bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association between mild behavioral impairment and hippocampal structural covariance in amnestic mild cognitive impairment
Authors: Yoon Eun Jin , Lee Jun‐Young , Kim Heejung , Kim Yu Kyeong 
Published: December 2023

AbstractBackgroundOur previous work reported that mild cognitive impairment (MCI) patients with multiple mild behavioral impairment (MBI) domain symptoms (complex group) revealed a higher risk of developing Alzheimer’s disease (AD) compared with those with no MBI symptoms (asymptomatic group) and cortical thinning in the parietal and frontal areas. However, MCI patients with only affective dysregulation (affective dysregulation group) were not associated with the risk of AD and revealed relative cortical thickening (Yoon EJ, Front Aging Neurosci 2023). To clarify relationships of cortical thickness changes and risk of progression to AD in MCI patients, we compared structural covariance patterns between hippocampal volume and cortical thickness among the MBI subgroups.MethodA total 201 older adults with amnestic MCI were classified based on profiles of MBI domain symptoms into asymptomatic, affective dysregulation, and complex groups. The FreeSurfer was used to estimate cortical thickness and volumes of hippocampal subfields (Fig 1). A vertex‐wise general linear interaction model was used to compare group map of covariance between volumes of hippocampus subfields and thickness at each of vertices. Correlations between the thickness in regions showing significant group differences and mini‐mental state examination (MMSE) scores were also assessed.ResultIn the affective dysregulation group, the structural covariance of left CA1, CA4/DG and molecular layer were increased in the left superior and inferior parietal cortex (Fig 2a), and the thickness of this region showed positive correlation with MMSE (spearman’s rho = 0.302, p‐value = 0.046). The structural covariance of left hippocampal tail for the affective dysregulation group was increased in left lateral occipital cortex, and those for the complex group was increased in left inferior parietal and lateral occipital cortex compared with the asymptomatic group (Fig 2b). Also, the complex group revealed decreased structural covariance of right subiculum with left rostral middle frontal cortex (Fig 2c).ConclusionOur findings suggest that the lateral parietal area might have an important role in compensatory mechanisms in the affective dysregulation group. On the other hand, the complex group may be associated with more advanced stages of disease in which the patterns of increased covariance of hippocampal subfields were disappeared or inversed.
Subclinical mesial temporal lobe activity in Alzheimer’s Disease
Authors: Devulder Astrid , Testelmans Dries , Bossche Maarten Van Den , Cleeren Evy , Theys Tom , Van Paesschen Wim ,   Laboratory for Epilepsy Research, KU Leuven
Published: December 2023

AbstractBackgroundAnimal and human studies of Alzheimer’s disease (AD) demonstrated that aberrant network activity with neuronal hyperexcitability plays a role in disease pathogenesis and cognitive functioning. Suppressing network hyperexcitability with levetiracetam improved cognitive functioning in familial AD mice and executive functioning in patients with AD and epileptiform activity. Manifestations of network hyperexcitability are unsensitive biomarkers since they are mostly subclinical and not visible on scalp EEG. (Lam et al. 2019, Vossel et al. 2021, Sanchez et al. 2012).
Our purpose was to identify subclinical epileptiform activity in two patients with mild cognitive impairment (MCI) and one patient with moderate AD, with a suspicion of network hyperexcitability based on either spikes on 24‐h scalp EEG or a history suspect for seizures without epileptiform discharges on scalp EEG.MethodThree patients were implanted with bilateral foramen ovale (FO) electrodes to obtain more direct measures of mesial temporal lobe epileptiform activity. Scalp EEG according to the 10‐20 system and polysomnography were simultaneously recorded in all subjects for three to five consecutive days. Polysomnography was scored according to the AASM scoring rules. Persyst 14 software was used for automatic spike detection.ResultInvasive recordings showed interictal epileptic activity in all three patients, which was occasional during wakefulness and abundant during sleep. In one patient two nocturnal unilateral mesiotemporal seizures, characterized by arousal, were recorded during N1 sleep, while at the same time no epileptiform activity was visible on scalp EEG.ConclusionIn patients with AD subclinical mesial temporal epileptiform activity can be present with a normal scalp EEG. Epileptic activity is predominantly found during sleep. Our findings suggest an important role for network hyperexcitability in AD disease pathogenesis.
The impact of co‐morbid LATE‐NC pathology in Alzheimer’s Disease.
Authors: Tomé Sandra O. , Tsaka Grigoria , Ronisz Alicja , Ospitalieri Simona , Gawor Klara , von Arnim Christina , Otto Markus , Vandenberghe Rik , Schymkowitz Joost , Rousseau Frederic , Thal Dietmar Rudolf ,   Neuropathology
Published: December 2023

AbstractBackgroundTDP‐43 is known to co‐accumulate in the brains of most Alzheimer’s Disease (AD) cases, in addition to amyloid‐β plaques and tau tangles, and it has been recently defined as limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC). TDP‐43 pathology is thought to worsen cognitive decline and neurodegeneration, but it is not yet understood whether TDP‐43 expression impacts AD pathogenesis, specifically tau pathology.MethodWe performed a histological evaluation of 85 human cases including controls, symptomatic AD cases with (ADNC+LATENC) and without (ADNC) LATE‐NC using paraffin‐embedded post‐mortem tissue. We quantitatively assessed pTau load and neuronal density. Additionally, we measured brain levels of p‐tauT181 and total TDP‐43 (1‐300aa.) through ELISA using fresh frozen tissue of controls, ADNC, ADNC+LATENC and FTLD‐TDP cases. Moreover, we tested the seeding potential of ADNC+LATENC and AD seeds in vivo, using a TDP‐43A315T transgenic mouse model as well as in vitro, using a tau biosensor cell line (HEK293T cells transfected with a tau PS301S mutation).ResultWe observed that ADNC+LATENC cases presented increased neuronal loss (p = 0.0231) and hippocampal tau pathology (p<0.0001) compared to ADNC and controls. Moreover, the ADNC+LATENC group showed increased levels of the p‐tauT181 in frontal (p = 0.0212) and entorhinal cortex (p = 0.0003) compared to the ADNC group. Total TDP‐43 levels were decreased in ADNC+LATENC and FTLD‐TDP cases compared to controls in entorhinal (p = 0.0151 and p = 0.0041, respectively) but not frontal cortex. Moreover, we observed that TDP‐43A315T mice injected with ADNC+LATENC seeds exhibited significantly increased p‐tau seeding compared to ADNC (p = 0.0163) and control‐injected animals (p = 0.0007). In line with these findings, ADNC+LATENC seeds also triggered increased p‐tau cell seeding in tau biosensor cells compared to ADNC seeds (p = 0.0048).ConclusionThese results highlight the synergy between TDP‐43 and tau proteins in the context of AD pathogenesis. Specifically, our data suggest that the presence of comorbid LATE‐NC in AD aggravates tau pathology, increasing its aggregation and seeding. Moreover, a decrease in total TDP‐43 in ADNC+LATENC and FTLD‐TDP groups points to a loss of function of this protein. We highlight the importance of considering comorbid co‐pathologies in the context of clinical diagnosis and patient stratification.
Nicotinic ACh receptor activation induces BACE1 transcription via MEK⁄ERK‐SP1 signaling pathway
Authors: Nakano Masaki , Mitsuishi Yachiyo , Saito Takashi , Saido Takaomi C. , Nishimura Masaki 
Published: December 2023

AbstractBackgroundEpidemiological studies showed that cigarette smoking increases a risk of Alzheimer disease. In contrast, nicotine treatment reportedly reduces brain Aβ deposition of APP‐transgenic mice. These findings seem inconsistent. Previously, we reported that nicotine perfusion using reverse microdialysis increased Aβ levels of the cerebral cortex of APP‐knockin mice (J Alzheimers Dis, 2021). In this study, we further examined nicotine effects on Aβ metabolism and the underlying mechanisms.MethodUsing AppNL‐G‐F mice and SH‐SY5Y neuronal cells, we analyzed nicotine effects on cellular and brain Aβ metabolism. (1)AppNL‐G‐F mice were exposed ad libitum to drinking water containing nicotine for 2 months and then brain Aβ of these mice was quantitatively evaluated by ELISA and immunostaining. (2) Effects of nAChR activation on Aβ production were examined using SH‐SY5Y cells. (3) We also evaluated nicotine effects on Aβ aggregation using an in vitro assay.ResultChronic treatment of AppNL‐G‐F
mice with nicotine resulted in increased contents of brain Aβ but had no obvious effect on aggregated Aβ deposition. We found that nAChR activation increased Aβ production of SH‐SY5Y cells, which was associated with induction of BACE1 transcription and activation of MEK/ERK‐SP1 signaling pathway. Further analysesindicated that nAChR stimulation upregulated SP1 transcription factor to induce BACE1 transcription, and that nicotine inhibited Aβ42 aggregation in vitro.ConclusionOur study revealed that nicotine has two major effects on Aβ metabolism; an increase in Aβ production and an inhibition of Aβ aggregation. Thus, nicotine could have opposite effects on brain Aβ deposition, which may explain inconsistency of previous studies on nicotine and Alzheimer disease.
Role of miR‐802 in brain insulin signaling and its impact on Down syndrome
Authors: Tramutola Antonella , Barone Eugenio , Pagnotta Sara , Domenico Fabio Di , Perluigi Marzia 
Published: December 2023

AbstractBackgroundDown syndrome (DS) individuals are characterized by a variety of pathological phenotypes that manifest with wide variability in the different tissues. At the level of the central nervous system, the accelerated aging phenotype is associated with the risk to develop Alzheimer‐like dementia. A central aspect of neurodegeneration is the close association between metabolic disorders and cognitive decline. Multiple studies have suggested a link between metabolic disorder and microRNAs (miR), small non‐coding RNAs acting as post‐transcriptional regulators of a plethora of genes. Among triplicated miRNAs on chromosome 21, we focus on miR‐802 because recent studies demonstrated its association with development on insulin resistance in obesity and diabetes. Considering these findings and based on the “gene dosage hypothesis” of DS, the goal of the study is to decipher how miR‐802 may contribute to aberrant insulin signaling (IS) and, in parallel to the risk to develop dementia early in life in DS.
MethodThe miR‐802 expression, protein levels and activation state of main components of the IS were evaluated (i) in the brain of autoptic cases from DS, DSAD and age‐matched controls and (ii) in the brain of euploid and Ts65Dn mice (a model of DS). Further, using bioinformatic tools we identified miR‐802 predicted target genes that are involved in the IS (PTEN and GSK‐3β).ResultThe IS alterations worsen in the transition from DS to DS/AD and similar findings were collected inTs65Dn mice where IS dysregulation persists with aging where neurodegeneration becomes significant. Intriguingly, these latter changes were driven by the over‐expression of miR‐802, which negatively regulates PTEN and GSK‐3β mRNA in the brain.ConclusionIn this picture, the identification of specific targets modulated by miR‐802 and involved in IS pathway, will provide molecular basis to develop novel therapeutic strategies to prevent/delay the onset of brain insulin resistance in DS.
Trajectories of cognition and functional ability in people with dementia: Two‐year longitudinal results from the IDEAL programme
Authors: Martyr Anthony , Ravi Madhumathi , Gamble Laura D , Morris Robin G. , Pentecost Claire , Matthews Fiona E , Clare Linda 
Published: December 2023

AbstractBackgroundImpairment in both cognition and instrumental activities of daily living (iADL) are key diagnostic features of dementia. Few studies have compared trajectories of cognition and iADL. By comparing trajectories of cognitive decline with both self‐rated and informant rated iADL, the study determines whether these aspects are related or decline in parallel and where there is a difference between perceptions of change.MethodData from the Improving the experience of Dementia and Enhancing Active Life (IDEAL) study were used. The study comprises 1537, 1183, and 851 people with dementia, and 1277, 977, and 749 carers at baseline (T1), 12 months later (Time 2, T2), and 24 months later (Time 3, T3), respectively. Cognition was assessed with the Addenbrooke’s Cognitive Examination‐III (ACE‐III), higher scores indicate fewer cognitive difficulties. iADL was assessed using the Functional Activities Questionnaire (FAQ), higher scores indicate more iADL difficulties. Both self‐ratings (FAQ‐S) and informant ratings (FAQ‐I) were collected. Because of the differences in the scale and distribution of FAQ and ACE‐III, scores were converted to ranks to enable comparison of trajectories between the two measures; deciles were calculated at T1 and imposed on T2 and T3 scores.ResultAs ACE‐III decreased both FAQ‐S and FAQ‐I increased suggesting that people with dementia with more cognitive difficulties were rated as having greater iADL difficulties by both people with dementia themselves and their carers. FAQ‐S declined on average by ‐0.10 (‐0.26, 0.06) decile points per timepoint more than ACE‐III. As confidence intervals overlapped zero this suggests that FAQ‐S and ACE‐III ratings declined at a similar rate. FAQ‐I declined on average by ‐0.31 (‐0.43, ‐0.19) decile points per timepoint more than ACE‐III. The trajectory over the two years suggests that FAQ‐I ratings declined at a significantly greater rate than ACE‐III scores.ConclusionBoth cognition and iADL, whether self‐ or informant‐rated declined over two years. Trajectory analysis suggests that self‐rated iADL was generally concordant with cognitive decline, whereas informant‐rated iADL reflected more perceived decline than cognition. Therefore, either cognition and perceived iADL decline at different rates or informants overestimate increasing iADL difficulties compared to both cognition and self‐ratings.
Misalignment in circadian‐regulated glymphatic clearance as a driver of neurodegeneration
Authors: Fagiani Francesca , Ciampi Clara , Pittaluga Anna Maria , Trabace Luigia , Raso Giuseppina Mattace , Meli Rosaria , Ghelardini Carla , Govoni Stefano , Mannelli Lorenzo Di Cesare , Lanni Cristina 
Published: December 2023

AbstractBackgroundGlymphatic system (GS) is a glial‐dependent perivascular network that under circadian regulation (Hablitz et al, 2020) controls the clearance of waste products in the central nervous system during the sleep (Xie et al, 2013) and its function is suppressed in several neurodegenerative diseases. Our aim is to investigate whether alteration in the circadian‐controlled dynamics of the GS may be the linker between the periphery and the brain. Our hypothesis is that the disruption of the gut‐brain dialogue, due to peripheral colonic inflammation, alters the circadian clockwork both in periphery and CNS, thereby impacting on the circadian‐regulated GS flux in the brain.MethodThe peripheral inflammation was obtained using an acute dextran sulfate sodium (DSS) mouse model of colitis. Alterations in GS dynamics and in the relative concentrations of selected metabolites in the brain have been evaluated by MRI and MRS, respectively. Aquaporin‐4, α‐syntropin, Connexin‐43 as well as clock genes expression have been assessed in colon, and in different brain areas, by real‐time PCR. AQP4 mis‐location has been evaluated by transmission electron microscopy.ResultOur data demonstrate that, in DSS‐driven acute colitis model, the inflammatory hit strongly impacts on the circadian clockwork both at peripheric and central level, by altering the expression of the core clock components. Such alteration in the clock components expression pattern correlates with changes in GS dynamics in the brain. In particular, colonic inflammation impacts on the expression of astrocyte aquaporin‐4, as well as of α‐syntropin and Connexin‐43, in both cerebellum and cortex, thus suggesting a potential molecular derangement in the regulation of glymphatic influx. Alterations in GS dynamics have also been detected in the relative concentrations of specific metabolites in selective brain areas by MRS. As a consequence of brain changes in GS dynamics, we observed an increased phospho‐tau deposition in the hippocampus of DSS mice.ConclusionThe characterization of the cascade of events and the relationship among gut inflammation, glymphatic influx alteration and brain waste product deposition has a novel significance since it will allow understanding how a persistent peripheral enteric hit may disorganize a central hierarchy thus triggering a self‐sustaining process prodromal of neurodegeneration.
Amyloid‐β immunotherapy induced microhemorrhages are associated with activated perivascular macrophages and peripheral monocyte recruitment in Alzheimer’s Disease mice
Authors: Taylor Xavier , Clark Isaiah , Oluoch Herold , Fitzgerald Griffin , Hole Justin T. , DeMattos Ronald B. , Wang Yaming , Pan Feng 
Published: December 2023

AbstractBackgroundAmyloid‐related imaging abnormalities (ARIA) have been identified as the most common and serious adverse events caused by pathological changes in the cerebral vasculature during several recent anti‐amyloid‐b (Aß) immunotherapy trials. However, the cellular and molecular mechanisms underlying how amyloid immunotherapy enhances cerebral amyloid angiopathy (CAA)‐mediated alterations of vascular permeability and microhemorrhages are not currently understood. Interestingly, brain perivascular macrophages have been implicated in regulating CAA deposition and cerebrovascular function however, additional studies are required to understand how perivascular macrophages play a role in enhancing CAA‐related vascular permeability and microhemorrhages associated with amyloid immunotherapy.MethodsWe study immune responses induced by amyloid targeting antibodies and CAA‐mediated microhemorrhages using histology and gene expression analyses in AD mouse models and primary culture settings.ResultsIn the present study, we show that anti‐Aβ (3D6) immunotherapy leads to the formation of an antibody immune complex with vascular amyloid deposits and induces the activation of CD169+ perivascular macrophages. We show that macrophages activated by antibody mediated Fc receptor signaling have increased expression of inflammatory signaling and extracellular matrix remodeling genes such as Timp1 and MMP9 in vitro and confirm these key findings in vivo. Finally, we demonstrate enhanced vascular permeability of plasma proteins and recruitment of inflammatory monocytes around vascular amyloid deposits, which are associated with hemosiderin deposits from cerebral microhemorrhages, suggesting the multidimensional roles of activated perivascular macrophages in response to Aβ immunotherapy.ConclusionsIn summary, our findings demonstrate that Aß antibodies engaged at CAA deposits are associated with the activation of perivascular macrophages and the upregulation of vascular permeability related genes. Whether this leads to increased susceptibility to microhemorrhages remains to be seen. Additional studies need to be performed to establish the role of CD169+ perivascular macrophages in enhancing CAA‐mediated vascular permeability, plasma protein extravasation, and infiltration of monocytes associated with microhemorrhages.
Vitamin C is protective against a microglial inflammatory phenotype following LPS exposure
Authors: Marino Amanda L , Wilcox Jordyn M , Harrison Fiona E. 
Published: December 2023

AbstractBackgroundNeuroinflammation is considered a key pathogenic feature of Alzheimer’s disease (AD) progression. Presence of reactive oxygen species is a driving factor in neuroinflammatory processes and deficiency of antioxidants in the brain can contribute to AD pathogenesis via this mechanism. However, more specifically depletion of ascorbic acid (ASC, vitamin C) may directly impact microglial function. Like neurons, microglia express the sodium‐dependent vitamin C transporter (SVCT2) and can store ASC at high concentrations. Nevertheless, specific roles for ASC and SVCT2 in the inflammatory response are not well understood. This present study investigated a protective role for vitamin C (ASC) following LPS administration to microglial cells.MethodHMC3 cells (P8‐12) were cultured in 6‐well plates in DMEM (10% FBS, 1% Pen/Strep) treated with ASC (0 or 200 mM) LPS (0, 1mg/mL or 10mg/mL) for 24 hours. After 24 hours, cells were collected to identify intracellular and extracellular (media levels) of ASC by high pressure liquid chromatography. Expression of a number of inflammatory and apoptosis linked genes was assessed by qPCR with reference to two housekeeping genes [GAPDH, ACTB]. Immunofluorescent staining of SVCT2 was performed in fixed cells that were co‐stained with Iba‐1.ResultIntracellular ASC was increased by ASC treatment and was not significantly changed due to LPS treatment. 1mg/mL LPS significantly induces inflammatory phenotype in HMC3 microglia including upregulation of mRNA levels of inflammatory cytokines including [IL‐1B, IL‐6, NF‐kB] and this effect was attenuated by ASC treatment. 10mg/mL induced cell death in HMC3 microglial cells and this effect was also at least partially mitigated by concurrent treatment with ASC.Conclusionuroinflammation is a critical component of AD neuropathology and ASC decreased inflammatory cytokine signaling and an inflammatory phenotype following LPS treatment in HMC3 microglia. These data suggest that maintaining adequate cellular ASC levels may preserve microglial function in the presence of inflammatory stimuli such as beta‐amyloid or delay neuroinflammation‐linked facets of Alzheimer’s disease pathology.
PRX005, a novel anti‐MTBR tau monoclonal antibody: results from a first‐in‐human double‐blind, placebo‐controlled, single ascending dose phase 1 study
Authors: Martenyi Ferenc , Campbell Brian , Kinney Gene G. , Lee Jun , Jin Yuying , Zago Wagner M. , Garren Hideki 
Published: December 2023

AbstractBackgroundMultiple lines of evidence indicate that tau protein spreads throughout the brain via synaptically connected pathways and that this propagation could be mediated by tau “seeds” containing the microtubule binding region (MTBR) of tau. In addition, cerebrospinal fluid (CSF) MTBR‐tau levels correlate with tau tangles and clinical stages of Alzheimer’s disease. To block the spread of tau pathology, we developed PRX005, a humanized monoclonal tri‐epitopic antibody that binds with high affinity to the R1, R2, and R3 repeats in the MTBR region of tau, and targets both 3R and 4R tau isoforms.MethodHealthy volunteers were randomly assigned to three dose cohorts and randomized in a 3:1 manner to receive either PRX005 or placebo. Primary endpoint was safety and tolerability with up to 2 months of follow‐up. Secondary endpoints included PRX005 pharmacokinetic parameters in plasma and CSF penetrance.ResultA total of 19 healthy volunteer participants received study drug or placebo. PRX005 was well tolerated and had a pharmacokinetic profile typical of IgG1 antibodies, with dose‐proportional increase in plasma concentration and central nervous system (CNS) penetrance. No persistent drug‐induced anti‐drug antibodies were observed following treatment with PRX005. Additional results from this Phase 1 will be presented.ConclusionIn this first‐in‐human, single ascending dose study, PRX005 was well tolerated and achieved CNS concentrations for pharmacological targeting of MTBR‐tau. Our results support the progression of the clinical development of PRX005 in an ongoing, multiple ascending dose study in patients with Alzheimer’s disease.