bluuebunny/crossref_metadata_2025_split huggingface dataset:
Visual classification of tau‐PET detects four subtypes with different long‐term outcomes
Authors: Boccalini Cecilia , Mathoux Gregory , Hristovska Ines , Ribaldi Federica , Peretti Débora Elisa , Arnone Annachiara , Scheffler Max , Frisoni Giovanni B. , Hansson Oskar , Vogel Jacob W. , Garibotto Valentina 
Published: January 2025

AbstractBackgroundSubstantial variability in tau accumulation patterns in Alzheimer’s disease (AD) population has now become accepted. Subtype and Stage Inference (SuStaIn) has distinguished four distinct spatiotemporal trajectories of tau pathology: limbic (S1), medial temporal lobe‐sparing (S2), posterior (S3), and lateral temporal (S4). A visual method to validate and identify them is a requirement for their clinical translation. Our study aims to provide evidence for multiple tau accumulation patterns in a clinical setting by developing and testing a novel topographic visual method for tau‐PET based on SuStaIn subtypes.MethodWe included 245 participants from the Geneva Memory Clinic, who underwent 18F‐Flortaucipir‐PET. All scans were classified into different subtypes by visual ratings and the automated SuStain algorithm. Cohen's kappa (k) tested the agreement between raters and between visual and automated subtypes. Chi‐squared and Kruskal‐Wallis tests were used to test differences in clinical features, tau, and amyloid (Aβ) loads between subtypes. Differences in cognitive trajectories were tested using linear mixed‐effects models, controlling for age, sex, and tau stages.ResultA substantial agreement between raters was found in visually interpreting tau pattern subtypes (k>0.65, p<0.001) and a fair agreement between visual and automated subtypes (k=0.39, p<0.001), with the automated approach detecting a higher rate of negative scans. According to the visual classification, individuals with S2 subtype were younger than S1 and S3 (p<0.001), had worse MMSE and verbal fluency scores (p<0.05) than S4 and S1, showed higher global tau than other subtypes (p<0.05), and a steeper cognitive decline.ConclusionOur results show that visual classification can reliably identify four tau patterns, differing in global tau loads, clinical characteristics, and long‐term outcomes, suggesting its clinical usefulness for the detection of higher‐risk AD variants. A clinically implementable classification in subtypes with faster decline is paramount for personalized diagnosis and therapy.
Brain Resilience to Targeted Attack of Resting BOLD Networks as a Measure of Cognitive Reserve
Authors: Argiris Georgette , Stern Yaakov , Habeck Christian G 
Published: January 2025

AbstractBackgroundRecent advancements in connectome analyses allow for more fine‐grained measurements of brain network integrity. One measure of integrity is resilience, or the capacity of the network to retain functionality when confronted with endogenous or exogenous perturbations that result in damage or error. We assessed the impact of individual differences in the resilience of resting BOLD connectivity on the relationship between cognitive and brain changes in a lifespan cohort of cognitively healthy adults over a 5‐year period.MethodOne hundred twenty‐six cognitively healthy participants from the Reference Ability Neural Network (RANN) longitudinal lifespan cohort (age 20‐80 years) underwent resting‐state fMRI to measure functional connectivity and an out‐of‐scanner neuropsychological battery at baseline and five‐year follow‐up. Undirected weighted adjacency matrices were generated from Schaefer et al. (2018) 400 parcellation atlas. As a measure of whole‐brain network resilience, we adopted a targeted attack approach, whereby nodes are sequentially removed from the connectome in order of nodal strength. At each iteration of attack, nodal strength is recalculated based on the effect of prior lesioning and the largest connected component (LCC) is measured. We inferred that more resilient individuals will sustain larger LCCs over longer iterations of lesioning before decay in LCC becomes evident, with resilience operationalized as the iteration of steepest slope in LCC.ResultWe tested whether our operationalization of brain resilience (BR) moderated the effect of brain integrity (i.e., cortical thickness; CT) on out‐of‐scanner neuropsychological test performance across four domains of cognition in the context of longitudinal change (∆) over time. After accounting for baseline differences in change variables and adjusting for the demographic factors of Age, Sex, NART IQ, and Education, we observed a significant negative interaction between ∆CT and ∆BR on ΔCognition for the Fluid Reasoning domain. That is, individuals with increased brain resilience over time were less sensitive to the effect of changes in cortical thickness on changes in cognition.ConclusionOur finding supports evidence for targeted attack as a measure of cognitive reserve, where higher brain network resilience may have permitted individuals with reduced brain integrity to better cope with structural loss and enhance preservation of cognitive function.
Systematic Review of Scalable Biomarkers of Alzheimer’s Disease
Authors: Suresh Shivani , Raymont Vanessa , Bauermeister Sarah 
Published: January 2025

AbstractBackgroundAlzheimer's disease (AD) impacts over 50 million individuals and imposes a substantial burden on patients, caregivers, and society at large. Recent research suggests that AD is a continuum comprising preclinical, prodromal, and dementia stages, with underlying pathology manifesting well before symptoms appear. Early and accurate diagnosis is therefore crucial for optimal clinical outcomes; yet current diagnostic methods, such as neuroimaging and cerebrospinal fluid lumbar puncture, are expensive and invasive. This highlights the need for more scalable and cost‐effective alternatives, particularly blood biomarkers. In addition to their diagnostic potential, these biomarkers can also screen at‐risk individuals and offer valuable prognostic insights. Therefore, a systematic review of existing literature on scalable AD blood biomarkers is essential to address the current literature gap and highlight advancements in the field.MethodTo conduct this systematic review, a comprehensive search of the literature will be performed across multiple databases, including PubMed, EMBASE, Global Health, Journals@OVID, and PsycINFO. In light of the recent NIA‐AA recommendations, focus will be laid on articles assessing the clinical utility of plasma phosphorylated tau‐217 (p‐tau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). The search criteria will be limited to human studies and English‐language journal articles published within the last 5 years. The review will include a qualitative synthesis of selected studies, and if feasible, a random‐effects meta‐analysis may be conducted. The meta‐analysis will pool studies based on the specific biomarkers under assessment to provide a quantitative overview of findings.ResultThe systematic review aims to highlight advancements in scalable AD biomarkers, with a specific focus on plasma p‐tau217, GFAP, and NfL. An initial search of the literature brought up 3086 papers. After removing duplicates and conducting a preliminary screening, 159 articles have been selected for review. Through the qualitative synthesis of selected studies and potential meta‐analysis, the review intends to provide a comprehensive overview of the clinical utility of these biomarkers.ConclusionThis review will contribute to laying the foundation for improved clinical care practices in AD by summarizing key findings, identifying gaps in the literature, and outlining future applications of blood biomarkers in the diagnosis and management of AD.
Mitochondrial DNA copy number from human blood is associated with specific cognitive function
Authors: Tian Qu , Zweibaum David A. , Oppong Richard , Qian Yong , Pilling Luke C , Casanova Francesco , Atkins Janice L , Melzer David , Ding Jun , Ferrucci Luigi 
Published: January 2025

AbstractBackgroundThe mitochondrial cascade hypothesis suggests that mitochondrial dysfunction plays an important role in the pathogenesis of Alzheimer’s disease dementia. Recent data have shown that mitochondrial DNA copy number (mtDNAcn) in human blood is associated with dementia risk and cognitive function, but which specific cognitive measures or domains are associated with mitochondrial dysfunction and whether this relationship is affected by health deterioration such as physical frailty or mitochondrial somatic mutations is not clear.MethodsWe measured mtDNAcn and heteroplasmies using fastMitoCalc and MitoCaller, respectively, from UK Biobank Whole Genome Sequencing (WGS) data at study entry (2006‐2010). Pre‐frail/frail status was determined by the presence of slow gait, weight loss, low grip strength, exhaustion, or low physical activity. Cognitive function was assessed in a subset of participants (mean age=64.1,51.7% women, 97.0% White) on average 8.9 years after study entry, including processing speed via Digit Symbol Substitution Test (DSST)(n=13,940), attention via Trail Making Test (TMT) part A(n=13,482), executive function via delta TMT(n=13,428) and tower rearranging task(n=13,819), memory via paired associative learning task(n=14,094), and fluid reasoning via matrix pattern completion task(n=13,935). We examined the associations between mtDNAcn and cognitive measures using multivariate linear regression, adjusted for demographic factors, smoking status, follow‐up time, measures related to mtDNAcn assessment, and Apolipoprotein E ε4 status. We then stratified the analysis by frailty status and levels of heteroplasmy load.ResultsOverall, more mtDNAcn was significantly associated with higher DSST (p=0.036) but not with other cognitive measures. After stratification by frailty status, mtDNAcn was associated with DSST, delta TMT, and paired associative learning in the pre‐frail/frail participants only (p=0.047,0.007, and 0.044, respectively). After stratification by a median split of heteroplasmy load, mtDNAcn was associated with DSST and paired associative learning in those with higher heteroplasmy load (p=0.039 and 0.031, respectively). Results remained similar after excluding participants with dementia diagnosis (n=15).ConclusionsHigher mitochondrial DNA copy number from human blood is associated with higher cognition in specific measures. The associations with processing speed, executive function, and memory are prominent in individuals with health deterioration of physical frailty or high level of mtDNA heteroplasmy. Future studies are warranted to understand the biological underpinnings.
Investigating covert awareness in individuals with Alzheimer’s Disease using functional near‐infrared spectroscopy (fNIRS)
Authors: Gupta Garima , Kolisnyk Matthew , Kazazian Karnig , Shahid Rafeh , Urian Diana , Novi Sergio , Pantazopoulos Koula , Abdalmalak Androu , Huntley Jonathan D , Debicki Derek , Pasternak Stephen H , Owen Adrian 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a form of dementia that impairs memory, language, and daily functioning. With disease progression, AD patients reportedly experience disturbances in their awareness of self, others, and their environment. These disturbances are associated with unfavourable clinical outcomes, which prompts critical questions about how AD patients experience the world around them. The present study utilizes a validated neuroimaging paradigm to ‘map’ conscious experiences through changes in brain activity. The premise is that similarity (i.e., synchrony) in conscious experiences of different people can be detected by investigating activity in fronto‐parietal areas linked with higher‐order processing essential for plot‐following. This paradigm was previously used to assess conscious states of behaviorally non‐responsive brain‐injured patients, showing that the internal mental experience of some patients was similar to that of healthy controls.MethodsIn this study, patients with mild‐moderate AD (n = 9) and age‐matched healthy controls (n = 29) underwent a 40‐minute functional near‐infrared spectroscopy (fNIRS) scan. During the scan, participants watched two short movies, each with an intact‐ and scrambled‐plot version. Scrambled versions were included to demonstrate that synchrony was associated with higher‐order processing rather than the mere presentation of audio‐visual stimuli. Inter‐subject correlations (i.e., Pearson correlation coefficients between the hemodynamic activity of one or more AD patients and the remaining participants, including healthy controls) were used as the metric for synchrony.ResultsCompared to the scrambled plot conditions, healthy controls showed robust synchronization in the frontal and parietal regions in the intact‐plot conditions. AD patients, in contrast, did not demonstrate a consistent pattern of synchronization in these regions during the intact‐plot conditions. Single‐subject analyses (i.e., comparing individual patients to the control group) further revealed that only one AD patient exhibited some degree of synchronization with the healthy controls during the audio‐visual stimuli.ConclusionThese preliminary findings indicate that AD patients may be experiencing the world differently from healthy individuals. The variability noted in synchronization across AD patients may be reflective of the heterogeneity in disease‐related impairments. Understanding deficits and patient needs from the lens of impaired conscious processing could support disease prognosis and promote improvements in person‐centered care.
Effect of Scanner on beta amyloid quantification in a head‐to‐head comparison of 18F‐NAV4694 Centiloid measurements between Biograph Vision, Gemini and Biograph mCT
Authors: Dore Vincent , Gillman Ashley G , Bourgeat Pierrick , Villemagne Victor L , Fripp Jurgen , Huang Kun , Williams Robert , Shishegar Rosita , O'Keefe Graeme , Cox Timothy , Li Shenpeng , Krishnadas Natasha , Feizpour Azadeh , Bozinovski Svetlana , Rowe Christopher C. 
Published: January 2025

AbstractBackgroundNew generation PET scanners achieve superior resolution and sensitivity, but the implications on beta amyloid (Aβ) quantitation are not well understood. The Centiloid (CL) scale (Klunk et al., 2015) was introduced to promote consistent Aβ burden quantification across different positron emission tomography (PET) tracers and quantification pipelines, but was not intended to control for hardware or reconstruction changes. Instead, post‐reconstruction smoothing harmonisation (Joshi, Koeppe, Fessler, 2009) is assumed to harmonise inter‐scanner Centiloid measurements. In this work, we compare paired Centiloid measurements between the Siemens Biograph Vision and one of Siemens Biograph mCT or Philips Gemini.Method28 AIBL participants underwent MPRAGE‐MRI and 18F‐NAV4694 imaging on two scanners (of Vision, mCT or Gemini) within a year, reconstructed per the ADNI protocols for each scanner. Centiloid was quantified using the standard SPM framework and corrected for expected accumulation between scans. We investigated difference in Centiloid and effectiveness of PET resolution harmonisation, i.e., smoothed to 6mm‐equivalent point spread function using estimates from Hoffman scans. Statistical significance was evaluated using empirical, one‐sided, non‐parametric bootstrap estimates.ResultsFigure 1 shows representative differences between the Vision and Gemini, and Figures 2,3 depict per‐scanner scatter and Bland‐Altman plots of Centiloid with and without resolution harmonisation, respectively. Even with harmonisation, Centiloid from Vision was found to be significantly higher than from Gemini (p=0.000) and from mCT (p=0.031); the difference followed a linear association with slope>1 (p=0.000 and p=0.010, respectively). The difference at 0CL was negligible, but at 100CL (Gemini) was +10.5% and at 100CL (mCT) was +11.7%. Resolution harmonisation only reduced ∼20% of scanner differences at most.ConclusionScanner changes led to different Centiloid quantification, with difference proportional to the participant’s Centiloid itself. The standard resolution harmonisation procedure did not correct for scanner difference. For high‐amyloid individuals, the measured difference between Vision and Gemini or mCT (> +10%) was greater than the expected annual accumulation rate and so significant for longitudinal studies. Some scanners may exaggerate measured changes in Centiloid, or longitudinal scanner changes may mask or amplify changes. The fact that the effect between scanners was found linear is promising that scanner calibration methods are possible, further investigation is warranted.
Seeding and propagation of Tau from the retina to the brain in TAU58 mice
Authors: Walkiewicz Grzegorz , Ronisz Alicja , Ospitalieri Simona , Tomé Sandra O. , Vandenberghe Rik , Groef Lies De , Thal Dietmar Rudolf 
Published: January 2025

AbstractBackgroundThe retina, an integral part of the central nervous system, can exhibit protein accumulation (Aβ and pTau) associated with neurodegenerative diseases such as Alzheimer’s disease (AD). Biochemical analysis revealed the existence of a distinct primary retinal tauopathy (PReT), differing from AD and primary age‐related tauopathy (PART) brain lysates, suggesting it as a potential precursor for AD tauopathy with possible diagnostic value. However, it remains unclear whether retinal pTau pathology can spread from the eye into the brain.MethodBrain lysates from human autopsy cases (PART and AD) from UZ Leuven biobank, Belgium, were homogenized and tau protein were extracted. Subretinal injections of brain homogenates, as well as phosphate‐buffered saline as negative control, were performed in two‐month‐old TAU58 mice (n=10/group) overexpressing human mutant 4‐repeat tau (P301S). Thirty‐three non‐injected TAU58 mice at various ages (6, 9, 12, 15 months) were used to examine age‐related retinal pTau pathology and neuronal loss. Paraffin‐embedded tissue sections were used for anti‐tau (AT8), anti‐RBPMS, and anti‐NeuN immunostainings, and Gallyas‐staining was used to visualize fibrillar tau pathology. Quantification of neuronal density and pTau pathology in brain samples and retinas were performed with QuPath software.ResultThe retinal changes associated with pTau in TAU58 mice were characterized. We observed pTau threads and cytoplasmic pTau accumulation, predominantly in the central retina, increasing with age. Retinal pTau was linked to neuronal loss in both central and peripheral retinal regions. Subretinal injection of the brain homogenates accelerated retinal pTau pathology without increased ganglion cell loss. Anterograde seeding of pTau from the eye to the brain occurred in mice receiving subretinal injections from AD brain lysates, showing significant pTau pathology in the zonal layer of the superior colliculus.ConclusionThese results suggest that subretinal injection of human brain homogenates can induce tau seeding in the retina. The anterograde spreading of pTau pathology from the retina to the brain requires abundant pTau seeds, notably present in the AD brain and absent in cognitively normal PART cases.Funding: SAO/FRA 2020/017
Optimizing PET Intensity Normalization for the Analysis of Cerebral Metabolism: A Study in Simulated and Real Data from an Alzheimer's Disease Model
Authors: Chamberlain‐Alvarado Helena , Cortes‐Canteli Marta , Casquero‐Veiga Marta 
Published: January 2025

AbstractBackgroundAlzheimer's Disease (AD) has a long preclinical stage, in which brain metabolic alterations precede the symptoms onset. Therefore, an early and proper diagnosis of AD is essential for prevention and therapeutic evaluation. Current diagnosis and staging procedures rely on neuroimaging techniques, such as positron emission tomography (PET), which require intensity normalization to ensure the correct interpretation of the data. However, the variety of normalization methods and lack of standardization produce a major drawback regarding the proper interpretation of AD data by these techniques.MethodWe formally analyzed the performance of six well‐established intensity normalization methods (proportional scaling and data‐driven approaches) on brain PET images of fluorodeoxyglucose (FDG) obtained from healthy mice (N=10). The accuracy of each method was determined based on the recovery of different computer‐simulated patterns in the FDG‐PET scans achieved with voxel‐wise analyses. Furthermore, we applied this newly acquired knowledge to evaluate differences in cerebral FDG uptake in 16 and 62 weeks‐old AD mice (N16w=7; N62w=10) of the TgCRND8 model, and their wild‐type littermates (N16w=10; N62w=5).ResultOur results showed a remarkable ambivalence between and within each normalization method under different simulation scenarios. They supported the use of an iterative histogram‐based normalization (iHN, Martí Fuster et al., 2013) when the data compared is not clearly biased (Figure 1B). Nonetheless, the reference cluster technique based on preserved regions (Yakushev et al., 2009) stood out for patterns with large and accentuated bias in the data (Figure 1A). Thus, the iHN method helped us to evaluate AD‐related differences in real FDG‐PET images, identifying genotypic effects that change with age (Figure 1C).ConclusionThis study evidences the crucial importance of understanding the distribution of the radiotracer uptake in PET studies before selecting an intensity normalization strategy. Furthermore, our results provide simple and accurate guidelines to help to choose a proper normalization method in preclinical PET imaging, demonstrating its applicability in real data from AD mice.References:Martí Fuster et al., 2013. Neuroinformatics 11(1), 77‐89.Yakushev et al., 2009. Neuroimage 44(1), 43–50.Funding: EU Joint Programme – Neurodegenerative Disease Research (JPND), BrightFocus Foundation, and JDC2022‐048922‐I funded by MCIN/AEI/10.13039/501100011033 and European Union NextGenerationEU/PRTR.