bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cognitive reserve, microstructural brain lesions, and cognitive function in dementia‐free adults in UK Biobank
Authors: Han Xiaolei , Huang Xin , Du Yifeng , Qiu Chengxuan , wang yongxiang 
Published: January 2025

AbstractBackgroundMicrostructural brain lesions have been linked to cognitive health. However, their combined effect and the role of the cognitive reserve (CR) remain unclear. We investigated the interplay of microstructural brain lesions and cognitive reserve in cognitive function in middle‐aged and elderly adults.MethodThis study used data from a prospective cohort of 26,490 UK Biobank participants in the MRI substudy. Markers of microstructural brain lesions included fractional anisotropy (FA), mean diffusivity (MD), intracellular volume fraction (ICVF), orientation dispersion (OD) indices, and isotropic volume fraction (ISOVF), which were estimated using diffusion magnetic resonance imaging (dMRI). Processing speed, reasoning, attention, executive function, and memory were assessed with neuropsychological tests, from which composite scores were derived. The composite CR indicator was generated from early‐life education, midlife occupation, physical activity, and social activity and was dichotomized into low and high CR based on mean CR score. We used multivariable linear regression models to examine the relation between markers of microstructural brain lesions and cognitive function while taking into account the potential interaction (interplay) of brain lesions and CR on cognitive function.ResultControlling for sociodemographic, vascular, and genetic factors, decreased FA and ICVF and increased MD, as markers of impaired integrity of white matter microstructure, were significantly associated with lower composite z‐score of processing speed, attention, and executive function. Reduced ISOVF was associated with higher z‐score of processing speed [multivariable‐adjusted β‐coefficient=‐0.03. 95% CI ( ‐0.041, ‐0.019), p<0.001]. In the stratified analysis by levels of CR, decreased FA and ICVF were significantly associated with lower z‐scores of reasoning and memory, respectively, only in participants with low CR.ConclusionThis study suggests that impaired integrity of white matter microstructure is associated with reduced processing speed, attention, and executive function and that high CR could modify the association of microstructural brain lesions with cognitive function (e.g., memory and reasoning).
Comparative study of neuroimaging evaluation between idiopathic normal pressure hydrocephalus and progressive supranuclear palsy
Authors: Inagawa Shoya , Yamamoto Ryo , Inagawa Yuta , Takenoshita Naoto , Shibukawa Shuhei , Yoshimaru Daisuke , Saito Kazuhiro , Shimizu Soichiro 
Published: January 2025

AbstractBackgroundIdiopathic normal pressure hydrocephalus (iNPH) and progressive supranuclear palsy (PSP) are considered to be different pathologies, but they have similar clinical features such as cognitive dysfunction and gait disturbance. Therefore, it is difficult to understand between the two diseases in actual clinical practice. The aim of study is whether the indivisual characteristic in MRI is useful to devide into two groups.Method15 iNPH patients and 9 PSP patients were enrolled. The subjects were recruited retrospectively from those who had been diagnosed in our department. The MRI device was 3 T MAGNETOM Vida (SIEMENS), and the Evans index and DESH score were measured using T2WI/FLAIR. Furthermore, we used FreeSurfer for 3D‐T1WI to measure the volumes of the brainstem, corpus callosum, and ventricles. Each brain region was adjusted using the whole brain volume, multiple corrections were performed on the final remaining regions, and comparisons were made between the two groups.ResultThere were no significant differences in brain stem volume between the two groups. However, Evans index (iNPH: 0.351 ± 0.0, PSP: 0.286 ± 0.0, p < 0.01), DESH score (iNPH: 6.87 ± 1.2, PSP: 2.44 ± 2.1), p<0.01), corpus callosum volume (iNPH:854.75±369.9 mm^3, PSP:532.16±186.1 mm^3, p<0.05), cerebrospinal fluid volume (iNPH:2220.26±657.5 mm^3, PSP :1544.38±338.1 mm^3, p<0.01), a significant difference was observed.ConclusionMRI findings related to the ventricles may be differentiating both diseases.
ATP1A3 as a target for isolating neuron‐specific extracellular vesicles from human brain and biofluids
Authors: Zhang Zhengrong , You Yang , Sultana Nadia , Ericsson Maria , Martens Yuka A , Sun Min , Kanekiyo Takahisa , Ikezu Seiko , Ikezu Tsuneya , Shaffer Scott A 
Published: January 2025

AbstractBackgroundNeuron‐derived extracellular vesicles (NDEVs) are a valuable resource for understanding brain conditions and discovering neurodegenerative diseases biomarkers, notably Alzheimer’s disease (AD). Recent interest focuses on capturing neuron‐specific EVs from patient‐derived samples, characterizing their contents as a pathological reflection of the central nervous system (CNS). Our recent study identified ATPase Na+/K+ Transporting Subunit Alpha 3 (ATP1A3) as a prevalent neuron‐specific EV marker specifically expressed in brains. This study systematically analyzes neuronal EVs to assess the specificity of ATP1A3 to NDEVs and its potential as a target for NDEV pulldown from accessible biofluids for disease monitoring. Additionally, ATP1A3 is compared with other proposed NDEV markers.MethodWe applied immunoelectron microscopy to detect ATP1A3, L1 cell adhesion molecule (L1CAM) and neural cell adhesion molecule 1 (NCAM1) in EVs isolated from iPSC‐derived excitatory neurons, brain tissue, cerebrospinal fluid (CSF) and plasma. Neuronal EV enrichment was achieved through immunoaffinity isolation, utilizing anti‐ATP1A3, L1CAM and NCAM1 antibodies separately. Evaluation involved quantitative mass‐spectrometry, immunoblotting and ELISA. To compare the enrichment of neuronal markers, EVs isolated from CSF and plasma samples were analyzed using ExoView and Nanoimager. Additionally, we investigated the potential of ATP1A3+ plasma EVs as AD biomarker by comparing the value of amyloid‐beta peptide (Aβ) in ATP1A3+ plasma EVs measured by Nanoimager and other plasma AD biomarkers as determined by SIMOA.ResultATP1A3, identified as a neuron‐specific protein, exhibits substantial enrichment in NDEVs isolated from induced human neurons, brain tissue, CSF, and plasma samples, surpassing NCAM1 or L1CAM. Both single‐ and bulk‐EV analysis consistently demonstrate a higher enrichment of ATP1A3 associated EVs in human samples. Immunoprecipitation of ATP1A3+ EVs from human brain tissues reveals superior neuronal cell‐type specificity over NCAM1+ and L1CAM+ EVs by label‐free mass spectrometry. Increased Aβ levels are observed in ATP1A3+ EVs derived from CSF and plasma of AD cases by SIMOA. Moreover, Aβ+ populations in ATP1A3+ EVs from plasma can distinguish AD from mild cognitive impairment and control cases via Nanoimager compared to the conventional quantification of AD markers.ConclusionOur findings demonstrate that ATP1A3 as a promising target for isolating NDEVs from biofluids, offering potential diagnostic advancements in neurological research.
Association of biological age with health outcomes and its modifiable factors
Authors: Yu Jin‐Tai 
Published: January 2025

AbstractBackgroundIdentifying the clinical implications and modifiable and unmodifiable factors of aging requires the measurement of biological age (BA) and age gap.MethodLeveraging the biomedical traits involved with physical measures, biochemical assays, genomic data, and cognitive functions from the healthy participants in the UK Biobank, we establish an integrative BA model consisting of multi‐dimensional indicators.ResultAccelerated aging (age gap >3.2 years) at baseline is associated incident circulatory diseases, related chronic disorders, all‐cause, and cause‐specific mortality. We identify 35 modifiable factors for age gap (p < 4.81 × 10−4), where pulmonary functions, body mass, hand grip strength, basal metabolic rate, estimated glomerular filtration rate, and C‐reactive protein show the most significant associations. Genetic analyses replicate the possible associations between age gap and health‐related outcomes and further identify CST3 as an essential gene for biological aging, which is highly expressed in the brain and is associated with immune and metabolic traits.ConclusionOur study profiles the landscape of biological aging and provides insights into the preventive strategies and therapeutic targets for aging.
Drawing the neurodegenerative line: plasma biomarkers and retinal OCTs shed light on pathophysiological and diagnostic similarities between Alzheimer's Disease and Multiple Sclerosis
Authors: Zeldich Dean , Cheng Chia Hsin , Guan Yi , Koo Bang‐Bon 
Published: January 2025

AbstractBackgroundRecent evidence suggests extensive myelin dysfunction in Alzheimer’s Disease (AD), lending to investigation of biomarkers previously implicated in both AD and Multiple Sclerosis (MS) to find objective and obtainable diagnostic screening tools. Glial fibrillary acidic protein (GFAP), Chitinase‐3‐like protein 1 (CHI3L1), Chemokine (C‐X‐C motif) ligand 13 (CXCL13), and neurofilament light chain (Nfl) have been known to mark neuronal pathology in both diseases making them attractive markers. Retinal Optical Coherence Tomography (OCT) becomes a popular diagnostic tool in both conditions as an inexpensive and rapid way of obtaining a window into the cerebrum.MethodAD (n=3952) and MS (n=1988) patients were selected from the UK‐Biobank using ICD10 codes. Past medical history of strokes and brain cancer were used as exclusionary criteria. Case‐control differences were analyzed in cognitive measures, retinal OCT, plasma proteins, and magnetic resonance imaging (MRI) data. AD subjects were further stratified. Correlation and predictability of plasma markers and retinal OCTs with cognitive and MRI measures were investigated with linear regression models, age‐ and sex‐controlled.ResultStable AD, MS, and AD converters showed significantly worse cognitive performances compared to controls. GFAP and Nfl were significantly elevated in MS (additionally, CHI3L1), AD patients, and AD converters as early as 5 to 10 years before diagnosis. Retinal OCT markers such as retinal nerve fiber thickness (RNFT) were significantly decreased in MS patients, while less clear patterns were observed for AD and converters. MRI measures obtained 10 years after baseline visit revealed significantly smaller hippocampal volumes and more white matter hyperintensities in both AD and MS patients compared to controls. Overall, retinal OCT measures (i.e., thinner RNFT, smaller optic disc diameter) significantly correlated with worse cognitive outcomes and elevated protein markers for both groups. While certain measures of cognitive decline (e.g., mean reaction time, numeric memory) better correlated with well‐established MRI hallmarks for neurodegeneration.ConclusionInexpensive and non‐invasive biomarkers such as plasma proteins and retinal OCT measures carry significant prognostic potential in AD and MS while allowing for a deeper characterization of the neuronal and glial pathology in both diseases.
Feasibility and Acceptability of Objective Pain Assessment Using Multimodal Sensing Signals in Older Adults with Alzheimer's Disease: Preliminary Results of a Pilot Study
Authors: Andrade Fernanda Souza , Ornelas Julie , Park JuYoung , Engstrom Gabriella , Shih Richard D. , Telkes Ilknur 
Published: January 2025

AbstractBackgroundChronic pain remains mostly untreated in those with Alzheimer’s disease and related dementias (ADRD), mainly due to limited capacity to verbalize pain. Development of reliable objective biomarkers of chronic pain could improve pain assessment and treatment. We explored feasibility and acceptability of using a wearable electroencephalograph (EEG) and a screen‐based eye tracker system to identify neural signatures of chronic pain in this population.MethodInclusion criteria were ADRD in an early to moderate stage defined by Mini‐Montreal Cognitive Assessment (Mini‐Moca) and Quick Dementia Rating System (QDRS) scores and chronic pain (3 months or longer). Participants underwent a single‐session test where participant‐reported outcome (PRO) measures were obtained with 32‐channel EEG. Neural signals were recorded at resting and during a cognitive task with visual stimuli. Attention to the stimuli was captured using an eye‐tracking system.ResultFive of 29 applicants met all criteria and were included. The majority were excluded due to dementia severity or lack of chronic pain. Four subjects (3 females) concluded the study. Participants' ages ranged from 76 to 93 years. They were diagnosed with Alzheimer’s disease, dementia of unspecified type, or dementia related to Parkinson’s disease. Mini‐Moca scores ranged from 2‐8 of 15 and QRDS ranged from 6‐20 of 30. On Visual Analog Scale for pain, three participants rated mild to moderate pain (2 to 5 out of 10) and one rated severe pain (9 out of 10). Three reported that pain significantly affected their ability to walk, relationships with people, and enjoyment of life. All participants reported feeling comfortable with the EEG cap and eye tracker, were satisfied with the study, and would recommend the study to others. In terms of feasibility, the major challenge was to calibrate the eye tracker system and the duration of the cognitive task which was 30 minutes.ConclusionWhile using a table‐top eye tracker was comfortable for all participants, the calibration phase was difficult. In one case, the image‐based task was not feasible which might be related to participant having moderate dementia. Our preliminary work suggests that wearable modalities may work better in people with ADRD and carry the potential to assess pain objectively.
Identification of Balance biomarkers using Inertial sensor for Early Detection of Dementia
Authors: Jamshed Mobeena , Shahzad Ahsan , Kim Kiseon 
Published: January 2025

AbstractBackgroundEarly‐stage dementia, Mild Cognitive Impairment (MCI), is challenging to diagnose since it is a transient condition distinct from complete cognitive collapse. Recent clinical research studies have identified that balance impairments can be a significant indicator for predicting dementia in older adults. Accordingly, we aimed to identify key balance biomarkers using wearable inertial sensors for early detection of dementia/MCI.MethodAt National Research Center for Dementia (South Korea), 60 participants (30 Cognitively Normal‐CN, 30 Mild Cognitive Impairment‐MCI) were selected based on assessments conducted by medical professionals at Chosun University Hospital / Chonnam National University Hospital (Gwangju). Shimmer‐3 inertial sensor was placed on lower back of participants, with a tri‐axial accelerometer and tri‐axial gyroscope. The data was collected under four different conditions: eyes‐open (EO), eyes‐closed (EC), right‐leg lift (RL), left‐leg lift (LL). A set of 76 postural sway measures were considered with 43 time‐domain and 33 frequency‐domain features.Feature ranking was executed through the utilization of "Leave‐One‐Subject‐Out (LOSO)" cross‐validation technique for each condition. Filter methods: one‐way‐ANOVA (Analysis of Variance), Mutual Information and Wrapper methods: Random Forest, Support Vector Machine (SVM) were utilized to evaluate feature subsets. The proportional value of each feature was calculated by the number of times it showed in the top feature list. The final score was obtained by combining scores from all the techniques, which indicated the relative weight of characteristics across the various approaches. Further feature analysis was conducted using SHAP (Shapley‐Additive‐exPlanations).ResultThe multi‐step methodology, for feature selection, adopted in our research ensured a rigorous process, combining the strengths of Filter and Wrapper methods. In time‐domain: root‐mean‐square, mean‐distance, 95%‐confidence circle sway‐area, path‐length, mean sway‐velocity were the key features identified. While in frequency‐domain: spectral edge‐frequency, mean‐frequency, peak‐frequency, centroid‐frequency, spectral‐entropy were found to be the principal features of relevance. These features were also included in the top list of features based on SHAP impact value, hence proving the effectiveness of our method in identifying important biomarkers for detection of MCI.ConclusionThe inertial sensors based postural balance assessment provides useful biomarkers that can facilitate early screening of MCI / dementia in home settings.
Concordance between biomarkers in cerebrospinal fluid (CSF), brain positron emission tomography with 18‐fluorodeoxyglucose (18F‐FDG‐PET) and clinical diagnosis in patients with cognitive impairment
Authors: Mimenza Alberto Jose , del Ángel Karen Leon , Martínez Rodrigo Hernández , Aguilar‐Navarro Sara Gloria 
Published: January 2025

AbstractBackgroundThe diagnosis of neurodegenerative diseases such as dementia due to Alzheimer's Disease (AD) and other dementias continues to be a challenge. The use of complementary studies in diagnosis is recommended in the main clinical guidelines for this pathology. Biomarkers in CSF (Aβ42, tTau and pTau) and by brain [18F]FDG‐PET are useful for diagnosis, since they increase its certainty. Objective: Establish diagnostic agreement between biomarkers in CSF, PET and clinical evaluation.MethodCohort, retrospective and comparative study. Patients with biomarkers were included for the diagnostic approach of cognitive impairment due to any cause in the INCMNSZ from July 2018 to September 2023. An analysis of concordance was carried out with the Kappa coefficient between the result of the biomarkers and the clinical assessment.Result77 patients were evaluated, with an average age of 71 years (SD ± 10.19) and 53.2% were men; 27.3% with a diagnosis of mild cognitive impairment (MCI) and 72.7% with dementia. The agreement between the initial diagnosis and the hypometabolism patterns by PET was moderate (kappa 0.461, p=0.011). The overall agreement between the biomarkers to differentiate between AD and other dementias was 88% (kappa 0.694, p=0.002). The change in diagnosis after taking the biomarkers occurred in 46% of the patients.ConclusionThis study demonstrates that the agreement between the use of CSF and PET biomarkers to differentiate between AD and other dementias is good. There was disagreement in 12% of the patients, which suggests that in cases with diagnostic doubt it is advisable to perform both biomarkers.
Complement proteins C1q, C3, and Factor H are associated with early tau pathology and synaptic integrity in persons with pre‐symptomatic Alzheimer’s disease
Authors: Loncke Julia , Picard Cynthia , Labonté Anne , Zetterberg Henrik , Blennow Kaj , Brinkmalm Ann , Breitner John C.S. , Poirier Judes ,   The PREVENT‐AD Research Group
Published: January 2025

AbstractBackgroundThe immune complement system is key to the elimination of redundant neural connections in the brain through a process called synaptic pruning. In neurodegenerative diseases such as Alzheimer's disease (AD), this system may result in excessive synapse loss, leading to brain atrophy and cognitive impairment. While increased cerebrospinal fluid (CSF) levels of complement proteins have been observed in patients with AD dementia, no studies have yet investigated the role of complement in the pre‐symptomatic phase of AD, nor throughout its progression.MethodWe used Luminex technology to assess complement protein levels in 566 CSF samples obtained over five years from 160 high‐risk asymptomatic subjects with familial history of AD [the PREVENT‐AD cohort; Breitner et al, 2016: JPAD 3,(4) 236]. Baseline complement levels were contrasted with CSF biomarkers of AD pathology (Aβ42, p(181) and total tau, NFL) and markers of synaptic dysfunction (GAP‐43, SYT1, SNAP‐25, ADAM22, ADAM23). Analyses were stratified by sex and ApoE4 carrier status. Currently pending are additional longitudinal analyses probing complement levels versus PET‐quantified cerebral amyloid and tau deposition, MRI volume of AD‐implicated structures, and cognitive ability (RBANS).ResultPreliminary analyses revealed significant positive associations between complement proteins and p‐(181)tau (C1q: R2 = .238, p < .0001; C3: R2 = .041, p = .0099; C3b: R2 = .027, p = .0384; Factor H: R2 = .128, p < .0001) and total tau levels (C1q: R2 = .247, p < .0001; C3: R2 = .023, p = .0543; Factor H: R2 = .128, p < .0001). Complement relationships with synaptic protein levels were more significant overall in females, which showed the following associations [GAP‐43 (C1q: R2 = .389, p < .0001; Factor H: R2 = .315, p = .0002); SNAP‐25 (C1q: R2 = .367, p < .0001; C3: R2 = .106, p = .0459; Factor H: R2 = .278, p = .0072); SYT1 (C1q: R2 = .316, p = .0002; Factor H: R2 = .246, p = .0015)].ConclusionThere is a clear association between complement levels, tau pathology, and synaptic markers in the asymptomatic phase of AD, especially in women. Longitudinal and multimodal investigation is ongoing to further characterize these relationships.
Culturally adapted intervention regarding decision‐making on feeding options for Chinese American dementia caregivers: A human‐centered approach
Authors: Pei Yaolin , Wang Jing , Schulman‐Green Dena , Fried Terri , Hanson Laura , Wu Bei 
Published: January 2025

AbstractBackgroundStudies show that tube feeding does not improve clinical outcomes, and professional guidelines recommend against its use for individuals with advanced dementia. Yet, our preliminary work demonstrates a preference for tube feeding among Chinese‐American dementia caregivers. We propose linguistic and cultural adaptation of “Making Choices: Feeding Options for Patients with Dementia (MCFODA) to create the Chinese version of this efficacious decision aid intervention. The study aims to inform the process and domains of the cultural adaptation.MethodThe first step of the adaptation process is interviews with Chinese‐American dementia caregivers to learn about their decision‐making experiences around feeding options. To identify participants, we collaborated with Caringkind, an agency of servicing dementia caregivers, and used purposive sampling. We began conducting semi‐structured interviews via Zoom with a target sample of 25. Participants completed a brief demographic questionnaire. Audio recordings were transcribed in Chinese and translated into English by a multilingual research assistant. Thematic analysis was used in this study.ResultCaregivers reported various strategies to prevent choking and ensure patients’ healthy eating, including adding thickness, blending food, and making soup. Caregivers and other family members participated in decision‐making regarding feeding options. To maintain family harmony, timely communication about patients’ health status is one of the important strategies they used for the family decision‐making about feeding options. Factors affecting family decision‐making of whether to use tube feeding included the PLWD’s health status, other people’s end‐of‐life experience of using tube feeding, PLWD’s preferences toward tube feeding and personality, the cultural importance of food, and caregivers’ perception of comfort in feeding options. PLWD’s wishes were perceived as important in decision‐making. However, family were often unaware of these wishes, as they had not been discussed, although some PLWDs expressed their wishes indirectly by discussing other people’s experience in movies or TV drama. Chinese translators were reported as critical during discussions between Chinese families and health care providers.ConclusionEngaging end‐users in the adaptation of MCFODA will optimize development of the culturally adapted intervention. For Chinese Americans, we plan to summarize caregivers’ practices used to manage PLWD’s eating, provide suggestions for good family communication, and how to identify PLWD’s wishes.