bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterizing the effects of calcineurin/NFAT inhibitor treatment on gray and white matter microstructure in the beagle model of Alzheimer's disease
Authors: Noche Jessica A. , Radhakrishnan Hamsanandini , Ubele Margo F. , Boaz Kathy , Mefford Jennifer L. , Jones Erin D. , Perpich Jessica A. , Meacham Beverly , Smiley Jeffrey , Bailey Stasia A. Bembenek , Puskas Laszlo G. , Powell David K , Sordo Lorena , Phelan Michael J. , Norris Christopher M. , Head Elizabeth , Stark Craig EL 
Published: January 2025

AbstractBackgroundIn the context of pathological aging and Alzheimer's disease (AD), the overexpression of calcineurin has been identified as a factor linked to astrocyte reactivity, neuronal death, and inflammation. This suggests that inhibiting calcineurin or downstream nuclear factor of activated T cells (NFAT) signaling could be a promising strategy for preventing or slowing down AD pathophysiology.MethodBaseline and annual MRI sessions including higher‐order diffusion‐weighted imaging was performed over four years on 43 dogs ranging from 5 to 8.7 years old (placebo n=14; tacrolimus n=15; Q134R n=14). Estimates from diffusion tensor and neurite orientation dispersion and density imaging (NODDI) models were assessed: orientation dispersion index (ODI), intracellular volume fraction (ICVF), isotropic volume fraction (ISOVF), fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (MD), axial diffusivity (AxD). We examined the percent changes from select gray matter regions of interest, including the posterior cingulate gyrus (PCG), orbital gyrus, caudate nucleus, and hippocampus, as well as voxel‐wise white matter microstructure across the brain.ResultAcross all groups, the PCG showed a 1% decrease in ODI, whereas the orbital gyrus had 1% increases in ODI and in ICVF. The orbital gyrus also had a 2% increase in MD and RD and a 26% increase in ISOVF. The hippocampus had a 0.8% increase in ODI. The caudate nucleus showed numerous changes, including a substantial 36% increase in ISOVF and 1.5% decrease in FA. Only Q134R‐treated dogs showed a 0.6% increase in AxD, and tacrolimus‐treated dogs showed 0.7% and 0.9% increases to MD and RD, respectively. Whole brain white matter demonstrated an anterior‐posterior gradient to diffusion changes similar to that of human aging across all groups: decreasing FA, increasing MD, increasing RD, and decreasing AxD.ConclusionMicrostructural alterations within gray and white matter of canines parallel human aging. The study suggests that Q134R and tacrolimus differentially impact gray matter microstructural changes within the caudate nucleus. Future investigations involving cognitive outcomes and histological evaluations will be crucial to understanding the neurobiological underpinnings of these diffusion changes and the effects of chronic tacrolimus and Q134R treatment on AD pathology and cognition.
Asymmetrical Neuroimaging Insights in CSF‐Validated Early‐Onset Alzheimer's: Integrating PET, MRI, and Cognitive Assessment
Authors: Özçelik Sinem , Yiğit Pınar , Bozdemir Tolga Can , Kaya Gamze Çapa , Yildirim Zerrin , Tee Boon Lead , Gurvit Hakan , Yener Görsev , Tempini Maria Luisa Gorno , Öz Didem 
Published: January 2025

AbstractBackgroundEarly‐onset Alzheimer's disease (EOAD), manifesting before age 65, demands nuanced diagnostic approaches. FDG18‐PET unveils metabolic insights, the MRI scale captures structural changes, and ACE‐R assesses cognitive impairment details. A holistic evaluation enhances diagnostic precision and enriches our understanding of cognitive decline in early‐onset presentations.MethodEarly‐onset Alzheimer's disease (EOAD), manifesting before age 65, demands nuanced diagnostic approaches. FDG18‐PET unveils metabolic insights, the MRI scale captures structural changes, and ACE‐R assesses cognitive impairment details. A holistic evaluation enhances diagnostic precision and enriches our understanding of cognitive decline in early‐onset presentations.ResultTwenty‐two patients (59.1% women) with a mean age at diagnosis of 55.3 (±6.52 StD) years participated. The mean disease duration was 5.06 (±2.95 StD) years. All of the patients were right‐handed. The mean Aβ42 and phos‐tau were 392.49 (±200.13 StD) and 130.93 (±142.56 StD) pg/ml, respectively. No significant difference was found between the right and left insular cortex in PET, and no statistically significant asymmetry was found between VAS scores in MRI (p > 0.05). There was no correlation between PET index with CSF Aβ42 and and phos‐tau values.ConclusionThis study underscores notable asymmetries in PET atrophy scores between the corresponding right and left brain regions in Alzheimer's patients. Given that EOAD manifests with atypical clinical symptoms, and all participants in this study exhibited left‐hemispheric dominance, the observed metabolic asymmetry, in the absence of a corresponding structural asymmetry, holds clinical significance.
Proteomic Dementia Risk Assessment in Chronic Kidney Disease
Authors: Zhao Bote , Wang Zhibo , Ning Yuye , Jia Jianping 
Published: January 2025

AbstractBackgroundChronic kidney disease (CKD) has relatively high prevalence and independently increases dementia risk. Currently, there is a lack of high‐performance dementia prediction tools designed for the CKD population in clinical practice. Through proteomics discovery, this study aimed to discover more efficient dementia risk models in CKD patients.MethodThis prospective cohort study utilized data from the UK Biobank, encompassing baseline assessments conducted between 2006 and 2010, with follow‐up extended until September 1, 2023. We included 1355 CKD patients, who were free of dementia at baseline and had available Olink blood proteomics data (approximately 3000 proteins). Feature selection was executed using a least absolute shrinkage and selection operator (LASSO) regression. Generalized Linear Models were employed to derive a proteomic risk model for dementia risk in CKD patients. The model was trained in a tested set of 949 CKD patients and validated in a set of 406 individuals. Mendelian randomization was employed to investigate the causal link between potential proteins and dementia.ResultThe proteomic risk model, comprised of 17 proteins, demonstrated superior performance compared to conventional clinical tools for dementia risk assessment, including demographic factors (age, sex, education year, APOE ε4 status) and cognitive assessments. During validation, the proteomic model achieved a receiver operating characteristic (ROC) area under the curve (AUC) value of 0.845, significantly surpassing the 0.543 to 0.627 range observed for conventional clinical models. The proteomic plus conventional assessment models did not obtain higher AUC values (ranging from 0.811 to 0.845) (Figure 1). After stratifying participants into two proteomic risk groups based on the median proteomic predicted risk value, the high‐proteomic risk group exhibited 15.14 times increase in the risk of dementia compared to the low‐ proteomic risk group (HR= 15.14, 95%CI: 6.62 ‐ 34.66) (Figure 2). Mendelian randomization analyses indicated a causal link between several proteins and dementia.ConclusionBased on the UK Biobank database, a proteomic risk model for dementia outperformed conventional clinical risk models in CKD patients. This plasma‐derived proteomic model is supposed to have great generalization potential, attributed to the accessibility of blood samples, thereby offering valuable guidance for dementia prevention in the CKD population.
Volumetric Characterization of Medial Temporal Lobe in Down Syndrome Along the Alzheimer's Disease Continuum
Authors: Zsadanyi Sara E , Buehner Bejamin J. , Morcillo‐Nieto Alejandra O. , Aranha Mateus Rozalem , Arriola‐Infante José Enrique , Vaqué‐Alcázar Lídia , Arranz Javier , Rodríguez‐Baz Íñigo , Maure‐Blesa Lucía , Videla Laura , Barroeta Isabel , Hoyo Laura Del , Benejam Bessy , Fernandez Susana , Hernandez Aida Sanjuan , Bargalló Núria , González‐Ortiz Sofía , Giménez Sandra , de Flores Robin , Alcolea Daniel , Belbin Olivia , Lleo Alberto , Carmona‐Iragui Maria , Fortea Juan , Bejanin Alexandre 
Published: January 2025

AbstractBackgroundIndividuals with Down Syndrome (DS) almost invariably develop Alzheimer's Disease (AD), but detecting early clinical changes is challenging due to comorbid intellectual disability, highlighting the importance of non‐invasive biomarkers. Neuroimaging of the medial temporal lobe (MTL), a key site of tau pathology, shows promise as an early AD biomarker. Here, we aimed to characterise volumetric patterns of the MTL in DS across the AD clinical continuum, and define associations with AD cerebrospinal fluid (CSF) biomarkers.Method253 adults with DS and 190 euploid controls from the Down Alzheimer Barcelona Neuroimaging Initiative underwent a 3T‐MRI protocol, and a comprehensive clinical assessment. T1‐weighted images were used to parse the medial temporal lobe using the Automated Segmentation of Hippocampal Subfields (ASHS) pipeline. Segmentation quality was visually inspected and W‐scores were computed for MTL subregions (anterior and posterior hippocampus, entorhinal cortex (ERC), parahippocampal cortex (PHC), and Brodmann areas Br35 and Br36) to adjust volumes for total intracranial volume, age and MRI scanner. Non‐parametric statistical tests were employed to assess volumes by AD clinical stage, age, and CSF biomarkers of AD.ResultHippocampal and Br36 volumes gradually decreased with AD clinical stage, and all subregions were decreased at the dementia stage (dDS) compared to asymptomatic (aDS) and prodromal (pDS) stages (Figure 1). Surprisingly, significantly larger ERC, PHC and Br35 volumes were found at the asymptomatic DS stage compared to controls. All subregions had decreased volumes with age, with inflexion points around 40y for the hippocampus, ERC and Br36, 45y for Br35 and 50y for PHC (Figure 2). Most subregions exhibited significant correlations with CSF Aβ42/40 ratio, p‐tau‐181 and neurofilament light chain, and the strongest associations were found with anterior and posterior hippocampus (Figure 3).ConclusionAD clinical stage and age are associated with progressive decreasing MTL volumes. Among all subregions, the hippocampus correlated best with CSF measures and appears particularly sensitive to detect early disease processes. These results indicate effectiveness of MTL volumes as a biomarker of early AD pathological changes in DS. Further studies are required to determine the pathological substrate of MTL atrophy and understand the increased volumes in some subregions.
Retinal Examination in Neurodegenerative Diseases of the Brain
Authors: Kayabasi Umur A. 
Published: January 2025

AbstractBackgroundAlzheimer's Disease (AD) is a chronic neurodegenerative disease characterized by loss of memory and cognitive decline associated with an increase in ß‐amyloid (Aß) plaque deposition, neurofibrillary tangle formation (NFT) and inflammation. Fundus Autofluorescein (FAF) can detect lipofuscin secreted by misfolded plaques during the neurodegeneration process. And Optical Scanning Tomography ( OCT ) is able to find out the retinal layers of the accumulation ( inner retinal layers in AD ). lt is also possible to measure macular thickness by OCT ( macular thinning being the earliest sign of AD).Method30 patients with PET proven AD were examined by FAF and OCT. Mean age was 71. Also 10 age matched healthy controls underwent retinal exam. 15 AD patients were given Curcumin tablets for 3 days to detect changes after the supplement.ResultAll the patients with AD revealed detectable accumulations by FAF and their location was the inner retinal layers as picked up bt OCT. ln the control group, typical accumulation styles were not seen.ConclusionRetinal examination is one of the best methods to detect AD. lt is safe, non‐invasive and reproducable.
Association of 18F‐flortaucipir PET with tau neuropathology in AD and other neurodegenerative disorders
Authors: Vrillon Agathe , Mejía‐Perez Jhony Alejandro , Spina Salvatore , Schonhaut Daniel R. , Yballa Claire , soleimani‐meigooni David N. , Boxer Adam L. , Dage Jeffrey L. , Rojas Julio C. , VandeVrede Lawren , Lago Argentina Lario , Jagust William J. , Miller Bruce L. , Rosen Howard J. , Seeley William W. , Grinberg Lea T. , Rabinovici Gil D. , Joie Renaud La 
Published: January 2025

AbstractBackgroundTau‐PET with [18F]Flortaucipir is FDA‐approved for the identification of AD tau neuropathology in the differential diagnosis of patients with cognitive impairment. However, its performance in detecting early AD stages requires further assessment. We aimed to i) examine the relationships between Flortaucipir‐PET and AD neuropathology, and ii) characterize the relationship between Flortaucipir‐PET and emerging plasma ptau217 biomarker in autopsy cases.MethodWe analyzed Flortaucipir‐PET consecutively acquired from 59 patients with a clinical diagnosis of various neurodegenerative diseases who underwent post‐mortem examination at the UCSF Alzheimer’s Disease Research Center (age=66±12, 32% female, median PET‐to‐autopsy=45 months, range 25‐60). Flortaucipir‐PET was acquired 80‐100 min post‐injection and processed using an MRI‐based pipeline to create Standardized Uptake Value Ratio (SUVR, reference: inferior cerebellar cortex). Amyloid‐PET‐negative cognitively unimpaired participants (n=103) without autopsy data were included as a reference. We examined the associations between i) Flortaucipir‐SUVR in two regions of interest (ROI): the temporal meta‐ROI (i.e. validated AD signature measure) and entorhinal cortex (i.e. early tau region), and ii) neuropathological diagnosis and neurofibrillary tangle Braak stages. Plasma p‐tau217 measurement on the Meso Scale Discovery platform was available for a sample of n=31 (median PET‐to‐plasma=3.5 months, range 1‐9).ResultsOur cohort included 30 patients with a primary neuropathological diagnosis of AD, 23 with various non‐AD tauopathies and 4 patients with non‐tau diseases. Flortaucipir‐SUVR was elevated in patients with primary AD neuropathology (Figure 1a,c) and differentiated them from non‐AD cases with high accuracy (areas under the curve>0.98 for both regions). When examining associations between Braak stage and Flortaucipir‐SUVR, we only detected consistent PET signal in patients with Braak VI (Figure 1b,d). Patients with both non‐AD tauopathies and non‐tau diseases displayed variable patterns of mild tracer uptake (Figure 2). Plasma p‐tau217 showed strong association with Flortaucipir‐SUVR (r≥0.73), fully driven by cases with Braak stages V‐VI (Figure 3).Conclusion[18F]flortaucipir‐PET can identify advanced AD‐tau neuropathology and is highly concordant with plasma p‐tau217. The lack of evidence for early‐stage detection should be interpreted with caution due to the low number of cases with Braak stages III‐V, and the delay between PET and autopsy.
Investigating Reactive Astrocytosis in Alzheimer's Disease Using [18F]Fluorodeprenyl‐D2 PET Imaging
Authors: Rauchmann Boris‐Stephan , Guersel Selim Üstün , Kurz Carolin Isabella , Lindner Simon , Franzmeier Nicolai , Buerger Katharina , Gnörich Johannes , Zaganjori Mirlind , Vogler Letitia , Sanzo Laura , Seelos Klaus , Perneczky Robert , Brendel Matthias 
Published: January 2025

AbstractBackgroundAlzheimer's Disease (AD) is often accompanied by neuroinflammation, which manifests prior to significant cognitive decline. Reactive astrocytosis is a hallmark of such inflammation, potentially serving as an early biomarker for AD pathology. Our study employs [18F]fluorodeprenyl‐D2 ([18F]F‐DED) positron emission tomography (PET) imaging to in vivo quantify astrocytosis comparing AD with healthy controls and examines its assocciation with cognitive deterioration in AD.MethodOur cross‐sectional study involved 12 early‐stage Alzheimer's Disease (AD) patients and 11 healthy controls, all undergoing [18F]F‐DED and MRI imaging. AD diagnosis was based on CSF amyloid‐β42/40 ratios under 5.5% and MMSE scores below 27, while controls had MMSE scores above 27 with no amyloid‐β pathology. We assessed differences in [18F]F‐DED uptake using ROI‐based analyses, processing data in PMOD software. This involved calculating the radioligand's volume of distribution in tissues and image‐derived plasma at equilibrium. For ROI analysis, we adapted the Automated Anatomical Labeling (AAL) atlas to each participant's gray matter masks and [18F]F‐DED maps, computing median uptake values per ROI. Cortical amyloid deposition was measured using [18F]flutemetamol β‐amyloid‐PET imaging. CSF biomarkers, including Aβ42, Aβ40, and phosphorylated tau, were analyzed using the Lumipulse G1200 platform. Cognitive performance was evaluated with the MMSE. We used ANCOVA and linear regression in R to explore correlations between cognitive performance and [18F]F‐DED uptake, adjusting for age and sex.ResultsIncreased [18F]F‐DED uptake was observed in AD‐affected areas comparing AD with controls, particularly in the bilateral occipital (Left: T:2.28, p=0.03; Right: T:2.51, p=0.02), temporal (Left: T:2.21, p=0.03; Right: T‐Stat 2.22, p=0.03), and frontal lobes (Left: T:2.46, p<0.02; Right: T:2.45, p<0.02). This increased uptake was significantly correlated with cognitive decline, especially in temporal regions, associated with lower cerebrospinal fluid amyloid‐β ratios and reduced MMSE scores (p<0.01), consistent after adjusting for age and gender.ConclusionOur findings indicate that [18F]F‐DED PET imaging can detect reactive astrocytosis in AD‐sensitive areas, potentially preceding severe cognitive symptoms. The correlation between increased tracer uptake and cognitive impairment underscores the value of [18F]F‐DED as an AD progression biomarker, offering promising prospects for early diagnosis and intervention in AD's initial stages.
Diagnostic performance of online cognitive assessment and plasma biomarkers in Alzheimer’s Disease and Subjective Cognitive Impairment using the Oxford Cognitive Testing Portal
Authors: Toniolo Sofia , Scholcz Anna , Amein Benazir , Ganse‐Dumrath Akke , Thompson Sian , Manohar Sanjay , Zetterberg Henrik , Husain Masud , Zhao Sijia 
Published: January 2025

AbstractBackgroundPlasma biomarkers have emerged as a promising tool to detect the presence of Alzheimer’s disease (AD) when cognitive symptoms have not yet emerged. However, there is also a pressing need to detect and track subtle cognitive change at the preclinical stage of AD for population screening purposes and to monitor disease progression at scale. A potential solution is remote cognitive assessment, yet it is still not extensively employed.Method114 participants (37 AD, 22 subjective cognitive impairment (SCI) patients and 55 age‐matched controls) were recruited from the Oxford Centre for Cognitive Disorders. They were tested on a newly developed, fully remote online cognitive assessment tool, Oxford Cognitive Testing Portal (OCTAL), which hosts a wide range of validated cognitive tasks, such as the Rey‐Osterrieth Complex Figure (ROCF), Trail Making Task (TMT), Digital Symbol Substitution task (DSST)), Corsi Block Task (CORSI), as well as novel visual short‐term memory (Oxford Memory task) and visual long‐term memory (Object‐in‐Scene task) tasks (Figure 1). All participants underwent standard in‐person cognitive testing, i.e. Addenbrooke's Cognitive Examination‐III (ACE). Plasma p‐tau181, GFAP, NFL, Aβ42/40 ratio were also measured. Logistic regression was used for group classification.ResultPerformance on OCTAL was able to discriminate between SCI from healthy controls with an AUC of 0.78 (Figure 2a), statistically outperforming standard neuropsychological testing (ACE), which had an AUC of 0.65. Combining plasma biomarkers to OCTAL further increased diagnostic accuracy, reaching an AUC of 0.82 in group classification. OCTAL also outperformed ACE in distinguishing individuals with AD from SCI (Figure 2b), where adding plasma biomarkers to performance at OCTAL achieved a perfect separation (AUC of 1) between the groups.ConclusionThese findings demonstrate the potential of OCTAL for widespread, cost‐effective cognitive testing. They also emphasise the utility of combining plasma biomarkers and digital cognitive tests to improve diagnostic accuracy across different stages of the disease. These accessible tools could pave the way to more scalable protocols for screening, stratification and monitoring of patients with preclinical AD.
A longitudinal real‐world study in patients with Alzheimer’s Disease dementia using frequent multi‐domain digital measurements at‐home performed on the Cumulus NeuLogiqTM Platform: usability and feasibility findings
Authors: Diggin Shannon , Alexander‐Sefre Azar , Murphy Brian , Nolan Hugh , Rowe James B , Rueda‐Delgado Laura M , Buick Alison R 
Published: January 2025

AbstractBackgroundMany outcome measures used in AD clinical trials require clinic visits and are paper based, making them infrequent and burdensome ‘snapshots’, subject to rater bias. A consortium of 10 pharma companies came together with Cumulus Neuroscience to design a solution for frequent, objective, real‐world measurement across a range of domains. We present a study that examined the feasibility of asking patients with mild dementia to use the neuroassessment platform repeatedly at home for one year.MethodSeven UK sites recruited Alzheimer’s type mild dementia patients (n=59, ACE‐III scores >60 and ≤88) and a matched cohort of controls (n=60). Participants had 2 weeks of at‐home familiarisation to become comfortable with the 8 assessments presented on a mobile tablet and EEG headsets, one for wake and another for sleep. A staggered longitudinal protocol followed, with burst sampling tapering to periodic sampling over the year. Benchmark paper‐based assessments (including ADAS‐Cog) and self‐reported usability were collected at months 0, 6 and 12. Additionally, plasma was collected at months 6 and 12 for later biomarker analysis.ResultFeedback collected at baseline showed differences in technology usage. Patients felt they required more technology support than controls (49% vs 17%). Nonetheless, they were successful in using the study technology at home on a regular basis and maintained a high level of adherence to the protocol. Overall compliance was 76.3% for dementia, 88.4% for controls and was highest in the latter stages of the study during periodic sampling (Stage 4 during wake EEG sessions: 80.8% dementia, 93.9% controls). System Usability Scale results indicated controls rated usability higher (63.8) than dementia participants (54.5) at baseline, increasing for both groups by Week 52 (74.4 controls; 58.3 dementia).ConclusionWith appropriate technology design, and provision of training and support, patients with Alzheimer’s disease dementia are capable and willing to provide repeated, real‐world samples of a broad range of objective digital endpoints for clinical research.