bluuebunny/crossref_metadata_2025 huggingface dataset:
Combining working memory and speech data in a digital app for early detection of cognitive impairment in primary care
Authors: Hilsabeck Robin C. , Keller Jeffrey N. , Henry Maya L. , Li J. Jessy , Pugalenthi Lokesh , Rathouz Paul , Toprac Paul , Chang Patrick , Chang Joshua , Schmitz Suzanne , Largent Avery , Foil Heather , Brouillette Robert , Lester‐Smith Rosemary A
Published: December 2023

Background

Cognitive screening to detect mild cognitive impairment (MCI) and dementia in primary care settings has proven to be a challenging task. The ideal solution would be a brief, low‐burden assessment tool appropriate for use with individuals from diverse educational and cultural backgrounds that requires limited time and expertise from primary care providers. The purpose of this project was to develop a digital cognitive screening app derived from widely used cognitive and speech tasks using machine learning techniques.

Method

Participants were 104 old adults, 53 who were cognitively normal (CN) and 51 who were cognitively impaired (CI). All participants completed a working memory task (WM), followed by four speech‐language tasks, followed by a second administration of WM (WM2) to investigate the added utility of practice effects. Participants also completed the Quick Mild Cognitive Impairment (Qmci) screen. Bayesian adaptive regression trees were used to test 11 models. All models contained sex, age, education, and marital status. One model contained WM and the WM2‐WM difference. Four models contained 26 acoustic and 34 linguistic variables derived from each of the four speech tasks, and four more models were identical, except with the two WM variables added. For comparison, two models with Qmci were fitted: one with and one without the two WM variables.

Result

Three models achieved cross‐validated classification accuracy of c = 0.90: WM by itself (estimated c = 0.91; Figure 1), WM and a personal narrative task (c = 0.94; Figure 2), and WM and a counting backwards task (c = 0.90). Models with picture description and procedural discourse tasks performed the worst. The QMCI‐only model yielded c = 0.91.

Conclusion

Combining WM, acoustic and linguistic variables involved in recounting personal memories, and the ability to benefit from prior exposure to a task discriminated CN from CI groups with a high degree of accuracy. This unique combination assesses key cognitive abilities known to be affected early in neurodegenerative diseases, executive functioning and memory, and includes both verbal and nonverbal tasks. Importantly, individuals with varying levels of cognitive functioning, including mild dementia, were able to use the app successfully, and the automated nature of the tool required minimal staff time or expertise.
Digital Elder Abuse Intervention for Older People Living with Dementia
Authors: Abujarad Fuad , Edwards Chelsea , Neugroschl Judith A. , Hwang Ula , Marottoli Richard
Published: December 2023

Background

A growing number of older adults experience elder abuse (EA) each year, and people living with dementia (PLWD) are at higher risk. Emergency departments (EDs) are opportune settings to identify EA and can provide interventions to those at high risk and direct them to appropriate health and social services. There is evidence that PLWD can report abuse despite cognitive challenges, but research is limited regarding self‐administered interventions to detect EA.

Method

We developed and tested our tablet‐based intervention to increase self‐reporting of EA among PLWD. The VOICES EA intervention combines educational resources, screening, multimedia elements, and brief psychoeducational interviewing to motivate PLWD to self‐identify and self‐report abuse. The goal of our study is to evaluate using VOICES among PLWD (ages 60+ years) at a geriatric memory clinic (N = 30) and the ED setting (N = 101). We previously demonstrated VOICES’ feasibility and efficacy with 1,000 cognitively intact participants (ages 60+) in the ED and wanted to compare patterns of use between users (with or without dementia). Participants were recruited, consented, and enrolled at Yale New Haven Health System in New Haven, Connecticut, USA. We used the Montreal Cognitive Assessment (MoCA) to assess cognition of participants, excluding participants with severe dementia.

Result

Older adults with MoCA scores between 14 and 25 were able to use VOICES similarly to those without cognitive impairments (i.e., MoCA >25) and were able to complete using the VOICES independently. From the memory clinic, 83% agreed that audio and visual tool aids were helpful, and 87% agreed that the tool’s instructions were easy to follow. In the ED setting, of the 101 participants who started VOICES, 100 completed VOICES independently (99% completion rate). Of participants who completed the post‐use questions (N = 99), 84% were satisfied with their ability to complete VOICES on their own without assistance, and 91% agreed VOICES was appropriate for learning about EA.

Conclusion

Our results suggest that the VOICES EA intervention is feasible (i.e., acceptable, practical, and satisfactory) for detecting EA in PLWD, specifically those with MoCA scores ranging from 14‐25. This may allow for enhanced early EA detection and intervention in this highly vulnerable population.
Are Digital Markers of Everyday Driving Comparable to Fluid Biomarkers in Identifying Preclinical Alzheimer Disease?
Authors: Bayat Sayeh , Babulal Ganesh M.
Published: December 2023

Background

Preclinical Alzheimer’s disease (AD) may have a subtle functional signature reflected in changes in everyday driving behaviour. Driving has the potential to serve as a digital marker for AD when captured continuously and characterized accurately. This study directly compares the diagnostic performance of digital markers of everyday driving, cerebrospinal fluid (CSF), and blood biomarkers in detecting amyloid deposition in AD, using amyloid positron emission tomography (PET) as the “gold standard”.

Method

Participants were enrolled in a longitudinal study on driving and preclinical AD biomarkers at Washington University School of Medicine. The Driving Real‐World In‐Vehicle Evaluation System (DRIVES) Project uses in‐vehicle GPS dataloggers to collect daily driving among cognitive normal drivers. This study included 121 drivers (aged 65+) with complete blood, CSF, and PET biomarker data. We employed three artificial neural network (ANN) to examine the relationship between everyday driving and PET‐amyloid status. The first model solely included driving features. The second ANN model (i.e., “non‐intrusive” model) added age and education level as additional features. The third model included all of the previous features plus APOE e4 status. Plasma Aß42/Aß40<0.1013 and CSF Aß42/Aß40<0.0673 were used to detect PET‐amyloid positivity. To compare the performance of the ANN models and the CSF and plasma biomarkers, area under the receiver operating curve (AUC) from 5‐fold cross‐validation were calculated.

Result

Individuals who were PET‐amyloid positive (n = 46) were more likely to be older (p<.05) and carry an APOE e4 allele (p<.0001). The two groups did not differ in sex or education. In predicting PET‐amyloid positivity, the five most important driving features were the number of left turns per mile, 80th percentile of jerk, minimum vehicle speed, speed variability, and the number of speeding incidents. The CSF biomarker achieved the highest performance (AUC = 0.96±0.04), followed by the model with driving, age, education and APOE e4 status (AUC = 0.88±0.05). The model with only driving features achieved lower performance (AUC = 0.74±0.07), while the non‐intrusive ANN model achieved comparable performance to the plasma biomarker (AUC: 0.82±0.11vs.0.83±0.12).

Conclusion

Digital markers of everyday driving along with age and education level offer a non‐intrusive and scalable diagnostic tool for preclinical AD that provides ongoing assessments.
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

Background

Music 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.

Method

Patient 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.

Result

Results 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.

Conclusion

The 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

Background

Alzheimer’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.

Method

Eye 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.

Result

The 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.

Conclusion

Oculographic 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

Background

Alzheimer’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.

Method

Spoken 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.

Result

With 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).

Conclusion

Altogether, 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

Background

Increasing 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.

Method

Two 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.

Result

25 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.

Conclusion

For 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

Background

Motor 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.

Method

We 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.

Result

Preliminary 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).

Conclusion

Automated 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

Background

ErbB3 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.

Method

we 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.

Result

Forebrain 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.

Conclusion

Ebp1 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

Background

Acid 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.

Method

To 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.

Result

In 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.

Conclusion

The 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

Background

Many 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.

Method

Articles 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.

Result

A 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.

Conclusion

It 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

Background

Herpes 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.

Method

We used recent technological advances in human 3D brain organoids and transcriptomics sequencing tools.

Result

We 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).

Conclusion

Our 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.
SARS‐CoV2 Nucleocapsid Protein induces Tau pathological changes in the mouse hippocampus
Authors: Orsini Franca , Bosica Marco , De Paola Massimiliano , Martucci Annacarla , Pascente Rosaria , Arancio Ottavio , Fioriti Luana
Published: December 2023

Background

Neurologic manifestations are emerging as an immediate consequence of SARS‐CoV2 infection, the etiologic agent of COVID19. Although little is known about the long‐term consequences of SARS‐CoV2 infection, there is the possibility that infection may trigger long‐term neurological effects. Exposure to pathogens in fact triggers inflammation in the brain and exacerbates Tau pathological changes in animal models of Alzheimer disease. Reports of the presence of SARS‐CoV2 in the brains of subjects with COVID19 are emerging and a study in brain organoids revealed that SARS‐CoV2 alters the phosphorylation and distribution of Tau in infected neurons, but the mechanisms are currently unknown. We hypothesize that these pathological changes are due to recruitment of Tau into stress granules (SG) operated by the Nucleocapsid protein (NP) of SARS‐CoV2.

Method

To address whether exposure to SARS‐CoV2 may predispose to develop dementia, we investigated whether NP interacts with Tau and induces hyperphosphorylation and aggregation of Tau in human iPSC cells and hippocampal neurons in vivo. We tested whether NP interacts with Tau by co‐immunoprecipitation experiments. Mechanistically, we tested whether posttranslational modification of NP and Tau by SUMO2 modulates their distribution in SG and their pathological interaction. We expressed NP for 2 months, with or without SUMO2, in the hippocampus of 6 months old wild type and JNPL3 mice, before performing Y‐maze. After behavioral assessment, the mice were sacrificed and brains were isolated to perform biochemical and immunofluorescence analyses.

Result

We found that NP and Tau co‐localize and physically interact in human cells. We also found that NP induces hyperphosphorylation of Tau and reduces the amount of synaptic proteins in neurons. This is also paralleled by a reduction in the cognitive abilities of mice infected with NP in their hippocampus. Finally we found that modulation of SUMOylation dramatically affects SG induced by NP in cells, Tau hyperphoshorylation, as well as cognitive performance in mice infected with NP.

Conclusion

Our data demonstrate that NP induces pathological changes in cells and animals expressing wild type Tau, and aggravates the pathology in neurons expressing mutant forms of Tau, both in vitro and in vivo. Moreover we demonstrate that SUMO2 conjugation ameliorates NP‐induced Tau pathology.
Insights into Neurocognitive Sequelae of COVID‐19 Infection from Studies of Brain Organoids
Authors: Ng Jing Han , Tan Eng King
Published: December 2023

Background

COVID‐19 has been associated with chronic neurocognitive changes which persist after resolution of the acute infection. Brain organoids composed of different neuronal cell types serve as a useful model to evaluate the underlying effects of SARS‐CoV‐2 infection to the brain and facilitate insights into the neurocognitive sequelae of COVID‐19.

Method

A review of studies which used brain organoids to evaluate the effects of COVID‐19 was conducted. The studies were identified from the PubMed/MEDLINE database using the search terms “SARS‐CoV‐2” or “COVID‐19” in combination with “organoid” or “brain” or “3D” or “iPSC”. Articles published in English between 1 Jan 2020 and 31 Mar 2023 were included.

Result

We identified a total of 16 studies which used brain organoids to study SARS‐CoV‐2 neurotropism and downstream effects. Although SARS‐CoV‐2 was able to infect neurons, the extent of neurotropism was limited. Instead, choroidal epithelial cells and glial cells including, astrocytes and microglial, demonstrated significant susceptibility to SARS‐CoV‐2 infection. Furthermore it was observed that certain downstream effects of SARS‐CoV‐2 infection were associated with pathways seen in neurodegenerative diseases like Alzheimer’s Disease (AD). These included findings of reactive astrogliosis, impairment of glutamate and choline transporters, microglial‐mediated synapse loss, increased pTau expression and beta amyloid protein accumulation. Overall, the studies suggested that the neurocognitive manifestations of COVID‐19 may be contributed by neuroinflammatory processes and pathways that are found in chronic neurodegenerative conditions like AD.

Conclusion

Although brain organoid technology remains a relatively new tool, it has provided important insights into the pathophysiology of COVID‐19. The use of “assembloids” to recapitulate interactions between different brain regions and development of high throughput evaluation to analyse transcriptome and epigenome changes of infected brain organoids may be further expanded to allow a better understanding of potential neurodegenerative pathways that may result in neurocognitive changes after a viral infection.
A Virtual Reality Memory Test for Assessing Visuospatial Memory
Authors: Kim Ko Woon , Lee Hyejoo , Choi Jong Doo , Chin Juhee , Lee Byung Hwa , Na Duk L
Published: December 2023

Background

Visuospatial memory impairment is one of the common symptoms of Alzheimer’s disease. However, impairment in visuospatial and visuospatial memory function has not been focused on as much as that of episodic memory function. We developed a visuospatial memory test, the Hidden Objects Test (HOT), that was designed for people to go around the living room of a house created by virtual reality (VR) and find hidden objects.

Method

This study group comprised 17 Alzheimer’s disease dementia (ADD), 14 amnestic mild cognitive impairment (aMCI), and 15 normal controls (NC). All participants completed a sandardized neuropsychological battery and magnetic resonance imaging (MRI). Out of 46 participants, 28 received amyloid positron emission tomography (PET). Participants performed a novel visuospatial memory test in a virtual environment using VR headset HTC Vive. Walking trajectory in the virtual environment was tracked with 13Hz sampling rate. Participants’ movement path was basically assessed by the total distance, duration, and mean speed.

Result

Total HOT score and five subtests scores were differed among ADD, aMCI, and NC (p <0.001). We performed walking trajectory pattern mining as well as basic trajectory feature analysis such as total distance, duration, and speed. Total duration was significantly greater in ADD than in NC (p = 0.008). The number of outliers, over 95% of estimated trajectory, was significantly higher in ADD than in NC (p = 0.002). The number of stay points, an index that participants stayed in the same position, were significantly higher in ADD and aMCI patients compared to NC (ADD vs. NC: p = 0.003, aMCI vs. NC: p = 0.019). Walking trajectory analysis suggested that ADD and aMCI patients wandered rather than going straight to the hidden objects.

Conclusion

Our study showed that HOT total scores differed among ADD, aMCI, and NC groups. In addition, our study provided application of trajectory data mining methods to explore the patterns of ADD and aMCI patients' walking trajectory, which could be applied to detect behavior of the patients in environments equipped with the internet of things such as future smart home or facilities.
Neuropathological Correlations of Alzheimer’s Dementia with Biomarker of Blood‐Brain Barrier Breakdown
Authors: Bolakale‐Rufai Ikeoluwapo Kendra , French Scott , Arias Juan C , Serrano Geidy E , Beach Thomas G , Weinkauf Craig
Published: December 2023

Background

The early stage of Alzheimer’s Dementia (AD) development has been linked to the breakdown of the blood‐brain barrier (BBB), which is maintained by pericytes and other cell types. Platelet‐derived growth factor receptor‐β (PDGFRβ) has been identified as a novel biomarker of BBB‐associated capillary pericyte damage. Our study aimed to explore the potential association between PDGFRβ and neuropathological diagnosis of Alzheimer’s Dementia, as well as GFAP levels‐ a widely recognized AD biomarker that is present in both serum and cerebrospinal fluid (CSF).

Method

A cohort of 48 subjects in the Arizona Study of Aging and Neurodegenerative Diseases (AZSAND) with serum and CSF samples, obtained at the time of death, were included in this cross‐sectional study. Enzyme‐linked immunosorbent assay (ELISA) was utilized to detect PDGFRβ and GFAP in serum and CSF. Statistical analyses were performed using Spearman’s rank correlation and Mann‐Whitney U test.

Result

Baseline characteristics were similar between AD (n = 28) and non‐AD groups(n = 20). There was a significant increase in levels of serum PDGFRβ in AD compared to unmatched non‐AD subjects (Mean: 6348.2pg/ml vs 4730.1pg/ml, p<0.05). In addition, PDGFRβ in both CSF and serum correlated with Glial Fibrillary Acidic Protein (GFAP), a well‐known biomarker associated with AD (Spearman’s 𝝆 = 0.42, P< 0.01, Spearman’s 𝝆 = 0.46, P< 0.01, respectively.)

Conclusion

PDGFRβ, a putative marker of BBB integrity, is elevated in the serum of individuals with Alzheimer’s Dementia (AD) and is correlated with GFAP levels measured in both serum and cerebrospinal fluid (CSF). While these findings are promising and suggest the potential use of PDGFRβ as a blood‐based biomarker for AD pathophysiology, further studies with larger sample sizes are warranted to validate the potential of PDGFRβ as a biomarker for AD.
Greater age‐related cognitive decline in perceptual discrimination of objects than scenes: A cross‐cultural study
Authors: D'Souza Aminette , Lawrence Andrew D , Alladi Suvarna , Graham Kim S
Published: December 2023

Background

According to the “PMAT” framework, two distinct cortico‐hippocampal networks – the posterior‐medial (PM) and anterior‐temporal (AT) networks – are involved in the processing of scene and object content respectively (Ranganath & Ritchey, 2012). It has been suggested that aging predominantly affects the AT network (Berron et al., 2018), and recent studies show evidence for early impairment in object relative to scene mnemonic discrimination with age (Reagh et al., 2016; Gusten et al., 2021). Age‐dependent impairments in object discrimination even exist outside the realm of episodic memory tasks, such as in perceptual oddity tasks (Graham et al., 2010). We aim to extend these findings with i) a digital Oddity perceptual discrimination task, and ii) a cross‐cultural sample.

Method

We tested healthy participants in the UK (n = 141) and India (n = 149) aged between 18‐70 years on a novel multi‐category Oddity discrimination task including object and scene categories. Using a combined speed‐accuracy measure, Inverse Efficiency Score (IES), we applied a mixed‐effects modelling approach to analyse the age trajectory of performance across categories.

Results

We found a significant decline in performance with age across stimulus categories and cultures, and object performance showed a significantly steeper decline than scenes in both cultures.

Conclusion

These findings are amongst the first to indicate that the Oddity discrimination task is sensitive and specific to age‐related cognitive decline across cultures. Notably, these findings support the idea that the object/ AT network is more sensitive to age (potentially reflecting tau pathology) than the scene/ PM network (Berron et al., 2020). Therefore, perceptual discrimination tasks may be a promising cross‐cultural assessment tool for the early detection and differential diagnosis of patterns of age‐related cognitive decline.
Hippocampal volume as mediator between physical fitness and cognitive performance in old age – preliminary results
Authors: Schwarck Svenja , Vockert Niklas , Müller Patrick , Molloy Eóin N. , Fischer Larissa , Hochkeppler Anne , Schumann‐Werner Beate , Kreißl Michael C. , Kreutz Michael R. , Düzel Emrah , Maass Anne
Published: December 2023

Background

Previous studies show that physical activity counteracts age‐related memory decline and is positively associated with hippocampal volume. However, only few studies examined if hippocampal volumes mediate the effect of physical activity on cognitive performance. Furthermore, exercise modalities other than aerobic activity are rarely considered in this context. Since sarcopenia (muscle atrophy) is associated with age‐related cognitive decline, muscular capacity seems to be another essential fitness indicator.

Method

Forty‐one cognitively unimpaired older adults (age: 72.94 ± 7.85yrs; 24 female) underwent a comprehensive neuropsychological test battery assessing, i.a., global cognitive performance using CERAD‐Plus (Consortium to Establish a Registry for Alzheimer’s Disease) and PACC5 (preclinical Alzheimer’s cognitive composite). Their physical fitness was measured in the form of both aerobic (VO2max) and muscular capacity (z‐normalized composite: grip strength, appendicular skeletal muscle mass and walking performance). Anterior (aHCV), posterior and whole hippocampal volumes (wHCV) were extracted from their T1w MRI images (3T MEMPRAGE, 0.8×0.8×0.8mm resolution) using the T1‐ASHS segmentation algorithm (manual correction of 32 hemispheres). Total gray matter volumes (GMV) were extracted using CAT12 in SPM12. Mediation analyses were performed to test the hypothesis that GMV or hippocampal volumes (corrected for intracranial volumes) mediate the positive effect of physical fitness on cognitive performance including age, sex and education years as covariates (bootstrapping approach: 10000 iterations).

Result

Higher aerobic capacity (VO2max) was related to better cognitive performance (CERAD, p = .048), as was higher muscular capacity (CERAD, p = .002; PACC5, p = .002). Higher muscular capacity, but not VO2max, further predicted aHCV (p = .021) and wHCV (p = .035). Only wHCV mediated the relationship between muscular capacity and global cognitive performance (PACC5, p = .045).

Conclusion

Our results provide further evidence that higher aerobic and muscular capacity are associated with better global cognitive performance in older adults. While preliminary, the results suggest that muscular capacity exerts its neuroprotective effects at least partially via greater structural integrity of the hippocampus. The absence of a mediation effect of GMV may support the specific importance of maintained hippocampal structural integrity against cognitive decline. However, our small sample size may limit the statistical power to detect effects.
Design of Small Fluorescent Probes for Imaging Alzheimer’s Disease Pathology
Authors: Kladnik Jerneja
Published: December 2023

Background

Despite enormous efforts, early diagnosis of Alzheimer’s disease (AD) remains difficult. To date, there is no reliable diagnostic tool to identify biomarkers in the developing stages of AD [1]. In recent years, our group has focused part of the research on the development of small fluorescent molecules capable of effectively labelling AD biomarkers such as amyloid β plaques and tau protein [2, 3].

Methods

We designed and synthesised a library of small fluorescent molecules that were tested in vitro for their binding affinity (Kd
) and change in optical properties upon binding to amyloid β fibrils. In addition, the most promising molecules were used to perform ex vivo labelling of post‐mortem AD brain tissue examined by fluorescence microscopy.

Results

Our synthesized fluorescent probes consist of three building blocks, i.e., electron‐donating (EDG) and electron‐withdrawing groups (EWG), linked to different unsaturated hydrocarbon (HC) linkers (Figure 1), which enable the so‐called “push‐pull” effect leading to fluorescence. First, we investigated how the individual building blocks affect the spectroscopic properties (absorption, emission, excitation, quantum yield) of the prepared molecules in different solvents, representing a simplified polarity model of the AD biomarker binding sites (Figure 2). Furthermore, the compounds evaluated in vitro bound to amyloid β1‐42 fibrils with submicromolar Kd
values. Moreover, the selected compounds were shown to successfully stain amyloid β plaques as well as tau proteins on AD brain slices (Figure 2).

Conclusion

Based on the results we conducted structure‐spectroscopic‐affinity relationship study and determined how the building blocks of our fluorescent probes affect the optical as well as affinity properties when bound to amyloid β fibrils. Through in vitro and ex vivo studies, our probes are being systematically tested to identify the best candidate capable of achieving our final goal – the early detection of AD biomarkers in the patient’s blood, which would lead to a generally applicable, minimally invasive, cost‐effective, and long‐term traceable diagnostic assay.

1. Hansson, O., et al., Alzheimers. Dement., 2022, 18, 2669‐2686.

2. Šarlah, D., et al., Molecules, 2016, 21, 267.

3. Rejc, L., et al., J. Med. Chem., 2017, 60,8741‐8757.