bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimating Alzheimer's Disease Progression Score Using Machine Learning on FreeSurfer‐Derived MRI Gray Matter Volumes
Authors: Sung Junhyoun , Shibata Dean , Chan Kwun Chuen Gary , Shui Lan , Haynor David R. 
Published: January 2025

AbstractBackgroundThe early diagnosis and monitoring of Alzheimer's disease (AD) presents a significant challenge due to its heterogeneous nature, which includes variability in cognitive symptoms, diagnostic test results, and progression rates. This study aims to enhance the understanding of AD progression by integrating neuroimaging metrics with demographic data using a novel machine learning technique.MethodWe used supervised Variational Autoencoders (VAEs), a generative AI method, to analyze high‐dimensional neuroimaging data for AD progression, incorporating age and gender as covariates. We used two non‐overlapping datasets: 257 samples from ADNI3 and 676 from ADNI2, analyzing 68 cortical and 48 subcortical grey matter volumes extracted from their MRI 3D T1 images. The VAE model aimed to minimize reconstruction error (MSE), Kullback‐Leibler divergence, and classification error, and to estimate latent variables for each subject. A Disease Progression Score (DPS) was calculated by encoding the extracted imaging features into a latent space and projecting test data onto a trajectory curve. The study used stratified sampling for robustness and assessed the model's performance using the area under the ROC curve (AUC), and correlated the mean DPS with cognitive assessment scores by applying Kendall’s Tau.ResultThe VAE model demonstrated excellent discriminative power in classifying AD progression stages, with ROC AUC values near 1, particularly when using all 116 features. Cortical volumes were more predictive than subcortical volumes. The mean DPS showed a statistically significant correlation with cognitive assessments (p<0.01), with Kendall's Tau values of 0.66 for CDR‐SB, ‐0.45 for MMSE, and ‐0.49 for MoCA, indicating its validity as a quantitative biomarker for cognitive decline in AD.ConclusionSupervised VAEs can effectively model the progression of Alzheimer’s disease brain atrophy on MRI and could potentially serve as imaging biomarkers in clinical trials. The strong correlation between the DPS and cognitive assessments highlights the potential of supervised VAEs to provide a quantifiable measure of AD severity, which would be useful for clinical assessments and for objectively monitoring disease progression. The study's methodology and findings contribute to computational neuroscience and offer a foundation for future research in early detection and personalized treatment strategies for Alzheimer's disease.
Developing Cryptic ACTL6B as Novel TDP‐43 Loss of Function Biomarker
Authors: Chen Margery JQ , Irwin Katherine E , Chang Koping , Jasin Pei , Braunstein Kerstin E , Sinha Irika , Troncoso Juan C , Ling Jonathan P , Wong Philip C 
Published: January 2025

AbstractBackgroundThe nuclear clearance and cytoplasmic aggregation of splicing repressor TAR DNA/RNA‐binding protein‐43 (TDP‐43) occur in approximately 50% of Alzheimer’s disease (AD) cases and about 45% of frontotemporal dementia (FTD). However, it is not clear how early such mechanism occurs in AD and FTD as there is no method of detecting TDP‐43 dysregulation in living individuals. Since the loss of nuclear TDP‐43 leads to cryptic exon inclusion, we propose that cryptic exon‐encoded peptides may be detected in patient biofluids as biomarkers of TDP‐43 loss of function.MethodWe developed antibodies against the TDP‐43‐dependent cryptic peptide within actin‐like protein 6B (ACTL6B) and characterized them through protein blot analysis using TDP‐43‐knockdown (KD) SH‐SY5Y neuroblastoma cell lysates. Next we performed immunofluorescent staining of patient brain tissues to determine whether cryptic ACTL6B can be found in patient neurons. We then developed a Meso Scale Discovery (MSD) ELISA using our cryptic ACTL6B antibody.ResultWhile the wild‐type (WT) ACTL6B antibody detected an expected band in both WT and KD SH‐SY5Y lysates, the cryptic ACTL6B antibody detected a band in only KD SH‐SY5Y. Using this antibody, we detected cryptic ACTL6B in FTLD and AD, but not control, brain tissues. The cryptic ACTL6B staining colocalizes with neurons that display TDP‐43 nuclear depletion and/or cytoplasmic aggregation. Using transfected SH‐SY5Y cells to overexpress either cryptic or WT ACTL6B, the MDS ELISA was sensitive and specific for cryptic ACTL6B, with 0.5 micrograms of lysate from SH‐SY5Y overexpressing cryptic ACTL6B showing MSD signal 5‐fold higher than 0.5 micrograms of lysate from SH‐SY5Y overexpressing WT ACTL6B (1546 vs. 290 units).ConclusionThe study provides evidence that our cryptic ACTL6B antibody is sensitive and specific for the ACTL6B cryptic peptide. This antibody could be used to determine TDP‐43 nuclear clearance/loss of function in patient brain tissues, providing a more sensitive approach to detecting TDP‐43 pathology than staining for TDP‐43 cytoplasmic aggregates. In the future, we will use our novel MSD ELISA to test the presence of cryptic ACTL6B in patients’ CSF and blood, which could aid in early‐stage disease detection.
Efficacy of a Muscarinic (M1) Positive Allosteric Modulator, SUVN‐I7016031 in Animal Models of Dementia
Authors: Abraham Renny , Medapati Rajesh Babu , Petlu Surendra , Subramanian Ramkumar , Badange Rajesh Kumar , Bojja Kumar , Shinde Anil , Molgara Parusharamulu , Nirogi Ramakrishna 
Published: January 2025

AbstractBackgroundSUVN‐I7016031 is a novel and selective positive allosteric modulator (PAM) of the M1 subtype of the muscarinic acetylcholine receptors (mAChRs). The proposed primary indication for SUVN‐I7016031 is in the treatment of dementia such as Alzheimer’s disease dementia (ADD) and Parkinson’s disease dementia (PDD). In the current research, the pharmacological properties of SUVN‐I7016031 in various types of dementia were investigated.MethodSUVN‐I7016301 was characterized using a calcium mobilization assay. The binding affinity towards the orthosteric M1 ‐ M5 site was investigated. The effect of SUVN‐I7016031 on neuronal spike rate in coronal hippocampal slice electrophysiology was studied in agonist and PAM modes of testing. The pharmacokinetic properties of SUVN‐I7016031 were studied both in rodent and non‐rodent species. The effect of SUVN‐I7016031 on MK‐801 induced memory deficits in rats using object recognition task (ORT) and on time‐induced social memory deficits in rats using social recognition task (SRT) was studied. The efficacy of SUVN‐I7016031 in a rat model of PDD was investigated. The effects of SUVN‐I7016031 (10‐60 mg/kg, p.o.) on inositol 1 phosphate (IP‐1) levels were studied in rats.ResultFunctionally, SUVN‐I7016031 was found to be a positive allosteric modulator at the M1 receptor with an allosteric potency EC50 of 355 nM. In hippocampal slice electrophysiology studies, the EC50 and EC30 values were ∼527 nM and ∼326 nM, respectively. No significant binding towards the orthosteric site at the muscarinic M1 to M5 receptor was observed. SUVN‐I7016031 showed good oral bioavailability in rats, dogs, and monkeys. SUVN‐I7016031 was found to have brain penetration properties with adequate free fraction. SUVN‐I7016031 reversed delay‐induced memory disruption in adult rats in a SRT and antagonized MK‐801 induced memory disruption in ORT. SUVN‐I7016031 was found to reverse haloperidol induced memory deficits, a rat model of PDD. Treatment with SUVN‐I7016031 produced a significant increase in striatal inositol 1‐phosphate (IP‐1) levels in rats, providing in‐vivo support for the activation of M1 mAChRs by SUVN‐I7016031.ConclusionSUVN‐I7016031 is a novel, potent, and selective M1‐PAM that demonstrated pro‐cognitive effects in animal models of PDD and ADD.
Exploration of Neuroanatomical Characteristics Relating to Progression from Preclinical to Prodromal Alzheimer's Disease
Authors: Kim Hak Hyeon , Kwon Min Jeong , Jo Sungman , Park Jieun , Kim Jiwon , Kim Jae Hyoung , Kim Sang Eun , Kim Ki Woong , Han Ji Won 
Published: January 2025

AbstractBackgroundTo investigate the neuroanatomical characteristics at the whole‐brain level associated with progression from amyloid‐positive preclinical to prodromal Alzheimer’s disease (AD) in relation to amyloid deposition and regional atrophy.MethodWe included 45 participants with amyloid‐positive preclinical AD and 135 participants with prodromal AD matched 1:3 by age, sex, and education, from participants in the Korean Longitudinal Study on Cognitive Aging and Dementia and visitors to the dementia clinic of Seoul National University Bundang Hospital. All participants underwent 18F‐florbetaben positron emission tomography and 3D structural T1‐weighted magnetic resonance imaging. We calculated the standardized uptake value ratios (SUVRs) and volumes in 80 regions of interest (ROIs) using the Desikan‐Killiany‐Tourville atlas and compared them between the preclinical and prodromal AD groups. We used the least absolute selection and shrinkage operator (LASSO) logistic regression model to identify ROIs associated with prodromal AD in relation to amyloid deposition, regional atrophy, and their interaction.ResultAlthough global SUVR did not differ between the amyloid‐positive preclinical and prodromal AD groups, the prodromal AD group showed a higher SUVR in the superior parietal cortex, right precuneus cortex, and right supramarginal gyrus. Regional volume differences between the two groups were observed in the overall cortex and subcortical areas, except in the occipital lobe, and the LASSO logistic regression model showed significant associations between prodromal AD and atrophy in the entorhinal cortex, inferior parietal cortex, both amygdalae, and left hippocampus. The mean SUVR in the right superior parietal cortex (beta coefficient = 0.0172) and its interaction with the regional volume (0.0672) were also selected in the LASSO model. The mean SUVR in the right superior parietal cortex was strongly associated with an increased risk of prodromal AD, particularly in participants with lower regional volume.ConclusionCompared with amyloid‐positive preclinical AD, patients with prodromal AD showed more regions with significant volume differences than amyloid deposition. Amyloid deposition in the right superior parietal cortex may play a significant role in the progression of prodromal AD, particularly in interaction with its reduced volume.
Associations of late mid‐life lifestyle with brain and cognitive changes in individuals on the AD vs. non‐AD continuum
Authors: Oomens Julie Elisabeth , Cody Karly Alex , Du Lianlian , Jonaitis Erin M. , Studer Rachel L , Artz Caitlin , Wintlend Madilynn , Köhler Sebastian , Visser Pieter Jelle , Vos Stephanie J. B. , Langhough Rebecca E. , Jansen Willemijn J. , Johnson Sterling C. 
Published: January 2025

AbstractBackgroundTo aid development of prevention strategies, we investigated whether a composite measure of late‐midlife lifestyle health was associated with (1) change in brain tau burden, vascular burden and neurodegeneration and (2) cognitive trajectories when accounting for these brain changes.MethodWe included 324 individuals from the Wisconsin Registry for Alzheimer’s Prevention. Late‐midlife lifestyle was assessed using the Lifestyle for Brain Health (LIBRA) score, encompassing 12 risk‐and protective factors for cognitive decline and dementia. Biomarker outcomes included regional tau PET burden in the entorhinal cortex (EC) and a meta‐temporal composite (MTC; mean(SD) FU time 2.4(0.6) years) as well z‐scores for WMH (FU time 2.6(0.77) years), hippocampal volume and global brain atrophy (HV; GBA; FU time 5.7(3.1) years). Cognitive outcomes included Preclinical Alzheimer’s Cognitive Composite (PACC‐3) and memory and executive domain performance (FU time 6.6(3.5) years; z‐scored). Amyloid status was determined based on global cortical average PiB DVR (cut‐off>1.16). We used linear mixed effect models to examine whether LIBRA modified age‐related tau, WMH, neurodegeneration and cognitive trajectories across amyloid positive and negative participants. Models for cognitive outcomes also accounted for MTC tau burden and GBA and their interactions with age.ResultParticipant characteristics are given in table 1. LIBRA did not modify age‐related biomarker trajectories, independent of amyloid status. Reduced models indicated LIBRA main effects on MTC SUVR and GBA, such that higher late‐midlife LIBRA scores, indicative of worse brain‐lifestyle, were associated with lower (better) MTC SUVR values and higher GBA z‐scores (indicating more atrophy; b=‐0.02, p=0.017 and b=0.05, p=0.018 respectively; Figure 1). LIBRA was differentially associated with executive function trajectories in amyloid positive vs. negative participants (p interaction 0.019; Figure 2) while there was no association of LIBRA with PACC3 or memory trajectories.ConclusionLifestyle health was differentially associated with executive function trajectories, but did not modify age‐related biomarker, PACC3 or memory trajectories. We saw a counterintuitive association of lifestyle health with tau burden, and lifestyle health was associated with GBA. Improving our understanding of the contribution of lifestyle factors to brain and cognitive changes in the pre‐dementia stage will aid the development of prevention strategies.
Performance assessment of novel chemiluminescence immunoassays for the detection of specific biomarkers for Alzheimer’s disease
Authors: Arendt Philipp , Römpler Katharina , Brix Britta , Franco Stephanie , Borchardt‐Lohölter Viola , Schulz Anette , Busse Mandy , Busse Stefan 
Published: January 2025

AbstractBackgroundTo support diagnosis of Alzheimer’s disease (AD), concentrations of Aβ1‐42, tTau and pTau(181) and the Aβ1‐42/Aβ1‐40 ratio are determined in cerebrospinal fluid (CSF). To increase standardization and comparability between diagnostic laboratories, certified reference material (CRM) is used to evaluate the trueness of novel assays. Due to lack of CRMs for tTau, pTau(181), and Aβ1‐40, comparability may be assessed by comparing assays from different manufacturers. This study compares the performance of novel chemiluminescence immunoassays (ChLIAs) developed by EUROIMMUN with established chemiluminescence assays.MethodBiomarker concentrations were determined in 110 CSF samples (patients without known diagnosis; mean age 57.2 years, range 11–94 years; 49 female, 60 male, 1 unknown) using the Beta‐Amyloid (1‐42), Beta‐Amyloid (1‐40), Total‐Tau and pTau(181) ChLIAs (all EUROIMMUN) and the corresponding Lumipulse G assays (Fujirebio). The assays were performed according to the manufacturers’ instructions on the fully automated random‐access devices IDS‐i10 (Immunodiagnostic Systems) and LUMIPULSE G 600II analyzer (Fujirebio), respectively. Agreement of results obtained with the two chemiluminescence systems was calculated.ResultOverall agreement ranged from 89.0% to 97.3%. Agreement for the determination of normal biomarker concentrations was 93.4%–100% and 57.7%–94% for abnormal concentrations. The level of agreement was highest for Aβ1‐42 determination. Pearson’s regression coefficient revealed high correlation of results (R=0.82 to R=0.99 for Aβ1‐42 determination). While concentrations determined using EUROIMMUN assays were generally higher, numerical differences had minor influence on the diagnostic evaluation.ConclusionUsing the EUROIMMUN ChLIAs, AD‐specific biomarkers can be measured with high precision and stability on fully automated random‐access devices. The highest level of agreement and correlation was found for Aβ1‐42 determination as assays are aligned to the respective CRMs. This indicates the need to introduce CRMs for standardization of tTau, pTau(181), and Aβ1‐40 assays.
Enhancing the insights of the Patient‐and care‐related benefits of amyloid PET imaging ‐ ENABLE ‐ study through a process evaluation: a study protocol
Authors: Grazia Alice , Goerss Doreen , Spottke Annika , Boecker Henning , Daamen Marcel , Graf Erika , Sahlmann Jörg , Buchert Ralph , Mohnike Wolfgang , Mohnike Konrad , Jessen Frank , Krause Bernd J , Boccardi Marina , Teipel Stefan , Kurth Jens 
Published: January 2025

AbstractBackgroundAmyloid PET imaging is an established diagnostic tool for Alzheimer's disease, but its successful integration into clinical practice requires a comprehensive understanding of its impact on patients and the healthcare system. In 2022, the coverage with evidence development (CED) ENABLE study has been approved by the German Federal Joint Committee (trial registration: DRKS00030839). The study is scheduled to start in early 2024. Primary outcome of ENABLE is the change in patients' functional abilities at 18 months after diagnosis with amyloid PET versus without amyloid‐PET. Here we describe the design of an ENABLE sub‐study aimed at performing a process evaluation.MethodWe will conduct an outcome and process evaluation using a pre‐post descriptive design nested in ENABLE (Figure), based on the Medical Research Council's Process Evaluation (PE) framework. The PE will focus on acceptability and reach of the target groups of patients and care providers, as well as fidelity of delivery (% of adherence to protocol, study duration), contextual changes and mechanisms (e.g., ability to mirror routine care). We will collect patients’ data independently, but in parallel with ENABLE, using interviews, surveys and checklists to assess acceptance of the intervention, fidelity of adherence to the follow‐up procedures, perceived benefits and challenges. Healthcare providers and administrators will be interviewed to identify implementation hurdles and facilitators, contextual factors influencing uptake and underlying mechanisms. For data analysis we will employ a mixed‐methods approach.ResultExpected outcomes will include acceptability and adherence, barriers and facilitators to implementation, contextual factors influencing implementation, perceived utility of the intervention by patients and providers, and mechanisms by which the intervention can be delivered as part of normal care.ConclusionThis process evaluation can inform researchers on how to design future CED studies to be implemented into clinical care. The lessons learned during the development and approval process of the ENABLE project in Germany, as well as its process evaluation, can benefit other European CED studies and policy‐makers stakeholders in making informed decisions. Likewise, these findings can be generalized beyond the context of amyloid PET to other diagnostic biomarkers, ultimately improving the diagnosis and management of Alzheimer's disease.
Lower amygdala and hippocampal volume correlates with TDP‐43 load in limbic‐predominant age‐related TDP‐43 encephalopathy (LATE)
Authors: Wesseling Alex J. , Calandri Ismael Luis , Ossenkoppele Rik , Bouwman Maud M.A. , Deshayes Natasja A. C. , van de Berg Wilma D.J. , Rozemuller Annemieke J.M. , Pijnenburg Yolande A.L. , Hoozemans Jeroen J.M. , Jonkman Laura E. 
Published: January 2025

AbstractBackgroundLimbic‐predominant age‐related TDP‐43 encephalopathy (LATE) is often described as occurring in older individuals, either with or without co‐occurring neurodegenerative disease. Because the presence of LATE can only be determined post mortem, little is known about the clinical and neuroimaging features of LATE. The current study aims to assess the correlation between LATE and MRI‐measured amygdala and hippocampal volume in Alzheimer’s disease (AD) and Lewy Body Diseases (LBD), including Parkinson’s disease (PD), PD dementia, and dementia with Lewy BodiesMethodsPost‐mortem in‐situ 3DT1 3T‐MRI data were collected for 51 cases (27 AD and 24 LBD) of which 17 had post‐mortem confirmed LATE neuropathological change (9 AD and 8 LBD), as well as 34 non‐LATE (18 AD and 16 PD) donors (matched on age, sex, and Braak stage). Right hemisphere amygdala and hippocampal volumes were calculated using Freesurfer. Pathological load of TDP‐43, p‐tau and α‐synuclein from the same regions were obtained using IHC and quantified using QuPath. Group differences were assessed with univariate analyses and correlations using linear mixed models, both using age, sex, post‐mortem delay and intracranial volume as covariates.ResultsTwo AD cases with a disease onset below 65 showed LATE pathology. In the combined cohort, brain donors with LATE neuropathological change showed significantly lower amygdala (p=.003) and hippocampal (p=.002) volumes, even when corrected for p‐tau and Lewy body load (Figure 1a). In AD, this difference remained (amygdala p=.001, hippocampus p=.007, corrected for p‐tau), but not in the LBD group. In donors with LATE, TDP‐43 load correlated negatively with MRI measured amygdala and hippocampal volume when corrected for p‐tau and Lewy body load (r= .70; p=.005) (Figure 1b). The same association was found in AD (r=.70; p=.015 corrected for tau load) but not in LBD donors.ConclusionThese results suggest that TDP‐43 inclusions plays a role in hippocampal and amygdala atrophy on MRI, even when correcting for effects of primary pathology. Moreover, a salient detail is that LATE also seems to play a role in the disease presentation of young‐onset dementia patients.
Influence of tau pathology and anxiety and depressive symptoms on metamemory in cognitively normal older adults
Authors: Crawford Jennifer L. , Adornato Alex , Matulonis Johanna , Hooker Jacob M. , Berry Anne S. 
Published: January 2025

AbstractBackgroundThe ability to accurately discern memory function (i.e., metamemory) decreases with age and is further diminished in Alzheimer’s disease (AD). As such, changes in metamemory may be a sensitive behavioral indicator of pre‐symptomatic AD.MethodCognitively normal older adult participants (N=48) completed a neuropsychological battery consisting of episodic memory tasks (California Verbal Learning Task, Face‐Name Associative Memory Exam) and self‐reported measures of metamemory (Multifactorial Memory Questionnaire) and anxiety and depressive symptoms (Geriatric Depression Scale, Penn State Worry Questionnaire, Mood and Anxiety Symptom Questionnaire). Z‐scores from each measure were combined into three separate composite scores: memory ability, metamemory, and anxiety and depressive symptoms. All participants also had a tau PET scan ([18F]MK‐6240) completed within 12.7 (SD = 11.6) months of neuropsychological testing in which standardized uptake value ratios (SUVR) referenced to the inferior cerebellar gray matter were calculated using Freesurfer‐defined ROIs for Braak I, Braak II, metatemporal, and amygdala regions of interest (ROIs). Linear regression models were used to test for the contribution of anxiety and depression symptoms, tau pathology, and memory ability on metamemory; education, age, and sex were entered as covariates in all models.ResultBehavioral analyses suggest that anxiety and depression symptoms (t = ‐2.1, p=0.046), but not memory ability (t = 0.4, p=0.698), were related to metamemory. Interestingly, tau pathology helped to explain additional variance in the relationship between metamemory and anxiety and depressive symptoms. Specifically, amygdala tau interacted with anxiety and depression symptoms to predict metamemory (t = ‐2.61, p=0.013), when controlling for age, sex, education, and memory ability, such that participants with both high levels of anxiety and depressive symptoms and high levels of amygdala tau pathology had lower self‐reported metamemory (Figure 1). This relationship was not observed in Braak I, Braak II, or metatemporal ROIs (ps > 0.07).ConclusionTogether, these results suggest that depressive and anxiety symptoms are an important metric to consider when examining the relationships between tau pathology and metamemory. Further, the results underscore that mechanisms supporting metamemory are likely distinct from those underlying memory ability and each merit unique consideration towards understanding their relationship to AD pathology.