bluuebunny/crossref_metadata_2025_split huggingface dataset:
Play It Again: Differential pupillometry responses to familiar and unfamiliar music: Findings from typical and atypical Alzheimer’s disease
Authors: Brotherhood Emilie V , Macdougall Amy , Firth Nicholas C. , Pavisic Ivanna M , Mengoudi Kyriaki , Yong Keir X X , Levett Benjamin , Warren Jason D , Camic Paul , Crutch Sebastian J 
Published: December 2023

AbstractBackgroundMusic has gained more attention than other art forms as a potent tool in supporting cognitive, emotional and social functioning in dementia populations. Methods for measuring moment‐to‐moment responses ‐ rather than comparing pre‐ and post‐stimulus effects ‐ may enable tailoring of musical experiences for the individual. The current study investigated whether differential pupillometry responses could be established for familiar/unfamiliar music in people living with early‐mid stages of typical, memory‐led Alzheimer’s disease (tAD), atypical ‘visual variant’ of Alzheimer’s disease (posterior cortical atrophy; PCA), and healthy age‐matched controls.MethodPatient groups [tAD = 18; PCA = 21] were recruited via the Specialist Cognitive Disorders clinic at the National Hospital for Neurology and Neurosurgery, London, UK. Healthy older adults [N = 90] were recruited opportunistically via departmental research databases/Join Dementia Research. Pupillometry responses were recorded while participants listened to 30 musical excerpts [classical (N = 5); 1960s (N = 10), 1970s (N = 10), reversed ‘de novo’ tracks (N = 5)], each rated for familiarity: (a) a priori (known/unknown); (b) self‐rated by participants (not familiar‐extremely familiar); and (c) whether the excerpt evoked a memory (yes/no). Background, basic clinical and music experience information was collected, alongside additional neuropsychological assessment in the patient groups. Separate linear regression models obtaining cluster robust standard errors were run to predict pupil response from a priori predicted‐ and subjective‐ratings of music familiarity in each participant group, controlling for demographic factors including disease severity.ResultResults indicate significant within‐group effects of familiarity on pupil response in controls and the tAD group. No effects were observed within the PCA group. Preliminary between‐group analyses including diagnosis as a predictor revealed that, for each music‐pupillometry model, tAD overall pupil dilation responses did not differ significantly compared to controls, however a significant difference was observed between PCA and control pupil dilation responses.ConclusionThe results are discussed in relation to the preliminary finding of preserved differential pupillometry responses to familiar/unfamiliar music in the tAD group. Although the PCA results question the utility of pupillometry in individuals with significant oculomotor dysfunction, pupillometry may serve as a useful non‐invasive ‘biosignal’ for establishing in‐the‐moment response to music, including in post‐verbal individuals in the later stages of dementia.
Multi‐task analysis of oculographic biomarkers to evaluate motoric and cognitive patterns in Alzheimer’s Disease
Authors: Li Deming , Meyer Trevor , Oh Esther S , Butala Ankur , Dehak Najim , Moro‐Velazquez Laureano 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is characterized by progressive loss or damage to the nervous system which can cause impairment in movement, coordination, and cognition. Due to the complexity of clinical features at different stages of the disease, it may require months for an accurate diagnosis. Oculomotor researchers have demonstrated the utility of examining eye movements for differentiating various neurodegenerative disorders including AD, Parkinson’s disease (PD), and other PD mimics (PDM). In this study, we propose an automatic pipeline to identify saccade, fixation, and blinks and extract response‐to‐stimuli‐derived interpretable biomarkers that could inform clinicians in making accurate assessment.MethodEye tracking data in smooth pursuit, pro‐saccade, and anti‐saccade tasks were recorded from 146 participants ‐ 14 with AD or Mild Cognitive Impairment (MCI), 46 with PD, 16 with PDM, and 70 age‐matched normal controls (CTL). Biomarkers based on the identified eye movement and interaction with the stimuli were extracted with our algorithms. Then, pairwise Kruskal‐Wallis H tests were conducted to determine if there were statistically significant differences between groups. The Benjamini‐Hochberg correction was performed to control the false discovery rate.ResultThe results show that, in the smooth pursuit task, the AD/MCI group had a significantly higher (p < 0.05) saccade count than CTL and PD groups. The AD/MCI group also exhibited significantly longer (p < 0.05) average saccade duration than CTL and PDM groups. The mean and standard deviation for the number of saccadic adjustments to reach and stay on the target significantly differed (p < 0.05) between AD/MCI and CTL and between PD and CTL in trials of the pro‐saccade task. The magnitude of overshoot or undershoot was significantly greater (p < 0.05) for AD/MCI, PD, and PDM compared to CTL. Moreover, the number of saccades in the wrong direction was significantly higher (p < 0.05) for AD/MCI and PD compared to CTL in the anti‐saccade task.ConclusionOculographic biomarkers can be leveraged within a machine learning framework and may be useful in distinguishing different types of neurodegenerative diseases in their early stages yielding more objective and precise protocols to monitor disease progression than current methods.
Evaluation of Interpretable Speech Biomarkers for Monitoring Alzheimer’s Disease and Mild Cognitive Impairment Progression
Authors: Favaro Anna , Dehak Najim , Thebaud Thomas , Oh Esther S , Moro‐Velazquez Laureano 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disease. Like for other dementias, biomarkers may help characterize distinct aspects of the underlying pathology, predict decline, and monitor disease progression. We extracted a composite array of 24 speech‐based biomarkers using machine learning and signal processing techniques. We then determined which of the given biomarkers was predictive of MCI and AD progression from baseline by conducting a correlation analysis.MethodSpoken responses to a Cookie Theft Picture description task were recorded from 2 subjects with AD, 4 subjects with Mild Cognitive Impairment (MCI) due to AD (biomarker confirmed AD), and 4 subjects with MCI. We automatically extracted acoustic, linguistic, and cognitive biomarkers using speech recognition, acoustic, and language modeling techniques. We later computed Kendall’s tau‐b (tb) correlation between the biomarker values and Montreal Cognitive Assessment (MoCA) scores. Recordings and MoCA scores were collected at baseline, at 6 months after baseline, and at 12 months for a subgroup of the subjects. To perform the correlation analysis, we used scipy.stats.kendalltau library in Python.ResultWith respect to the acoustic biomarkers, a strong negative correlation (tb = ‐0.50) was observed between the MoCA scores and features such as pause time, pause percentage, and pause speech ratio, while a moderate positive correlation (tb = 0.2) was found for rhythm standard deviation. With respect to the linguistic biomarkers a strong positive correlation(tb = 0.50) for the features of corrected type‐token ratio, average sentence length in words, and noun count was reported, while a moderate positive correlation (tb = 0.27) was found for the features of word type count, word token count, and moving average type‐token ratio. The other acoustic, linguistic, and cognitive biomarkers showed a very weak (tb = 0.00 ‐ 0.10) or weak correlation (tb = 0.10 ‐ 0.20).ConclusionAltogether, these results suggest that speech‐based interpretable biomarkers may help clinicians to diagnose AD at earlier stages and monitor disease progression. Our preliminary data suggest that AD patients encounter more problems delivering longer and linguistically elaborated narratives as the disease progresses.
Spatial navigation metrics differentiating preclinical and prodromal Alzheimer’s disease: a systematic review
Authors: Newton Coco , Cepukaityte Giedre , Chan Dennis 
Published: December 2023

AbstractBackgroundIncreasing evidence suggests that impairments of spatial navigation, orientation and memory may represent one of the earliest features Alzheimer’s disease (AD), preceding deficits in other cognitive domains. This is consistent with early pathological tau and amyloid deposition in temporal and parietal brain regions implicated in spatial processing. However, it remains unclear which metrics and spatial behaviours can i) differentiate high‐risk, preclinical or prodromal AD individuals, and ii) may be captured with digital devices suitable for future deployment at scale in clinical practice. We addressed this knowledge gap with a systematic review.MethodTwo databases (PubMed/Web of Science) were searched following PRISMA guidelines. Medical subheading keywords for different dementia types were combined with prodromal, preclinical and genetic or disorder risk factor terms. We included studies published until October 2022 that collected digital or physical objective measures of egocentric or allocentric processing (wayfinding, orientation, reference frame translation, route learning or path integration). We excluded diagnoses of other conditions or dementia, cross‐sectional MCI studies without biomarkers, young adults, case studies, interventional studies or studies without appropriate controls.Result25 articles were included from 316 identified abstracts. None investigated non‐AD dementias. 131 metrics were extracted from 38 different tasks, of which 31 where digital (81%). 82 metrics showed differentiation of predementia AD groups (63%). We harmonised these into 21 distinct summary metrics covering four domains of active or passively tracked spatial behaviours. Across all domains, metrics capturing decreased navigation efficiency (i.e. distance or time required to find goals) and accuracy (i.e. distance or angle from goal) were most frequently reported, but egocentric better differentiated prodromal than preclinical groups. Metrics for path integration and passive tracking of everyday GPS data were promising but relatively under‐explored.ConclusionFor future clinical use, spatial tests will require standardisation and validation against established markers of disease. These review data will inform the selection of digital tools to assess spatial behaviours in at‐risk, preclinical and prodromal AD populations as part of the EDoN Initiative.
Handwriting characteristics analysis for Alzheimer’s Disease and Mild Cognitive Impairments Assessment
Authors: Thebaud Thomas , Chen Casey , Moro‐Velazquez Laureano , Dehak Najim , Oh Esther S 
Published: December 2023

AbstractBackgroundMotor changes are early signs of neurodegenerative diseases such as Alzheimer’s disease (AD), but they are often difficult to detect, especially in the early stages. In the past, the examination of handwriting has been used to investigate motoric changes in different neurodegenerative diseases. In this study, we explore a wide array of explainable characteristics of the handwriting of patients obtained with signal processing, and study their potential for assessment of Mild Cognitive Impairment (MCI) and AD.MethodWe collected the written tasks from 37 participants, 7 with AD, 17 with MCI, and 13 for the control group (CTL) on a digital tablet. We analyzed 14 different tasks, including holding the pen over a point, copying images, free writing/drawing, and memory copying. We extracted multiple movement characteristics, including the length of each stroke, the ratio of the time the pen spent on‐air vs in‐tablet and the standard deviation of the distance between consecutive points. The drawings of each subject were manually supervised, then processed to extract multiple characteristics, and compared to identify the ones providing the most significant differences between the three studied groups using Welch’s t‐test, with false discovery rate (FDR) correction.ResultPreliminary results showed that the ratio between the time with the pen in contact with the tablet and without (on‐air vs in‐tablet) for writing tasks, significantly differentiate between AD and CTL patients (p‐value<0.01), as well as the position standard deviation when asked to maintain the pen at a fixed position (p‐value<0.05). The comparison between MCI and CTL populations also showed that the length of the strokes for drawings and copying tasks can deliver clues to distinguish both groups (p‐value<0.05).ConclusionAutomated analysis of a large variety of handwriting segments employing machine learning techniques can provide an assessment of patients with AD and MCI that may be useful in their early diagnosis and assessment of progression.
ErbB3 Binding Protein 1(EBP1), Novel Modulator of PS2/γ –Secretase, Blocks PS2/ γ –Secretase Cleavage of APP, Reducing Intraneuronal Aβ Generation
Authors: Ahn Jee‐Yin , Kim Byeong‐Seong , Hwang Inwoo 
Published: December 2023

AbstractBackgroundErbB3 binding protein 1 (Ebp1) is a multifunctional protein that is involved in various cellular events including cell survival, proliferation, differentiation, and cell cycle progression either in the embryogenesis or human disease. Apart from its roles in brain development, Ebp1 may be involved in neurodegenerative diseases such as Alzheimer’s disease (AD) as its expression was plunged after birth and older brain. AD patients usually have severe synapse and neuron loss, leading to memory decline, which are also occurred in the Ebp1 deficient mice brain. We thus investigated whether alteration of Ebp1 expression affects AD pathology.Methodwe show that in AD patients’ brain and in the 5X‐FAD transgenic mice, Ebp1 level is inversely correlated with Aβ deposition and loss of Ebp1 (Ebp1flox/flox
::CaMKIIa‐Cre) or Ebp1 cleavage by AEP escalates Aβ production in vitro/ex vivo/in vivo studies.ResultForebrain deletion of ErbB3 binding protein 1(Ebp1) in mice model exerted abnormal Aβ deposition and cognitive dysfunction. Ebp1 is greatly reduced, cleaving by asparagine endopeptidase (AEP) in postmortem AD patients and 5X‐FAD mice brains. Besides prominent neuronal death and degeneration, cleaved Ebp1 N84 and N204 fragments notably escalate intraneuronal Aβ generation and aggregates with Aβ in the brain. Whereas Ebp1 associates with APP and presenilin 2 (PS2), a catalytic subunit of γ ‐secretase, protecting APP cleavage by PS2/γ‐secretase in the neuron, AEP‐mediated Ebp1 cleavage liberate blockage of PS2 access to APP in the neurons of 5X‐FAD mice. Accordingly, reinstatement of Ebp1 using AAV2‐ Ebp1 WT or uncleavable mutant expression into brain of 5X‐FAD mice improved behavioral impairment and alleviates Aβ generation.ConclusionEbp1 is a pathological substrate of AEP in AD conditions, eliciting intracellular Aβ production, blocking PS2 access to APP. Targeting APP‐PS2 interaction by non‐cleaved mutant form of Ebp1or elevating intact Ebp1 levels in AD condition may represent a novel intervention opportunity to reduce intracellular Aβ levels.
ISU203 relieves Th17‐mediated neuroinflammation and facilitates removal of amyloid‐β plaques, resulting in the improved cognition in Alzheimer’s disease mouse model
Authors: Lee Hosuk , Park Min Hee , Cho Jeong‐In , Lee Ha‐young , Jin Hee Kyung , Bae Jae‐sung , Park Jang‐June 
Published: December 2023

AbstractBackgroundAcid sphingomyelinase (ASM), which localized in endolysosome and plasma membrane, generates ceramide by hydrolyzing sphingomyelin. The enzymatic activity of ASM is elevated in elderly people. Interestingly, it was reported that the activity of ASM was significantly upregulated in patients with several inflammatory diseases, as well as Alzheimer’s disease (AD). Moreover, the inhibition of its activity by treatment of inhibitors or antibody ameliorates the AD pathologies, indicating that ASM is a feasible therapeutic target for AD.MethodTo understand the efficacy and mechanism of action, we administered ISU203 in AD mouse model (APP/PS1) via intraperitoneal injection at 50mg/kg, biw for 8 weeks. To evaluate the cognitive function, Morris Water Maze and Fear conditioning test were utilized. After behavioral tests, mice were sacrificed to demonstrate the deposition of amyloid‐β plaque and phagocytic function of microglia by using immunohistochemistry assay in cortex and hippocampus. To further investigates the neuroinflammation mediated by Th17, pro‐ and anti‐inflammatory gene levels were demonstrated by RT‐qPCR.ResultIn two behavioral tests, we found the improvement of cognitive function of ISU203‐treated group. Morris Water Maze test showed the declined escape latency time by 30%. Furthermore, it showed the significantly increased freezing ratio in ISU203‐treated group in fear conditioning test. ISU203‐treated group also showed alleviation of Th17‐mediated neuroinflammation. In line with this finding, pro‐inflammatory genes were downregulated. On the other hand, anti‐inflammatory genes were upregulated. In addition, we also found the decreased deposition of amyloid‐β plaques, which is an important pathological hallmark of AD. Furthermore, ISU203‐treated group showed that the more microglial cells were colocalized with amyloid‐β plaques, indicating the increased phagocytosis of amyloid‐β by microglia.ConclusionThe treatment of ISU203 showed the relief of Th17‐mediated neuroinflammation and enhanced the removal of amyloid‐β plaques by microglia in AD mouse model. As a result, ISU203 improves cognitive function, suggesting the ISU203 as a novel antibody therapeutics for AD.
Effects of the social network on health in community‐dwelling older adults: a systematic review
Authors: An Hyunseo , Kim Mi Kyeong , Lee Hamin , Yun Sohyeon , Kim Inhye , Park Hae Yean 
Published: December 2023

AbstractBackgroundMany studies have been conducted to analyze the effects of social networks in the elderly, who experience a decline in social networks but only focus on their relationship with one variable. In addition, few studies have analyzed the impact of social networks on the elderly by integrating them into two dimensions of the structural and functional aspects of social networks. This study aims to synthesize the effects of social networks by analyzing the factors related to social networks of the elderly living in the community, including both the structural and functional aspects of the social network.MethodArticles from the last 10 years were searched through RISS, NDSL, PubMed, and Embase. Among a total of 1,352 articles, 14 articles were finally selected according to selection and exclusion criteria. The quality of literature was evaluated using the Newcastle‐Ottawa Scale (NOS). The general characteristics of the study, measurement tools, data analysis method, and research result data were extracted and coded.ResultA total of 16 factors related to social networks were derived from 14 studies: frailty, institutionalization, functional decline, mortality, fall risk, chronic pain, depression, loneliness, quality of life, advance care planning discussion, self‐efficacy, healthy aging, self‐perception of aging, self‐rated health, health status, health promoting behavior. These factors were classified into five health areas: physical health, mental health, socio‐emotional health, and perceived health and health behavior. Among the 16 factors related to social networks, ‘quality of life’ was found to be the most studied.ConclusionIt was confirmed that the social network of the community‐dwelling adults had a significant impact not only on socio‐emotional health, but also on the remaining various health areas such as physical, mental, perceived health, and health behavior of the elderly. Therefore, it is necessary to improve the overall health level of the elderly and to promote and revitalize the social network in terms of prevention of negative health consequences due to aging. At this time, both the structural and functional aspects of the social network should be considered. Finally, this study is expected to serve as basic data for developing intervention programs using social networks.
Transcriptomics‐based investigation of herpes simplex virus 1 infections and acyclovir treatment in human cerebral organoids
Authors: Orszulak Adrian R , Chigas Samantha M , Tran Khanh , Dawes Pepper , Olson Meagan N , Murray Liam F , Barton Nathaniel J , Aylward Aimee J , Wang Qi , Oh HyungSuk , Church George M , Young‐Pearse Tracy , Knipe David M , Readhead Benjamin , Chan Yingleong , Lim Elaine T 
Published: December 2023

AbstractBackgroundHerpes simplex virus 1 (HSV‐1) has been associated with pathogenesis of Alzheimer’s Disease (AD) through several landmark studies. We explored the transcriptomics landscape of HSV‐1 infection and anti‐viral treatment using acyclovir on AD‐associated genes using large‐scale bulk RNA sequencing to identify biomarkers, cell types and cell type specific interactions.MethodWe used recent technological advances in human 3D brain organoids and transcriptomics sequencing tools.ResultWe found that HSV‐1 infection in cerebral organoids from a single individual resulted in transcriptomic perturbations were enriched for AD‐associated genes. ACV treatment restored HSV‐1 induced host transcript perturbations in cerebral organoids for most genes in a dosage‐dependent manner, demonstrating that immediate anti‐viral treatment of HSV‐1 infection is effective in our human cellular model. However, we also observed off‐target transcriptomic effects from ACV treatment that were enriched for AD‐associated genes and genes associated with autoimmune diseases.HSV‐1 infection in cerebral organoids also resulted in significantly decreased Abeta42/40 and Abeta42/38 ratios detected from the supernatant, compared to uninfected control cerebral organoids. HSV‐1 infection followed by immediate ACV treatment rescued the Abeta42/40 ratios detected from the supernatant, but did not rescue the Abeta42/38 ratios. We found that influenza A (IAV) infection did not result in an enrichment of AD‐associated transcriptomic perturbations and both Abeta42/40 and Abeta42/38 ratios were not significantly changed in the supernatant between IAV‐infected cerebral organoids and uninfected cerebral organoids.We explored cell type specific effects of HSV‐1 infection and ACV treatment in cerebral organoids through cell type enrichment analyses of the bulk RNA sequence data and flow cytometry experiments. We found complex cell type interactions perturbed by HSV‐1 infection with varying degrees of rescue by ACV, such as increased proportions of reactive astrocytes and decreased proportions of live neurons.Finally, we correlated the transcriptomic signature of HSV‐1 infected cerebral organoids with transcriptomes of post‐mortem brain samples from LOAD patients and discovered a high correlation with subtype A (31% of patients).ConclusionOur work is an unbiased study to identify biomarkers and novel therapeutic pathways, as well as potential off‐target effects associated with HSV‐1 infection and ACV treatment in AD.