bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multimodal omics analytic framework identifies microglial immunometabolism endophenotypes underlying sex differences in Alzheimer’s disease
Authors: Hou Yuan , Xu Jielin , Bekris Lynn M. , Pieper Andrew A. , Cummings Jeffrey L. , Leverenz James B , Cheng Feixiong 
Published: December 2023

AbstractBackgroundAlthough Alzheimer’s disease (AD) is sexually dimorphic in prevalence, incidence, symptomology, and neuropathology, the molecular mechanisms underlying AD sex differences are incompletely understood.MethodIn this study, we investigated the interplay between cellular metabolism and immune responses (termed the “immunometabolism endophenotype”) by unique integration of single nuclei transcriptomics (snRNA‐seq) and metabolomics from the AD knowledge portal, the Alzheimer’s Disease Metabolomics Consortium, and the Cleveland Alzheimer’s Disease Research Center. We conduced pathway activity score (PAS) to investigate metabolic alteration in microglia and astrocytes from brain cortex, with PAS > 0 indicating a specific cell type with higher average gene expression within a pathway, relative to all remaining cell types.ResultWe found that female AD subjects had a reduced PAS score within the TNFR2 non‐canonical NF‐kB pathway in microglia compared to male AD subjects, indicating reduced anti‐inflammatory effects of microglia in women. In addition, women with AD also showed lower PAS score within the branched chain amino acid pathway. Integrative sc/snRNA‐seq data analysis also shows sex‐specific metabolic cell‐cell communications among microglia, astrocytes and neurons. For example, male AD subjects have higher metabolic communication between astrocytes and excitatory neurons. In particular, astrocytes show lower PAS distribution across 84 metabolic pathways in women with AD, compared to men with AD. Astrocytes in female AD subjects showed deceased PAS within creatine metabolism pathways and increased PAS within threonine catabolism pathways.ConclusionThis study demonstrates proof‐of‐concept of microglial immunometabolism underlying sex differences in AD.
The Evaluation on the Challenges of Current Assessment Tools Measuring Caregiver Intensity
Authors: Tkatch Rifky 
Published: December 2023

AbstractBackgroundFamily members caring for individuals with Alzheimer’s disease demonstrate higher levels of burden and stress than other caregivers. Caregiver intensity is characterized as the number of tasks and hours caregivers care for the recipient and, as a construct, has demonstrated a more comprehensive assessment of the caregiver experience. Furthermore, because caregiver experience is intertwined within the patient journey, current measures of caregiver burden/intensity do not encapsulate the full construct as described and can be difficult to administer in real world settings.ObjectiveThis session reviews and evaluates current assessment tools measuring caregiver intensity/burden, gaps in measurement, methodology used to implement these measures, associated health economic outcomes, and challenges implementing these measures.MethodsA systematic review of the current assessment tools including the Zarit Burden Interview‐S, Caregiver‐Perceived Burden Questionnaire, Caregiver Burden Scale and the Caregiver Burden Inventory. Domains within each measure, length and burden to respondent and associated outcomes will be assessed.ResultsCurrent measures of caregiver burden/intensity have strengths and limitations in their use. Some do not fully capture the caregiver burden/intensity construct, are limited to a single domain, and exclude recipient progression.ConclusionThe inadequate nature caregiver intensity/burden measurement suggests the construct and its associated clinical, psychosocial, and economic outcomes are likely underreported. The practicality of implementing lengthy and complex measures in a real‐world setting is challenging. Unique approaches that include the intensity of caregiver experience, the patient and caregiver as a “dyadic patient” navigating the patient journey, and multiple domains (financial, social, physical etc.) should be considered. This would provide meaningful information when designing and implementing both caregiver and patient interventions.
Effect of Alcohol Use on Progression to Mild Cognitive Impairment and Dementia
Authors: Joshi Pallavi , Chen Yinghua , Su Yi , Reiman Eric M. 
Published: December 2023

AbstractBackgroundAddressing modifiable risk is an important part of a comprehensive strategy to reduce the risk of incident mild cognitive impairment (MCI) and dementia. Alcohol use is one modifiable risk factor with good potential for early identification and intervention. Substantial evidence demonstrates that chronic and heavy alcohol use increases the risk of dementia, but the effect of infrequent alcohol use versus moderate to heavy use on the risk for progression from cognitively unimpaired (CU) to MCI or from MCI to dementia is not known.MethodWe used data from Alzheimer’s Disease Research Center participants at least 65 years of age in the National Alzheimer’s Coordinating Center (NACC) database to examine the relationship between two levels of self‐reported alcohol use on rates of clinical progression from CU to MCI and from MCI to dementia. Cox proportional hazard models were used to characterize and compare rates of clinical progression over 84 months in a) 418 CU and 137 participants who reported no/infrequent use and b) 49 CU and 203 MCI participants who reported moderate/heavy use, after controlling for age, sex, educational level, presence or absence of APOE4, and Hispanic ethnicity. Kaplan‐Meier survival analysis was used to assess the progression odd‐ratio and time to conversion differences between the moderate/heavy alcohol users and no/infrequent users as the primary statistical method, and simple Chi‐square test to secondarily examine prevalence differences.ResultThere was no significant difference in alcohol use in CU and MCI impaired groups at baseline and no significant differences in risk of progression from either CU to MCI (p = 0.14) or from MCI to dementia (p = 0.32).ConclusionThis study was unable to detect a significant difference between self‐reported low/infrequent and moderate/heavy alcohol use on rates of progression to MCI and dementia. Larger studies could address potential differences with greater statistical power; and emerging blood‐based biomarkers could be used in legacy plasma samples to clarify the extent to which different levels of alcohol use have any preferential impact on Alzheimer’s disease and related disorders.
QEEG‐based TabNet classifier for dementia pathologies: Alzheiemer’s disease and Lewy body disease
Authors: Jeong Hyerin , Park Ukeob , Baik Kyoungwon , Ye Byoung Seok , Kang Seung Wan 
Published: December 2023

AbstractBackgroundEarly screening and prevention of dementia are widely discussed and studied in the current healthcare paradigm. However, about 70 percent of dementia diagnoses are categorized into Alzheimer’s disease (AD), neglecting the presence and influence of Lewy body. The present study aims to distinguish Alzheimer’s disease dementia (pure AD) and Lewy body dementia (pure LBD) through quantitative electroencephalogram (QEEG)‐based classification algorithm. The mixed dementia that exhibits both AD and LBD related propensities were further tested for the verification of the established classification model.Method19 channel EEG data were recorded in accordance with the 10‐20 system in eyes‐closed resting state. The acquired data were bandpass filtered into the range of interest (1‐45Hz) and re‐referenced into common average reference. Artifacts were removed by bad epoch rejection and independent component analysis (ICA) through an automated, cloud‐based QEEG analysis platform iSyncBrain®. Henceforth, sensor‐level features were extracted and computed for the training of TabNet structure. Due to the data imbalance (N = 146, Pure AD = 48, Pure LBD = 102), time window‐based augmentation has been applied to establish the final dataset (N = 7292, Pure AD = 3376, Pure LBD = 3916), which were then split into 8 to 2 ratio for the training and testing of the classification model. In addition, mixed dementia (N = 136) data were used to further validate the model’s performance.ResultThe best classification model yielded test accuracy of 80% with pure AD sensitivity at 80% and pure LBD sensitivity 80%. Moreover, the predicted probability distribution for the mixed dementia data were prominently concentrated around 0.5, which reflect that both pure AD and LBD properties exist.ConclusionAlong with the promising classification performance of the established classification model, the centered probability distribution of the mixed dementia data reflect that the model can well distinguish the characteristics that are specific to pure AD and LBD.
Tau pathology relates to regional microstructural alterations of cerebral white matter in older adults with diverse cognitive spectrum
Authors: Kong Nayeong , Yi Dahyun , Byun Min Soo , Jung Joon Hyung , 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 
Published: December 2023

AbstractBackgroundGrowing evidences suggest that degeneration of cerebral white matter (WM) occurs in Alzheimer’s disease (AD) independently of cerebrovascular risks or injury. Previous studies using diffusion tensor imaging (DTI) have reported a loss of WM microstructural integrity in the corpus callosum (CC) and cingulum (CG) in AD dementia and mild cognitive impairment (MCI). However, only limited information is available for the relationship of in vivo AD‐specific pathologies including beta‐amyloid (Aβ) and tau accumulation with WM microstructal alterations. Thus, we aimed to examine the association between in vivo AD pathologies and microstructural integrity of the CC and CG through cross‐sectional and longitudinal approaches.MethodA total of 170 (74 cognitively normal, 58 MCI, and 38 AD dementia) older adults from the Korean Brain Aging Study for the Early diagnosis and prediction of Alzheimer’s disease cohort were included. All participants underwent comprehensive clinical assessment and multi‐modal brain imaging including [11C]‐Pittsburgh‐Compound‐B‐positron emission tomography (PET), 18F‐AV‐1451 PET, and DTI. The mean fractional anisotropy (FA) values were obtained for 2 regions of interests, the CC and CG on DTI. The data was analyzed using linear regression model adjusted for age, sex, APOE4 positivity, and vascular risk factor score. Regression‐based mediation analysis was also conducted to assess the mediation of tau for the relationship between Aβ and FA.ResultIn cross‐sectional analyses for baseline data, global tau deposition had a significant negative association with both CC and CG FA (β = ‐0.013, p = 0.004 and β = ‐0.011, p = 0.002), while global Aβ retention showed a negative association with only CG FA (β = ‐0.015, p = 0.004). Longitudinal analyses revealed that higher tau deposition at baseline was associated with both greater reduction of both CC and CG FA over 2 years (β = ‐0.010, p = 0.001 and β = ‐0.005, p = 0.046), whereas Aβ was associated with neither CC nor CG FA change over the period. Additional mediation analysis demonstrated that the cross‐sectional association between Aβ and CG FA was mediated by tau deposition, while there was no direct relationship between the two.ConclusionOur findings suggest that regional alterations of WM microstructural integrity in MCI and AD dementia, which occurs independently of vascular risks, are mainly related with tau pathology rather than amyloid pathology.
The relationship between executive dysfunction‐associated activities of daily living (ADL) and the pattern of Clinical Dementia Rating (CDR) in patients with vascular dementia and age‐matched patients with Alzheimer’s disease
Authors: Park Joon Hyuk , Yang Hyun‐Ju 
Published: December 2023

AbstractBackgroundClinical dementia rating (CDR) scale was originally developed to stage the severity of Alzheimer’s dementia (AD) but is now used globally regardless of types of dementia. This study aims to investigate the relationship between the characteristic pattern of CDR domains, neuropsychological findings, and activities of daily living (ADL) in patients with vascular dementia (VaD), compared with age‐matched patients with AD.MethodVery mild to mild VaD and AD patients matched for age were recruited among the first visitors to a dementia clinic. All subjects were administered a standardized clinical interview, physical and neurological examinations, and laboratory tests including the brain MRI according to the protocol of the Korean version of the CERAD assessment battery.ResultOne hundred and five pairs of VaD and AD patients participated in this study. Although the adjusted scores on MMSE were similar between two groups and the performances on Boston naming, word list memory, word list recall, word list recognition, constructional recall test were better in VaD patients, the scores on global CDR, CDR sum of box (SOB), and ADL‐related CDR domains were higher in VaD patients than in AD patients (p<0.001). The poor performances on disability assessment for dementia scale, frontal assessment battery, executive clock drawing task, and Stroop tests were observed in VaD patients.ConclusionDespite similar general cognitive function and better memory function, patients with VaD tend to be staged as severer dementia on the CDR scale than patients with AD because of more impaired ADL associated with executive dysfunction.
Comparison of two semi‐quantitative amyloid PET analysis methods with and without MRI in Alzheimer’s Disease Spectrum Disorder
Authors: Yang Dong Won , Lee Chonghwee , Cho Jung hee , Hong Yun Jeong , Shin Seong A 
Published: December 2023

AbstractBackgroundStandardized uptake value ratio (SUVR) is a standard method for amyloid PET analysis. 3D T1 MRI imaging is required for accurate spatial normalization in SUVR measurement to overcome regional cortical atrophy in neurodegenerative disorders like Alzheimer’s disease spectrum disorders. The SUVR method without 3D MRI has recently been developed for clinical application. We compared two SUVR methods with and without 3D MRI for the semi‐quantitative analysis of global and regional amyloid loading in Alzheimer’s disease spectrum disorders.Method75 subjects (normal cognition 8, subjective cognitive decline 20, mild cognitive impairment 23, Alzheimer’s disease dementia 24) were selected in the single dementia clinic for the analysis. For the SUVR measurement with 3D T1 MRI, in‐house software with SPM8 and MATLAB was used. For the SUVR measurement without 3D T1 MRI, AI‐based automated PET quantitative analysis software (called ‘BTXBrain‐Amyloid‐Research’) was developed by Brightonix Imaging Inc. With the visual PET reading as a gold standard, we compared regional and global SUVR between groups. Intra‐class correlation coefficient(ICC) was used to test the validity of the two methods.ResultGlobal SUVR was higher in amyloid PET positive SCD group (SUVR with MRI (1.205 V.S. 1.635), SUVR without MRI (1.210 V.S. 1.599)). The mean global SUVR with MRI and without MRI of 75 subjects were 1.400 (S.D. 0.264) and 1.390(S.D. 0.237). ICC of global SUVR between the two methods was 0.950, p = 0.0001. Regional SUVR ICC were 0.941 in the prefrontal cortex, 0.953 in the orbitofrontal cortex, 0.947 in the anterior cingulate, 0.844 in the posterior cingulate, 0.955 in the lateral parietal cortex, 0.962 in the precuneus, 0.959 in the lateral temporal cortex, and 0.94 in the occipital cortex. The area under the curve of ROC curve analysis of both two methods to diagnose amyloid PET positivity was 0.98 and 0.97.ConclusionAI‐based automated PET quantitative analysis software of Brightonix imaging without MRI was valid as an MRI‐based SUVR method in Alzheimer’s disease spectrum disorders with variable brain atrophy. Short processing time (30 ‐40 seconds) and reliable SUVR measurement without 3D MRI benefit the Alzheimer’s disease diagnosis in clinical practice.Grant from the Ministry of Health and Welfare, HI18C0530, Seoul R&BD Program(BT200151)
Neuroprotective effect of inosine against aluminium chloride (AlCl3) induced experimental dementia of Alzheimer type in Wistar Rats
Authors: Agrawal Mohit , Singhal Manmohan , Chaudhary Hema 
Published: December 2023

AbstractBackgroundAlzheimer disease is a neurodegenerative disorder that is identified by the loss of memory, cognitive function and muscle coordination and various memory related task. Various studies throughout the decades have shown that oxidative stress plays one of the key role in initiating the Alzheimer Disease.MethodAs the oxidative stress is majorly caused by the reactive oxygen species it is proven in various studies that the antioxidants are quite effective against the ROS to induce the oxidative stress in the brain the AlCl3 chemical is used as it is proven that AlCl3 model for the inducing dementia is a neurotoxic metal that can cause neurodegeneration by oxidative stress. As the Inosine is one of the naturally occurring potent antioxidant it can be quite effective against the ROS and protecting the brain from the oxidative stress and could help in improving the various memory and motor dysfunctionsResultIn this study we have selected 36 Wistar rats divided in a 6 group each containing 6 rats each weighing 150gm‐200gm. Various behavioural analysis were conducted at every week which were, Morris Water Maze, Novel Object recognition Test, open field test and Actophotometer. And the day of 30th day the brain was isolated from the rats specifically the cortex and the hippocampus region of the brain for various biochemical estimations which are Lipid Peroxidation, Glutathione Reduction (GSH), Superoxide Dismutase and Nitrite Estimation in the Brain.ConclusionThe present study suggests that Inosine show beneficial effects in treating Alzheimer diseases. Our data demonstrated that Inosine could be effective in the protection of toxicity induced by Aluminium chloride (AlCl3)
Vascular contribution to the preclinical Alzheimer’s disease pathological changes: Insights from the EPAD cohort
Authors: Lorenzini Luigi , Maranzano Alessio , Tranfa Mario , Collij Lyduine E. , Sudre Carole H , Wolz Robin , Haller Sven , Blennow Kaj , Frisoni Giovanni B , Payoux Pierre , Martinez‐Lage Pablo , Ewers Michael , Chetelat Gael , Waldman Adam , Wardlaw Joanna M , Fox Nick C , Ritchie Craig W , Scheltens Philip , Visser Pieter Jelle , Wink Alle Meije , Mutsaerts Henk‐Jan , Gispert Juan Domingo , Ingala Silvia , Barkhof Frederik 
Published: December 2023

AbstractBackgroundThe role of cardiovascular risk factors and cerebral small vessel disease (CSVD) on the sequences of Alzheimer’s Disease (AD) pathological events remains to be determined.MethodWe included 1592 non‐demented participants from EPAD‐LCS (Table‐1). Linear models were used to study associations between the Framingham score (FRS) and CSF‐Aβ1‐42; CSVD indices (visual assessment for perivascular spaces [PVS] in the basal ganglia [BG] and centrum‐semiovale [CS], periventricular and deep white matter hyperintensities [WMHs], presence of lobar or deep cerebral microbleeds [CMBs], and lacunes, and quantification of global and lobar WMH volumes) and Aβ1‐42 and p‐Tau181, including an interaction between CSVD indices and Aβ1‐42 for the latter. Hippocampal volumes (HCV) were quantified using LEAP. Structural equation models (SEM) were used to assess the association between clinical variables as described in Figure‐1. Models were corrected for age, sex, site and multiple comparisons.ResultHigher FRS scores were associated with lower CSF Aβ1‐42 (β = ‐0.18; p<0.001) and higher P‐tau181 (β = 0.21; p<0.001). Aβ1‐42 was negatively associated with all CSVD markers (all p<0.001; Figure‐2).We found stronger association between Aβ1‐42 and P‐tau181 in participants with higher Fazekas deep and periventricular (p‐interaction<0.005) scores, and higher regional WMH (all p‐interactions<0.005) volumes.Using SEM, the CSVD‐burden latent factor fully mediated the association between FRS and Aβ1‐42 (indirect effect: β = ‐0.03; p<0.001). Aβ1‐42 did not significantly predict the CSVD‐burden latent factor. We observed a significant direct effect of Aβ1‐42 on P‐tau181 levels (β = ‐0.14; p<0.001) and HCV (β = 0.06; p<0.05), and of P‐tau181 levels onto HCV (β = ‐0.05; p<0.05). A significant indirect, but not direct, effect of the latent factor on both P‐tau181 (indirect effect: β = 0.36; p < 0.05) and HCV (indirect effect: β = ‐0.24; p < 0.05) through Aβ1‐42 was observed.ConclusionExpression of cerebrovascular pathology fully mediates the effects of vascular risk factors on amyloid and accelerates manifestation of downstream biomarkers in the preclinical phases of AD, stressing the importance of vascular‐protective treatments.
Deficits in mitochondrial function and glucose metabolism seen in sporadic and familial Alzheimer’s disease derived Astrocytes are ameliorated by increasing hexokinase 1
Authors: Bell Simon M , Wareing Hollie , Hamshaw Alexander , De Suman , New Elizabeth , Shaw Pamela , De Marco Matteo , Venneri Annalena , Blackburn Daniel J , Ferraiuolo Laura , Mortiboys Heather 
Published: December 2023

AbstractBackgroundAstrocytes have multiple roles including providing neurons with metabolic substrates and maintaining neurotransmitters at neuronal synapses. Astrocyte glucose metabolism plays a key role in learning and memory with astrocytic glycogen a key substrate supporting memory encoding. The homeostatic role the astrocyte provides for neurons leads to metabolic demands, meaning that abnormalities in the function of astrocyte mitochondria and glycolysis could affect this relationship. Changes to cellular metabolism are seen early in Alzheimer’s disease (AD). Understanding cellular metabolism changes in AD astrocytes could be exploited as a new biomarker or synergistic therapeutic agent when combined with anti‐amyloid treatments in AD.MethodsIn this project, we characterised mitochondrial and glycolytic dysfunction in astrocytes derived from patients with sporadic (n = 6) and familial (PSEN1, n = 3) AD, and associated controls (n = 9). Astrocytes were derived using direct reprogramming technology. Astrocyte metabolic outputs; ATP, and extracellular lactate levels were measured using luminescent and fluorescent protocols. Mitochondrial respiration and glycolytic function were measured using a Seahorse XF Analyzer. Hexokinase deficits identified where corrected by transfecting astrocytes with an adenovirus viral vector containing the hexokinase 1 gene.ResultsIn sAD astrocytes a 20% reduction (p = 0.05) and in fAD a 48% (p<0.01) reduction in total cellular ATP was seen. A 44% reduction (p<0.05), and 80% reduction in Mitochondrial spare capacity was seen in sAD and fAD respectively. Reactive oxygen species (ROS) where increased in both AD astrocyte types (p = 0.05). Mitochondrial complex I and II was significantly increased in sAD (p<0.05) but not in fAD. Astrocyte glycolytic reserve and extracellular lactate was significantly reduced when compared to controls in both sAD and fAD (p<0.05). We identified that astrocytes had a deficit in the glycolytic pathway enzyme hexokinase, and that correcting this deficit restored total cellular ATP levels, extracellular lactate and reduced ROS in sAD but not fAD astrocytes.ConclusionAD astrocytes have abnormalities in functional capacity of mitochondria and the process of glycolysis. These deficits are likely to impede metabolic support for neurons. These functional deficits can be improved by correcting hexokinase deficits. This suggests that hexokinase 1 deficiency could potentially be exploited as a new therapeutic target for AD.