bluuebunny/crossref_metadata_2025_split huggingface dataset:
Studying protein interactions in human synapses using array tomography
Authors: Holt Kristjan , Taylor Lewis W. , McGeachan Robert I. , Simzer Elizabeth , Colom‐Cadena Martí , Sánchez‐Aced Érika , King Declan , Davies Caitlin , Hamby Mary E. , Horrocks Mathew H. , Lleo Alberto , Durrant Claire S. , Spires‐Jones Tara L. 
Published: January 2025

AbstractBackgroundSynapse loss represents the closest correlate of cognitive decline in Alzheimer’s Disease (AD). Standard microscopy, due to increased diffraction of light with tissue depth, imposes a limit on axial resolution extending to ∼ 700nm. Array tomography (AT), developed by Micheva & Smith (2007), extends this axial limit via physical sectioning of resin‐embedded tissue into ribbons of 70nm contiguous sections that are serially imaged and reconstructed into 3D volumes; thus, allowing for nanometric synaptic puncta to be resolved at the mesoscale. Our group has, for the past decade, adapted AT to investigate synapse loss in human post‐mortem brain tissue from people who died with Alzheimer’s disease; other neurodegenerative diseases, and control subjects. We have published recent developments to AT that further improve X‐Y resolution, permitting in‐depth investigation of synapse‐protein interactions. Highlighted here are Förster Resonance Energy Transfer (FRET), Reconstruction Microscopy (dsSTORM) and DNA‐PAINT to assess interactions between Aβ, tau and protein binding partners, at the synapse. This work was funded by Cognition Therapeutics, Medical Research Council (MRC), UK Dementia Research Institute (UKDRI) and Race Against Dementia.MethodFixation, embedding, sectioning and immunostaining are detailed in work published previously by Kay et al. (2013). Advances to AT presented here include FRET, dsSTORM, DNA‐PAINT, and investigation of synaptic composition in organotypic human brain slices from surgical resections challenged with disease‐relevant proteins. Further, we report advances in our image analysis pipeline with scripts available to use on https://github.com/Spires‐Jones‐Lab.ResultFRET‐AT has been used to profile over 1 million individual synaptic puncta in the temporal cortex and generates sufficient signal to indicate molecular interaction between Aβ and putative binding partners including TMEM97 in control (n = 9) and Alzheimer’s disease (n = 11) human brain tissue. FRET‐AT also suggests interaction between p‐tau Ser356 and synaptic terminals (n = 5/group). This, coupled with evidence of synaptic tau from dsSTORM/DNA‐PAINT, provides indirect evidence of disease progression via tau‐synapse interaction.ConclusionAT can be combined with other methodologies, allowing for in‐depth investigation of synapse‐protein interactions at a scale larger than afforded by electron microscopy (EM). This provides important insight into neurodegenerative disease and presents targets for potential therapeutics disrupting protein‐protein interactions.
Cryo‐EM structures of amyloid beta and tau filaments in down syndrome
Authors: Fernandez Anllely , Hoq Md Rejaul , Hallinan Grace , Li Daoyi , Bharath Sakshibeedu R. , Vago Frank S. , Ozcan Kadir A. , Newell Kathy L , Garringer Holly J. , Jiang Wen , Ghetti Bernardino , Vidal Ruben 
Published: January 2025

AbstractBackgroundDown syndrome (DS) is the most common and best‐known chromosomal disorder in humans and the most frequent cause of intellectual disability of genetic origin, affecting about 6 million people worldwide. Individuals with DS may develop Alzheimer disease (AD) by age 55‐60 years, and sometimes as young as 40 years due to the triplication of the amyloid β precursor protein (AβPP) gene, which is located on chromosome 21. The AD neuropathological phenotype in DS includes amyloid‐β (Aβ) deposition (parenchymal and vascular) and neurofibrillary tangles comprised of tau protein. Aβ peptide species ending at 42 (Aβ42) are the main component of senile plaques and diffuse deposits in AD and AD in DS, while Aβ peptides ending at position 40 (Aβ40) are the predominant Aβ peptides found in both leptomeningeal and cortical vessels. Whether there is a difference in the structures of Aβ and tau filaments between AD and AD in DS, is unknown.MethodWe used cryo‐electron microscopy (cryo‐EM) to study the structure of Aβ and tau filaments extracted from the brains of two individuals with DS. Both individuals had been clinically diagnosed with AD, which was neuropathologically confirmed.ResultWe found two types of Aβ42 filaments (I and II) identical to those found in sporadic and familiar AD and two novel Aβ40 filaments (type IIIa and IIIb) that differ from those previously reported in AD. Tau filaments (paired helical filaments, PHFs, and straight filaments, SFs), were identical to those from AD and related diseases.ConclusionThis cryo‐EM study emphasizes the similarities and differences between amyloid filaments in AD and AD in DS. The relevance of the structural differences between Aβ40 filaments in cerebral amyloid angiopathy in AD and DS is unknown. Further research is needed to determine whether type IIIa and IIIb Aβ40 filaments are unique to DS. Tau filaments (PHFs and SFs) were identical to those in AD, supporting the notion of a common mechanism through which amyloids trigger aggregation of tau. This knowledge is crucial for understanding AD in individuals with DS and assessing whether adults with DS could be included in AD clinical trials.
Validation that miRNAs altered in Alzheimer’s disease in human cerebrospinal fluid also function as miRNA biomarkers for Alzheimer’s disease in human plasma
Authors: Saugstad Julie A , Sandau Ursula S , Wiedrick Jack , McFarland Trevor J. , Galasko Douglas R. , Quinn Joseph F 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is the most common cause of dementia, and the fifth leading cause of death for those 65 and older. Brain changes in AD begin 10‐20 years before symptoms appear, yet markers for early brain changes are lacking. We discovered and validated miRNAs in human cerebrospinal fluid (CSF) that differentiate AD from Controls. However, as blood is a preferred biofluid for biomarker profiling, we evaluated 1) the intraindividual longitudinal stability of human miRNAs in plasma, then 2) expression of the CSF AD miRNAs in plasma.MethodFor the longitudinal stability study, blood was collected by venipuncture biweekly over 3 months from 22 donors who had fasted overnight. For the CSF‐plasma miRNA correlation, we obtained 320 donor‐ and date‐ matched CSF and plasma AD and Control samples from the AD Neuroimaging Initiative. We isolated total RNA from 1) 200 µL of platelet‐free plasma or 2) 250 µL of CSF and plasma. MiRNA expression was assessed by qPCR using custom TaqMan human arrays. All studies were approved by OHSU IRB00009707.Result1) For the longitudinal stability study, of 134 miRNAs amplified, 74 had high test‐retest reliability and low percentage level drift. Importantly, 13 candidate miRNA biomarkers for AD were stable in plasma over 3 months, and we found that hemolysis and tobacco use had the greatest impact on miRNA levels and variance. 2) For the CSF‐plasma study, the data revealed that individual plasma miRNAs are more predictive than CSF for AD, and a combination of plasma miRNAs are more predictive for AD than CSF. In addition, the highest‐probability plasma model for AD contains 2 complementary miRNAs, one positive (increased log fold change in expression), and one negative for fold change (decreased log fold change in expression).ConclusionThese studies revealed plasma miRNAs that are stable over the 3‐month time, including candidate AD biomarkers. They also revealed miRNAs that are not stable over the 3‐month time, including miRNAs previously reported as biomarkers AD. In addition, the CSF‐plasma studies validated that AD CSF miRNAs differentiate AD from Controls in plasma, supporting the use of plasma for further development of AD miRNA biomarkers for clinical assays.
Investigating Alzheimer’s disease progression using a radiomics approach: The hippocampal‐amygdala border in FDG‐PET Scans
Authors: Rasi Ramin , Guvenis Albert 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and cognitive decline. Detecting AD early and tracking its development is essential for better management. This study delves into the potential of radiomics to identify the AD stages and monitor its progression using FDG PET images. The particular objective is to explore the potential of tracking progression using a reduced and meaningful set of imaging biomarkers at the borders of neighboring brain regions.MethodOur study analyzed 18FDG‐PET scans from 931 participants across five stages of AD from the ADNI database. Focusing on 95 brain regions, we employed the PyRadiomics tool and eight feature selection techniques. The Hippocampus, Amygdala, and Entorhinal regions emerged as consistently important across these methods. We delineated the connecting regions between these regions using a sliding window approach and identified the best two features that help detect AD by the use of a random forest classifier. We then plotted the values of the two features to track progression.ResultThe connectivity area between the hippocampus and amygdala demonstrated superior efficacy for diagnosing AD progression. The two most important features for this region, namely “Shape Mesh Volume“ and SDLGLE ”GLDM Small Dependence Low Gray Level Emphasis" exhibited the highest classification capability for predicting AD versus control normal individuals (Accuracy = 0.77, sensitivity = 0.73, specificity = 0.81). We plotted these two features across deteriorating stages. The features mean values were able to demonstrate the incremental deterioration. The variance of the feature values increased for deteriorating cases.ConclusionWe found that the small connection border between the hippocampus and the amygdala can serve as a biomarker to help us partially detect and interpret the presence and severity of AD. In particular, we found that changes in the volume and a measure called SDLGLE within this small border region were strongly linked to AD progression. The SDLGLE increase suggests a potential weakening of the tissue structure, possibly due to neurodegeneration. This preliminary finding highlights the power of a minimal set of radiomic features to not only detect and potentially explain the mechanisms behind AD progression but also to help track disease severity.
Revised Criteria for Diagnosis and Staging of Alzheimer’s Disease
Authors: Jack Clifford R. 
Published: January 2025

AbstractThe National Institute on Aging and the Alzheimer’s Association (NIA‐AA) convened three separate work groups in 2011 and a single work group in 2018 to create recommendations for the diagnosis and characterization of Alzheimer’s disease (AD). Several fundamental principles emerged from these efforts. These include, AD should be defined biologically, not by clinical syndromes. The disease is a continuum that is first evident with the appearance of brain pathologic changes in asymptomatic individuals and progresses through stages of increasing pathologic burden eventually leading to appearance/progression of clinical symptoms.The Revised Criteria for Diagnosis and Staging of Alzheimer's Disease is the product of a work group sponsored by the Alzheimer’s Association. The revised Criteria update the 2018 Research Framework in response to major recent developments. First, since 2018, for the first time, treatments that target core disease pathology have received regulatory approval. Second, accepted biomarkers in 2018 were either CSF assays or imaging. Since then, plasma‐based biomarkers were developed, and some (but not all) demonstrate excellent diagnostic performance.The objective of the work group was to propose objective criteria for diagnosis and staging AD to serve as a bridge between research and clinical care. These criteria are not intended to be specific clinical practise guidelines, but rather criteria for diagnosis and staging of AD that reflect current science.Defining neurodegenerative diseases by their underlying biology rather than by non‐specific syndromic presentations has gained momentum in recent years. In addition, investigators increasingly recognize that across the spectrum of neurodegenerative disorders, the disease progresses along a continuum that begins with the appearance of the defining neuropathology while patients are asymptomatic. This symposium will examine the unifying theme of biologically based diagnosis and staging across neurodegenerative diseases.
Non‐clinical evidence for modulating synaptic CSF biomarkers by E2511, a novel small molecule TrkA biased positive allosteric modulator
Authors: Hiramatsu Naoki , Tomioka Takeyasu , Sasaki Kazunari , Saxena Satya , Wildsmith Kristin R , Sachdev Pallavi , Penner Natasha , Giorgi Luigi 
Published: January 2025

AbstractBackgroundCholinergic innervation is particularly vulnerable in many neurodegenerative diseases such as Alzheimer’s diseases. Nerve growth factor (NGF) plays a major role in the maintenance and function of cholinergic neurons, and a decrease in trophic signalling by NGF‐Tropomyosin receptor kinase A (TrkA) contributes to cholinergic and synaptic degeneration. E2511 is a novel small molecule TrkA biased positive allosteric modulator showing an increase in specific trophic signalling via direct binding to TrkA with a potential to recover and reinnervate damaged cholinergic neurons. We have shown that multi‐platform global proteomic approaches identified novel candidate PD biomarkers for E2511 using pre‐ and post‐treatment CSF samples from E2511‐A001‐005 (a multiple‐ascending dose study in healthy volunteers). Modulation of proteins related to cholinergic pathway, neurotrophin/Trk signalling and synaptic pathway was demonstrated for E2511 relative to placebo (CTAD2023, ADPD2024). Here we examined the mechanism of each biomarker changes by E2511 by non‐clinical study.MethodThe effect of E2511 on gene expression of candidate PD biomarkers identified using multi‐platform global proteomic approaches was assessed by qPCR in septum, one of the basal forebrain regions and where cholinergic nerves are localized, of normal SD rats treated with once‐daily oral E2511 for 14 days. The effect of cholinesterase inhibitor (ChEI) on gene expression was also investigated in rats treated with TID oral donepezil for 4 days.ResultE2511 increased gene expression of several candidate biomarkers related to cholinergic pathway, neurotrophin/Trk signalling and synaptic pathway. In contrast, treatment with donepezil which resulted in an increase in ACh levels failed to elicit such effects on the candidate biomarkers. These results suggest that the increase in gene expression related to cholinergic pathway, neurotrophin/Trk signalling and synaptic pathway by E2511 is via NGF‐TrkA signal activation and E2511 has a mechanism of action distinct from ChEIs.ConclusionThe mechanism of modulating novel candidate PD biomarkers in human CSF by E2511 was clarified by non‐clinical study using rats. The convergence of clinical global proteomics data and non‐clinical data have identified PD biomarkers for E2511 consistent with the proposed mechanism of action. Results are supportive of continued development of a E2511‐specific biomarker panel and suggestive of pathway activation in healthy volunteers.
Impact of Yoga in Transformation of Quality of Life of Alzheimer’s disease cases
Authors: Kaushik Meenakshi 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) constitutes a formidable challenge, profoundly affecting the fabric of individuals' lives and intricately entwined with disturbances in their quality of life. This study embarks on a mission to unravel the transformative potential of a carefully crafted 12‐week yoga intervention, specifically tailored to address the multifaceted dimensions of quality of life. Our aim is to unravel the impact of a yoga intervention on their overall quality of life with AD and mild cognitively impairment subjects.MethodA case control yoga interventional study was conducted on 30 subjects (male‐18 and female‐12) were enrolled from the department of neurology and neurocognitive assessments were done in department of Anatomy, AIIMS, New Delhi, India. All the participants, aged >60 years were recruited. The 12‐week yoga intervention entailed daily hour‐long sessions over 6 days. The multifaceted evaluation encompassed the Geriatric Depression Scale (GDS) including the evaluation of 15 questions and the Montreal Cognitive Assessment (MoCA) scale including for overall quality of life assessment with measuring language, memory, attention, visuospatial, naming, delayed recall, abstraction, and orientation for quality‐of‐life of the AD subjects.ResultThe AD subjects cohort exhibited statistically significant enhancements (P < 0.001) in quality‐of‐life scores (GDS & MoCA) pre and post Yoga intervention. GDS scores of 15 questions experienced a remarkable transition from pre‐yoga (8.36 ± 2.7) to post‐yoga (5.13 ± 3.0). While total MoCA scores ascended from pre yoga (18.65 ± 4.13) to post yoga (25.06 ± 6.3). MoCA scores of individual points pre yoga includes language (1.10 ± 0.2), memory (no points), attention (3.54 ± 1.8), visuospatial (4.0 ± 1.30), naming (2.16 ± 0.4), delayed recall (3.55 ± 0.25), abstraction (0.50 ± 0.0), and orientation (3.80 ± 0.18). MoCA scores of individual points post yoga includes language (2.16 ± 0.6), memory (no points), attention (4.60 ± 1.3), visuospatial (4.90 ± 2.50), naming (2.85 ± 0.75), delayed recall (4.85 ± 0.50), abstraction (1.40 ± 0.20), and orientation (4.30 ± 0.45).ConclusionThis discerning study illuminates the transformative potential of a 12‐week yoga program, showcasing significant enhancements in the quality of life of individuals grappling with mild to moderate Alzheimer’s disease.
Assessing and illuminating the Impact of Ultra‐Processed Food Intake on Alzheimer’s Disease‐A Systematic Review and Meta‐Analysis:
Authors: Khalifa Mostafa A. , Elsead Jana Ahmed 
Published: January 2025

AbstractBackgroundAs there is currently no therapy available for Alzheimer’s disease, efforts are now focused on improving quality of life through various means, one of them is dietary intake. While several studies have demonstrated that consuming ultra‐processed food may contribute to the development of chronic diseases such as diabetes, there is insufficient evidence to directly link the consumption of ultra‐processed food to an increased risk of developing Alzheimer’s disease. However, it has been established that ultra‐processed foods have negative effects on biological mechanisms, such as oxidative stress and inflammation. Therefore, it is our role to clarify the impact of ultra‐processed food on Alzheimer’s diseaseMethodOur systematic review will include all records in Medline and Web of Science up to 2024 that describe the relationship between ultra‐processed food and Alzheimer’s disease as determined by the NOVA classification system. There were no limitations placed on the earliest search date. Studies not classified by NOVA were excluded, and we adhered to the PRISMA guidelines. Our systematic review is currently in progress and is expected to be completed by the end of 2024.ResultOur research yielded a total of 7560 observational studies. After removing 700 duplicate records, we screened the titles and abstracts of 6860 papers, excluding 6760. We then proceeded to review the full text of 100 papers, 10 of them met the inclusion criteria. A pilot study was conducted on 5 of these papers, revealing that all studies demonstrated a significant increase in the risk of developing Alzheimer’s disease among individuals with a high intake of ultra‐processed food.ConclusionBased on our preliminary findings, we suggest that a high intake of ultra‐processed food may contribute to the development of Alzheimer’s disease. Further clinical trials are needed to illustrate the association between ultra‐processed food and Alzheimer’s disease.
Association of insomnia with incident dementia – considering the competing risk of death
Authors: Sulkava Sonja , Haukka Jari , Paunio Tiina 
Published: January 2025

AbstractBackgroundSleep disturbances have been suggested as potential risk factors for neurodegenerative diseases. However, longitudinal studies on insomnia and dementia have mostly had too short follow‐up time to separate etiological risk factors from prodromal symptoms. Moreover, the impact of mortality as a competing risk has been overlooked. This study aims to clarify the relationship between insomnia symptoms and dementia incidence, considering the competing risk of death, within a large cohort from the Finnish population.MethodThe National FINRISK study, collected every five years from 1972 to 2012, included 63 013 Finns with baseline data. Approximately 12% (7638) developed dementia according to the health care registers. The follow‐up time varied from 7 to 47 years (mean = 25 years). We studied association of self‐reported insomnia (never, sometimes, often) at baseline with dementia incidence using in parallel Poisson model and Fine‐Gray model accounting for the competing risk of death. Additional analysis directly examined this competing risk. Study year, follow‐up time, sex, education, and cardiovascular risk factors were adjusted for. Sensitivity analyses included individuals with over 10 years of follow‐up.ResultIn the Poisson model, insomnia symptoms “sometimes” (IRR = 1.10[1.05‐1.16]) and “often” (IRR = 1.18[1.09‐1.28]) showed significant association with incident dementia and a dose‐response relationship. The results survived the sensitivity analyses. In the Fine‐Gray model, insomnia “sometimes” (HR = 1.07[1.02‐1.12) but not “often” (1.07[0.99‐1.16]) showed significant associations. Significant associations with the competing risk of death surpassing that of dementia were detected for both categories with IRRs of 1.12[1.09‐1.15]) and 1.32[1.27‐1.37]), respectively.ConclusionThe findings from the Poisson model suggest that insomnia may serve as an etiological risk factor for dementia. However, the Fine‐Gray model, which focuses on the incidence of dementia in the presence of competing risk, did not show significant association with insomnia “often”. This suggests that individuals with insomnia face a higher risk of death before potentially developing dementia, implying that insomnia might not increase the true dementia incidence, despite being a risk factor. These results highlight the significance of including the competing risk of death in dementia epidemiological studies to fully understand the associations with risk factors.