bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vivo tau deposition in the brain stem nuclei and circadian rest‐activity rhythm change in non‐demented older adults
Authors: Jeon So Yeon , Yi Dahyun , Byun Min Soo , Jung Joon Hyung , Kong Nayeong , Chang Yoon Young , Keum Musung , Jung Gijung , Ahn Hyejin , Lee Jun‐Young , Lee Yun‐Sang , Kim Yu Kyeong , Kang Koung Mi , Sohn Chul‐Ho , Lee Dong Young ,   KBASE Research group
Published: December 2023

AbstractBackgroundCircadian rest‐activity rhythm (RAR) alterations are common in the early stage of Alzheimer’s disease (AD) disease. Given that the brainstem nuclei, the locus coeruleus (LC) and dorsal raphe nucleus (DRN) in particular, play key roles in modulating arousal and the sleep‐wake cycle, tau pathology in the brain stem nuclei, which occurs even before cortical tau progression, may relate to circadian RAR alteration in older individuals. Therefore, we aimed to test the hypothesis that in vivo tau deposition in the LC and DRN correlates with circadian RAR in non‐demented older adults.MethodA total of 63 non‐demented older adults from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) were included. All participants underwent [11C] PiB PET and [18F] AV1451‐PET. Circadian RAR variables were measured using actigraphy for 8 consecutive days. Tau deposition of the LC and DRN (LC‐tau and DRN‐tau, respectively) was measured in the regions of interest (ROI) masks for each participant prepared in native space using the Harvard arousal network atlas for the LC and DRN. For the purpose of comparison, tau deposition in the substantia nigra (SN‐tau) was also measured in the neuromelanin sensitive MRI‐based ROI for the SN.ResultIncreased LC‐tau and DRN‐tau were significantly correlated with delayed acrophase (β = 0.303, p = 0.024 for LC‐tau and β = 0.398, p = 0.003 for DRN‐tau; Table 1 & Figure 1). In contrast, SN‐tau did not related with any RAR variables. Even after controlling for global tau deposition, the significance did not changed (β = 0.321, p = 0.021 for LC‐tau and β = 0.367, p = 0.008 for DRN‐tau, Table 1). In addition, Aβ positivity showed a significant moderation effect on the relationship between LC‐tau with acrophase. Subgroup analyses showed that increased LC‐tau significantly related with delayed acrophase in Aβ‐positivegroup (β = 0.427, p = 0.004), but did not in Aβ‐negative group (β = 0.099, p = 0.615)(Figure 2)ConclusionOur findings support the possibility that the tau pathology in the LC and DRN underlie circadian RAR alteration, more specifically delayed phase, in non‐demented older adults. In addition, such relationship appears to be more prominent in individuals with brain Aβ pathology.
The associations between handgrip strength asymmetry and future cognitive impairment in older adults
Authors: Chen Jen‐Hau 
Published: December 2023

AbstractBackgroundThe incidence and prevalence of dementia continue to increase exponentially as people age. Finding a pre‐clinical marker to detect dementia early is paramount in clinical practice. There are few prospective studies evaluating handgrip strength, handgrip strength asymmetry, and their combination on cognitive impairment. This study aimed to investigate the association of handgrip strength and handgrip strength asymmetry with future global and specific cognitive domain impairment.MethodThis is a seven‐year prospective cohort study (Fig 1). We used data from the ongoing Taiwan Initiative of Geriatric Epidemiological Research (TIGER), wave 3 (2015‐2017) to wave 5 (2019‐2022), with wave 3 as the baseline (n = 446). Low handgrip strength was defined as the lowest tertile of sex‐specific handgrip strength. Handgrip strength asymmetry was defined as a handgrip strength ratio <0.85 or >1.15 (i.e., a 15% difference). The cognitive assessment included global and specific cognitive domains. Generalized linear mixed models were used to assess the association of handgrip strength asymmetry and cognitive performance adjusted for age, years of education, cigarette smoking, alcohol drinking, hypertension, diabetes, hyperlipidemia, and physical activity.ResultThe mean age of participants was 75.7 years, and 55% were female. Participants with handgrip strength asymmetry were mostly female, never smokers, and more likely to have lower handgrip strength. Handgrip strength asymmetry was associated with poor global cognition [ = ‐2.14, 95% confidence interval (CI): ‐3.60, ‐0.68] and digit span‐forward ( = ‐0.69, 95% CI: ‐1.25 to ‐0.14) over time in men. Low handgrip strength was associated with cognitive impairment (global cognition: = ‐1.13, 95% CI: ‐2.07 to ‐0.19; immediate free recall: = ‐0.48, 95%CI: ‐0.87 to ‐0.09; delayed free recall: = ‐0.45, 95% CI: ‐0.85 to ‐0.08); Trail Making Test‐ A: = ‐0.43, 95% CI: ‐0.75 to ‐0.12), and digit span‐forward ( = ‐0.67 to 95% CI: ‐1.02 to ‐0.31) over time in men. Concomitant weakness and handgrip strength asymmetry had greater impairment in cognitive function in men.ConclusionIn this community‐dwelling older population, those with low handgrip strength and handgrip strength asymmetry had an increased risk of cognitive impairment. This relationship seems more prominent in men than women.
Individual bioenergetic capacity as a potential source of resilience to Alzheimer’s disease
Authors: Arnold Matthias , Buyukozkan Mustafa , Doraiswamy P. Murali , Wu Tong , Nho Kwangsik , Gudnason Vilmundur , Launer Lenore J J. , Wang‐Sattler Rui , Adamski Jerzy , De Jager Philip L , Ertekin‐Taner Nilufer , Bennett David A. A , Saykin Andrew J. , Peters Annette , Suhre Karsten , Kaddurah‐Daouk Rima F. , Kastenmuller Gabi , Krumsiek Jan ,   the Alzheimer’s Disease Neuroimaging Initiative and the Alzheimer’s Disease Metabolomics Consortium
Published: December 2023

AbstractBackgroundBrain glucose hypometabolism is among the earliest pathogenic changes in Alzheimer’s disease (AD). This metabolic dysfunction points to the personal bioenergetic capacity, defined as the ability to maintain energy homeostasis under all circumstances including deregulated glucose uptake, as a potential source of resilience to the disease. Fasting blood acylcarnitine profiles are a central readout for this capacity in the absence of dietary glucose and capture the activity and efficiency of glucose‐independent routes of mitochondrial energy metabolism.MethodWe used fasting serum acylcarnitine profiles of 1,531 participants (465 with normal cognition, 762 with mild cognitive impairment, and 304 with clinical AD) from the AD Neuroimaging Initiative to perform unsupervised subgroup identification using hierarchical clustering. Identified subgroups were investigated for differences in A/T/N biomarker profiles and cognitive status. The contributions of genetic and potentially modifiable factors defining the subgroups were quantified using analysis of explained variance. The influence of the strongest determining factors on longitudinal cognitive trajectories was estimated using linear mixed‐effects models and gene‐by‐environment interaction analysis.ResultWe found several bioenergetically distinct subgroups with significant differences in AD biomarker profiles and cognitive function. The strongest genetic contribution to this bioenergetic endophenotype seems to be specifically linked to succinylcarnitine metabolism and significantly modulates the rate of future cognitive decline. In contrast, potentially modifiable sustainment of beta‐oxidation efficiency seems to decelerate bioenergetic aging, thus creating a bioenergetic reserve that delays progression of cognitive decline. Using gene‐by‐environment interaction analysis, we demonstrate that this molecular framework identifies a subgroup of individuals that is likely to benefit significantly from personalized therapeutic, dietary or lifestyle interventions tailored to increase resilience against bioenergetic disturbances in AD.ConclusionOur study reports on a set of genetic and metabolic markers that define bioenergetically distinct subgroups with significant differences on the AD biomarker and cognitive level. Longitudinal data suggest that targeting the modifiable fraction of this endophenotype might be a promising strategy to slow down disease progression in individuals with specific allelic configurations.
ABHD6 inhibition alleviates memory deficits in an Alzheimer’s disease mouse model
Authors: Zhu Xiaolei , Xu Yun 
Published: December 2023

AbstractBackgroundSynaptic dysfunction plays a crucial role in the pathogenesis of Alzheimer’s disease (AD). α/β‐hydrolase domain‐containing 6 (ABHD6) inhibition has shown potential therapeutic values in several neurological disorders. However, the role of ABHD6 in AD has not been fully defined.MethodAdeno‐associated virus (AAV) mediated shRNA targeting ABHD6 (AAV‐sh‐ABHD6) was slowly injected into bilateral hippocampus of APPswPS1dE9 (APP/PS1) mice, or ABHD6 inhibitor wwl70 was intraperitoneally injected into APP/PS1 mice for 30 days. The behavioral tests including Open field, New object recognition, Y maze, Morris water maze and Fear condition were performed. Synaptic transmission, dendritic spine density and synaptic proteins levels were investigated by electrophysiological tests, Golgi staining and western blot respectively. The protein levels of amyloid β peptide (Aβ), GFAP and Iba1 were determined by Immunostaining.ResultThe expression of ABHD6 was significantly increased in the hippocampus of APP/PS1 mice. AAV‐sh‐ABHD6 treatment attenuated synaptic dysfunction and memory impairment of APP/PS1 mice, while it didn’t affect the Aβ levels and neuroinflammation in the brains. In addition, intraperitoneal injection of wwl70 improved the synaptic plasticity and memory function in APP/PS1 mice. Furthermore, wwl70 significantly decreased the Aβ levels and neuroinflammtion in the hippocampus of AD mice, which indicated that wwl70 might exert the neuropreotctive effects not only by neuronal ABHD6 inhibition.ConclusionWe demonstrate firstly that ABHD6 contributes to the memory impairment in AD, and ABHD6 inhibition enhances synaptic plasticity and memory functions in APP/PS1 mice, indicating that ABHD6 inhibition is a promising therapeutic strategy for AD treatment.
Multiple patterns of structural brain change trajectories in AD: MRI deep learning verification with enhanced sequential pattern analysis
Authors: Pan Dan , Zeng An , Song Xiaowei 
Published: December 2023

AbstractBackgroundOur recently proposed interpretable Ensemble 3DCNN deep learning (DL) technique has allowed the derivation of a P‐score based on brain structural magnetic resonance imaging (sMRI) modelling to predict patterned neurodegeneration in AD (https://doi.org/10.1002/advs.202204717). Sequential association rules with a support rate greater than 18% have been used to define a neurodegenerative progression pattern. To more prudently test the meaningfulness of the patterns found, we further calculated the lift values of the various sequential patterns underlying the suggested longitudinal sMRI changes.MethodThe lift value of an association rule is defined as the rule’s confidence rate divided by the support rate of the rule consequent, i.e., the support rate of the rule divided by the product of the support values of the rule consequent and the rule antecedent. For example, with {L.NAC}→{L.NAC, R.NAC} (https://doi.org/10.1002/advs.202204717), among the 167 AD subjects employed for analyzing neurodegenerative progression patterns, the number (N) of the subjects with at least an sMRI image containing both L.NAC and R.NAC as neurodegenerative regions at all time points examined was firstly calculated. Secondly, among the above‐mentioned 167 AD subjects, the number (M) of the subjects with at least an sMRI image containing only L.NAC as neurodegenerative regions at all time points examined was counted and the time point (P) corresponding to the selected (earlier/earliest) sMRI image was saved. Thirdly, among the above selected M subjects, the number (K) of the subjects with at least an sMRI image containing both L.NAC and R.NAC as neurodegenerative regions at all time points latter than the P was computed. Thus, lift value = (K/M)/(N/167).ResultThe lift values of the fifty sequential association rules reported in the recent paper (https://doi.org/10.1002/advs.202204717) ranged between 1.27 and 2.59(i.e., all > 1; Table 1), further confirming the longitudinal sMRI change patterns in AD.ConclusionThis study analyzing the lift values of the sequential association rules further verified the multiple patterns of longitudinal sMRI trajectories in AD brains, as reported recently. The research demonstrated featured and heterogeneous whole‐brain structural degeneration with AD progression.
Reduced visual associative learning is linked to Alzheimer’s disease pathology
Authors: Dubbelman Mark A. , Tomassen Jori , van der Landen Sophie M. , Bakker Els D. , Kamps Suzie , van Unnik Annemartijn A. J. M. , Glind Marie‐Christine M.A.B.J. , van der Vlies Annelies , Koene Teddy , Barkhof Frederik , van Harten Argonde C. , Teunissen Charlotte E. , Giessen Elsmarieke , van der Flier Wiesje M. , Sikkes Sietske A.M. 
Published: December 2023

AbstractBackgroundReduced learning is an early sign of memory impairment and relevant in the context of Alzheimer’s disease. The Visual Association Test (VAT) is a brief visual associative memory task comprising two sets (A and B) of six interactive pictures (e.g., a monkey holding an umbrella). We hypothesized that the VAT may be able to elicit learning deficits on set B when administered directly following set A, particularly in patients with Alzheimer’s disease‐related episodic memory deficits. We related learning on the VAT to medial temporal lobe atrophy (MTA) and amyloid‐β positivity.MethodWe selected 3,599 patients (63.9±8.9 years, 41% female) who completed two VAT sets. Patients had subjective cognitive decline (n = 1,369, 38%), mild cognitive impairment (n = 756, 21%), Alzheimer’s disease dementia (n = 856, 24%), or other types of dementia (n = 618, 17%). Average MTA scores of both hemispheres from magnetic resonance imaging were available for all; amyloid‐β status was obtained from cerebrospinal fluid or positron emission tomography for n = 2,769 (77%). We modeled learning curves on both VAT sets using linear mixed models, including an interaction with amyloid‐β status. Using logistic regressions, we analyzed the relationship between learning of associations on both sets (either all associations on both sets, or all associations on the first, but not the second set) and MTA, as well as amyloid‐β status.ResultMost patients learned all associations on both sets (n = 2,442, 68%). Patients who learned all associations on the first, but not the second set (n = 640, 18%) were more likely to have higher MTA scores and to be amyloid‐β positive than those who learned all associations (Table 1). Figure 1 shows learning curves on both sets of the VAT, stratified by amyloid‐β status. Less steep learning curves seem to suggest that amyloid‐β positive patients benefited less from completing a first set than amyloid‐β negative patients.ConclusionWe observed reduced learning on the second set, with those who did not learn all associations on both sets having more medial temporal lobe atrophy and more often being amyloid‐β positive. The VAT may be a useful, simple tool to assess early episodic memory deficits in the presence of Alzheimer’s disease pathology.
Dynamical irreversibility, high‐order interactions, and whole‐brain modeling of gamma oscillations in neurodegeneration
Authors: Cruzat Josefina A , Herzog Ruben A , Coronel‐Oliveros Carlos , Prado Pavel , Gonzalez‐Gomez Raul , Moguilner Sebastian , Medel Vicente , Rosas Fernando E. , Taglizucchi Enzo , Ibanez Agustin 
Published: December 2023

AbstractBackgroundAbnormal gamma oscillations (γ) have been systematically reported in preclinical animal models of Alzheimer’s disease (AD) and human AD patients. However, little is known about the underlying mechanisms, non‐linear dynamics, and high‐order interactions of γ in dementia.MethodTo bridge this gap, we combined EEG and fMRI with three novel approaches to offer a comprehensive pathophysiological characterization of γ oscillations: We assessed the irreversibility of large‐scale brain dynamics to provide a precise signature capable of distinguishing AD at the global, local and network levels and at different oscillatory regimes (study 1). A high‐order functional connectivity (HOFC) multivariate information theory approach capturing interactions between 3 or more regions across spatiotemporal scales was compared with standard connectivity metrics for dementia characterization (study 2). A whole‐brain semi‐empirical model with a perturbational approach combined EEG, structural connectivity, and atrophy to explain the disrupted high‐order interactions observed in AD (study 3).ResultsStudy 1: AD was associated with a breakdown of temporal irreversibility at the global, local, and network levels at γ and other oscillations. The irreversibility of brain dynamics provided higher accuracy and more distinctive information than classical neurocognitive measures when differentiating AD from controls. Study 2: EEG‐HOFC revealed hypoconnectivity in γ between frontal, limbic, and sensory regions in AD, and large effect sizes, compared to standard pairwise metrics, proving a more accurate and parsimonious characterization of AD and frontotemporal dementia (FTD) patients. Study 3: whole‐brain modeling showed that a combined mechanism involving reduced structural integration (DTI) and hypo‐excitability (altered excitation/inhibition balance) triggered the altered high‐order interaction γ dynamics observed in AD and FTD. A perturbational approach identified physiopathological regions (SFG, MTG, precuneus) deviating the trajectories from disease to a healthy brain state.ConclusionThe present results offer new evidence regarding the pathophysiological link, mechanistic processes, and non‐linear whole‐brain dynamics between altered resting‐state γ rhythms and the characterization of AD and FTD, opening new avenues for dementia research at different levels.
Alabama Brief Cognitive Screener scores correlate proportionally with MoCA and DRS‐2 scores and vary appropriately by diagnosis
Authors: Pilonieta Giovanna , Murchison Charles F , Love Marissa C. Natelson 
Published: December 2023

AbstractBackgroundThe Alabama Brief Cognitive Screener (ABCs) was developed as a nonproprietary replacement for the MMSE (Mini‐Mental State Examination) in order to screen for cognitive deficits. It requires 5‐10 minutes to complete and participants can score up to 30 points.MethodTo assess the clinical correspondence of Alabama Brief Cognitive Screener (ABCs) scores relative to both the Montreal Cognitive Assessment (MoCA) and Dementia Rating Scale (DRS‐2) and also compare score differences by education attainment and the subject’s clinical diagnosis‐ of either Normal Cognition (NC), Mild Cognitive Impairment (MCI), or Dementia. Participants from the UAB Alzheimer’s Disease Center (ADC) from 2018 to 2022 were analyzed retrospectively. The ABCs, MoCA, and DRS‐2 were administered at the initial visit to subjects (n = 116) and their scores were compared to each other using Spearman’s rank correlation along with their clinical diagnosis which included NC (n = 47), MCI (n = 41) and Dementia (n = 28) and their previous education using the Kruskal‐Wallis test.ResultMedian scores for all three assessments were found to be associated with clinical diagnosis (MoCA: χ2 = 62.3, p = <.0001; ABCs: χ2 = 51.3, p = <.0001; DRS‐2: χ2 = 56.5, p = <.0001) and education level (MoCA: χ2 = 24.8 p = <.0001; ABCs: χ2 = 18.1, p = 0.0001; DRS‐2: χ2 = 11.15, p = 0.0038). Cognitive differences observed higher scores in the cognitively unimpaired relative to either MCI or subjects with dementia and in subjects with college or graduate degrees compared to those with only a high school education. Strong correspondence was observed between all assessments with significant correlations for all pairwise comparisons (MoCA v ABCs: ρ = 0.73; MoCA v DRS‐2: ρ = 0.72; ABCs v DRS‐2: ρ = 0.61, p = <.0001). When comparing sub‐types of the ABCs and DRS‐2, significant correlations were observed in the domains of memory (ρ = 0.61, p<0.001), attention (ρ = 0.26, p = 0.0054), construction (ρ = 0.37, p<0.001), and conceptualization (ρ = 0.30, p = 0.011).ConclusionABCs correlates proportionally with MoCA and DRS‐2 scores while also varying appropriately by diagnosis. ABCs shows promise as a non‐proprietary alternative to the MMSE for use as a screening instrument to identify and assess severity of cognitive deficits in medical practice, as well as measure progression of those deficits in patients with neurodegenerative disease.
Computerized Games versus Crosswords Training in Mild Cognitive Impairment: The COG‐IT trial
Authors: Devanand Davangere P. 
Published: December 2023

AbstractBackgroundMild cognitive impairment (MCI) increases the risk of dementia. The efficacy of cognitive training in MCI is unclear.MethodIn a two‐site, single‐blinded, 78‐week trial, participants with MCI — stratified by age, severity (early/late MCI), and site — were randomly assigned to 12 weeks of intensive, home‐based, computerized training with Web‐based cognitive games or Web‐based crossword puzzles, followed by six booster sessions. In mixed‐model analyses, the primary outcome was change from baseline in the 11‐item Alzheimer’s Disease Assessment Scale‐Cognitive (ADAS‐Cog) score, adjusted for baseline. Secondary outcomes included change from baseline in neuropsychological composite score and Functional Activities Questionnaire score at 78 weeks, adjusted for baseline. Changes in hippocampal volume and cortical thickness on magnetic resonance imaging were assessed.ResultAmong 107 participants (n = 51 [games]; n = 56 [crosswords]), ADAS‐Cog11 score worsened slightly for games and improved for crosswords at week 78 (least squares [LS] means difference, 21.44; 95% CI 22.83 to 20.06; P = 0.04). From baseline to week 78, mean ADAS‐Cog score worsened for games (9.53 to 9.93) and improved for crosswords (9.59 to 8.61). The late MCI subgroup showed similar results (LS means difference, 22.45; SE, 0.89; 95% CI 24.21 to 20.70). Among secondary outcomes, the Functional Activities Questionnaire score worsened more with games than with crosswords at week 78 (LS means difference, 21.08; 95% CI 21.97 to 20.18, p = 0.02). Other secondary outcomes showed no differences. Decreases in hippocampal volume and cortical thickness were greater for games than for crosswords (LS means difference, 34.07; SE, 17.12; 95% CI 0.51 to 67.63, p < .05 [hippocampal volume]; LS means difference, 0.02; SE, 0.01; 95% CI, 0.00 to 0.04, p = .02 [cortical thickness]).ConclusionHome‐based computerized training with crosswords demonstrated superior efficacy to games at 78 weeks. Common directionality was observed in the primary outcome of ADAS‐Cog (cognition) and the secondary outcomes of FAQ (function) score and changes in MRI hippocampal volume and cortical thickness (neurodegeneration). If these effects are replicated and expanded in future trials with the inclusion of a control group that does not receive cognitive training, crossword puzzles training could become a home‐based, scalable, cognitive enhancement tool for individuals with MCI.