bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detection of PART in vivo using tau‐PET: preliminary findings using [18F]RO948
Authors: Leuzy Antoine , Binette Alexa Pichet , Janelidze Shorena , Strandberg Olof , Ossenkoppele Rik , Smith Ruben , Hansson Oskar 
Published: December 2023

AbstractBackgroundPrimary age‐related tauopathy (PART) is a neuropathological entity describing tau pathology in the entorhinal cortex and hippocampus in the absence of amyloid‐β (Aβ) plaques. Though cross‐sectional work using [18F]flortaucipir tau‐PET has shown an association between medial temporal lobe signal and worse cognitive performance, longitudinal studies are needed to examine whether medial temporal lobe tau is associated with cognitive decline and cortical tau accumulation in cognitively unimpaired (CU) individuals. We here aimed to investigate whether CU individuals who are Aβ‐negative and tau‐PET positive in the medial temporal lobe show cognitive decline and increases in CSF phosphorylated tau (P‐tau) or tau PET over time.MethodsUsing BioFINDER‐2, PART was defined as i) CU individuals (not fulfilling criteria for mild cognitive impairment of dementia), ii) age ≥ 60 years, iii) Aβ‐negative (Centiloids < 20 and negative CSF Aβ42/40), and iv) an [18F]RO948 tau‐PET standardized uptake value ratio (SUVR) >1.26 (cut‐off based on Gaussian mixture modelling in BioFINDER‐2, n = 1754) in a volume‐weighted ROI encompassing the entorhinal cortex and hippocampus. [18F]RO948 data was collected 70 to 90 min post‐injection with longitudinal follow‐up collected after ∼2.5 years (average 2.73 ± 1.14 years). Longitudinal P‐tau217 was measured using immunoprecipitation‐mass spectrometry (average 2.67 ± 1.12 years). Longitudinal cognitive measures (average 2.75 ± 0.94 years) included the MMSE and modified PACC. For both longitudinal [18F]RO948, CSF P‐tau217 and cognition, change was assessed using slopes derived from linear mixed models.Results38 individuals fulfilled inclusion criteria (Table 1). These individuals showed significant increases in [18F]RO948 SUVR in the entorhinal cortex/hippocampus (p<0.05, t‐test vs 0)—but not in the temporal cortex—and in CSF P‐tau217 (p<0.01, t‐test vs 0) over time (Figure 1A). This group also showed cognitive decline over time using the PACC (p<0.01, t‐test vs 0) but not the MMSE (Figure 1B). Additional analyses are ongoing using two additional tau‐PET tracers and additional CSF‐based P‐tau measures.ConclusionsThese preliminary findings using [18F]RO948 suggest that PART can be detected in vivo using tau‐PET and that Aβ‐negative CU individuals who are tau‐PET positive in the medial temporal lobe are at risk for focal tau accumulation and cognitive decline.
Targeted bisulfite sequencing analysis of Alzheimer’s disease candidate genes reveals differential methylation across neurofibrillary tangle burden in the prefrontal cortex.
Authors: Wheildon Greg , Smith Adam R. , Soanes Darren , Smith Rebecca G. , Moore Karen , O'Neill Paul , Morgan Kevin , Thomas Alan J , Love Seth , Francis Paul T , Mill Jonathan , Pishva Ehsan , Lunnon Katie 
Published: December 2023

AbstractBackgroundRecent epigenome‐wide association studies (EWAS) identified several loci in specific genes showing robust and reproducible alterations in DNA methylation in Alzheimer’s disease (AD) brain samples. Standardly, assessing methylation in EWAS is done using microarrays, which target a limited number of sites in each gene. Here, we performed targeted bisulfite sequencing of candidate genes associated with AD to determine the exact extent of methylation changes across neurofibrillary tangle burden (NFT) within these loci.MethodPrefrontal cortex brain samples from 58 individuals were grouped by Braak stage (control 0‐II; intermediate III‐IV; AD V‐VI). Following DNA extraction, 30 genomic regions were captured using Agilent SureSelect target baits. After next‐generation bisulfite sequencing, reads were aligned and the methylation status of cytosine residues called using the Bismark program. Differentially methylated positions (DMPs) were analyzed across the three groups. Furthermore, the presence of differentially methylated regions (DMRs), made up of several DMPs was assessed. Methylation levels in genomic features, such as promoters and gene bodies, of the target regions were also compared.ResultMethylation levels were quantified for each group. Linear regression controlled for co‐variation before differences were examined using a one‐way ANOVA, with Tukey’s post‐hoc test. Sites in several genes showed stepwise increases in DNA methylation across the groups. Interestingly, amongst the most robust sites, differences in methylation in the intermediate group when compared to the control and AD samples were observed. DMRs were observed in the groups, as were methylation differences between promotors and gene bodies in several targeted regions.ConclusionThis work provides further evidence that dysregulation of methylation is associated with pathological changes in AD prefrontal cortex. Differential methylation with intermediate NFT pathology, at sites showing no difference between control and AD samples, potentially indicates early pathological changes. As DNA methylation is reversible, this could present potential targets for pharmacological intervention.
Culture‐sensitive dementia diagnostics and care: a best practice for a diverse patient population
Authors: Lazaar Najoua , Franzen Sanne , van Bruchem‐Visser Rozemarijn L. , De Jong Frank Jan , Raso Francesco U S Mattace , Papma Janne M. 
Published: December 2023

AbstractBackgroundThe elderly population in Europe is becoming more diverse. In order to provide effective dementia diagnostics and care, healthcare professionals need to cater more to diversity in terms of culture, language, educational attainment or (health) literacy. Therefore, the implementation of culture‐sensitive diagnostic instruments and a shift in approach to adapt to this group is necessary within memory clinics. We preformed semi‐structured interviews to gather the knowledge and experience of healthcare professionals on the topic of culture‐sensitive dementia diagnostics and care. The findings are summarized in a best practice.MethodFor the best practice we used qualitative methods and preformed 14 semi‐structured interviews. We interviewed healthcare professionals that work with a diverse patient population within different memory clinics in the Netherlands. We investigated their definition of culture‐sensitive care, the specific adjustments made in the diagnostic trajectory and discussed organizational aspects related to culture‐sensitive care. These interviews were transcribed verbatim and analyzed using Atlas.ti.ResultSeveral requirements for effective dementia diagnostics have been mentioned, such as working with experienced translators, the use of culture‐sensitive diagnostic instruments, and language specific information material. Other adjustments consider communication between healthcare professionals and patients. First, healthcare professionals put extra effort into estimating the level of (abstract) reasoning of patients. In this way the language used by the healthcare professional is adapted in order to optimize the communication. Second, there is more attention for nonverbal communication if patients have a different cultural background. Lastly, healthcare professionals take more time to provide care for a multicultural patient group.ConclusionLearnings and experiences from healthcare professionals working at memory clinics across the Netherlands give valuable insights. A best practice for culture‐sensitive dementia diagnostics and care may help with accurate dementia diagnosis and provide tools for healthcare professionals to cater to a diverse patient population.
Longitudinal morphometry of medial temporal lobe subregions in earlyAlzheimer’s disease
Authors: Baumeister Hannah , Gellersen Helena M , Kleineidam Luca , Wolfsgruber Steffen , Bürger Katharina , Laske Christoph , Perneczky Robert , Peters Oliver , Priller Josef , Schneider Anja , Spottke Annika , Teipel Stefan , Wiltfang Jens , Heneka Michael T. , Düzel Emrah , Jessen Frank , Berron David 
Published: December 2023

AbstractBackgroundStructural MRI is frequently used to track Alzheimer’s disease (AD) progression in clinic, research, and pharmacological trials. It has been shown that established MRI‐derived measures lack diagnostic sensitivity particularly in early stages of AD. Here, we investigate if the utility of structural MRI for tracking early AD progression can be increased when focusing on subregions of the medial temporal lobe (MTL) which are known to exhibit earliest AD‐related neuropathological change.MethodWe used data from N = 143 participants enrolled in the DZNE Longitudinal Cognitive Impairment and Dementia Study (DELCODE). This included cognitively unimpaired participants who were either Aβ‐negative (CU Aβ‐; n = 67) or Aβ‐positive (CU Aβ+; n = 20), Aβ+ participants with subjective cognitive decline (SCD Aβ+; n = 38), and Aβ+ participants with MCI (MCI Aβ+; n = 18).Participants underwent annual assessments up to three years after baseline, including MRI (2.19 ± 0.86 follow‐ups) and a neuropsychological testing (2.18 ± 0.83 follow‐ups). Segmentations of MTL subregions were generated using a longiudinal, template‐based implementation of the Automated Segmentation of Hippocampal Subfields (ASHS; Yushkevich et al., 2015, Hum Brain Mapp.) algorithm (Figure 1). Linear mixed models were fitted to derive volumetric slopes and to test their relationship with longitudinal changes in Preclinical Alzheimer Cognitive Composite (PACC‐5) scores.ResultWe observed significant volume losses across diagnostic groups with the MCI Aβ+ group exhibiting the fastest rates. Compared with the CU Aβ‐ group, there were accelerated volume losses in the subiculum and dentate gyrus in the SCD Aβ+ group and, additionally, in the entorhinal cortex and Brodmann areas 35 and 36 in the MCI Aβ+ group. There was also a trend towards faster volume losses in the entorhinal cortex in the CU Aβ+ group. Higher rates of MTL subregional volume losses, particularly in the cornu ammonis 1 subfield, were related to a faster decline on the PACC‐5 in the MCI Aβ+ group. This effect remained significant when controlling for baseline volumes.ConclusionOur findings highlight the viability of subregional MTL morphometry for tracking earliest neurodegeneration and related cognitive decline due to AD.
Performance of plasma pTau181 and pTau217 measured with fully automated LUMIPULSE G prototype immunoassays
Authors: Vanbrabant Jeroen , De Meyer Steffi , Van Loo Maxime , Lambrechts Charlotte , Accou Flore , Dekeyser Filip , Rubel Carrie E. , Czerkowicz Julie , Fraser Kyle , Graham Danielle , Inaoka Daigo , Aoyagi Katsumi , Vanmechelen Eugeen , Poesen Koen , Vandenberghe Rik , Stoops Erik 
Published: December 2023

AbstractBackgroundThere is a need for scalable, robust and precise Alzheimer’s Disease (AD) plasma phosphorylated Tau (pTau) biomarker tests to support clinical trials and clinical practice. This study evaluated the performance of novel plasma pTau181 and pTau217 assays developed on the LUMIPULSE G1200 automated immunoassay platform and compared them to Quanterix homebrew assays.MethodHomebrew Quanterix Simoa assays for plasma pTau181 and pTau217 were transferred to the LUMIPULSE G instrument using recombinantly expressed versions of respectively α‐pTau181 mAb ADx252 and α‐pTau217 mAb RD‐084 (capture) both combined with an ALP‐conjugated Fab fragment digested from α‐N‐terminal Tau recombinant ADx204/RD‐073 (detector). Analytical performance evaluated specificity, LLOQ and precision. Performance in patient samples was evaluated using a prospective memory cohort of 42 biomarker confirmed AD patients in the prodromal or dementia stage as well as 35 healthy spouse controls. LUMIPULSE G results were compared with results from the Quanterix homebrew assays designed by ADx using the same antibody configuration.ResultRobust LUMIPULSE G1200 measurements (mean intra‐run CV 3%) distinguished AD patients from spouse controls with an area under the curve (AUC) of 0.81 and 0.88 for pTau181 and pTau217, respectively. The Quanterix homebrew assays demonstrated higher AUC of 0.98 for pTau181 (pDeLong = 0.002) and of 0.95 for pTau217 (Figure 1A). Addition of age, sex and ApoE4 status to the LUMIPULSE G‐based models increased the performance of both pTau181 and pTau217 to predict AD diagnosis – relatively to univariate models ‐ with AUCs of respectively 0.91 and 0.95 (Figure 1B, both pDeLong < 0.05), approximating Simoa‐based pTau performance. PTau values measured on both platforms correlated significantly (p<0.0001) for pTau181 (r = 0.66) and pTau217 (r = 0.77).ConclusionThe LUMIPULSE G platform is a scalable, automated, real‐time‐testing platform that is globally available. These data demonstrate that two assays on this platform, pTau181 and pTau217, are capable of distinguishing AD from controls in plasma. The sensitivity and specificity are slightly less on LUMIPULSE G when compared to an assay using the same antibodies developed on the Simoa instrument. Thus, additional experiments are required on the LUMIPULSE G to optimize analytical performance of these assays using an IVD‐grade automated system.
Sex‐specific metabolomics‐derived blood biomarkers of Alzheimer’s disease.
Authors: Clark Christopher , Laczko Endre , Rabl Miriam , Stojkovic Slavisa , Popp Julius 
Published: December 2023

AbstractBackgroundReadily accessible diagnostic tools are crucial for early detection of Alzheimer’s disease (AD). Here, we sought to identify peripheral metabolism biomarkers predicting the presence of AD pathology.MethodUntargeted liquid chromatography‐mass spectrometry was used to quantify 2286 serum metabolites in participants on a longitudinal memory clinic study. Unbiased between‐group analysis using Orthogonal Partial Least Squares Discriminant Analysis, Linear Discriminant analysis and Principal Component Analysis were performed to build a classifier for AD as indicated by CSF biomarkers. MetaboAnalyst was subsequently used for selection of the most relevant metabolites. Pathway enrichment was used to determine biological pathway alterations related to AD.ResultNo biomarker signature of AD was found in the whole cohort. Stratification according to sex allowed building a classifier for AD using 14 serum metabolites in males and 9 in females. Thirteen enriched pathways were identified, including arachidonic acid and tryptophan metabolism (Figure 1). The selected metabolites significantly improved the prediction of cognitive decline in females compared to a reference model (Figure 2, AUC 0.874 vs. 0.719).ConclusionSex specific peripheral metabolism biomarker profiles are useful to predict cerebral AD pathology and cognitive decline, and detect related metabolic alterations. This highlights the need for personalised diagnostic and therapeutic approaches in AD.
Locus coeruleus integrity, cerebrovascular health, and plasma Alzheimer’s biomarkers in cognitive aging
Authors: Dutt Shubir , Bachman Shelby L , Li Yanrong , Yew Belinda , Jang Jung Yun , Ho Jean K , Nashiro Kaoru , Min Jungwon , Yoo Hyun Joo , Gaubert Aimee , Nguyen Amy , Blanken Anna E , Sible Isabel J , Marshall Anisa J , Kapoor Arunima , Alitin John Paul M , Hoang Kim , Shenasa Fatemah , Martini Alessandra Cadete , Head Elizabeth , Rodgers Kathleen E. , Shao Xingfeng , Wang Danny J.J. , Mather Mara , Nation Daniel A. 
Published: December 2023

AbstractBackgroundThe locus coeruleus (LC) innervates the cerebrovasculature and plays a critical role in optimally regulating cerebral blood flow. However, few studies have examined potential relationships between these systems in humans with widely available neuroimaging methods, and none have explored how relationships may change in the presence of growing Alzheimer’s disease (AD) pathology.MethodParticipants were 66 community‐dwelling older adults free of dementia (ages 55‐87) recruited at the University of Southern California. Pseudocontinuous arterial spin labeling (pCASL) MRI measured regional perfusion, and T1‐fast spin echo (T1‐FSE) MRI quantified rostral LC contrast, a well‐established measure of LC structural integrity. Subsets of participants underwent neuropsychological testing (n = 36) as well as fasting venipuncture to measure plasma AD biomarker concentrations of Aβ42/40 ratio (n = 56) and ptau181 (n = 35). Multiple linear regression models examined associations among regional perfusion, LC integrity, and cognition (episodic memory, attention, executive function). Moderation analyses included additional terms for plasma AD biomarker concentrations and plasma x LC interaction effects.ResultHigher LC‐MRI contrast was linked to higher frontal (medial and lateral orbitofrontal) perfusion but lower limbic (amygdala and entorhinal) perfusion. Greater LC‐MRI contrast was also associated with better episodic memory recall and recognition but not measures of attention or executive function. Plasma Aβ42/40 ratio and ptau181 moderated LC‐perfusion relationships such that associations significantly weakened in the presence of greater pathology.ConclusionThis is the first human study to directly investigate associations between LC integrity and perfusion in a well‐characterized sample with neuroimaging, cognitive, and AD biomarker data. LC integrity tracked episodic memory performance along with cerebral perfusion, while greater AD pathology in preclinical populations disrupted LC‐perfusion relationships, suggesting that growing amyloid and tau pathology may negatively impact the LC’s ability to optimally regulate cerebral blood flow. Taken together, our findings highlight the importance of tracking the LC over the AD disease course. Concurrent multimodal imaging of the LC and cerebrovascular function may have potential as a novel non‐invasive biomarker, and future studies should track its utility longitudinally and its relationship with disease severity and other disease markers (e.g., grey matter atrophy, amyloid/tau PET).
The disintegration of cognitive reserve: exploring the association between years of education, delirium, and baseline cognition in hospitalized older adults
Authors: Avelino‐Silva Thiago J , Campora Flavia , Curiati Jose A E , Jacob‐Filho Wilson 
Published: December 2023

AbstractBackgroundCognitive reserve helps maintain cognitive function in the face of accumulating brain pathology and potentially delays the onset of clinical dementia. However, there is a lack of research examining the role of cognitive reserve in delirium, particularly in the context of preexisting neurocognitive disorders. We aimed to investigate the interaction between years of education and baseline cognition in their association with delirium occurrence in hospitalized older adults.MethodsProspective cohort study including acutely ill patients aged ≥60 admitted to the geriatrics unit of a university hospital in Sao Paulo, Brazil (2009‐2020). Candidates underwent comprehensive geriatric assessments in the first 24 hours of hospitalization. Delirium occurrence was defined using the CAM, completed daily during the hospital stay. Baseline cognition was determined using the CDR and the CDR‐SB. Years of education were used as a proxy for cognitive reserve. We investigated the association between delirium occurrence and years of education using logistic regression models; we then completed interaction analyses exploring the effect of baseline cognition on that association.ResultsWe included 3,863 participants (mean age = 80; female = 62%; mean years of education = 6). Overall, 1,346 (35%) participants experienced delirium during hospitalization. Additionally, 777 (20%) participants had normal baseline cognition (CDR = 0), 2,068 (54%) had mild cognitive impairment or mild dementia (CDR = 0.5‐1), and 1,018 (26%) had moderate or severe dementia, with a median CDR‐SB of 4. After adjusting for age and sex, we found that participants with ≥12 years of education were less likely to experience delirium (OR = 0.75, 95%, 95%CI = 0.59‐0.96, p = 0.022). However, we found that the association was significantly modified by baseline cognition (p = 0.024) (Figure 1) and that having more years of education was protective against delirium only in the absence of preexisting cognitive impairment (Figure 2).ConclusionMore years of education were protective against delirium occurrence in hospitalized older adults, but only in the absence of preexisting cognitive impairment. Our results suggest that after the onset of clinical neurocognitive disorders, previous markers of cognitive reserve no longer contribute to a lower risk of delirium.
Strategy for absolute quantification of phospho‐Tau epitopes in cerebrospinal fluid by mass spectrometry
Authors: Gomes Bárbara Fernandes , Sauer Mathias , Weiner Sophia , Andreasson Ulf , Blennow Kaj , Zetterberg Henrik , Gobom Johan 
Published: December 2023

AbstractBackgroundMass spectrometry is used as reference method for protein quantification by measuring tryptic peptides derived from the target protein relative to a stable isotope‐labeled standard. Existing targeted mass spectrometric methods to measure total tau (tTau) and phosphorylated tau (pTau) species in cerebrospinal fluid (CSF) rely either on immunoaffinity enrichment of the protein or exploit the unusual property of tau being soluble in 2.5% perchloric acid (PA), to precipitate abundant sample proteins. Both strategies, however, carry risk of introducing bias: immunoaffinity enrichment relies on the specificity of the used antibodies, which may not have equal affinity for all of the large number of processed or modified forms of tau, and PA may partially precipitate some tau forms. To address this problem, we have developed an antibody‐ and PA‐free method to measure tau and pTau epitopes in CSF by targeted mass spectrometry.MethodCSF samples (100 µl) from healthy individuals (HC) and Alzheimer’s disease (AD) patients were spiked with stable isotope‐labeled tau peptide standards containing the phospho‐epitopes pTau181, pTau231, pTau217, pTau205, and non‐phosphorylated Tau212‐221, and subjected to tryptic digestion. Desalted samples were fractionated by strong anion‐ and strong cation‐ exchange (SAX and SCX, respectively) solid phase extraction with step‐wise pH elution. The fractions were analyzed by parallel reaction monitoring on a nano‐flow LC‐MS on a Quadrupole‐Orbitrap hybrid mass spectrometer.ResultSeveral tau peptides were detected with both SAX and SCX, including pTau181, pTau217, pTau205, and Tau212‐221. The reproducibility of the new assay was assessed, and its performance was compared with PA‐based sample preparation and immunoassays for tau and pTau in a pilot study of AD patients and controls.ConclusionThe method described here allows for the detection of multiple tau/pTau peptides, while avoiding the need for selective protein isolation methods such as immunoaffinity enrichment or PA precipitation, thereby eliminating bias toward more/less soluble tau species.