bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of Plasma Glial Fibrillary Acidic Protein in Real‐life Memory Clinics in Thailand
Authors: Taweephol Thanapoom , Pongpitakmetha Thanakit , Thanapornsangsuth Poosanu , Booncharoen Kittithatch , Khieukhajee Jedsada , Luechaipanit Watayuth , Haethaisong Thanaporn , Chongsuksantikul Adipa , Likitjaroen Yuttachai , Hemachudha Thiravat 
Published: January 2025

AbstractBackgroundThe roles of reactive astrogliosis in response to the accumulation of amyloid‐β (Aβ) and early tau phosphorylation in Alzheimer’s disease (AD) have been more elucidated. Plasma glial fibrillary acidic protein (GFAP) has taken the spotlight, following phosphorylated tau (p‐tau), in evaluating patients with AD. In this study, we aimed to assess the performance of plasma GFAP compared to other biomarkers.MethodWe consecutively evaluated patients with cognitive complaints from two memory clinics in Bangkok, Thailand: Memory Clinic, King Chulalongkorn Memorial Hospital and the Neurology Clinic at the Prasat Neurological Institute. Individuals who underwent CSF analysis for core AD biomarkers or Amyloid PET to predict AD status were classified as Aβ positive (Aβ+) or negative (Aβ‐). The plasma biomarkers were measured, and their diagnostic performances were assessed using receiver operating characteristic curve. Cohen’s d was utilized to estimate the effect size of each plasma biomarkers between the Aβ+ and Aβ‐ groups. Loess regression models were employed to illustrate the trends between plasma biomarker levels and amyloid PET centiloid.ResultAmong 127 participants, 87 were female. The median age was 68 years (interquartile range: 61, 75). (Table 1) There were 72 patients with Aβ+. Plasma GFAP demonstrated an area under the curve (AUC) of 0.74 (95% confidence interval [CI] 0.65‐0.84) for detecting Aβ+ in patients with cognitive complaints. Comparatively, plasma p‐tau217, p‐tau181, neurofilament light chain, and the base model (BM, comprising age and APOE status) had AUC of 0.94 (95%CI 0.90‐0.98), 0.86 (95%CI 0.80‐0.92), 0.49 (95%CI 0.39‐0.60), and 0.70 (95%CI 0.61‐0.80), respectively. Unlike plasma p‐tau, the AUC of plasma GFAP showed no significant difference from the BM (p=0.555). (Figure 1) Plasma levels of GFAP, p‐tau217, and p‐tau181 have large effects on determining Aβ status, with Cohen’s d = 0.81 (95%CI 0.44‐1.18), 2.23 (95%CI 1.78‐2.68), and 1.54 (95%CI 1.14‐1.95), respectively. Furthermore, the loess regression showed an early increase in plasma GFAP, together with p‐tau in memory clinic patients (n=63). (Figure 2)ConclusionPlasma GFAP increases alongside p‐tau from early stages of AD, as indicated by amyloid PET centiloid. Nevertheless, the diagnostic performance does not differ from that of the BM.
Tau‐PET imaging in Progressive Supranuclear Palsy and relationship with biomarkers and clinical markers
Authors: Dilcher Roxane , Malpas Charles B , O'Brien Terence J , Vivash Lucy 
Published: January 2025

AbstractBackgroundIdentifying biomarkers for primary tau pathologies like Progressive Supranuclear Palsy (PSP) is crucial for diagnosis and treatment development. The novel positron emission tomography (PET) radiotracer 18F‐PI‐2620 shows promise in detecting tau protein in PSP and this study investigates its correlation with clinical markers.MethodsWe conducted a cross‐sectional analysis on 20 patients with clinically diagnosed probable PSP (Richardson’s Syndrome), who underwent T1‐weighted MRI, lumbar puncture, blood testing, and 0‐60 min dynamic 18F‐PI‐2620 PET scanning. Binding potential (BD) and Standardized uptake value ratios (SUVr) were generated for regions of interest. Clinical assessments included the Digit Span Memory task, Hayling, Stroop, Trail Making Test, NIH toolbox subtasks, the BRIEF‐A, and the PSP‐RS. Voxel‐wise and region‐based multiple regression analyses were employed to examine relationship between PET metrics and clinical markers using FSL, SPM, and R software.ResultsPreliminary results revealed a significant negative correlation between basal ganglia tau uptake and the Digit Span Reverse task or the BRIEF‐A (voxel‐wise, SUVr: p<0.01; BD: p<0.05). Region‐based analyses (SUVr) showed basal ganglia tau uptake significantly correlated with impairments in the Digit Span Forward and Reverse task (p<0.01), working memory subtask of the NIH (p<0.05), and the BRIEF‐A (‘Never’‐scores, p<0.05). Significant interaction effects (p<0.05) showed that these associations were predominantly localized in the basal ganglia as compared to frontal or occipital regions. Additionally, basal ganglia atrophy was negatively associated with tau uptake (SUVr) in the basal ganglia and brainstem. Ongoing analysis explores associations with CSF/blood biomarkers (GFAP/NfL/tau).ConclusionsOur findings highlight the potential of 18F‐PI‐2620 as an in‐vivo tau biomarker in PSP diagnosis, demonstrating significant links between tau uptake in the basal ganglia, brain atrophy, executive dysfunction, and disease severity. These insights could drive the development of new biomarkers, advancing future clinical trial prospects.
Plasma Biomarkers Predict Cognitive Decline in Alzheimer's Disease
Authors: Guillén Núria , Sarto Jordi , Esteller Diana , Perales Iria , Ríos‐Guillermo Jose , Augé Josep Maria , Naranjo Laura , Ruiz‐García Raquel , Juncà‐Parella Jordi , Tort‐Merino Adrià , Fernandez‐Villullas Guadalupe , Alberique Ainoa , González Yolanda , Antonell Anna , Borrego‐Écija Sergi , Castellví Magdalena , Bosch Bea , Val‐Guardiola Andrea , Balasa Mircea , Sánchez‐Valle Raquel , Martínez Neus Falgàs , Lladó Albert 
Published: January 2025

AbstractBackgroundAlzheimer's disease (AD) features a complex interplay of factors influencing cognitive decline. While CSF and plasma biomarkers have widely demonstrated their diagnostic utility, whether they may add prognostic value remains unrevealed. With this longitudinal study we aim to address this knowledge gap by evaluating the predictive value of several fluid biomarkers over cognitive decline in a cohort of biomarker‐confirmed AD individuals.MethodWe included 139 participants with biologically‐confirmed AD (A+T+N+). Four cerebrospinal fluid (CSF) biomarkers (Amyloid‐Beta1‐42 [Aβ1‐42], tau phosphorylated at threonine 181 [p‐tau181], total tau [t‐tau], and neurofilament light chain [NfL]) were determined with enzyme immunoassay, and three plasma biomarkers (p‐tau181, NfL and glial fibrillary acidic protein [GFAP]) were determined with single‐molecule array. Biomarkers were stratified into tertiles. Comprehensive neuropsychological assessments were administered at baseline (n=139) and annually (Year 1 n=108, Year 2 n=78, Year 3 n=25, Year 4 n=3 and Year 5 n=3; mean follow‐up time 1.7 years [SD 0.3]). Mixed Models for Repeated Measures explored the effectof CSF and blood biomarkers on Mini‐Mental State Examination (MMSE) score progression.ResultParticipants had a mean age at onset of 65.7 (SD 6.4) years, 17% were non‐amnestic, 58% were APOEε4 carriers. Higher baseline plasma p‐tau181 and GFAP concentrations correlated with MMSE score decline (p=0.009 and p=0.002, respectively) (Table 1, Table 2, Figure 1). Conversely, no significant associations were observed between plasma NfL or CSF biomarkers concentrations and MMSE decline.ConclusionThis longitudinal study highlights the potential prognostic value of baseline plasma p‐tau181 and GFAP concentrations for cognitive decline progression in AD.
Accrual of Alzheimer’s Disease pathology as a function of proximity to parental dementia onset
Authors: Ziukelis Elina T , Mak Elijah , Ritchie Craig W , O'Brien John T , Aarsland Dag 
Published: January 2025

AbstractBackgroundThere is emerging evidence to substantiate temporal proximity to parental onset (PPO) of dementia as a proxy stage marker in studies of late onset Alzheimer’s Disease (AD). PPO predicts accrual of amyloid pathology cross‐sectionally and longitudinally. However interactions with gender, age, and APOE‐𝜀4 carriage have been inconsistent across datasets and amyloid measures.MethodWe investigated cross‐sectionally a subset of the European Prevention of Alzheimer's Dementia (EPAD) study cohort (n=688) (Table 1). PPO was calculated by substracting a subject’s age from the youngest age of diagnosis of an affected parent. Regressions were used to determine whether PPO predicts CSF fluid Aβ1‐42 in the whole sample or p‐tau in an amyloid‐positive subgroup (n=226). Possible interactions with age, gender, education, APOE‐𝜀 status, family history load, gender of affected parent and CDR score were explored.ResultNearer PPO predicted lower CSF Aβ1‐42 level (p<0.001), interacting significantly with APOE‐𝜀4 carriage only (β=12.683; T=3.295; p=0.001) accounting for effects of age, gender and education level. In APOE‐𝜀4+ subjects, APOE‐𝜀2 provided a protective effect (Figure 1). At least half of APOE‐𝜀4+/APOE‐𝜀2‐ subjects (n=255) within ten years of age of parental onset were amyloid positive (Figure 2). PPO did not predict p‐tau levels in amyloid positive subjects (n=226) (p=0.414).ConclusionIn APOE‐𝜀4+/APOE‐𝜀2‐ individuals, PPO predicts accrual of amyloid but not tau pathology, independently of age. Selectively examining this population as they approach age of parental onset may better elucidate the natural history of preclinical late onset AD.
Multimodal phenotyping of successful cognitive aging
Authors: Behrenbruch Niklas , Molloy Eóin N. , Schwarck Svenja , Schumann‐Werner Beate , Garcia‐Garcia Berta , Vockert Niklas , Morgado Barbara , Rullmann Michael , Hochkeppler Anne , Fischer Larissa , Baldauf Kathrin , Schulze Peter , Müller Patrick , Stephens Andrew W. , Patt Marianne , Schildan Andreas , Behnisch Gusalija , Seidenbecher Constanze I. , Schott Björn H. , Esselmann Hermann , Wiltfang Jens , Barthel Henryk , Sabri Osama , Kreißl Michael C. , Düzel Emrah , Maass Anne 
Published: January 2025

AbstractBackgroundWhile some memory decline in old age is “normal”, there are some older individuals with maintained high cognitive performance. Using a multimodal approach including neuroimaging, fitness, genetic and questionnaire data (Figure 1A), we aimed to identify factors that are related to successful cognitive aging and whether these differ between sexes.MethodWe analyzed 165 cognitively normal older adults age ≥ 60 years from an ongoing study (SFB1436) (age=71±8years, 43% female). For all participants, we determined plasma Abeta1‐42/Abeta1‐40. Temporal lobe tau burden was estimated by [18F]PI‐2620 in a subsample (see Figure 1A for sample sizes). We assessed global white matter hyperintensity (WMH) volumes and gray matter thickness for medial temporal lobe (MTL), anterior cingulate cortex (ACC) and whole brain. We measured aerobic and muscular capacity (and blood pressure) by fitness assessment and trait/state anxiety by self‐reports. Genetic profiling included KLOTHO and KIBRA polymorphisms and APOE genotype. To phenotype successful cognitive aging, we i) grouped individuals age ≥ 79.5 years into SuperAgers (N=18) based on delayed verbal recall performance ≥ normative values at age of 50‐60 years versus typical agers (N=19). For the whole sample we ii) calculated cognitive age gap (CAG) as the difference between cognition‐predicted age and chronological age (Figure 3A). We assessed how markers of pathology, brain structure, fitness, mental health and genetics were related to CAG, covarying for chronological age, sex and education.ResultSuperAgers and typical agers did not differ in age, sex, education, fitness, anxiety or Abeta42/40 (all p‐values>0.1). However, SuperAgers had less WMH volume, higher ACC thickness, lower blood pressure and less temporal lobe tau‐tracer binding (small subgroup; ). In the whole sample, younger cognitive age related to higher MTL and global cortical thickness, less temporal tau‐tracer binding, less anxiety (all p<0.05; Figure 3B) and marginally to higher muscular capacity (p=.06). Only the association between anxiety measures and CAG was moderated by sex (Figure 3B). CAG was not related to genotype.ConclusionOur results suggest that successful cognitive aging is related to resistance against age‐related pathology and higher brain integrity. Younger cognitive age is linked to better mental health, especially in females.
The impact of tau‐PET in a selected memory clinic cohort: design and rationale of the TAP‐TAU study
Authors: Vermeiren Marie R. , Somsen Joost , Luurtsema Gert , Reesink Fransje E. , Verwey Nicolaas A. , Hempenius Liesbeth , Tolboom Nelleke , Biessels Geert Jan , Biesbroek J. Matthijs , Vernooij Meike W. , van Zanten Sophie E.M. Veldhuijzen , Seelaar Harro , Coomans Emma M. , Teunissen Charlotte , Lemstra Afina Willemina , van Harten Argonde C. , Visser Leonie N.C. , van der Flier Wiesje M. , van de Giessen Elsmarieke , Ossenkoppele Rik 
Published: January 2025

AbstractBackgroundTau‐PET is a diagnostic tool with high sensitivity and high specificity for discriminating Alzheimer Disease (AD) dementia from other neurodegenerative disorders in well‐controlled research environments. The role of tau‐PET in “real‐world” clinical practice, however, remains to be established. We hypothesize that tau‐PET will lead to some changes of the pre‐PET clinical diagnosis and will improve diagnostic certainty and patient management in patients with considerable diagnostic uncertainty. The aim of the TAP‐TAU study is therefore to investigate the impact of tau‐PET in clinical practice.MethodThe TAP‐TAU study, is a prospective, longitudinal multi‐center study in 300 patients (≥50 years old) with prodromal or mild dementia recruited in six Dutch memory clinics. Patients are eligible if diagnostic certainty is <85% after routine dementia screening and if the differential diagnosis includes AD. For example, patients i) are suspected of having mixed pathology (e.g., AD and vascular pathology), and/or ii) have an atypical clinical presentation, and/or iii) show conflicting or inconclusive outcomes on other biomarkers (e.g., magnetic resonance imaging or cerebrospinal fluid). Participants will undergo a [18F]flortaucipir tau‐PET scan, blood‐based biomarker sampling, and fill out patient wellbeing surveys (Figure 1). The primary outcome measures are change (pre‐ versus post‐ tau‐PET) in diagnosis, diagnostic certainty, patient management and patient wellbeing. Secondary outcome measures are head‐to‐head comparisons between tau‐PET and less‐invasive, lower cost and more scalable diagnostic tools such as novel blood‐based biomarkers and artificial intelligence based classifiers. A control group will be formed by patients who do not wish to undergo any study intervention (n=60). All participants will be followed for a year in the memory clinic.ResultThe first participants will be enrolled in March 2024.ConclusionIn TAP‐TAU, we will investigate the added clinical value of tau‐PET in a real‐world clinical setting, including memory clinic patients with limited diagnostic certainty after routine work‐up. Findings of our study may contribute to recommendations regarding which patients may benefit most from assessment with tau‐PET. This study is timely in the dawning era of disease‐modifying treatments as vigilance concerning mixed pathologies and atypical presentations in the memory clinic population grows.
Neurobiological correlates of grey matter morphometry changes in preclinical Alzheimer’s disease
Authors: Pelkmans Wiesje , Cacciaglia Raffaele , Salvadó Gemma , Fauria Karine , Minguillón Carolina , Kollmorgen Gwendlyn , Quijano‐Rubio Clara , Molinuevo Jose Luis , Grau‐Rivera Oriol , Wilson Rachael E , Jonaitis Erin M. , Langhough Rebecca E. , Blennow Kaj , Zetterberg Henrik , Johnson Sterling C. , Suárez‐Calvet Marc , Gispert Juan Domingo 
Published: January 2025

AbstractBackgroundThe driving mechanisms of structural brain alterations in the earliest stages of Alzheimer's disease (AD) are not well understood. Previous heterogeneous findings in preclinical AD, including subtle atrophy and also increased grey matter (GM) volume, underscore the need for further exploration. This study uses an extensive fluid biomarkers panel to identify pathological drivers behind longitudinal GM changes in cognitively unimpaired (CU) adults.MethodWe investigated 632 CU individuals (age 61.8±6.3, mean±SD) from the ALFA+, Wisconsin ADRC, and WRAP cohorts (Table 1), with available longitudinal MRI and cerebrospinal fluid biomarkers of Aβ42/40, p‐tau181, neurogranin, NfL, total‐tau, α‐synuclein, GFAP, YKL‐40, sTREM2, s100B, and IL‐6 measured using the NeuroToolKit panel of robust prototype assays (Roche Diagnostics International Ltd). We used non‐negative matrix factorization to decompose biomarkers into latent components. The per‐subject component weights were associated with voxel‐wise GM volume changes (years 3.5±0.9, mean±SD) and longitudinal performance on the preclinical Alzheimer's cognitive composite (PACC) using mixed model analysis.ResultSix biomarker components (C1‐C6) were identified (Figure 1). High expression of astrocyte biomarkers (C1) was related to GM volume increases in frontotemporal and subcortical regions, and faster cognitive decline in A+ individuals, while axonal damage with glial reactivity (C2) was associated with temporal atrophy. Microglial reactivity (C3) showed subtle associations with both increases and decreases in GM volume in different regions. A component primarily based on Aβ pathology (C4) was strongly associated with widespread GM volume loss and faster cognitive decline. IL‐6 (C5) reflected non‐AD related inflammation. Finally, the co‐expression of tau pathology, neuronal injury, and synaptic damage (C6) showed robust associations with frontotemporal atrophy and cognitive decline in A+ individuals.ConclusionIn a large longitudinal sample, we provide in vivo evidence that in the earliest stages of AD, Aβ pathology is also a strong contributor to future neuronal loss and cognitive decline besides neurofibrillary tangles and neuroaxonal damage. Astroglial reactivity (i.e. GFAP, s100B) in preclinical AD was associated with an increase in GM volume, which may suggest a neuroinflammatory response, and was associated with worse cognitive performance. These findings underscore the dynamic nature of structural brain changes within preclinical AD, shaped by the contributions from diverse pathophysiological processes.
Plasma phospho‐tau 217 rises with and not before early tau aggregation measured by MK6240 PET
Authors: Feizpour Azadeh , Dore Vincent , Doecke James D. , Masters Colin L , Rowe Christopher C. 
Published: January 2025

AbstractBackgroundRise in plasma phospho‐tau (pTau) is hypothesized to reflect a physiological response to brain Aβ plaques, preceding the formation of neurofibrillary tangles (NFT). An alternate explanation is poor sensitivity of tau PET for detection of early NFT formation. The tau tracer MK6240 has very low background “off‐target” binding and may better detect early tau aggregation. Choice of tau PET regions for analysis may also influence early detection of tau.MethodParticipants included 105 cognitively unimpaired (CU) and 178 cognitively impaired (CI), with plasma pTau217 Lumipulse® assay, 18F‐NAV4694 Aβ PET and 18F‐MK6240 tau PET data. The entorhinal, amygdala and meta temporal (MT) ROI 18F‐MK6240 SUVR and pTau217 levels were modelled as a function of Centiloid (CL).ResultRise in plasma pTau217 slightly lagged the rise in amygdala MK6240 binding and paralleled the rise in the meta temporal ROI (Figure 1), consistent with our previous report using Janssen p217+Tau measured by Simoa®1. Our findings also suggest that amygdala and meta temporal ROI were more robust for early detection of aggregated tau than the entorhinal cortex possibly related to PART and small ROI volume producing wide variance in the entorhinal normal range in Ab‐ CU.ConclusionThis data suggests that the amygdala is a robust region for detecting early tau aggregation by MK6240 PET and that a rise in plasma pTau217 is associated with early formation of NFT rather than a direct physiological response to brain Aβ plaques prior to NFT formation.Figure 1 legend: Modeling of 18F‐MK6240 quantification and pTau217 as a function of Centiloid. Biomarker values Z‐scored using the results from Aβ‐ cognitively unimpaired to define the normal range for p217+tau level and each tau PET ROI SUVR. The horizontal line is +2 standard deviations (SD).1Doré V, Doecke JD, …, Rowe CC. Plasma p217+tau versus NAV4694 amyloid and MK6240 tau PET across the Alzheimer's continuum. Alzheimers Dement (Amst). 2022 Apr 5;14(1):e12307. doi: 10.1002/dad2.12307. PMID: 35415202; PMCID: PMC8984092.
Experts envision a valuable role for tau‐PET in clinical practice and drug trials
Authors: Vermeiren Marie R. , Calandri Ismael Luis , van der Flier Wiesje M. , van de Giessen Elsmarieke , Ossenkoppele Rik 
Published: January 2025

AbstractBackgroundRecent advancements in Alzheimer’s disease (AD) biomarker research and AD drug trials prompt reflection on the value and appropriate use of tau‐PET in future clinical practice and trials. We therefore conducted a survey among dementia and PET experts worldwide to investigate how they envision the future role of tau‐PET in clinical practice and trials.MethodAn online survey was distributed to dementia clinicians and researchers who were invited to participate through personalized emails, social media channels and/or presentations at relevant conferences. With this approach we intended to recruit participants from different countries with diverse backgrounds and expertise. The survey questions explored experts’ opinions on the value of tau‐PET in clinical practice and in drug development and trials. We used a mix of multiple choice questions, statements with a 5‐point Likert scale (“strongly disagree” to “strongly agree”) and a few open questions.ResultIn total 269 dementia experts, comprising 144 clinicians and 121 researchers, covering six continents completed the survey (Figure 1). The vast majority (90%) fosters a positive attitude on the added value of tau‐PET in clinical practice, particularly for staging, diagnosing, monitoring and prognostication in a cognitively impaired memory clinic population (Figure 2). When confronted with clinical case vignettes, our findings suggest that a tau‐PET scan is perceived particularly useful in patients with an atypical presentation (78%) or suspicion of mixed pathology (66%) and less useful in a typical AD case (25%). Experts are confident that a tau‐PET scan could influence patient management in current practice (median 4 “agree” [IQR 4‐5]) and this would increase when effective disease‐modifying treatments are available (median 4 “agree” [IQR 3‐4]) (Figure 2). Experts anticipate an important role for tau‐PET for participant selection (76‐100%) and measuring endpoints (75‐97%), in both anti‐amyloid and anti‐tau drug trials (Figure 3).ConclusionOur global survey shows that dementia experts envision an important role for tau‐PET in the future, both in clinical practice and in drug trials.