioblastoma (GBM) (n = 1) cases with antibodies against markers of early senescence gamma H2A.x (yH2A.x) and p21, late senescence, p16, and a senescence‐associated secretory phenotype, HMGB1. Positively stained nuclei were quantified. Immunofluorescence (IF) was employed on postmortem cases using either glial fibrillary acidic protein (GFAP) or Neurofilament H (NF‐H) antibodies with yH2A.x, p16, p21 and HMGB1 markers in order to qualitatively and quantitatively measure the prevalence of senescent astrocytes and neurons in tauopathies.ResultImmunohistochemistry revealed yH2Ax expression was observed in AD, PSP, and CBD cases. Immunofluorescence experiments employing yH2AX co‐stained with astrocytic and neuronal markers revealed expression in AD, PSP and CBD cases. Minimal expression of yH2Ax was revealed in the CTE and healthy control cases. Results from p21 stains were inconclusive. Preliminary evidence reveals HMGB1 expression in CBD and PSP cases utilizing IF techniques, and p16 expression in cells employing IHC.ConclusionOverall, results indicate that DNA damage may be broadly associated with astrocytes in tauopathies. Utilizing alternative approaches to recognize and evaluate astrocyte senescence in post‐mortem human tissue will provide further insight into these findings.
A prospective study evaluating the clinical utility of tau‐PET in the diagnostic work‐up of patients with cognitive symptoms
Authors: Smith Ruben , Hägerström Douglas , Pawlik Daria , Klein Gregory , Jögi Jonas , Ohlsson Tomas , Stomrud Erik , Hansson Oskar 
Published: December 2023

AbstractBackgroundDetermining the added value of tau‐PET in the diagnostic work‐up of patients with cognitive symptoms is of great importance before implementation of the method in clinical practice. We therefore aimed to prospectively study the added clinical value of including tau‐PET in the clinical work‐up.Method878 patients referred for cognitive complaints to secondary Memory clinics in southern Sweden were consecutively recruited to the Swedish BioFINDER‐2 cohort study (May 2017 – Sept 2021). Participants underwent a baseline diagnostic work‐up including clinical examination, medical history, cognitive testing, blood and CSF sampling, and MRI of the brain. A tau‐PET ([18F]RO948) scan was added onto this clinical diagnostic work‐up. The tau‐PET scans were visually read as: normal, early AD pattern, late AD pattern or inconclusive scan. The primary end points were change in diagnosis and change in Alzheimer disease drug therapy or other drug treatment between the pre‐ and post‐PET visits. Secondary end point was the change in diagnostic certainty between the pre‐ and post‐PET visits.ResultThe tau‐PET visual read result led to a change in diagnoses in 66 participants (7.5%, p<0.001) and a change in medication in 48 participants (5.5%, p<0.001) (Figure 1). There was an overall increase in the diagnostic certainty after tau‐PET in the whole dataset [6.9±2.3 vs 7.4±2.4; p<0.0001]. The certainty was higher in participants with a pre‐PET diagnosis of AD [7.6±1.7 vs 8.2±2.0; p<0.0001] (Figure 2) and increased, as expected, even further in participants with a tau‐PET positive result supporting an AD diagnosis [8.0±1.4 vs 9.0±0.9; p<0.0001]. The impact of tau‐PET results was strongest in participants with pathological Ab‐status, whereas no significant change in diagnoses was seen in participants with normal Ab‐status.ConclusionWe report a significant change in diagnoses and medication of patients when tau‐PET is added to an already extensive diagnostic work‐up that included CSF AD biomarkers. Tau‐PET led to a significant increase in certainty of underlying etiology. The additive effect on certainty of etiology and to diagnosis was predominantly seen in Ab‐positives and we suggest that clinical use of tau‐PET is limited to populations with biomarkers indicating Ab‐positivity.
Testing reflective tools to support care home residents living with dementia with their spiritual needs
Authors: Luijnenburg Olivia Anna 
Published: December 2023

AbstractThe needs of older people with a ‘diverse’ cultural or faith background are not well represented in social care research in general, and particularly of those living in care homes where an estimated 70% of residents are living with dementia. Additionally, the spiritual needs of care home residents are often overlooked or misunderstood by care workers, resulting in a double lack of recognition. It is common for care workers to relate spirituality primarily to religion. This can be the case, but spirituality mainly reflects (the need for) a purpose and meaning in life. Evidence demonstrates that spirituality and religion can help reduce or stabilise cognitive disorders or enable people to develop coping strategies to help accept a cognitive disorder, maintain relationships, hope, and find meaning in their lives, thus improving their sense of wellbeing. Recent studies have highlighted the importance of creating dementia‐specific spiritual assessment tools and stakeholder training. This proposed study helps fill that gap.Pre‐liminary findings will be presented on a Reflective Spirituality Tool (RST) that is tested in care homes in England. Through interviews with care home residents living with dementia, their relatives/friends, care home staff, managers, and faith leaders, the RST will be re‐developed to ensure it reflects the diversity of people living in residential care. Furthermore, care home residents were asked to bring an artefact to their interview that represented a sense of peace, safety, or wellbeing to them. The artefacts were then photographed and collected in a ‘Gallery of Spiritualities’. These two tools aim to inform people involved in dementia care and reflect upon the diverse spiritual needs that care home residents have. Furthermore, the tools help inform care home managements, care home staff, nursing students and policy makers on how to improve spiritual care for people living with dementia in residential care.
Genetics to MRI‐DTI: HFE mutation delays AD white matter degeneration in ApoE4 carriers
Authors: Pang Ran , Wang Jianli , Karunanayaka Prasanna , Kanekar Sangam , Beselia Gela , Kaneka Samika , Connor James R , Yang Qing 
Published: December 2023

AbstractBackgroundThe HFE gene involves iron metabolism that directly participates in white matter (WM) myelination process. ApoE4 are known to affect normal myelination through disruptions of iron and lipid metabolism in AD. Thus, we investigated the effect of HFE SNP concurred with the ApoE4 gene mutation in AD WM degeneration. Associations of a neuronal inflammation marker, CSF sTREM2, with DTI measures and cognitive decline were explored for a mechanism under the context of iron metabolism in AD WM degeneration.MethodWhite matter degeneration of ApoE4 carriers with and without HFEH63D polymorphism was investigated using DTI from ADNI database.1 Soluble TREM2 (sTREM2) and pathological protein concentrations in CSF were measured for each CN and AD patients with and without HFE SNP concurred with the ApoE4 gene mutation.ResultMean diffusivity and radial diffusivity of DTI demonstrated an extensive and precipitous age‐related WM degeneration in ADWT/ApoE4+ carriers (as shown in Figure1). This WM degeneration was significantly attenuated in the ADH63D/ApoE4+ subjects with lessened cognitive decline (as shown in Table1, Figure1). The decreased CDR‐cognitive impairment in AD subjects was negatively associated with sTREM2 and positively associated with RD of bilateral inferior longitudinal fasciculus and PTAU (as shown in Table2).ConclusionThe attenuation of WM degeneration and cognitive decline by HFEH63D in AD ApoE4 carriers during aging may involve an effect of reducing neuroinflammation during aging, consistent with reports that HFEH63D establishes a neuroprotective milieu2 and attenuates AD WM neurodegeneration.3 Our in‐vivo data establish a link between interactions of genetic mutation of ApoE with HFE and AD WM degeneration during aging.Reference1.	Meadowcroft MD, Wang J, Purnell CJ, et al. Reduced Cerebral White Matter Integrity Assessed by DTI in Cognitively Normal H63D‐HFE Polymorphism Carriers. J Neuroimaging. 2018;28:126‐133.2. Wang L, Johnson EE, Shi HN, Walker WA, Wessling‐Resnick M, Cherayil BJ. Attenuated inflammatory responses in hemochromatosis reveal a role for iron in the regulation of macrophage cytokine translation. J Immunol. 2008;181:2723‐2731.3. Urrutia PJ, Hirsch EC, González‐Billault C, Núñez MT. Hepcidin attenuates amyloid beta‐induced inflammatory and pro‐oxidant responses in astrocytes and microglia. J Neurochem. 2017; 142:140‐152.
4. An innovative clinical trial designed to evaluate the effects of ACI‐24.060 in Alzheimer’s Disease and in Down syndrome (ABATE Study)
Authors: Sol Olivier , Lê Bénédicte , Wagg Jonathan , Delpretti Saskia , Fiorini Emma , Vukicevic Marija , MacSweeney Emer , Borejko Olga , Aarsland Dag , Arús Xavier Morató , Boada Mercè , Matias‐Guiu Jordi A , Lleo Alberto , Fournier Nicolas , Valatsou Elena , Feige Agnès , Rongere Julien , Gray Julian JG , Hliva Valerie , Fortea Juan , Strydom Andre , Rafii Michael S , Kosco‐Vilbois Marie , Pfeifer Andrea , Streffer Johannes 
Published: December 2023

AbstractBackgroundSporadic Alzheimer’s disease (AD) and Down syndrome related AD (DSAD) share a common neuropathologic picture, with hallmark amyloid plaques and neurofibrillary tangles. The key constituents, amyloid beta (Abeta) and tau, respectively, define the biomarker picture shared between sporadic AD, DSAD and autosomal dominant AD. Small Abeta oligomers and fragments such as Abeta 1‐42 and pyroglutamate Abeta3‐42 (pGlu‐Abeta3‐42) are key for disease initiation and neurotoxicity. ACI‐24 is a liposomal vaccine targeting Abeta. Initial clinical data demonstrated safety and pharmacodynamic response, both in sporadic AD and people with DS. Preclinical data recently demonstrated that a new, optimized formulation of ACI‐24 (ACI‐24.060) has significantly improved immunogenicity against key toxic species, i.e., Abeta oligomers, Abeta 1‐42 and pGlu‐Abeta3‐42.MethodRecent clinical trials evaluating monoclonal antibodies targeting Abeta in AD have successfully employed translational biomarkers, including amyloid PET, as surrogate markers to predict clinical benefit. These biomarkers can now be more effectively used in clinical trials for both patient selection and demonstrating treatment efficacy.ResultThe ABATE study’s (NCT05462106) innovative translational clinical trial design evaluates the effects of ACI‐24.060 in sporadic AD (Part 1) and in people with DS (Part2). The biomarker‐based design with multiple interim analyses, enables (I) early assessment of safety and immunogenicity, (II) appropriate dose selection using readouts on translational biomarkers including amyloid PET, (III) the safe transition into the DS population and (IV) informed transition into pivotal studies. The use of these shared biomarkers in predictable and pre‐specified trajectories allows effective cross‐learnings between sporadic AD and DSAD and has been enabled by the recent results with anti‐Abeta monoclonal antibodies, strongly enabling this translational approach for an amyloid immunotherapy. Initial safety and immunogenicity data will be presented.ConclusionThe field of biomarker‐based translational medicine has been mobilized by the clinical evaluation of targeting of toxic abeta fragments and aggregates in monoclonal antibody trials. As shown we are utilizing these advances in an innovative clinical trial design for an efficient, evidence‐based translational medicine approach to test ACI‐24.060 as a novel Abeta vaccine candidate. This approach allows the parallel investigation of ACI‐24.060 for the treatment and prevention of both sporadic AD and DSAD.
Examining the overlap between patterns of tau deposition and cortical neurite microstructure in preclinical Alzheimer’s disease
Authors: Gozdas Elveda , Avelar‐Pereira Bárbara , Hosseini Hadi 
Published: December 2023

AbstractBackgroundIncreased Amyloid‐beta (Aβ) is associated with the neuropathological features of Alzheimer’s disease (AD), and it has been suggested to amplify tau spreading in the brain that leads to neurodegeneration. However, little is known about how the pattern of tau spreading overlaps with that of cortical microstructural neurodegeneration in the preclinical stages of the disease. Here, we utilized molecular imaging and neurite orientation dispersion and density imaging (NODDI) to identify the spreading pattern of tau pathology with the disease progression in cross‐sectional data and interaction with the degradation of cortical neurite microstructures.MethodsThe study consisted of normal controls (CN) and patients with mild cognitive impairments (MCI) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (Table 1). All participants had structural and multi‐shell diffusion magnetic resonance imaging (MRI), and positron emission tomography (PET) scans using 18F‐florbetapir (AV45) for and 18F‐flortaucipir (AV1451) for tau. The preprocessed PET images were used to generate the standardized uptake value ratio (SUVR) values in each hemisphere consisting of 180 cerebral cortical brain regions defined by the Glasser atlas. The preprocessed dMRI data were used to compute cortical NODDI coefficients (neurite density (intracellular volume fraction; ICVF), orientation dispersion index (ODI), and isotropic volume fraction (FISO)). The tau and NODDI microstructural values are then normalized compared to the Aβ− CN group by adjusting the values for age and sex. The tau spreading order was defined based on the frequencies of the normalized tau values that exceeded the given threshold and compared the patterns with the neurite microstructures.ResultsWe found a sharp increase of tau deposition in patients with Aβ+ MCI, and the medial temporal regions were identified as the earliest region to become tau positive and continue to spread to inferior temporal and inferior parietal regions. Most importantly, we found significant patterns of cortical ODI degradation with the tau spreading in the right entorhinal cortex (p = 0.004) and the right hippocampus (p = 0.02).ConclusionThe findings of this cross‐sectional study provide that regional cortical neurite imaging could provide higher sensitivity to changes in the pathological process of tau spreading in tau epicenters in AD.
Impact of rater change on data variability in ADAS‐Cog and CDR assessments
Authors: Negash Selam , Echevarria Barbara , Blattner Raymond , DiGregorio Danielle T , Randolph Christopher 
Published: December 2023

AbstractBackgroundThe past decade has seen numerous research trial failures in Alzheimer’s Disease. The CDR and ADAS‐Cog are the two most frequently used primary outcome measures of memory and cognition in clinical trials of Alzheimer’s Disease (AD). Given the high number of failed AD trials in recent years, data reliability of these measures is paramount. In an effort to minimize data variability and increase data quality, study designs often require the same rater assesses the subject/caregiver at each study visit. However, the impact of rater change on data reliability of these measures is largely unknown. This analysis investigates the impact of rater change on data variability in these measures.MethodData from 13 multinational clinical trials of early symptomatic and mild to moderate AD were analyzed. ADAS‐Cog and CDR assessments conducted by site raters were arranged according to visit sequence and divided into two groups: Rater Change (different raters administered subject’s consecutive visits) and No Rater Change (same rater administered consecutive visits). Visit‐to‐visit absolute score changes for CDR‐SB and ADAS‐Cog Total Score were calculated, and frequency distributions were evaluated.ResultWelch corrected, two sample t‐tests were conducted to compare score changes between rater change groups. For CDR, the Rater Change group showed a higher mean visit‐to‐visit score change (mean = 1.26, SD = 1.32) compared to the No Rater Change (mean = 1.02, SD = 1.13) group. The Rater Change group also showed a higher mean score change on ADAS‐Cog (mean = 4.44, SD: 3.77 and mean ‐ 4.06, SD = 3.50, for Rater Change and No Rater Change Groups, respectively). These group differences reached significance for both ADAS‐Cog (t = ‐7.2925, df = 9769.1, p < .001) and CDR (t = ‐11.228, df = 6122.7, p < .001).ConclusionThe analysis indicates significantly different score changes when there is a rater change between visits than not for both CDR and ADAS‐Cog assessments. These findings highlight the importance of rater consistency in reducing variability in an effort to improve data quality in AD trials.