bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diffusion MRI subnetwork efficiency is associated with cognitive resilience to AD pathology in cognitively unimpaired older adults at risk of AD dementia
Authors: Qiu Ting , Liu Zhen‐Qi , Strikwerda‐Brown Cherie , St‐Onge Frederic , Binette Alexa Pichet , Descoteaux Maxime , Villeneuve Sylvia ,   the PREVENT‐AD Research Group
Published: June 2023

AbstractBackgroundWhile higher levels of Aβ and tau pathology are typically associated with more pronounced cognitive decline in Alzheimer’s disease (AD), some older adults exhibit normal cognition even with a substantial burden of AD pathology. This phenomenon is known as ‘cognitive resilience’. The potential role of structural connectivity in cognitive resilience remains inconclusive. The present study tested whether higher global efficiency in structural brain networks moderate the relationship between AD pathology and cognitive performance in the preclinical phase of AD.MethodWe studied 118 cognitively normal older adults from the family history enriched Prevent‐AD cohort. Diffusion‐weighted MRI was used to measure the structural connectome, PET to measure global Aβ (18F‐NAV4694) and entorhinal tau (18F‐Flortaucipir) pathology, and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to evaluate cognitive performance. We first used graph theory analyses to calculate global efficiency of networks known to be affected in early AD (i.e., limbic and default mode network (DMN)). Then multiple linear regressions were performed to examine relationships between Aβ / tau pathology, cognitive performance, and global efficiency of the two subnetworks. Interaction analyses were used to examine whether network efficiency attenuates the relationships between AD pathology and cognitive performance.ResultAs expected, higher levels of Aβ and tau pathology in the brain were associated with worse cognitive performance in individuals at risk of AD (Figure 1). Higher entorhinal tau pathology was also associated with lower global efficiency in the limbic network (Figure 2). Subsequent interaction analyses showed that global efficiency in the limbic moderated the relationships between AD pathology and cognitive performance. Specifically, higher global efficiency was associated with an attenuated effect of both amyloid and tau pathology on delayed memory performance (Figure 3).ConclusionIndividuals with higher global efficiency in the limbic structural network exhibit better memory performance at a given level of AD pathology in preclinical stages of the disease. Structural network properties of the brain may play an important role in maintaining cognitive performance in the face of AD pathology, and could serve as a potential biomarker for cognitive resilience.
CaMKIIα signaling is required for the neuroprotective effects of Dl‐3‐n‐butylphthalide in Alzheimer’s disease
Authors: Li Bingqiu , Xu LingZhi , Jia Jianping 
Published: June 2023

AbstractBackgroundAlzheimer’s disease (AD) is the most common form of neurodegenerative disease and most anti‐AD drugs have failed in clinical trials, hence it is urgent to find effective potential drugs against AD. DL‐3‐n‐Butylphthalide (NBP) is a compound extracted from celery seed and is a multiple‐target drug, and we have demonstrated NBP was effective for improving cognitive and global functioning in patients with subcortical vascular cognitive impairment without dementia and exhibited good safety. Even though there are several studies that have demonstrated the neuroprotective effects of NBP on cognitive impairment, and the mechanisms of NBP remains relatively unexplored.MethodCell viabilities was observed by MTT. Apoptosis and the level of intracellular Ca2+ were examined by flow cytometry. The activation of CaMKIIα signaling was detected by western blotting and immunofluorescence.ResultIn this study, we found that NBP could alleviated the increase of intracellular Ca2+ and reverse down‐regulation of Ca2+/calmodulin‐dependent protein kinase alpha (CaMKIIα) signaling, and rescue neuronal apoptosis in SH‐SY5Y cells treated by Aβ oligomers. Further, we found that these neuroprotection of NBP on neuronal damage and CaMKIIα signaling were abolished when CaMKIIα expression was knock‐downed or its activity was inhibited.ConclusionThus, our findings suggested that CaMKIIα signaling was required for the neuroprotective effects of NBP in AD, and provide an improved basis for elucidation of the mechanism and treatment of NBP in AD.
Comparison of manual dexterity of people with Alzheimer’s disease and cognitively healthy older adults: The impact of cognition
Authors: Menengiç Kübra Nur , Ovacık Uğur , Güngör Feray , Çınar Nilgün , Yeldan İpek 
Published: June 2023

AbstractBackgroundAlzheimer’s disease (AD) not only effects the cognitive level, but also leads to significant decline in motor skill. Manual dexterity emerges with the interaction of cognitive and motor processes and is seen as an important predictor of functional independence. The aim of this study was to compare manual dexterity in people with AD with healthy older adults and to investigate the effect of cognitive level on manual dexterity.MethodThe Nine Hole Peg Test (NHPT) was used for manual dexterity assessment. Cognitive function were assessed with Montreal Cognitive Assessment (MoCA). Statistical analysis was performed by Mann Whitney U Test and regression analysis in SPSS 22.0 package program.ResultTwenty nine people with AD (78.04±6.49, 48.27% female) and ten cognitively healthy older adult (74.8±7.22, 30% female) included study. NHPT results of the dominant hand were 31.87±7.33 sec. and 21.66±2.85 sec.; MoCA scores were 13.79±5.76 and 24.5±2.32, respectively, in the people with AD and cognitively healthy older adults. There was significant difference in NHPT results between groups (p<.001). Significant correlation was found between NHPT and MoCA (p<.001, r = .648). It was found that cognitive level significantly predicted manual dexterity (β = .648, R2 = .42, F [1,27] = 19.58, p<.001).ConclusionManual dexterity in AD shows a significant decrease compared to the cognitively healthy older adults. In our study, it was shown that the decrease in manual dexterity occurs with the effect of cognition at a rate of 42%. Deteriorating manual dexterity with decreased cognition is likely to accelerate patients' withdrawal from activities of daily living. Also, rehabilitation programs that include activities for manual dexterity may slow down the process of participation restriction in AD.
Analysis of Interaction Characteristics Between Amyloid β and Lecanemab by HDX‐MS
Authors: Yamauchi Emiko , Kimura Ayano , Hagiwara Koji 
Published: June 2023

AbstractBackgroundSoluble amyloid‐β (Aβ) aggregates including protofibrils (PFs) have been reported to be more toxic than insoluble fibrils. Recently, pharmaceutical antibodies targeting these soluble Aβ aggregates have been developed. The structural dynamics and heterogeneity of soluble Aβ aggregates have made it difficult to analyze the structural characteristics and tertiary structure. To investigate conformational recognition of lecanemab to Aβ aggregates, the structural characteristics of Aβ PFs and their change upon binding to lecanemab, an antibody with preferential binding to Aβ protofibrils, were studied using hydrogen‐deuterium exchange mass spectrometry (HDX‐MS).MethodAβ (1‐42) PFs were prepared in vitro. The hydrogen/deuterium (H/D) exchange status for Aβ (1‐42) PFs and monomeric Aβ (1‐40) were studied by HDX‐MS in phosphate buffered saline (PBS) to explore characteristics of their regional structural dynamics. The effects of the anti–Aβ PF antibody lecanemab on H/D status of Aβ (1‐42) PFs and monomeric Aβ (1‐40) were studied to explore the structural basis for the characteristics of antibody‐ Aβ interaction and specificity against Aβ PFs.ResultAβ (1‐42) PFs were more protected from H/D exchange throughout the molecule than monomeric Aβ (1‐40), though the N‐terminal and the mid region of Aβ still showed relatively higher H/D exchange in Aβ (1‐42) PFs. Upon interaction with lecanemab, the mid region of Aβ (1‐42) PFs was also protected further in addition to the N‐terminal region, and its protection level of Aβ (1‐42) PFs was higher than monomeric Aβ (1‐40). The higher protection from H/D exchange both on N‐terminal and mid regions of Aβ PFs is considered to be characteristics of interaction between Aβ (1‐42) PFs and lecanemab.ConclusionThe results indicate that the mid region of Aβ has relatively high flexibility in PFs in addition to N‐terminal region. The mid region is suggested to be involved in the interaction with lecanemab as well as its N‐terminal region, and the conformational epitope formation was expected, though there are still possibility of structural change in the mid region upon lecanemab binding. The results indicated that the combinational action on the N‐terminal and mid regions of Aβ are involved in the modulation of Aβ PFs by lecanemab.
A transcriptome association study of AD risk genes in the pathogenesis of Alzheimer’s disease
Authors: McCorkindale Andrew N , Guennewig Boris , Eteleeb Abdallah M , Harari Oscar , Sutherland Greg T 
Published: June 2023

AbstractBackgroundAlzheimer’s disease (AD) affects millions of people with no effective treatments making it vital to identify potential therapeutic targets. Genome‐wide association studies (GWAS) have consistently identified AD susceptibility loci or ‘hits’. Few of these are differentially expressed in brain transcriptomic studies, meaning that their effects may be manifest via interacting or downstream transcripts. We have recently used machine learning on human brain transcriptomic data to identify and validate an association between lactoferrin and amyloid (1). Here we apply the same method to identify the transcripts associated with AD susceptibility ‘loci’.MethodAnalyses were performed on the disease‐linked genes from our machine learning analyses (LTF, ADAMTS2, PPDPF, PRTN3) and the combined 58 GWAS risk loci from two recent studies (2, 3). Boruta was used to find transcripts associated with each GWAS ‘hit’ and our genes of interest in two pathologically confirmed AD cohorts (Religious Orders Study and Memory and Aging project, Mount Sinai Brain Bank). The GWAS hits and associated transcripts were correlated with disease markers (cognition, plaque number, Braak score, CERAD score) to find direct and indirect effects.ResultsTREM2 was the GWAS ‘hit’ most correlated with disease markers in both cohorts but most GWAS ‘hits’ were either not correlated or negatively correlated with disease markers. Among the GWAS ‘hit’‐associated transcripts, SWAP70, EMP3, and WWTR1 were positively and VGF negatively correlated with disease markers in both cohorts. For our genes of interest, ADAMTS2 and PPDPF shared overlaps between their associated transcripts and that of GWAS ‘hit’ ABCA7. LTF was linked with TREM2 and associated with plaques in both cohorts.ConclusionThis study has teased apart nascent associations between known susceptibility genes and gene expression data from the AD brain, but it also hints that consideration of pathological sub‐phenotypes are required to make greater progress in understanding AD pathogenesis.1. Tsatsanis et al. The acute phase protein lactoferrin is a key feature of AD …. Mol Psychiatry. 2021;26(10):5516‐31.2. Yang et al. A human brain vascular atlas reveals diverse cell mediators of AD risk. BioRxiv [Preprint]. 2021.3. Wightman et al. A GWAS with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease. Nat Genet. 2021;53(9):1276‐82.
Deletions/duplications in GRN and MAPT genes is not common in frontotemporal dementia
Authors: Shpilyukova Yuliya , Abramycheva Natalya , Grishina Dinara , Fedotova Ekaterina , Illarioshkin Sergey 
Published: June 2023

AbstractBackgroundFrontotemporal dementia (FTD) is an umbrella term for several syndromes with behavioural and/or language symptoms. Mutations in GRN and MAPT genes are the most frequent genetic cause of FTD in different populations. Our previous data indicate that the frequency of mutations in GRN gene is up to 12.5% in familial FTD cases in Russian cohort of patients. Mutations in MAPT gene were absent in the same cohort. According to the literature, not only point mutation in these genes, but also deletions/duplications can be the genetic cause of FTD.MethodWe analyzed DNA from 50 patients with clinical diagnosis of behavioural variant of FTD, bvFTD (N = 33) and primary progressive aphasia, PPA (N = 17), picture 1. There were 26 familial and 24 sporadic FTD cases. Exon rearrangements were analyzed by MLPA method (SALSA MLPA P275‐C3, MRC‐Holland, Netherlands) using standard protocol. PCR products were separated by size with capillary electrophoresis using genetic analyzer Nanofor 5 (Syntol, Russia). The analysis of result was performed with GeneMarker V3.0.1.ResultWe did not find any deletion or duplication of exons in the GRN and MAPT genes. The results may indicate that this type of mutation is not common in Russian patients with FTD.ConclusionIn 2017‐2021, we identified several point mutations in GRN in Russian patients with FTD; here we show that exon rearrangements in GRN and MAPT genes are not frequent in Russia. According to the literature, only 1.5% of individuals with GRN‐associated forms have deletion or duplication in GRN gene. The data about exon rearrangements in MAPT gene are absent. However, in the case of typical clinical phenotype of GRN‐ or MAPT‐associated form of FTD, MLPA analysis can be recommended.
Chronic brain changes caused by severe systemic inflammatory episode
Authors: da Silva Eduarda J.F. , Bellaver Bruna , da Rocha Andreia Silva , Ferreira Pamela C.L. , Da Ros Lucas Uglione , Venturin Gianina Teribele , Greggio Samuel , da Costa Jaderson Costa , Souza Diogo O. , Zimmer Eduardo R. 
Published: June 2023

AbstractBackgroundSepsis‐associated encephalopathy (SAS) is a neurological complication of a severe systemic inflammatory episode that compromises brain function. This neurological impairment can lead to cognitive dysfunction that appears to precede neurodegenerative disorders such as Alzheimer’s disease. However, the events by which systemic inflammation causes such significant damage to the brain are not yet fully established. With that in mind, this study sought to investigate persistent brain changes after a severe systemic inflammatory episode.MethodMale Wistar rats (90 days old) were divided into two experimental groups: sham (n = 33) and sepsis (n = 37). For the induction of severe systemic inflammation, the animals underwent cecal ligation and perforation (CLP). Animals were followed for 30, 60 and 120 days. In all time‐points, we performed the object recognition task to evaluate declarative memory and Western Blotting to assess astrocyte‐related proteins (GFAP, GLT‐1 and Mao‐B). At 30 and 120 days, we evaluated the ΒBB integrity [cerebrospinal fluid (CSF) albumin levels and cellularity by HCLP] and brain glucose metabolism (FDG‐PET imaging).ResultOur results show that CLP model compromised long‐term memory at 60 and 120 days. Furthermore, we found higher levels of albumin in the CSF in CLP animals compared to sham at 30 (p = 0.023) and 120 days post‐sepsis (p = 0.002). In addition, we also observed an increase in CSF cellularity in CLP animals after 30 days after sepsis induction. We also found persistent glucose whole brain hypometabolism at 30 (local maxima, t(12) = ‐3.7) and 120 days (local maxima, t(9) = ‐8.45), suggesting persistent metabolic abnormalities. Finally, we observed changes in astrocyte‐related proteins. At 30 days, hippocampal GLT‐1 (p<0.001) and cortical GFAP (p < 0.0001) immunocontents were reduced in CLP rats compared to sham. At 60 days, we observed decreased hippocampal GFAP (p < 0,05) and MAO‐B (p < 0.01) immunocontents. At 120 days, we found decreased MAO‐B in the hippocampus (p<0.05).ConclusionWe found that a severe systemic inflammation episode causes persistent changes in brain glucose metabolism and BBB integrity, which seems associated with long‐term memory impairment. In addition, astrocytes seem to be reacting by changing their protein expression, a typical feature of reactive astrocytes.
Relevance of plasma biomarkers to imaging biomarkers
Authors: Nakamura Akinori , Tokuda Takahiko , Kaneko Naoki , Kato Takashi , Tatebe Harutsugu , Nihashi Takashi , Sakurai Keita , Takeda Akinori , Arahata Yutaka , Ito Kengo ,   BATON study group
Published: June 2023

AbstractBackgroundRecent advances in blood‐based biomarkers have shown promising abilities to estimate brain pathological statuses related to amyloid‐β (Aβ) deposition, phosphorylated tau deposition, and neurodegeneration using minimally invasive methods. The objective of this study was to evaluate the potential of blood‐based ATN classification, by analyzing relevance of plasma biomarkers to imaging biomarkers.MethodThere were 161 subjects, consisting of 62 cognitively normal (CN), 13 MCI, 40 Alzheimer’s dementia (AD) and 46 non‐Alzheimer’s dementia (non‐AD) individuals. Plasma Aβ composite biomarker was measured using immunoprecipitation‐mass spectrometry assay by combining plasma ratios of APP669‐711/Aβ1‐42 and Aβ1‐40/Aβ1‐42. Plasma levels of p‐tau 181, glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) were measured using the SimoaⓇ platform. PiB‐PET, THK5351‐PET, FDG‐PET and structural MRI images, and their representative semiquantitative values; PiB‐SUVR, THK‐SUVR, FDG‐PET scores (representing the degree of AD‐like glucose hypometabolism), and VSRAD® scores (representing the degree of medial temporal atrophy), respectively, were used to analyze the relationships with the plasma biomarkers.ResultThe ROC analyses showed that AUCs of plasma Aβ composite, p‐tau 181, GFAP and NfL to discriminate Aβ status (PiB‐positive vs. negative) were 0.934, 0.835, 0.720 and 0.583, respectively. Whereas AUCs of those to discriminate clinical status (CN/MCI vs. dementia) were 0.649, 0.655, 0.800 and 0.803, respectively. Correlations to PiB‐SUVR were stronger in Aβ composite (r = 0.657) and p‐tau 181 (r = 0.551). Both p‐tau and GFAP showed higher correlations to THK‐SUVR (r = 0.444 and 0.416, respectively), and to FDG‐PET scores (r = 0.533 and 0.541, respectively) compared with other biomarkers. Correlations to VSRAD scores were only significant in NfL (r = 0.319). NfL also showed the highest correlation to MMSE scores (r = ‐0.583) (all the above r values were p < 0.001). These results were supported by multiple regression analyses between each imaging data and each plasma biomarker values using SPM8 adjusting for age and sex.ConclusionThe results demonstrated reasonable relationships between the plasma biomarkers and imaging biomarkers, suggesting clinical utility of blood‐based ATN classification. GFAP and NfL are expected to reflect different aspects of neurodegeneration like FDG‐PET and structural MRI.
Subjective cognitive concerns differ by race/ethnicity among einstein aging study (EAS) participants: Implications for assessment and interpretation of self‐perceived cognitive functioning
Authors: Katz Mindy J. , Qin Jiyue , Wang Cuiling , Rabin Laura 
Published: June 2023

AbstractBackgroundSubjective cognitive concerns (SCC) play an important role in the identification of preclinical dementia, especially among individuals who have experienced health disparities. It is critical to discern differential patterns of SCC endorsement among racially/ethnically diverse groups to enhance the ability to accurately capture current and future cognitive status. Moreover, it is important to determine whether the association of SCCs and objective neuropsychological test scores vary by racial/ethnic background.MethodUsing data from the EAS, a longitudinal community residing cohort aged 70+, SCCs were captured using an expanded version of the Cognitive Change Index (CCI‐40), which taps multiple cognitive domains. Objective cognition was measured using the FCSRT and tests from the Uniform Data Set, Neuropsychological Battery (UDSNB3.0). Linear regression models evaluated racial/ethnic differences in SCC at baseline. Additional models for objective cognition examined its association with SCC adjusting for racial/ethnic groups, and furthermore the interaction effects between race/ethnicity and SCC. Covariates included demographics, depressive symptoms, income, and co‐morbidities.ResultWe included 313 participants of non‐Hispanic (NH) White (47%), NH Black (40%) and Hispanic/Latino (13%) racial/ethnic groups who were not demented at baseline. NH Blacks and Hispanic/Latino participants reported significantly more SCC than NH Whites after adjusting for covariates. Higher CCI‐40 scores were associated with worse FCSRT free recall and Trail Making Test Part B performing, adjusting for race and other covariates. When interactions between race/ethnicity and CCI‐40 were included, higher levels of SCC were associated with lower MoCA and FCSRT free recall scores for NH Whites but not for NH Blacks.ConclusionStronger perceptions of self‐reported cognitive decline do not necessarily correspond to worse performance on memory and global cognitive tasks for all racial groups. Although racial/ethnic differences were found in levels of SCC, it is important to investigate factors that may influence self‐perceived cognitive functioning for specific groups (e.g., health status, social support), and the consequential impact on access to healthcare settings (where assessment and diagnosis typically occur). In addition, researchers should consider diversity variables when setting cut points on self‐report questionnaires to enhance diagnostic sensitivity and inform optimal assessment and monitoring needs.
A joint model of network spread and selective vulnerability explains tau pathology spread in Alzheimer’s disease mouse models
Authors: Torok Justin , Raj Ashish 
Published: June 2023

AbstractBackgroundThe propagation and spread of pathology in Alzheimer’s disease (AD) results from the interplay of many complex biological processes. Two key hypotheses have been proposed to help explain the characteristic Braak stageing patterns that define typical AD tau pathology1: network spread, which posits that trans‐synaptic spread of tau determines how pathology progresses2, and selective vulnerability, which states that the regions most affected by tau pathology contain high densities of cell types particularly sensitive to the presence of tau3. Here we explore the explanatory power of each hypothesis in the context of mouse tauopathy models.MethodsWe implemented a mathematical network spread model that extends the Network Diffusion Model2 by adding a linear accumulation term (sNDM). We also utilized the cell type distributions recently made available by the MISS algorithm, which deconvolves spatial transcriptomic data into cell type densities using scRNAseq information4. We fit the sNDM to the Iba, et al. PS19 tauopathy model seeded at the hippocampus5 (IbaHippInj) and the Hurtado, et al. unseeded PS19/PDAPP model6 (Hurtado).ResultsWe find that although network spread is the single‐best correlate of tau pathology, there are many cell types that are highly correlated at the regional level, particularly Layer‐2/3 glutamatergic neurons and Lamp5‐expressing GABAergic neurons (Figure 1). A combined linear model using sNDM predictions and these two cell types (Figure 2) yields higher R2 values than the sNDM predictions alone (Figure 3).ConclusionWe demonstrate that both the network spread and selective vulnerability hypotheses contribute meaningful information for explaining tau pathology in mouse models, indicating that more sophisticated modeling approaches taking into account the full biological complexity of AD have more explanatory power.References:1. Braak, H. & Braak, E. Acta Neuropathol. 82, 239‐259 (1991).2. Raj, A., Kuceyeski, A. & Weiner, M. Neuron (2012).3. Fu, H., Hardy, J. & Duff, K. E. Nat. Neurosci. 21, 1350‐1358 (2018).4. Mezias, C., Torok, J., Maia, P. D., Markley, E. & Raj, A. PNAS. (In press).5. Iba, M. et al. J. Neurosci. 33, 1024‐1037 (2013).6. Hurtado, D. E. et al. Am. J. Pathol. 177, E4376–E4385 (2010).