bluuebunny/crossref_metadata_2025_split huggingface dataset:
Elucidating emerging therapeutics: P75 receptor modulation reverts tauopathy associated alterations in synapse‐relevant gene expression signatures
Authors: Latif‐Hernandez Amira , Losada Patricia Moran , Yang Tao , Tran Kevin C. , Liu Harry , Lehallier Benoit , Massa Stephen M. , Longo Frank M. 
Published: December 2020

AbstractBackgroundIn tauopathy mouse models, activity‐dependent synaptic plasticity, as measured by long‐term potentiation (LTP), is compromised. Treatment of tauopathy mice with LM11A‐31, a small molecule modulator of p75 neurotrophin receptor signaling, normalizes LTP. In the present study, we determined whether activity‐dependent gene expression profiles would be altered in stimulated hippocampus (HC) of tauopathy mice, and if prior in vivo treatment with LM11A‐31 would normalize elements of their transcriptional signature.Method6 month‐old wildtype and PS19 (P301S) mice were treated daily by oral gavage for 3 months with vehicle or LM11A‐31. Late‐LTP was used in acute HC slices to induce activity‐dependent changes at synapses. After completion of recordings, a RNA sequencing approach was followed to analyze activity‐dependent gene expression and generate transcriptomic profiles, using cutoffs of q<0.05 and fold change > 1.5.ResultAnalyses of the 36,175 expressed transcripts revealed that samples clustered based on the absence (‐) or presence (+) of LTP. Differential gene expression was found in WT/‐LTP vs WT/+LTP (550 upregulated, 176 downregulated genes); in Tau/‐LTP vs Tau/+LTP (1327 upregulated, 702 downregulated genes) and in Tau/+LM11A‐31/‐LTP vs Tau/+LM11A‐31/+LTP (338 upregulated, 143 downregulated genes). There was strong enrichment in pathways involving genes upregulated by LTP induction in all groups, including NF‐kappa B signaling. In contrast, cytokine activity was enriched within the transcripts that were upregulated with LTP in WT and Tau/+LM11A‐31 but not in the Tau group. Next, we analyzed LTP slices from all groups and found that altered gene expression between WT and Tau mice (996 upregulated and 320 downregulated genes) was changed in Tau/+LM11A‐31 (264 upregulated and 409 downregulated genes). GO, KEGG and Reactome enrichment analyses in WT/+LTP vs Tau/+LTP demonstrated that Tau mice show downregulated genes in neuronal system, calcium signaling, glutamatergic synapse and long‐term potentiation; and upregulated genes in aging, apoptosis and glial cell development pathways. Remarkably, the expression levels of genes from these pathways were largely reverted to WT pattern in Tau mice treated with LM11A‐31.ConclusionModulating p75NTR might restore tauopathy‐related alterations in synapse‐relevant gene expression profiles. These findings point to candidate signaling modules for understanding synaptic impairment and therapeutic strategies.
Assessment of cortical vulnerability of the anterior cingulate cortex in the behavioral variant of Alzheimer’s disease
Authors: Berendrecht Evi , Gami‐Patel Priya , Blujdea Raluca E. , Singleton Ellen H. , Bouwman Femke , Pijnenburg Yolande A.L. , Scheltens Philip , van Swieten John C. , Papma Janne M. , Hoozemans Jeroen J.M. , Ossenkoppele Rik , Dijkstra Anke A. 
Published: December 2020

AbstractBackgroundThe anterior cingulate (ACC) and frontoinsular cortex (FI) are key regions implicated in behavior and social cognition. These regions harbor a novel cortical neuronal group, characterized by expression of the GABA subunit theta (GABRQ) and inclusion of Von Economo Neurons (VENs). This neuronal group is selectively vulnerable in the behavioral variant of frontotemporal dementia (bvFTD), but not in typical Alzheimer’s disease (typAD)(1). Currently, it is unknown whether this neuronal population is affected in the behavioral variant of AD (bvAD) compared to controls and typAD and whether there is a difference in local pathological burden and morphology between bvAD and typAD.MethodHuman post‐mortem tissue of the ACC was used to quantify the GABRQ‐neuronal population and burden and morphology of amyloid beta and tau pathology. We included 10 controls, 8 bvAD donors, and 10 typAD donors. One slide of 10 μm from each donor was used for quantification of Layer 5 GABRQ‐expressing VENs and pyramidal neurons. Layer 5 GABRQ‐negative neurons were counted using Stereoinvestigator software. Burden of pathology was assessed in sequential slides, where diffuse, coarse‐grained, and core amyloid‐beta plaques were quantified. Local tau pathology burden was assessed using ImageJ software. Tissue of the FI will be analyzed in a similar manner.ResultThe total number of GABRQ‐expressing neurons and VENs in the ACC of bvAD donors is similar compared to controls (p=0,22) and typAD (p=0,64)(Figure 1). Furthermore, no significant differences were observed in amyloid‐beta (p=0,38) and tau burden (p=0,09) or presence of different morphological amyloid‐beta plaques in the ACC. Results of FI analysis will be ready at AAIC 2020.ConclusionOur data suggest that the bvAD phenotype cannot be explained by ACC vulnerability to AD pathology. Future analysis of the selective vulnerability of the FI may elucidate whether GABRQ‐expressing neurons are disproportionally affected in bvAD.
Effect of decreased visual acuity on cortical thickness: A possible risk factor for neurodegeneration
Authors: Kim Ji Sun , Han Gyule , Park Yuhyun , Kang Sung Hoon , Kim Jaeho , Lee Jong Min , Seo Sang Won , Lim Dong Hui , Kim Hee Jin 
Published: December 2020

AbstractBackgroundCortical thickness is a biomarker for neurodegeneration. Ample evidence supports the idea that decreased sensory stimuli lead to degeneration of relevant central areas in the brain. We hypothesized that decreased visual stimuli might be associated with cortical atrophy in visual processing areas. Therefore, we investigated the association between visual acuity (VA) and cortical thickness in cognitive normal adults.MethodWe retrospectively analyzed the health screening data from the Health Promotion Center at the Samsung Medical Center from 2008 to 2014. In total, 2,810 cognitive normal subjects who checked corrected VA and Brain MRI were identified. The subjects were divided into 3 groups according to the VA of better eye: Group 1 (VA The higher VA value indicates better VA. Using multivariate regression analysis, cortical thickness of Group 1 and 2 were compared with Group 3. We also analyzed linear association between VA and cortical thickness. The analyses were performed after controlling for age, sex, hypertension, diabetes, hyperlipidemia, and intracranial volume.ResultCompared to Group 3, Group 1 showed cortical thinning in the bilateral occipital, lateral temporal, and lateral parietal areas. Compared to Group 3, Group 2 also showed cortical thinning in the bilateral occipital, right lateral temporal, and bilateral lateral parietal areas. Linear association analysis showed that the lower VA was associated with cortical thinning in the bilateral occipital areas.ConclusionOur results showed that cognitive normal individuals with lower VA have cortical thinning in the posterior part of the brain which is responsible for visual processing. This suggest that good VA may have preventive effect for neurodegeneration.
Left frontal hub connectivity enhances task‐related brain network segregation and cognition in aging: Implications for reserve
Authors: Frontzkowski Lukas , Franzmeier Nicolai , Neitzel Julia , Luan Ying , Habeck Christian , Stern Yaakov , Ewers Michael 
Published: December 2020

AbstractBackgroundGlobal connectivity of the left frontal cortex (LFC), a hub of the cognitive control network, is associated with higher fluid intelligence and relatively preserved cognition despite age‐ and Alzheimer’s disease (AD)‐related brain changes, rendering LFC‐connectivity a candidate substrate of reserve (Franzmeier et al. Brain 2018). Yet, the mechanisms by which LFC‐connectivity supports cognition at the functional network level remain unclear. Functional network‐segregation within the brain guards against diffuse network organization and is a fundamental brain property central to efficient cognitive processes. Given that the control network, and in particular the LFC, is thought to orchestrate activity of other functional networks (Cole, Nat Neurosci, 2013), we hypothesized that the association between LFC‐connectivity and higher cognitive abilities such as executive function is mediated via enhanced network‐segregation.MethodsWe applied 3 fMRI‐tasks per cognitive domain (i.e. fluid‐reasoning, memory, speed, vocabulary) in 255 non‐demented participants from the RANN study. We determined atlas‐based (Fig.1) whole‐brain functional connectivity during task‐fMRI using psycho‐physiological‐interaction analyses. Global LFC‐connectivity was assessed as mean task‐related LFC‐connectivity to the remaining ROIs. Network‐segregation was assessed as the difference of within‐network and between‐network connectivity normalized to within‐network connectivity (Chan et al., PNAS, 2014). For the three tasks per cognitive domain, we determined domain‐specific performance, LFC‐connectivity and network segregation scores via principal‐component analysis. Using linear regression and mediation analysis, we tested for each cognitive domain whether 1) higher LFC‐connectivity was associated with better cognition 2) and subsequently whether this association was mediated by network‐segregation.ResultsHigher task‐related LFC‐connectivity was associated with better performance in fluid‐reasoning (β=0.178, p=0.003,Fig.2A) but not in other cognitive domains (p>0.05). Higher LFC‐connectivity during fluid‐reasoning tasks was associated with network‐segregation (β=0.308, p<0.001, Fig.2B), which was associated with fluid‐reasoning performance (β=0.352, p<0.001, Fig.2C). In mediation analyses, we found that LFC‐connectivity effects on fluid‐reasoning performance were mediated by network‐segregation (bootstrapped mediation effect: β=0.0981,95%CI[0.0481;0.16], p<0.001).ConclusionsLFC‐connectivity supports higher fluid reasoning performance in normal aging via enhanced brain network segregation, suggesting a potential mechanism by which LFC‐connectivity supports reserve in AD.
Language impairment in progressive supranuclear palsy and corticobasal syndrome: MLSE screening and its neural correlates
Authors: Peterson Katie A. , Jones P. Simon , Patel Nikil , Ingram Ruth , Patterson Karalyn , Rowe James B. , Garrard Peter 
Published: December 2020

AbstractBackgroundProgressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) change speech and language as well as motor function. Here, we used the new Mini Linguistic State Examination (MLSE), a brief, yet comprehensive language assessment tool, to investigate structural correlates of language impairment in PSP and CBS, alongside patients with the nonfluent variant of primary progressive aphasia (nfvPPA).MethodTwenty‐eight patients (PSP N=8, CBS N=10 and nfvPPA N=10) and 24 aged‐matched controls completed the MLSE, the Addenbrooke’s Cognitive Examination III, and 3T PRISMA structural MRI. T1‐weighted images were processed using Freesurfer 6.0. The groups were compared using an ANCOVA of cortical thickness including age, gender and MLSE total score as covariates.ResultPSP and CBS patients’ MLSE total scores were significantly (p<0.001) impaired compared to controls but better (p<0.05) than nfvPPA. For the MLSE subscores, compared to controls, PSP impaired motor speech (p=0.003), while CBS impaired phonology, semantics, and syntax (p<0.05). There was a positive correlation between cortical thickness with MLSE total score in the left inferior frontal gyrus pars triangularis, middle temporal gyrus, and supramarginal gyrus (p<0.001 unc).ConclusionThe MLSE screening tool identifies speech and language deficits in PSP and CBS. Impairments were associated with atrophy in key regions of left hemisphere frontotemporal language networks. Future work will identify multisite scalability of the MLSE and its imaging correlates.
The association between polygenic hazard scores and clinical markers of Alzheimer’s disease following stratification for APOE genotype
Authors: De Marco Matteo , Manca Riccardo , Kirby Janine , Hautbergue Guillaume , Blackburn Daniel J , Wharton Stephen , Venneri Annalena ,   the Alzheimer's Disease Neuroimaging Initiative
Published: December 2020

AbstractBackgroundGenome‐wide association studies have confirmed the APOE ε4 allele as the single‐nucleotide polymorphism (SNP) best associated with Alzheimer’s disease. These same studies, however, have found that a considerable number of other SNPs are associated with Alzheimer’s disease. The statistical association yielded by these other SNPs, however, is considerable weaker than that of the APOE ε4. It is unclear, therefore, whether these non‐APOE SNPs have similar effects in APOE ε4 carriers and non‐carriers. In this study, we investigated the association between a polygenic hazard score (PHS) for sporadic Alzheimer’s disease and clinical profiles of a large cohort non‐demented participants stratified by APOE ε4 status.MethodA cohort of 776 participants was shortlisted from the entire ADNI database: 262 cognitively unimpaired participants (185 with a ε3ε3 genotype and 77 with a ε4ε3 genotype) and 514 participants with a diagnosis of MCI (241 with a ε3ε3 genotype, 212 with a ε4ε3 genotype and 61 with a ε4ε4 genotype). This same cohort was also split according to cerebrospinal amyloid (Aβ) positivity status, resulting into 275 Aβ‐ and 501 Aβ+ participants. Genome‐wide data, a structural brain MRI and cognitive profiles were available for each dataset. Genetic information was used for the calculation of a PHS, following the methodology by Desikan and colleagues [1]. Memory and executive composite scores were calculated for each dataset based on previously described procedures [2,3]. A voxel‐based morphometry was carried out to process T1‐weighted MRI images and obtain grey‐matter maps analysable at a group level. Linear models were devised in each sub‐cohort and for each APOE ε4 status to test the association between PHS and cognitive composites and between PHS and volumetric grey‐matter maps.ResultPHS was a predictor of mediotemporal volume in MCI patients and a predictor of memory and executive functioning both in MCI and Aβ+ participants. Following APOE stratification, PHS predicted memory and executive functioning in ε4ε3 MCI patients, memory in ε3ε3 MCI patients, and memory in ε4ε3 Aβ+ participants. PHS also predicted volume in sensorimotor regions in ε3ε3 MCI and ε3ε3 Aβ+ participants.ConclusionThese results suggest that clinical phenotypes might be influenced by complex genetic interactions.
Identifying and predicting heterogeneity in cognitive decline among individuals with prodromal Alzheimer's disease using a latent class analysis
Authors: Jutten Roos J. , Sikkes Sietske A.M. , Papp Kathryn V. , Van Berckel Bart N.M. , Teunissen Charlotte E. , van Der Flier Wiesje , Scheltens Philip , Tijms Betty M. 
Published: December 2020

AbstractBackgroundIndividuals with prodromal Alzheimer’s disease (AD) show heterogeneity in their rates of cognitive decline, which is problematic for measuring (therapeutic) effects on cognition. We aimed to identify subgroups with homogeneous cognitive trajectories among individuals with prodromal AD in two large independent cohorts, and investigate which clinical and/or biological AD risk factors predict progression rate.MethodIndividuals with an abnormal amyloid marker (determined by either CSF Aβ‐42 levels or Florbetaben/Flutametamol/Florbetapir‐AV45 PET imaging) and mild cognitive impairment who had longitudinal cognitive data available were selected from the Amsterdam Dementia Cohort and ADNI (N=340, age =71.5±8.4, 43% female). We performed latent class mixed models (LCMM) to identify subgroups based on similarity of their trajectories on the Mini‐Mental State Examination (MMSE), and performed mixture modelling using individual MMSE slopes to validate those subgroups. We compared subgroups on baseline age, sex, years of education, ApoE‐e4 status, CSF tau and phosphorylated tau (p‐tau) and hippocampal volume using univariate logistic regression, and subsequently performed stepwise logistic regression with backward elimination to identify which baseline characteristics best predicted progression.ResultParticipants had 2.3±1.8 repeated assessments and a follow‐up of 2.3±1.6 [range=1‐8] years. LCMM identified three subgroups of MMSE progression, which were confirmed by mixture modelling: Group 1 (n=303, 88%) showing slowest progression (i.e. average 0.7 [range=0.4–1.9] points annual decline on MMSE); Group 2 (n=30, 10%) intermediate progression (average 2.6 [range=1.9–4.2] points annual decline on MMSE) and Group 3 (n=7, 2%) showing fastest progression (average 4.7 [range=3.3–6.2] points annual decline on MMSE) (Figure 1). No effects on progression were observed for age, sex, education and ApoE‐e4 (Table 1). Compared to individuals who slowly progressed, those with intermediate‐to‐fast progression had higher tau (OR=1.01, 95%CI=[1.01‐1.02], p<.001) and p‐tau (OR=1.03, 95%CI=[1.02‐1.05], p<.001) levels and lower hippocampal volume (OR=0.57, 95%CI=[.37‐.84], p=.006) at baseline. The model including both p‐tau (OR=1.03, 95%CI=[1.02‐1.05], p<.001) and hippocampal volume (OR=0.55, 95%CI=[.34‐.85], p=.01) best predicted fast progression.ConclusionAmong individuals with prodromal AD, we identified three subgroups with different rates of decline on the MMSE, and demonstrated that baseline neurodegeneration markers were associated with faster decline. These findings have practical implications for clinical trial enrollment and predicting disease progression.
CSF biomarkers for frontotemporal dementia and its pathological subtypes
Authors: Campo Marta Del , Peeters Carel F.W. , Chen‐Plotkin Alice , van Der Flier Wiesje , Meeter Lieke H.H. , van Swieten John C. , Hu William T. , Irwin David J. , Pijnenburg Yolande A.L. , Teunissen Charlotte E. 
Published: December 2020

AbstractBackgroundFrontotemporal dementia (FTD) is caused by frontotemporal lobar degeneration (FTLD) and is characterized mainly by the presence of aggregates of the proteins tau (FTLD‐Tau) or TDP43 (FTLD‐ TDP) in the brain, which likely require distinct pharmacological therapy. However, the clinical presentation of the pathological subtypes is heterogeneous and overlapping, making this diagnostic subtyping at present virtually impossible. Thus, there is a strong unmet need to identify body‐fluid biomarkers to discriminate FTD and its pathological subtypes. Most biomarker studies performed to date have analyzed pathologically heterogeneous populations. The few studies analyzing antemortem cerebrospinal fluid (CSF) with known underlying neuropathology have revealed several candidate biomarkers (e.g. p/tTau ratio). Despite these promising results, their specificity is still not optimal, most of the identified markers are awaiting further validation and their diagnostic accuracy remains to be evaluated.MethodWe have recently taken advantage of a novel high‐multiplex and sensitive antibody‐based proteomic technology to analyze >600 proteins in a large multicenter cohort providing CSF samples from controls (n=195) and FTD patients (n=199). For a subset of FTD cases, the underlying specific pathology was known (FTLD‐Tau=34: 18 autopsy‐confirmed and 27 MAPT mutation carriers; FTLD‐ FTLD‐TDP=54: 27 autopsy‐confirmed and 18 C9orf72 and 9 GRN mutation carriers). Differences in the protein expression profile were analyzed by GlobalTesting. Generalized linear modeling was used to identified classification protein signatures.ResultWe identified CSF protein biomarker signatures for specific diagnosis of FTD (8‐9 proteins, AUC>0.85). The proteins identified were related to mechanisms involved in immune system, extracellular remodeling and cell killing. There were no between‐group differences in the CSF protein profiles of the FTLD groups. However, differences in the absolute levels of some proteins were detected when autopsy‐confirmed cases and mutation carriers were analyzed separately.ConclusionThe similarity of the CSF profiles between FTLD groups suggests shared pathological mechanisms. Alternatively, each subtype may be heterogeneous, which possibly results from analyzing together familial and autopsy‐confirmed cases. Taken together, the FTLD studies performed to date indicate a highly complex disorder challenging the development of efficient diagnostic and therapeutic markers.
Global shifts in DNA methylation and DNA hydroxymethylation across multiple brain regions in transgenic models of tau and amyloid pathology
Authors: Castanho Isabel , Murray Tracey K. , Harvey Joshua , Leung Szi Kay , Lunnon Katie , Ahmed Zeshan , Mill Jonathan 
Published: December 2020

AbstractBackgroundThere is increasing evidence to support a role for altered DNA modifications in Alzheimer’s disease (AD). Global changes in both DNA methylation (5mC) and DNA hydroxymethylation (5hmC) have been robustly reported in cancer, but not widely studied in AD. We quantified global levels of 5mC and 5hmC across multiple brain regions in two transgenic models of AD pathology, relating these to the progressive changes in tau and amyloid observed in the same samples.MethodWe investigated global DNA modification levels in brain tissue from rTg4510 and J20 mice using two independent approaches. We quantified hippocampal global DNA methylation in rTg4510 and J20 transgenic (TG) and wild‐type (WT) littermate control mice using an enzymatic‐based methylation assay combined with pyrosequencing. Using immunohistochemistry, we directly quantified levels of both 5‐methylcytosine (5mC) and 5‐hydroxymethylcytosine (5hmC) in multiple brain regions in rTg4510 and J20 mice.ResultWe identified both genotype‐associated and progressive temporal changes (interaction between genotype and age) in 5mC and 5hmC in rTg4510 TG and J20 TG mice compared to WT littermate controls in several brain regions. Levels of both 5mC and 5hmc were negatively correlated with levels of tau and amyloid pathology, reflecting some evidence from human AD brain.ConclusionWe identified decreased levels of two DNA modifications (5mC and 5hmC) associated with accumulation of tau and amyloid pathology. Both genotype‐associated and progressive changes in 5mC and 5hmC measured by immunohistochemistry were observed, with these changes notably stronger in rTg4510 TG relatively to J20 TG mice, particularly in the hippocampus.