bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene co‐expression network analyses in Mild cognitive impairment
Authors: Dorsant‐Ardon Valerie , Sanjay Apoorva Bharthur , Rocha Luis M , Correia Rion Brattig , Apostolova Liana G. 
Published: December 2023

AbstractBackgroundMultiomic data analysis has been extensively developed in recent years. Particularly, microarray data can be used as biomarkers of disease of progression specially in pathologies as cancer, autoimmunity and others. (Dahinden et al., 2010; Soleimani Zakeri et al., 2020). This modality of data analysis can also be employed in other multifactorial diseases as Alzheimer’s disease including the progression from normal cognition to mild cognitive impairment and finally to dementia. These genes work in intricate relationship with each other. The establishment of computational gene interaction networks shows the intricacy of the biological systems but increases the complexity of the analysis, for this reason, the removal of redundant edges leaves a network backbone revealing important driver nodes that are essential for the observed interactions, reducing the number of genes of interest and narrowing potential diagnostic or therapeutic targets. (Gates et al., 2021)MethodsWe used data from the ImaGENE study and the Weighted gene co‐expression network analysis (WGCNA) pipeline to analyze gene‐gene interactions of mRNA transcripts obtaining hierarchical clustering of genes and eigengenes in a sample of 160 individuals (Table 1). The backbones were obtained using the shortest path computation. (Gates et al., 2021; Simas et al., 2021). Gene ontology was used to classify processes associated with these genes.ResultsWe identified 42 hubs of differentially expressed genes and we analyzed the top 5 groups with the strongest association with amnestic mild cognitive impairment (MCI) phenotype (pfdr<0.0001). This cluster consisting of 46 genes was further classified according to function and interactions with other nodes in the backbone identifying processes like calcium signaling, nucleotide excision repair, fatty acid metabolism among others.ConclusionThere is an identifiable difference in gene expression in individuals with MCI compared to normal controls. The analysis of the backbone of the gene hubs allowed to reduce the number of genes of interest. This approach can help to elucidate important biological interactions, potential therapeutic targets and could eventually be used as risk factors markers for the development of MCI and AD.
The role of aquaporin‐4 localization in glymphatic impairment and tau aggregation in post‐traumatic neurodegeneration
Authors: Braun Molly , Sevao Mathew , Gino Elizabeth , Keil Samantha A , Pedersen Taylor J , Agarwal Sanjana , Jang Jay , Swierz Justyna , Sanderson Keith , Jansson Deidre , Iliff Jeffrey J 
Published: December 2023

AbstractBackgroundTraumatic brain injury (TBI) is a leading cause of death and disability worldwide and has been established as a risk factor for neurodegenerative diseases such as Alzheimer’s disease (AD). Neurofibrillary tangles (NFTs), aggregates of intracellular tau, are hallmarks of AD and are observed in the post‐TBI brain; however, the mechanisms that contribute to tau aggregation and accumulation are not well understood. One key mechanism that may contribute to this tau aggregation is decreased clearance by the glymphatic system, a perivascular pathway that clears solutes, including tau, from the brain.MethodPS19 mice with tau pathology were crossed with Aqp4−/− mice lacking the astroglial water channel aquaporin‐4 (AQP4) or Snta1−/− mice lacking perivascular localization of AQP4. Behavioral tests were performed on the PS19Aqp4 transgenic crosses at 4 months or 6 months of age. Brain tissue was collected and stained for markers of p‐tau pathology.A mild closed‐skull controlled cortical impact TBI model was established and validated. Sham or TBIs were performed on PS19Snta1 transgenic crosses at 3 months of age. Behavioral testing was performed at 4 months (1 month post‐TBI) or 6 months (3 month post‐TBI). Brain tissue was collected and stained for markers of p‐tau pathology.ResultWe confirmed the previous finding that glymphatic influx is impaired following a closed‐head controlled cortical impact TBI. We also observed that Aqp4 deletion was sufficient to exacerbate tau pathology in PS19 mice at 6 months old, in the absence of TBI, and more advanced tau pathology was observed in PS19+Snta1−/‐ mice at 6 months old (3 months post‐TBI) compared to PS19+Snta+/+ that also received a TBI.ConclusionLoss of AQP4 or loss of perivascular AQP4 promotes tau pathology in a mouse model of tau pathology. These studies may provide a mechanistic basis for the vulnerability of the post‐traumatic brain to tau aggregation and neurodegeneration and suggest that targeting glymphatic dysfunction may be useful in the prevention and treatment of neurodegeneration.
Gut microbiota genus network reflects Alzheimer’s disease clinical stages
Authors: Lima Amanda Muliterno Domingues Lourenço , Rosa Morghana Machado , Machado Luiza Santos , Salgaço Mateus Kawata , Cassia Pessotti Rita , Saverio Stephani , Guimarães Cristiano Ruch Werneck , de Freitas Miller Nunes , Sivieri Katia , Bastiani Marco Antônio De , Zimmer Eduardo R. 
Published: December 2023

AbstractBackgroundBidirectional communication through the gut‐brain axis is fundamental to maintaining physiological functions. Imbalance in the intestinal microbial composition due to taxonomic or functional dysbiosis may be related to increased deposition of amyloid‐β plaques and tau tangles, which are the main hallmarks of Alzheimer’s disease (AD). We hypothesized that dysfunctional associations between the bacterial groups of the gut microbiota could be associated with AD clinical stages. Thus, we compared gut‐microbiota networks in cognitively unimpaired (CU), mild cognitive impaired (MCI), and AD dementia individuals.MethodsWe selected 16S rRNA gene sequencing data from fecal samples of CU, MCI and AD (n = 30, per group) available at NCBI repository (PRJNA489760). Individuals of both sexes aged between 57 and 73 years were included in the study. Adaptors were removed from the FASTQ files using the Trimmomatic tool for each sample and submitted to the DADA2 pipeline. Briefly, after filter and trimming, amplicon sequence variants (ASVs) were inferred using the dada function, taxonomic assignment was implemented using the SILVA resource and normalized by rarefaction without replacement. Afterward, normalized centered‐log ratio transformed abundance data were used to construct correlation networks between genus for CU, MCI, and AD.ResultsWe observed different correlation patterns between bacterial genera in CU, MCI, and AD. More especially, we found a progressive increase in network density toward AD clinical progression. Genus reportedly associated with cerebral amyloidosis and tau show few connections in the CU individuals (Figure 1A), which are increased in MCI (Figure 1B) and highly connected in AD (Figure 1C). Interestingly, we also noted that the opportunistic pathogen Escherichia_Shigella, strongly associated with AD pathology, was exclusively present in the AD network and showed a negative correlation with Faecalibacterium, a reportedly indicator of health.ConclusionMicrobial association networks at the genus level reflect different pathological stages of AD and could provide insights into preventive therapeutic strategies aiming to delay disease progression through the modulation of the gut microbiota.
Pregnancy‐Related Cardiometabolic Disease and Dementia Risk: A Twin Study
Authors: Foret Janelle T , Saelzler Ursula G , Gatz Margaret , Gillespie Nathan A. , Panizzon Matthew S. 
Published: December 2023

AbstractBackgroundPregnancy related complications such as gestational diabetes mellitus (GDM) and pregnancy‐induced hypertension (PIH) have been shown to increase risk of cardiometabolic disease and may subsequently contribute to all cause dementia. While GDM and PIH have been genetically associated with their later life, non‐pregnancy related counterparts, it remains to be seen if these conditions independently contribute to dementia risk. This study investigated the degree to which GDM and PIH are genetically associated with dementia.MethodData were analyzed from 5,930 females in the Swedish Twin Registry who reported at least one pregnancy. Traditional twin analyses were conducted to determine the degree to which GDM and PIH are genetically influenced, as well as the degree of genetic and environmental overlap with the non‐pregnancy related variant of these conditions. Survival analyses examined relationships between 1) GDM and dementia and 2) PIH and dementia. Hypertension and diabetes outside of pregnancy were included in their respective models as covariates.ResultFor individuals who reported having been pregnant, risk of later life cardiometabolic risk factors were significantly increased if the similar conditions were experienced during pregnancy (P<.001). Both GDM and PIH showed evidence of significant familial associations, with a higher OR in MZ twins for both conditions (GDM OR = 6.74; 95% CI, 1.06 to 2.76; PIH OR = 8.27; 95% CI, 1.89 to 2.38). The survival models indicated that while neither pregnancy‐related condition was independently associated with dementia risk, diabetes outside of pregnancy was associated with a more than three‐fold increase in dementia risk (HR = 3.77, 95% CI = 1.17 – 1.63).ConclusionIn this large, population‐based cohort we found significant associations between pregnancy conditions and their respective cardiometabolic conditions. Cross‐twin associations further indicated that the association between pregnancy and non‐pregnancy cardiometabolic risk factors was driven by genetic influences. However, GDM and PIH did not appear to convey risk for dementia. These findings suggest that mechanisms driving diabetes and hypertension during pregnancy, while related to their later‐life counterparts, do not increase risk of neurocognitive decline.
Digital pathology analysis reveals TDP‐43 pathology as a strong predictor of glial activation in Alzheimer’s disease
Authors: Kouri Naomi , Frankenhauser Isabelle , Boon Baayla D.C. , Labuzan Sydney A. , Peng Zhongwei , Tranovich Jessica F. , Lesser Elizabeth R. , Crook Julia E. , Lachner Christian , Ertekin‐Taner Nilufer , Duara Ranjan , Graff‐Radford Neill R. , Dickson Dennis W. , Carter Rickey E. , Murray Melissa E. 
Published: December 2023

AbstractBackgroundGlial activation plays a critical role in Alzheimer’s disease (AD) pathogenesis and is associated with amyloid‐β plaques and neurofibrillary tangles composed of phosphorylated tau (phospho‐tau). With approximately 40%‐60% of AD cases having limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC), TDP‐43 pathology has become more the rule than the exception in AD brains. However, the effect of LATE‐NC in AD‐related glial activation is unknown.MethodWe analyzed the effect of TDP‐43 pathology on glial activation in three AD subtypes: hippocampal sparing (HpSp) AD, typical AD, and limbic predominant AD. Twenty cases of each subtype (n = 60 total) were selected from the FLorida Autopsied Multi‐Ethnic (FLAME) cohort. Cases were immunohistochemically evaluated on serial sections of the hippocampus in the CA1 and subiculum subsectors, and superior temporal, inferior parietal, and mid‐frontal cortices with antibodies to CD68 (phagocytosis), GFAP (astrogliosis), GT‐38 (conformation‐specific AD‐type tau), 6F/3D (amyloid‐β), and phospho‐Serine 409/410 of TDP‐43 (pTDP‐43). Digital pathology was employed to quantify immunohistochemical staining. Multivariable regression modeling was utilized to understand the relationship between glial activation and AD pathologies.ResultThe level of glial activation, defined as % of immunoreactive surface area for CD68 and GFAP, was lowest in HpSp AD (0.54%, 13%), whereas typical AD (1.3%, 33%) and limbic predominant AD (1.3%, 30%) had similar levels suggesting a ceiling effect, or plateau, of gliosis levels (both p<0.001). HpSp AD was more often male (p<0.001) and younger at disease onset (p<0.001) compared to both typical AD and limbic predominant AD. Multivariable regression modeling of CD68 (subiculum R2 = 0.60) identified advanced tau to be a significant predictor of CD68 in all brain regions. LATE‐NC stage predicted increased CD68 levels in limbic brain regions. Multivariable regression modeling of GFAP (CA1 R2 = 0.60) showed that Aβ was the strongest predictor of astrogliosis in CA1 and subiculum (p<0.001). Advanced tau in CA1 and parietal cortex, LATE‐NC in subiculum and temporal cortex, and APOE4 genotype in CA1 predicted a significant increase in GFAP.ConclusionThese findings highlight the significant role TDP‐43 pathology plays in affecting the microenvironment and interplay between neuroinflammation and neurodegeneration and have important implications for therapeutic strategies in AD with co‐morbid LATE‐NC.
Age‐associated biomarker profiles in a non‐human primate model of sporadic CAA
Authors: Karimi Sohail , Patel Akash G , Nehete Bharti P , Nehete Pramod N , Debure Ludovic , Levine Dafna T , Cho Olivia , Rami Dina , Soliman Muhammad T , Llanos Michael , Gray Stanton B , Hopkins William D , Wisniewski Thomas , Scholtzova Henrieta 
Published: December 2023

AbstractBackgroundAdvancements of novel therapeutic interventions for Alzheimer’s disease (AD) have been hindered by a lack of animal models in preclinical research that naturally recapitulate the pathologic features of disease with age. Our prior work demonstrated the utility of squirrel monkeys (SQMs), a non‐human primate (NHP) model of sporadic AD pathology with abundant cerebral amyloid angiopathy (CAA), as an opportune species to assess the potential therapeutic outcomes and safety profile of our novel immunomodulatory approach using TLR9 agonist CpG‐ODN. Here we provide the first longitudinal and cross‐sectional study on aging and disease pathogenesis in SQMs by characterizing blood/CSF biomarker signatures of AD/CAA pathology.MethodSIMOA, ELISA, and Luminex platform immunoassays were utilized to investigate age‐associated profiles of plasma and CSF biomarkers involved in neurodegeneration (NfL, GFAP), brain and peripheral inflammation/glia activation (YKL‐40/CHI3L1, sTREM2), and cerebrovascular dysfunction/BBB integrity (albumin index, bFGF, VCAM‐1, MMPs).ResultCross‐sectional analysis revealed statistically significant differences in plasma NfL and GFAP levels between age groups ranging from 6 to 23 years old (NfL: one‐way ANOVA, f(6,84)) = 6.395, p<0.0001; GFAP: one‐way ANOVA, f(6,84)) = 8.111, p<0.0001). Preliminary assessments revealed significantly higher plasma YKL‐40/CHI3L1 and MMP1 levels, while VCAM‐1, bFGF, and MMP2 levels were significantly lower in the geriatric SQMs when compared to the young group. CSF analyses demonstrated significantly higher YKL‐40/CHI3L1 and bFGF levels, and an elevated albumin index among the geriatric cohort when compared to young monkeys. Moreover, a longitudinal follow‐up of a separate SQM cohort over three years (19‐22 years old) revealed a significant increase in plasma sTREM2 levels; neurogranin levels appeared to increase, but differences were not significant (p = 0.0625, Wilcoxon signed‐rank test). Further characterizations of fluid biomarker trajectories and their relationships with age‐associated changes in cognition and neuroimaging markers are forthcoming.ConclusionSQMs present a valuable opportunity to evaluate biomarker signatures associated with aging and the development of cerebrovascular amyloid pathology. The use of this advantageous model is important to enhance the translational potential of novel therapeutics for human benefit.
MRI CHANGES FOLLOWING TREATMENT OF GLP‐1 ANALOGUE, LIRAGLUTIDE IN ALZHEIMER’S DISEASE
Authors: Edison Paul , Femminella Grazia Daniela , Ritchie Craig , Nowell Joseph , Holmes Clive , Walker Zuzana , Ridha Basil H , Williams Gareth , Lawrence Robert M , McFarlane Brady , Archer Hilary , Coulthard Elizabeth , Underwood Benjamin , Koranteng Paul , Karim Salman , Perneczky Robert , Prasanna Aparna , Junaid Kehinde , McGuinness Bernadette , Nilforooshan Ramin , Donaldson Andrew , Thacker Simon , Russell Gregor , Mate Vandana , Knight Lucy , Kshemendran Sajeev , Holscher Christian , Mansouri Anita , Chester‐Jones Mae , Holmes Jane , Harrison John E , Tadros George , Passmore Anthony Peter , Ballard Clive G 
Published: December 2023

AbstractBackgroundPreclinical evidence in transgenic models of Alzheimer’s disease (AD) suggests that liraglutide, a GLP1 analogue, exerts neuroprotective effects by reducing amyloid oligomers, normalising synaptic plasticity and reducing insulin resistance, and increasing the proliferation of neuronal progenitor cells. ELAD is a 12‐month, multi‐centre, randomised, double‐blind, placebo‐controlled, phase IIb trial of liraglutide in participants with mild to moderate AD conducted at 24 centres in the UK.MethodAs a part of this study, a total of 204 Alzheimer’s participants were randomised to receive either liraglutide or placebo as a daily subcutaneous injection for 12 months. All subjects underwent volumetric MRI scans at baseline and during follow up. Volumetric changes from baseline to follow up in MRI scans were evaluated using both regional volume analysis and voxel based morphometric analysisResultMRI analysis demonstrated that temporal lobe volume, total grey matter volume and frontoparietal volume change was lower in liraglutide treated patients compared to the placebo group. Voxel based morphometry (VBM) analysis demonstrated that liraglutide‐treated participants showed a slower reduction in whole cortical grey matter, frontal, temporal and parietal lobe volume in participants treated with liraglutide compared to placebo.ConclusionIn the ELAD study, participants with mild to moderate AD who received liraglutide had slower reduction in MRI volume and cognition compared to the placebo demonstrating a potential benefit of liraglutide in the treatment of Alzheimer’s disease. These findings highlight the potential of GLP‐1 analogues in the treatment of Alzheimer’s disease
The Sporadic Early‐Onset Alzheimer’s Disease Signature of Regional Atrophy
Authors: Touroutoglou Alexandra , Katsumi Yuta , Brickhouse Michael , Eloyan Ani , Carrillo Maria C. , Rabinovici Gil D. , Apostolova Liana G. , Vemuri Prashanthi , Dickerson Brad C. 
Published: December 2023

AbstractBackgroundIn EOAD, the localization of neurodegeneration is often more prominent in posterior lateral temporal, lateral and medial parietal, frontal, or occipital cortex relative to the medial and ventral temporal cortical localization of typical LOAD. Convergently, neuropathological investigations have identified a “hippocampal‐sparing” form of AD that is often present in younger patients. For these reasons, imaging biomarkers of neurodegeneration in EOAD, such as Magnetic Resonance Imaging (MRI) measures of atrophy, likely need to be different than those of neurodegeneration in typical LOAD. Although prior neuroimaging work has advanced our understanding of anatomical abnormalities in EOAD, these studies have included small samples, most composed of amnestic EOAD dementia and none focused on developing an MRI biomarker specific to EOAD. Such a disease‐signature MRI biomarker has been established and validated in LOAD dementia and has proven to be powerful in predicting progressive decline in people with MCI or who were cognitively unimpaired and in predicting molecular biomarker status. An a priori‐defined regional atrophy signature may also be helpful in constraining the analysis of MRI data in studies of putative disease‐modifying therapies.MethodLEADS is an observational study which includes annual MRI. In this analysis, we used FreeSurfer to define the sporadic EOAD atrophy signature in a small sample of MGH EOAD patients, and investigated its reproducibility in LEADS, as well as the magnitude of atrophy and its relationship to clinical measures.ResultThe EOAD signature is robustly reproducible across the two independent patient cohorts, with prominent atrophy in caudal lateral temporal cortex, inferior parietal lobule, and posterior cingulate and precuneus cortex, with relative sparing of medial temporal lobe structures. Comparing patients to controls, Cohen’s d effect sizes within various regions ranged from 0.99 to 1.98.ConclusionThis study demonstrates the specific cortical regions with most prominent atrophy in patients with sporadic EOAD; this signature of regional atrophy will be used to examine longitudinal change.
The association between anxiety and Alzheimer’s disease plasma biomarkers across stages
Authors: Bernard Mark A , Boutajangout Allal , Debure Ludovic , Briggs Anthony Q , Vedvyas Alok , Marsh Karyn , Osorio Ricardo S , Wisniewski Thomas , Masurkar Arjun V. 
Published: December 2023

AbstractBackgroundAnxiety is associated with faster progression of Alzheimer’s disease (AD) and related imaging biomarkers. However, the association of anxiety with plasma biomarkers of AD is unclear. We investigated the relationship between various plasma AD biomarkers and anxiety at different AD stages.MethodThe study included 192 older adults evaluated at the NYU Alzheimer’s Disease Research Center with a consensus diagnosis of cognitively normal (CN, n = 99), mild cognitive impairment (MCI, n = 52), and mild AD dementia (AD, n = 41). Anxiety and depression were measured by study partner report via the Neuropsychiatric Inventory Questionnaire (NPI‐Q). Plasma levels of Aβ40, Aβ42, neurofilament light (NfL) and total tau were measured using ultra‐sensitive, single‐molecule array (SIMOA) technology. Secondarily‐calculated measures included Aβ42/Aβ40 and tau/Aβ42 ratios.ResultAnxiety had a prevalence of 14%, 48%, and 24% at CN, MCI, and AD, respectively. Comparing plasma biomarkers from participants with and without anxiety within each stage, anxiety associated with a significantly higher plasma tau/Aβ42 ratio in AD (p = 0.0127). In contrast, while depression had a higher prevalence of 37% at the AD stage, it was not associated with a significant difference in tau/Aβ42 ratio (p = 0.6459). Comparing stages, plasma tau/Aβ42 was significantly elevated in AD versus CN only among participants with anxiety (p = 0.034). In contrast, plasma NfL was significantly elevated in AD versus CN among participants with (p = 0.0475) and without (p < 0.0001) anxiety.ConclusionThe presence of anxiety uniquely modulates the levels of specific plasma biomarkers depending on stage, as well as the ability of specific biomarkers to distinguish AD stages. These results highlight a complex relationship between neuropsychiatric symptoms and plasma biomarkers that warrants further study.