bluuebunny/crossref_metadata_2025_split huggingface dataset:
A multimodal digital biomarker of functional deficits in early‐stage Alzheimer’s disease: results of the RADAR‐AD study
Authors: Vairavan Srinivasan , Lentzen Manuel , Muurling Marijn , de Boer Casper , Atreya Alankar , Curcic Jelena , Hinds Chris , Conde Pauline , Grammatikopoulou Margarita , Scebba Gaetano , Lazarou Ioulietta , Nikolopoulos Spiros , Brem Anna‐Katharine , Coello Neva , Visser Pieter Jelle , Fröhlich Holger , Narayan Vaibhav A , Wittenberg Gayle , Aarsland Dag 
Published: December 2023

AbstractBackgroundRemote monitoring technologies (RMTs), such as smartphone apps, smartwatches, and in‐home sensors, are rapidly changing the way functional and cognitive performance is measured in Alzheimer’s disease (AD) patients. Here, we present results from the European RADAR‐AD study on the use of multimodal data streams for the identification of functional deficits across all syndromic stages of AD.MethodFour study groups (Healthy controls (HC), preclinical AD (pre. AD), prodromal AD (pro. AD), and mild AD) were included in this cross‐sectional study. The RMT features (gait measures from Timed up and Go (TUG), Dual Task Effect (DTE) using physilog, acoustic features from Speech task in Mezurio, neurocognitive function using Altoida, managing finances with Banking app) with in‐clinic neuropsychological (NP) tests, activities of daily living with Amsterdam IADL and demographics (age, gender, education years) were analyzed for different combinations of the multimodal digital biomarker of disease stage in AD across different pairwise comparisons. The analysis includes data from 175 participants (HC = 67, Pre.AD = 26, Pro.AD = 50, Mild AD = 32) collected for 8 weeks. An extreme gradient boosting (XGBoost) machine learning model was trained to obtain a multimodal biomarker of AD disease stage with repeated cross‐validation (5‐fold with 4 repeats) (Figure 1). This investigation is part of the ongoing RADAR‐AD study.ResultThe multimodal combination of RMTs achieved a mean AUC of > 0.60 in all pairwise comparisons with a mean AUC > 0.65 for HC vs (Pre.AD, Pro.AD and Mild) (Figures 2 and 3). The addition of NP tests increases the performance considerably across all pairwise comparisons except HC vs Pre.AD.ConclusionOur results highlight the advantage of combining RMTs to identify functional deficits in the early stage of AD. In particular, in prodromal and mild AD patients, a combined signal shows much more strength compared to individual tests.
This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (grant No 806999). www.imi.europa.eu. This communication reflects the views of the RADAR‐AD consortium and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein.
Motor‐cognitive dual tasking in the clinical setting: a sensitive measure of functional impairment in early Alzheimer’s disease
Authors: Brem Anna‐Katharine , Scebba Gaetano , Curcic Jelena , Muurling Marijn , de Boer Casper , Coello Neva , Atreya Alankar , Conde Pauline , Fröhlich Holger , Grammatikopoulou Margarita , Hinds Chris , Lazarou Ioulietta , Lentzen Manuel , Narayan Vaibhav A , Kozak Rouba , Nikolopoulos Spiros , Vairavan Srinivasan , Visser Pieter Jelle , Wittenberg Gayle , Aarsland Dag ,   RADAR‐AD Consortium
Published: December 2023

AbstractBackgroundGait is a complex everyday activity that depends upon supraspinal activity and a host of cognitive functions such as attention and executive functions. As cognition declines in neurodegenerative diseases, the interaction and competition for neuronal resources during motor‐cognitive dual‐tasking (e.g., walking while talking) might be a sensitive measure of subtle functional impairments in early Alzheimer’s disease (AD). Here, we aim to identify gait deficits due to neuronal competition across the AD spectrum.MethodThis investigation is part of the ongoing Remote Assessment of Disease and Relapse – Alzheimer’s Disease (RADAR‐AD) study. We attached three inertial measurement units (accelerometer and gyroscope) to both feet and one hip to assess dual task effects (DTE) assessing gait performance with/without concurrent serial subtraction‐by‐1 task in four groups: 1) amyloid negative healthy controls (HC, N = 59); and 2) amyloid positive preclinical AD (PreAD, N = 30); 3) prodromal AD (ProAD, N = 51); and 4) mild‐to‐moderate AD dementia (MildAD, N = 44) (Table 1). We furthermore investigated associations of DTE with observer‐reported cognition.ResultGroup comparisons showed that dual‐tasking induced lower cadence and increased stance, which were significantly different between HC and ProAD. Several DTE measures of variability differed significantly between PreAD and MildAD, with variability in the path length separating best between PreAD and ProAD (Table 2, Figure 1). DTE measures were associated with observer‐rated divided attention only in the MildAD group.ConclusionNeuronal competition as assessed with motor‐cognitive dual‐tasking, specifically the DTE variability, might reflect functional deficits already in early AD, and could be a valuable additional measure to detect early impairments not captured by cognitive or motor tests alone. Future studies should implement an adaptive cognitive load to improve sensitivity/specificity in early AD stages and investigate the use of sensor technologies in predicting and monitoring changes in gait and fall prevention in later stages of the disease.
This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (grant No 806999). www.imi.europa.eu. This communication reflects the views of the RADAR‐AD consortium and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein.
First insights exploring Activities of Daily Living performance captured through activity sensors in a Smart Home Environment as an indicator of cognitive decline: A cross‐sectional Analysis
Authors: Alepopoulos Vasilis , Grammatikopoulou Margarita , Lazarou Ioulietta , Mpaltadoros Lampros , Nikolopoulos Spiros , Oikonomou Vangelis P , Stavropoulos Thanos G , Tsolaki Magdalini , Kompatsiaris Ioannis 
Published: December 2023

AbstractBackgroundSmart homes offer a unique potential not only for supporting various users’ needs but also for monitoring their activities. Herein the findings of the RADAR‐AD Smart Home study are presented. Using data from activity sensors installed in a smart home environment simulating real‐life conditions, we aim to detect deficits while performing Activities of Daily Living (ADLs) in three known groups of people in different stages of cognitive decline related to Alzheimer’s Disease (AD).MethodIn a fully equipped Smart Home (https://smarthome.iti.gr/), Fibaro smart plugs (to monitor power consumption), motion‐, door‐, flood‐sensors and panic buttons were installed. During their 24 hour visit, participants [13 Healthy Control (HC), 14 Preclinical AD (PreAD), 13 Prodromal AD (ProAD)] (Table 1) followed a protocol listing a number of ADLs (e.g., meal/beverage preparation) (Table 1). Data collection, feature extraction (i.e., activity duration, number of repetitions) and visualization of ADLs were performed through the CARL data collection and analysis platform for assisted living (https://carl.iti.gr/). (Figure 1). Two‐Way ANOVA and Mann‐Whitney were used to test the statistical significance between the groups.ResultComparing Activity Duration for different ADLs and groups (Figure 2), HC executed the ADLs in less time compared to PreAD and ProAD, while PreAD showed no difference in the majority of the tasks compared to ProAD. Three activities were completed by 50% of the HC, 36% of the PreAD and only 17% of the ProAD. Two‐way ANOVA revealed a statistically significant interaction between the effects of cognitive decline and Activity Duration F(3,106) = 3.504, p = 0.034. Mann‐Whitney analysis for the complex task “Meal Preparation” showed decreased duration for HC compared to PreAD (U = 33.00, p = 0.042) and ProAD (U = 17.00, p = 0.052).ConclusionThe RADAR‐AD Smart Home study provides a proof‐of‐concept for the use of home‐based sensors for investigating ADLs in patients with cognitive decline.
This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (grant No 806999). www.imi.europa.eu. This communication reflects the views of the RADAR‐AD consortium and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein.
Involving patients, participants and the public in designing research analysis: a case study
Authors: Gregory Sarah , Robertson Martin , Ross David , Penman Eileen 
Published: December 2023

AbstractBackgroundThe importance of patient and public involvement (PPI) throughout the research cycle is becoming increasingly recognised. Despite this, PPI contributors remain absent from the data analysis stage in many quantitative studies. Here we report on the experience of incorporating PPI in the statistical analysis planning stage of a project investigating associations between cortisol and brain health in the EPAD Scotland cohort. The aim of the initial planning meeting was to explore public and patient understanding of cortisol and brain health and identify important research questions to these contributors.MethodsPPI contributors responded to adverts circulated in three established PPI groups in the United Kingdom (UK), signing up to attend an online meeting. PPI contributors were sent a meeting pack prior to the meeting, including brief pre‐reading and refreshment to enjoy during the meeting. The online meeting began with a brief presentation giving an overview of the topic, with interactive polls and open discussions incorporated into the session plan. All PPI contributors were sent a voucher to recognise their time commitment.ResultsNine PPI contributors joined the meeting, and generally reported a good awareness of the association between cortisol and psychological stress, with less confidence of the association with physical health (Figure 1). Picking from a list of possible analysis options, PPI contributors were most interested in exploring associations between cortisol and depression, sleep and personality, in the context of brain health research (Figure 2). PPI contributors gave insights from their personal experience of neurodegenerative disease and posed further questions for research.ConclusionPPI contributors were valuable stakeholders in the statistical analysis planning process, identifying a number of research topics that would be valuable to explore. Future work will continue to involve PPI contributors to explore questions around cortisol and depression, sleep and personality, as well as associations with occupational and lifetime exposure to stress which were highlighted as topics of interest in the open discussion.
Development of an innovative computerized assessment of instrumental activities of daily living
Authors: Reppermund Simone , Numbers Katya T. , Lin Pinghsiu , Delbaere Kim , Wesson Jacqueline , Clemson Lindy , Ginige Jeewani Anupama , Trollor Julian N , Draper Brian , Brodaty Henry 
Published: December 2023

AbstractBackgroundFunctional impairment is a diagnostic criterion for dementia and distinguishes mild cognitive impairment (MCI) from dementia. Self‐ or informant reports are most commonly used but can be biased and may not reflect actual functional ability. Alternatives include performance‐based assessments, such as the Sydney Test of Activities of daily living in Memory disorders (STAM). The aim of this study is to develop, and validate, a new computerised diagnostic tool (C‐STAM) to assess functional ability that can be administered remotely to increase accessibility. The C‐STAM will realistically simulate everyday activities to assess functional performance.MethodThe C‐STAM is being developed by a multidisciplinary team of psychologists, old age psychiatrists, occupational therapists, and computer scientists. A Delphi study with 31 international experts was conducted to select and refine suitable tasks. An additional step is consultation with consumers (i.e., older people with and without cognitive impairment) and caregivers who have an active role in shaping the C‐STAM. A pilot study with 30 people aged 60+ with normal cognition, MCI, and dementia plus their informants will assess feasibility and user‐experience. After adjustments based on the pilot study, we will conduct a validation study with 180 participants and their informants.ResultThe Delphi study resulted in nine C‐STAM tasks, addressing the domains of communication, shopping, dressing, community mobility, handling finances, managing medications, and memory. Feasibility and acceptability of these tasks will be confirmed through pilot testing and the validation study. We will develop an automated scoring and interpretation guide, age‐ and sex‐specific norms, and clinical cut‐offs to differentiate the three diagnostic groups. Automated data exporting and reporting will be useful for clinical referrals and in research and will facilitate interpretation and communication of results across different clinical settings.ConclusionThe C‐STAM will facilitate early diagnosis of dementia and MCI and will enable a better understanding of disease progression by monitoring functional ability in a time‐ and resource‐efficient way. Results will be used to inform service development to better meet the needs of people with dementia for access to appropriate assessments of functional performance. The C‐STAM will be freely available for use by clinicians and in research.
Brain gray matter volume mediated the relationship between plasma p‐tau and cognition of early Alzheimer’s disease
Authors: Wan Ke , Yin Wenwen , Tang Yating , Zhu Wenhao , Wang Zhiqiang , Zhou Xia , Zhang Wei , Zhang Cun , Yu Xianfeng , Li Chenchen , Zhao Wenming , Zhu Xiaoqun , Sun Zhongwu 
Published: December 2023

AbstractBackgroundCognitive deterioration and atrophy of the brain gray matter volume (GMV) are the main symptoms of Alzheimer’s disease (AD). Accumulated pieces of evidence have shown that plasma concentrations of phosphorylated‐tau (p‐tau) performed better in early diagnosing, differentiating, and monitoring the progression of AD. However, the relationship between plasma p‐tau concentrations, the GMV of brain regions, and cognitive function remains poorly understood. Previous studies indicate that brain GMV may mediate the relationship between biomarkers and cognitive function, and in this study, we aimed to investigate whether GMV plays a mediating role in the association between plasma p‐tau concentrations and cognition.Method99 participants in total, including 47 patients with a diagnosis of early AD and 52 cognitively unimpaired (CU) individuals, were enrolled in this study. All participants completed laboratory tests, magnetic resonance imaging scans, and neuropsychological assessments. Plasma p‐tau217 and p‐tau181 concentrations were measured using an enzyme‐linked immunosorbent assay kit. Voxel‐based morphometry was performed to assess brain GMV. Partial correlations and mediation analyses were performed in the AD group.ResultConcentrations of both plasma p‐tau217 and p‐tau181 were significantly higher in the AD group than in the CU group. Patients with AD had significant brain GMV atrophy in the right hippocampus, bilateral middle temporal gyrus, and right inferior temporal gyrus. In the AD group, there were significant correlations between plasma p‐tau217 concentrations, GMV, and Mini‐Mental State Examination (MMSE) scores. Brain GMV of the right hippocampus mediated the association between plasma p‐tau217 concentrations and MMSE scores. We did not find a significant correlation between plasma p‐tau181 concentrations and MMSE scores.ConclusionThe findings indicate that p‐tau217 was a promising biomarker for central processes affecting brain GMV and cognitive function. It may provide potential targets for future intervention and treatment of tau‐targeting therapies at the early stage of AD.
Role of Hearing‐Health‐Care Professionals in supporting Patients with Dementia Risk.
Authors: Jayakody Dona 
Published: December 2023

AbstractBackgroundFor those aged over 65, hearing loss is another major chronic illness. Our findings have revealed that untreated hearing loss is associated with an increased risk of frailty (Tian et al 2021), emotional loneliness (Jayakody et al 2022), and depression (Jayakody et al., 2018). Further, we found an association between hearing loss and cognitive impairment and dementia in non‐tonal language, (Jayakody et al 2018; Ford et al 2018) and tonal language speakers (Fu et al; 2021, 2022, Nicholas et al., 2021).MethodIn this presentation we will discuss the following: knowledge, attitudes and current practices of hearing health care professionals in treating older adults with comorbid hearing loss and cognitive impairment, hearing biomarkers to identify those at risk of dementia and hearing rehabilitation of older adults at risk of cognitive impairment.ResultsThe outcomes of Knowledge, Attitudes and Practice surveys conducted in Australia, China, India, Sri Lanka, Turkey and USA identified gaps in the knowledge and practices of hearing healthcare professionals in cognitive impairment and hearing loss.Our findings also suggest that those with subjective memory complaints, mild cognitive impairment and dementia perform significantly worse than healthy controls in both subjective central auditory processing tasks and objective electrophysiological assessments (Jayakody et al., 2020, Tarawneh et al., 2022).Finally, our results revealed rehabilitation using cochlear implants and hearing aids reduce the rate of cognitive decline in older adults (Jayakody et al., 2017, 2020)ConclusionsHearing healthcare professionals play an essential role in supporting older adults at risk of Dementia. A better understanding of the consequences of untreated hearing loss, providing training to reduce the gaps in their knowledge and practices in treating older adults at risk of comorbid hearing loss and dementia and providing training to use suitable assessment tools to identify cognitive impairment in clinical settings early would be helpful.
GRIN2B genotypes and APOE haplotypes affect the age at onset of Alzheimer’s dementia as well as variations in dementia staging according to the use of Memantine
Authors: de Oliveira Fabricio Ferreira , de Almeida Thais Emanuele , de Almeida Sandro Soares , Smith Marilia Arruda Cardoso , Bertolucci Paulo Henrique Ferreira 
Published: December 2023

AbstractBackgroundMemantine antagonizes the N‐methyl‐D‐aspartate (NMDA) type of glutamate receptor leading to possible behavioral improvement and a synergistic effect with cholinesterase inhibitors on slower functional and cognitive decline in Alzheimer’s dementia (AD). Some receptor genes can contribute to variable excitotoxicity and pharmacological response. NR2B is a common subunit of functional NMDA receptors, whereas the GRIN2B gene is mapped to 12p12, and rs3764028 has been associated with variable GRIN2B transcription and human susceptibility to AD. We sought to evaluate associations of promoter GRIN2B genotypes and APOE haplotypes with the age at onset of AD and cognitive and functional response to Memantine.MethodsIn this prospective pharmacogenetic study, participants with late‐onset AD according to National Institute on Aging – Alzheimer’s Association criteria were screened with the Clinical Dementia Rating Sum‐of‐Boxes, the Index of Independence in Activities of Daily Living, Lawton’s Scale for Instrumental Activities of Daily Living, the Mini‐Mental State Examination, the Severe Mini‐Mental State Examination, and a 15‐item Clock Drawing Test, and followed for one year. Genotyping was undertaken with TaqMan® Real‐Time Polymerase Chain Reactions for rs429358 and rs7412 (APOE haplotypes), and with Polymerase Chain Reactions for rs3764028 (GRIN2B). Associations of APOE haplotypes and rs3764028 genotypes with the age at dementia onset were assessed and, after stratification according to APOE‐ε4 carrier status, the presence of each genotype of rs3764028 was linked with use of Memantine or not for test score variations, significance at p<0.05.ResultsAmong 190 consecutive outpatients, 141 used Memantine (74.2%); mean age at dementia onset was 73.23±6.4 years‐old, with 128 women (67.4%) and 62 men (32.6%), 101 APOE4+ carriers (53.2%) and 89 APOE4‐ carriers (46.8%). APOE‐ε4/ε4 carriers had earlier AD onset by almost five years (p = 0.004), whereas the A allele of rs3764028 had a cumulative effect on later onset of AD (p<0.0001). Memantine protected APOE4‐ carriers of the CC genotype of rs3764028 regarding Clinical Dementia Rating Sum‐of‐Boxes variations (p = 0.018), but not regarding other test score variations.ConclusionsGenotypes of rs3764028 and APOE haplotypes are associated with the age at onset of AD, as well as with variations in dementia staging according to the use of Memantine. (Supported by FAPESP grant #2015/10109‐5)
The Role of Cerebrospinal Fluid Flow in the Subarachnoid Space in Beta‐Amyloid Clearance
Authors: Kim Jeongchul , Barcus Richard A. , Lipford Megan E. , Yuan Hongyu , Hudson Jeremy Patton , Sai Kiran K. Solingapuram , Lockhart Samuel N. , Craft Suzanne , Whitlow Christopher T. 
Published: December 2023

AbstractBackgroundRecent studies identified the lymphatic drainage system in the brain. Here, cerebrospinal fluid (CSF) carries waste from brain tissue. However, it is still not well understood how CSF flow in the brain affects waste removal. In this study, we hypothesize that CSF flow patterns in the subarachnoid space will be correlated with beta‐amyloid deposition in the brain.MethodThirteen participants (7 Cognitively Normal and 2 Mild Cognitive Impairment, Age = 68±7.7 yrs. M/F = 5/4) who had prior amyloid PET imaging were recruited for CSF flow MRI from the Wake Forest Alzheimer’s Disease Research Center. The CSF flow patterns during the cardiac cycle were measured using the phase‐contrast MRI at the cerebral aqueduct, pontine cistern and cerebellomedullary cistern (Fig. 1). Images were acquired for 40 cardiac cycles with a pulse oximeter and CSF flow profiles were estimated using the retrospective cardiac gating method. PET Amyloid burden in the whole gray matter (GM) was measured as the standardized update value ratio (SUVR, cerebellar gray matter as a reference region) from the prior PET imaging and corresponding MRI.ResultCSF flow amplitude normalized by the brain tissue volume demonstrated moderate to strong correlations with beta‐Amyloid SUVR in GM (Fig. 2); Pearson’s correlation coefficient (rho) was ‐0.59 (p = 0.036) and ‐0.84 (p = 0.004) at pontine cistern and cerebellomedullary cistern, respectively. The lateral ventricle volume normalized by brain volume was also moderately correlated with GM SUVR (rho = 0.495).ConclusionAt an early stage of AD, the CSF circulation in the subarachnoid space could be correlated with beta‐Amyloid deposition. Therefore, CSF flow in the subarachnoid space could be a useful imaging marker to predict the clearance of beta‐amyloid in the brain.