bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma CycleGAN: Integrating Blood‐based Biomarkers for Cross‐modality Translation from MRI to PET
Authors: Chen Yanxi , Su Yi , Fu Yu , Chen Kewei , Weidman David , Caselli Richard J. , Reiman Eric M. , Wang Yalin 
Published: January 2025

AbstractBackgroundCross‐modality translation between MRI and PET presents significant challenges due to the distinct mechanisms underlying those modalities. Currently, the leading method for this translation is CycleGAN. Previous studies have proved a strong correlation between BBBMs and brain amyloid status measured by PET. However, the impact of blood‐based biomarkers (BBBMs) on PET image synthesis has not yet been thoroughly evaluated. In this study, we propose Plasma CycleGAN, a generative model based on CycleGAN to synthesize PET images from MRI, while also incorporating BBBMs and other clinical covariates. We show that Plasma CycleGAN outperforms the state‐of‐the‐art CycleGAN for MRI‐to‐PET translation. Our method is the first to integrate BBBMs in a conditional cross modality translation from MRI to PET.MethodOur model was built on CycleGAN architecture, while the backbone was improved by integrating BBBMs as additional conditions in the input domain. To be specific, we introduce a masked perturbation in the MRI image, whose voxel‐level magnitudes are learnable parameters in the neural network. The dataset we used to evaluate our model is downloaded from the ADNI database. The cohort contains 160 subjects with matching BBBM, T1‐weighted MRI images, amyloid PET, and clinical features, including age, sex, weights, etc. The synthesized PET images are compared with the ground truth PET images for performance evaluation using traditional metrics like structural similarity index (SSIM), peak‐signal‐to‐noise ratio (PSNR) and mean square error (MSE). In addition, the Pearson correlation coefficients (PCCs) of the masked SUVR ratios were calculated.ResultWe evaluated the baseline CycleGAN model using MRI input, as well as combined inputs of MRI+BBBM and other clinical features. Our model achieved an SSIM of 0.72±0.16 and PSNR of 22.8±2.3 in PET image synthesis task using MRI+ Aβ42/40, both yielding the best results among all input combinations. MRI+sex achieved the best result using MSE measurement. PCCs of all experimental results ranged from 0.44 to 0.5.ConclusionWe introduce Plasma CycleGAN, the first generative model to integrate BBBMs and clinical features in PET image synthesis from MRI images. In PET image synthesis task, our proposed integrated model outperforms the baseline CycleGAN model.
Association Between Late‐Life Depression and Amyloid Beta Burden in Older Adults Without Cognitive Impairment: A. Systematic Review and Meta‐Analysis
Authors: Castro Natalia Pozo , Paradela Regina Silva , Allen Isabel Elaine , Ruiz‐Castillo Karla Paulina , Vrillon Agathe , Delgado Carolina , Windon Charles 
Published: January 2025

AbstractBackgroundLate‐life depression (LLD) is a risk factor for cognitive impairment. Some studies have shown an association between higher amyloid‐beta (Aβ) burden, a known marker of Alzheimer’s Disease (AD), and LLD, but research findings are mixed. We performed a systematic review and meta‐analysis to compare the Aβ burden between cognitively unimpaired subjects with and without LLD.MethodWe searched MEDLINE, Embase, and ScienceDirect for studies comparing Aβ burden between LLD patients and controls (molecular imaging and/or fluid‐biomarker confirmation) and included subjects aged ≥60 years with LLD, and absence of cognitive impairment (MMSE ≥24 and/or description of normal cognition). The review process was performed by 2 independent reviewers (Covidence‐software). A random effects meta‐analysis was executed to evaluate the pooled difference of Aβ burden between LLD and control groups (JASP‐software).Result372 studies were identified and eight met the inclusion‐exclusion criteria (combined sample: 725 LLD subjects and 885 controls). The weighted‐mean age was 69.3 and 68.9 years for subjects and controls. Six studies evaluated Aβ in blood (4 on serum and 2 on plasma, one of them also evaluated PET‐Aβ), and two evaluated cerebrospinal fluid (CSF) (table 1). One of the serum studies (Namekawa) included two subgroups, one with subjects that besides depression after 60 years old also had a history of depression before age 60, and one with participants with a first episode of major depressive disorder after 60 years old. Both subgroups were analyzed separately in the meta‐analysis. The meta‐analysis of plasma and serum studies showed that individuals with LLD had lower levels of Aβ42 (estimate ‐0.344, p<0.001) (Fig. 1) and higher levels of Aβ40/42 ratio (estimate 0.428, p<0.001) compared to controls (Fig. 2). The results remained significant when plasma and serum were analyzed independently.ConclusionIn this systematic review and meta‐analysis, we found significantly lower levels of Aβ42 and higher levels of Aβ40/42 ratio in cognitively unimpaired older adults with LLD compared to controls. These findings support the idea that LLD is associated with AD pathology. This is a relevant area of research for increasing the understanding of AD’s clinical presentation that could potentially impact access to early diagnosis and treatment.
Design of YΦ motif peptides to promote 20S proteasome mediated degradation of tau
Authors: Ryder Bryan D. , Yan Nicholas L. , Gestwicki Jason E. ,   ALBORADA Drug Discovery Team
Published: January 2025

AbstractBackgroundAn optimized 6 amino acid peptide (NLSYYT; herein YΦ) derived from the C‐terminus of h19S proteasome activator Rpt5 has been shown to activate the 20S proteasome and promote tau degradation. Further analysis of this peptide has identified the highly conserved leucine in position 5 (P5) as a key part of the 20S activation mechanism to drive degradation of tau monomers in the absence of proteasome activator complexes.MethodRecombinant peptides were used to identify key amino acids required for binding and activating the h20S proteasome. Degradation activity from YΦ‐mediated activation was measured with small peptide markers. Using archaeal activator complex aPA26 with YΦ and P5 mutants cloned onto its tails, P5 was shown to use hydrophobic interactions to stabilize YΦ interactions with the h20S α‐subunit ring. Finally, YΦ activation of the h20S proteasome increased tau degradation in vitro, in cell lysates, and in cells.ResultIn vitro tau degradation experiments show that simultaneous binding of linked YΦ peptides is sufficient to promote degradation of tau monomer in an ATP‐independent and ubiquitin‐independent system. Mutations to the P5 leucine result in a 3‐fold reduction in h20S proteasome activity for aromatic substitutions, and complete loss of activity for all other natural amino acid substitutions. However, P5 substitutions do not have as dramatic of an effect on binding, demonstrating that the role of P5 leucine uncouples activity and binding, unlike the other amino acids. In the context of aPA26, YΦ mediated activation clears 80% of native tau monomer over the course of 30 minutes, with similar results observed in degrading tau derived from cell culture.ConclusionStructure‐activity relationship data of YΦ activation of the 20S proteasome provides insight into future designs of proteasome activators. With an improved understanding of the role of P5 leucine, a more refined interaction network can be considered when designing h20S proteasome activators for clearing disease‐associated tau in cells.
Relationship between electrophysiological performance during an incidental memory task and cholinergic integrity in a pilot study in adults with Down syndrome
Authors: Conley Alexander C , Russell Jason K , Begnoche John Patrick , Boyd Brian , Key Alexandra P , Rosenberg Adam J , Stranick Allison , Schlossberg Rachel , Martin Dann , Acosta Lealani Mae Y. , Wilson Jo Ellen , Rafii Michael , Newhouse Paul A 
Published: January 2025

AbstractBackgroundAdults with Down syndrome (DS) are at a high risk of developing Alzheimer’s disease (AD) due to the triplication of the amyloid precursor protein on chromosome 21. Despite the high incidence of AD within the DS population, there is less understanding of how AD progresses, although it may be reflected in an accelerated aging phenotype. Compared to typically developing populations, there is less understanding of the decline of cholinergic integrity with aging in adults with DS. In this pilot study we are investigating the impact of cholinergic system integrity using [18F]‐FEOBV PET on cortical structure and cognitive function in adults with DS. One measure of cognitive function that we used was attention and memory processes recorded by high‐density electroencephalography (EEG).MethodNine non‐demented adults with DS (4 female, aged 37.8±7.7 years), recruited from the Trial Ready Cohort – Down syndrome, completed an MRI, [18F]‐FEOBV PET scan and an EEG recording. Participants completed an incidental memory task, a passive memory task with a series of complex images half of which are novel, and half repeated. Oscillatory power across the frontal, central and parietal regions was defined as a repeated–novel power. [18F]‐FEOBV PET images were coregistered to structural MR images and referenced to the supraventricular white matter. Initial analyses focused on memory‐related evoked power from the delta, theta, alpha and beta frequency bands, and their association with [18F]‐FEOBV PET uptake.ResultUnexpectedly, recognition memory for repeat vs novel stimuli was associated with reduced power for delta, theta and beta bands and increased alpha power. This pattern of results reflect memory processes identified with older adults in the typically developing population rather than an age‐matched sample. Increased cholinergic uptake was associated with this pattern of older age‐like power across all frequency bands.ConclusionEvoked oscillatory activity on a recognition memory task in a small sample of adults with DS displayed similar characteristics as older adults in the typically developing population. Cholinergic integrity was associated with evoked power during recognition memory. These results demonstrate functional markers of accelerated aging in adults with DS as well as their relationship with cholinergic integrity.
Phase 2 Clinical Trials of NA‐831 for the Treatment of Alzheimer’s Disease and Major Depressive Disorder, support the Neurogenesis Hypothesis
Authors: Tran Lloyd , Tran Zung Vu , Vu Fern 
Published: January 2025

AbstractBackgroundAdult Hippocampal Neurogenesis has been shown to be involved in Major Depressive Disorder (MDD) and Alzheimer’s disease (AD) pathology. NA‐831 is a small drug molecule, exhibiting neuroprotection, neurogenesis and memory enhancing properties.MethodFor AD: A randomized clinical trial of NA‐831 was performed in 112 participants with mild and moderate Alzheimer’s disease (AD), half received the drugs and half received placebo. The patients with MCI received 10 mg of NA‐831 and patients with mild and moderate AD received 30 mg of NA‐831 or placebo orally per day.Subjects with MCI met the NIA‐AA core criteria. CDR score of 0.5 and a Memory Box score of 0.5 or greater at Screening and Baseline. MMSE score ≥22. Subjects with mild & moderate AD to meet the NIA‐AA core criteria. MMSE: 17‐21.For MDD: A randomized, clinical study was conducted to investigate the efficacy and safety of two fixed doses (20 and 40 mg/d) of NA‐831 vs. that of placebo after 6‐week treatment in 32 adult patients with major depressive disorder (MDD).ResultFor AD: NA‐831 showed a significant improvement for patients with mild and moderate AD with the ADAS‐Cog‐13 score change of an average of 4.1 as compared to the placebo after 24 weeks of treatment (p = 0.001; ITT). CIBIC‐Plus showed 78% patients improved (p = 0.01; ITT). mNA‐831 was well‐tolerated at 30 mg/day. There were no serious adverse events observed.For MDD: The difference between active treatment and placebo of ∼7 points on the MADRS translates into a clinically relevant difference in response rates of 32.5% units, compared to an average of 16% units for antidepressants approved by the USA FDA. Treatment with NA‐831 for 6‐week was well tolerated and efficacious in reducing depressive and anxious symptoms in patients with MDD.ConclusionThe Neurogenesis Hypothesis has been shown to be a viable approach for further research for Alzheimer’s disease and Major Depressive Disorder. Phase 3 trials of NA‐831 for the treatment of AD and MDD are being conducted. Results of the clinical trials will be provided as soon as they are available.
Daily Perceptions of Dementia Symptoms Within Care Dyads: Links to Diurnal Cortisol Rhythms in Couples Living With Early‐Stage Dementia
Authors: Polenick Courtney A. , Turkelson Angela , Garner Charity , Daniel Nikita R , Salwi Shreya M , Kaba Diarratou , Birditt Kira S. 
Published: January 2025

AbstractBackgroundSymptoms of Alzheimer’s disease and related dementias (ADRD), including memory problems, are often stressful for people living with dementia (PLWD) and family caregivers. However, we know little about daily perceptions of ADRD symptoms and links to physiological stress reactivity within care dyads. We evaluated how daily ADRD symptom stress (i.e., perceived stress related to ADRD symptoms) reported by PLWD and their spouse caregivers predict diurnal cortisol rhythms among heterosexual couples living with early‐stage ADRD.MethodParticipants included 39 PLWD (M = 72.1 years, SD = 7.6, range = 52‐86 years) and their spouse caregivers (M = 70.7 years, SD = 9.0, range = 49‐88 years) who both completed 7 consecutive days of brief morning and evening phone interviews and collected saliva samples (four times per day) during four of those days. Outcomes included the cortisol awakening response (AR; awakening to 30 min post‐awakening), decline (DEC; 30‐min post‐awakening to bedtime cortisol), and total area under the curve (AUC). Multilevel models controlled for study day, age, gender, and education.ResultHigher caregiver‐reported daily ADRD symptom stress was associated with their own higher AR on the next day when PLWD‐reported daily ADRD symptom stress was high (b = 1.04, SE = 0.38, p = .006). Higher caregiver‐reported daily ADRD symptom stress was associated with a higher AUC among caregivers (b = 2.51, SE = 0.87, p = .006) but a lower AUC among PLWD (b = ‐1.65, SE = 0.69, p = .021) on the same day. Higher caregiver‐reported daily ADRD symptom stress was associated with a lower PLWD AUC on the next day when PLWD‐reported daily ADRD symptom stress was low (b = ‐5.75, SE = 1.90, p = .002) but a higher PLWD AUC when PLWD‐reported daily ADRD symptom stress was high (b = 5.27, SE = 1.51, p < .001). Caregiver‐reported and PLWD‐reported daily ADRD symptom stress were not associated with DEC.ConclusionDaily ADRD symptom stress reported by spouse caregivers was associated with physiological stress reactivity among caregivers and PLWD. These findings inform targets of clinical care and interventions to improve the well‐being of both care dyad members.
Blood transcriptomics of preclinical Alzheimer’s Disease patients
Authors: de Bittencourt Marcelo Madrid , De Bastiani Marco , Ferreira Pamela C.L. , Zimmer Eduardo R. , da Rocha João Batista Teixeira 
Published: January 2025

AbstractBackgroundBlood transcriptomic differences have been described in patients with Alzheimer’s disease (AD). However, blood transcriptomic core molecular programs in cognitively unimpaired (CU) individuals positive to biomarkers of Amyloid and Tau pathology, defined as preclinical AD, remains to be explored. Therefore, we aimed to establish blood molecular core programs in preclinical AD.MethodWe selected 63 CU individuals negative or positive to amyloid‐B (A) and Tau (T) but negative for neurodegeneration from the ADNI database, with blood transcriptomics available (Fig. 1A). We performed microarray data analysis in R, utilizing the limma method, for identifying differentially expressed genes (DEGs) in CU A‐T‐; CU A+T‐ and CU A+T+. Amyloid‐B and Tau positivity was defined based on CSF levels of Aß(1‐42) and p‐tau (cutoffs of 977 pg/mL for Aß and 24 pg/mL for Tau). Gene Ontology (GO) enrichment analysis was conducted for all categories, separately for each comparison. P‐value < 0.05 was considered statistically significant.ResultThe comparison with the CU A‐T‐ group revealed 765 DEGs for CU A+T‐ and 1315 DEGs for CU A+T+. By comparing CU A+T+ with CU A+T‐, we identified 1171 DEGs. Only 29 DEGs were shared across all comparisons (Fig. 1B). Enrichment analysis identified 6 terms for CU A+T‐ versus CU A‐T‐, 17 terms for CU A+T+ versus CU A‐T‐, and 9 for CU A+T+ versus CU A+T‐. Only the second and the third comparisons shared the same terms, of which are “ATP‐dependent activity, acting on DNA“ and “single‐stranded DNA binding “. Among the non‐shared terms, CU A+T+ versus CU A‐T‐ included “ATP hydrolysis activity“, “ chromosomal region“, “tubulin binding“; for the CU A+T‐ versus CU A‐T‐, “cytoskeleton‐dependent intracellular transport“, “microtubule‐based transport“, “neuroprojection cytoplasm“; and for CU A+T+ versus CU A+T‐, “mononuclear cell differentiation”, “lymphocyte differentiation”, “regulation of macrophage chemotaxis”(Fig. 2).ConclusionOur results suggest changes in blood transcriptomics among preclinical individuals with Amyloid and/or Tau pathology. Amyloid was related to disruptions in immune‐mediated and cytoskeleton proteins, while individuals positive for amyloid and Tau presented disturbances in inflammatory responses. Altogether, both Amyloid and Tau contribute to deregulations in cell cycle and DNA repair systems compared with CU individuals with no pathology.
Integration of GWAS summary statistics with cell type‐specific eQTLs prioritizes potential causal genes for Alzheimer’s disease
Authors: Liu Shiwei , Huang Yen‐Ning , Park Tamina , Chaudhuri Soumilee , Cho Min Young , Rosewood Thea Jacobson , Bennett David A. , Saykin Andrew J. , Nho Kwangsik 
Published: January 2025

AbstractBackgroundAnalyzing disease‐linked genetic variants via expression quantitative trait loci (eQTLs) is crucial for identifying disease‐causing genes. Previous research prioritized genes by integrating Genome‐Wide Association Study (GWAS) results with tissue‐level eQTLs. Recent studies explored brain cell type‐specific eQTLs, but they lack a systematic analysis across various AD GWAS datasets, nor did they compare effects between tissue and cell type levels or across different cell type‐specific eQTL datasets. Here, we integrated brain cell type‐specific eQTL datasets with AD GWAS datasets to identify potential causal genes at the cell type level.MethodTo prioritize disease‐causing genes, we used summary data‐based Mendelian Randomization (SMR) and Bayesian colocalization (COLOC) methods to integrate the AD GWAS summary statistics with cell type‐specific eQTLs in human brain. We utilized five latest AD GWAS datasets and a cell type‐specific eQTL dataset comprising 424 participants of the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP) cohort. We replicated our analysis using a cell type‐specific eQTL dataset of 192 participants from Bryois et al., 2021. For comparison, we utilized a previous tissue‐level metabrain eQTL dataset from a meta‐analysis of 14 datasets. Furthermore, we visualized the colocalization of novel candidate causal genes using eQTpLot.ResultWe identified 17 cell type‐specific candidate causal genes using the ROSMAP eQTL dataset. Our results showed that the largest number of candidate causal genes are identified in microglia, followed by astrocytes, oligodendrocytes, excitatory neurons, inhibitory neurons, and oligodendrocyte progenitor cells (OPCs). Four candidate causal genes were common across different cell types. Interestingly, JAZF1, detected as a candidate causal gene affected by the same leading variant in both microglia and OPCs, showed a congruous (same direction) colocalized SNP effect on the gene expression level and AD in OPCs, but an incongruous (opposite direction) colocalized SNP effect in microglia. After comparing our results with previously known prioritized causal genes, we identified PABPC1 in astrocyte as a novel potential causal gene.ConclusionWe systematically prioritized AD candidate causal genes based on cell type‐specific molecular evidence. The integrative approach enhances our understanding of molecular mechanisms of AD‐related genetic variants and facilitates the interpretation of AD GWAS results.
Assessment of Baseline Plasma p‐tau217 in TANGO, a Randomized, Placebo‐controlled Phase 2 Study of Gosuranemab in Patients with Early Alzheimer’s Disease
Authors: Czerkowicz Julie , Zhang Rong , Collins Jessica , Rubel Carrie E. , O'Gorman John , Shulman Melanie , Graham Danielle 
Published: January 2025

AbstractBackgroundTANGO was a Phase 2 clinical study designed to assess the safety and efficacy of gosuranemab, an anti‐tau monoclonal antibody, in participants with mild cognitive impairment due to Alzheimer’s disease (AD) or with mild AD dementia. Despite robust target engagement of unbound N‐terminal tau, the clinical efficacy endpoint was not met. In this exploratory analysis of TANGO participants, we examine plasma p‐tau217 levels to assess the feasibility of using this biomarker to identify patients with AD pathology and predict disease progression.MethodsPlasma was collected from 554 randomized TANGO participants at baseline and up to Week 78. Plasma p‐tau217 was measured using the ALZpath Quanterix Simoa assay. Plasma p‐tau181 was measured using the Quanterix Simoa p‐tau181 V2 Advantage assay. Tau PET was measured in a sub‐study of 357 participants at baseline and Weeks 52 and 78 using 18F‐MK‐6240. Amyloid PET was measured at screening using 18F‐florbetapir in n = 322 participants Clinical decline was measured using the CDR‐SB, MMSE, ADAS‐Cog13 and ADCS‐ADL cognitive assessment scales. Statistical analysis was performed using Spearman correlation coefficient.ResultsPlasma p‐tau217 and plasma p‐tau181 were correlated at baseline (Spearman = 0.7617, p‐value <0.0001). Baseline plasma p‐tau217 levels were correlated with both baseline amyloid PET using SUVR in a composite region of interest (Spearman = 0.4294, p‐value <0.0001) and baseline Tau PET using SUVR in composite regions of interest corresponding to Braak stages I‐II, III‐IV, and V‐VI (Spearman range = 0.4075‐0.6163, p = value <0.0001). Participants with higher concentrations of plasma ptau217 at baseline showed a greater rate of clinical decline at Week 78.ConclusionsThe correlations of plasma p‐tau217 with amyloid and tau PET at baseline suggest a relationship with both underlying pathological hallmarks of AD. Similar to results from observational cohorts, correlation of baseline plasma p‐tau217 and clinical decline observed during the TANGO trial supports the utility of plasma p‐tau217 as a potential prognostic biomarker of disease. Data from additional studies are needed to define appropriate use cases and relevant thresholds for plasma p‐tau217 as a biomarker of disease pathology that can be used to prescreen patients in clinical trials.