bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overexpression of Aha1 and FKBP52 does not affect learning or mood‐like behavior in human tau (hTau) mice
Authors: Criado‐Marrero Marangelie , Esquivel Abigail R. , Blair Laura J. 
Published: June 2023

AbstractBackgroundTau plays a critical role in neurodegeneration, thus targeting this protein to control its accumulation is important to prevent or delay neurotoxicity in tauopathies like Alzheimer’s disease (AD). Discrete molecular chaperones, like Aha1 and FKBP52, are known to affect the stability of tau by promoting its phosphorylation, aggregation and, in some mouse models, neuronal death. However, one limitation of preclinical tau models is that various contain tau mutations which do not represent most AD cases. Our study is important because it investigates biological mechanisms and behavioral phenotype in a humanized tau (hTau) mouse model absent of tau mutations. We hypothesize that overexpression of Aha1 in in hTau mice will accelerate tau tangle formation and cognitive deficits.MethodTo test this, Tau KO and hTau mice were bilaterally injected into the hippocampus with AAV9‐Aha1, AAV9‐FKBP52, and AAV9‐mKate (control) virus. At 11 and 13 months of age, animals were tested for cognitive and behavioral phenotypes.ResultsWe found that overexpression of these chaperones does not affect anxiety, spatial working memory, and locomotion in hTau mice. We further confirmed that short‐term working memory in the learning and extinction of fear memories remained unaltered by the high levels of Aha1 and FKBP52 at these ages. Ongoing analyses will examine tau pathology in these brains by measuring tau levels, neuronal density, and cell death markers.ConclusionAt this timepoint, Aha1 and FKBP52 did not induce behavioral differences in these mice. We recently reported that overexpression of these chaperones promotes tau pathological changes in 16‐months‐old wild‐type. Thus, it is possible that behavioral differences can be detected as tau pathology progresses at an older age.
What a single electroencephalographic (EEG) channel can tell us about Alzheimer's disease patients with mild cognitive impairment
Authors: Tucci Federico , Percio Claudio Del , Lopez Susanna , Noce Giuseppe , Lizio Roberta , Soricelli Andrea , Ferri Raffaele , Nobili Flavio , Arnaldi Dario , Famà Francesco , Buttinelli Carla , Giubilei Franco , Marizzoni Moira , Güntekin Bahar , Yener Görsev , Stocchi Fabrizio , Vacca Laura , Frisoni Giovanni B , Babiloni Claudio 
Published: June 2023

AbstractBackgroundAbnormalities in the neurophysiological oscillatory mechanisms generating dominant resting‐state eyes closed electroencephalographic (rsEEG) rhythms portray the Alzheimer’s disease (AD) continuum, from the preclinical to the dementia stage. Here, we tested whether these abnormalities may be reproducible by analyzing the rsEEG signals acquired in bipolar configuration with a montage consisting of only four centro‐parietal and parieto‐occipital channels (C3‐P3, C4‐P4, P3‐O1, and P4‐O2) in patients with mild cognitive impairment (MCI) due to AD (ADMCI).MethodTo evaluate the study hypotheses, clinical, neuropsychological, anthropometric, genetic, cerebrospinal fluid (CSF), MRI, and rsEEG data in 70 Nold and 75 ADMCI subjects from an international archive were used in the present study. The subgroups were matched for age, gender, and education. In all subjects, rsEEG recordings lasted about 3‐5 minutes. The rsEEG data were recorded with a sampling frequency of 128‐512 Hz and related antialiasing bandpass between 0.01 Hz and 60‐100 Hz. Electrode montage included 19 scalp monopolar sensors placed following 10‐20 System. The rsEEG rhythms were investigated at individual delta, theta, and alpha frequency bands as well as fixed beta (14‐30 Hz) and gamma (30‐40 Hz) bands.ResultResults confirmed previous evidence about the abnormalities of the delta, theta, and alpha rhythms in ADMCI patients compared to Nold subjects. Moreover, as compared to the Nold group, the ADMCI group showed increased delta power density and decreased alpha power density at the C3‐P3, C4‐P4, P3‐O1, and P4‐O2 bipolar channels. Increased theta power density for ADMCI patients was observed only at the C3‐P3 bipolar channel. Best classification accuracy between the ADMCI and Nold individuals reached 81% (area under the receiver operating characteristic curve) using Alpha2/Theta power density computed at the C3‐P3 bipolar channel.ConclusionThe current findings provide evidence in the potential use of rsEEG low‐channel portable devices as a topographic biomarker of cognitive decline within the extensive screening of in elderly population at risk of developing AD‐ or other dementia‐related disorders. Moreover, the confirmation of this hypothesis would have exciting applications in the framework of telehealth home monitoring of global brain functions.
Hippocampal subfields’ sex differences in EOAD
Authors: Contador José , Pérez‐Millan Agnés , Guillén Núria , Sarto Jordi , Tort‐Merino Adrià , Balasa Mircea , Martínez Neus Falgàs , Castellví Magdalena , Borrego‐Écija Sergi , Juncà‐Parella Jordi , Bosch‐Capdevila Beatriz , Fernandez‐Villullas Guadalupe , Ramos‐Campoy Oscar , Antonell Anna , Bargalló Núria , Sanchez‐Valle Raquel , Sala‐Llonch Roser , Lladó Albert 
Published: June 2023

AbstractBackgroundIn healthy ageing, there is evidence of sex differences in vulnerability of hippocampal subfields to volume loss. However, this has not been investigated in early‐onset Alzheimer’s disease (<65 years; EOAD).MethodWe included 106 subjects: 62 EOAD (A+T+N+, MMSE>15) and 44 healthy controls (HC; A‐T‐N‐) that underwent lumbar puncture for analysis of AD biomarkers, 3T‐MRI scan and neuropsychological assessment. Hippocampal subfield segmentation was performed using T1‐weighted images and Freesurfer 6.0. Volume was adjusted by intracranial volume. Adjusted linear models were used to analyze differences between EOAD and HC and differences between sexes. We calculated Cohen’s d as a measure of the effect size of volume change by sex, restricted to volume differences between EOAD and HC. In EOAD, we used linear models adjusted by age and education to investigate the association of volume loss with 18 cognition z‐scores. Results were adjusted using Bonferroni correction for multiple comparisons.ResultThere were no demographic differences across groups. APOEε4 carriers were higher in EOAD‐female/EOAD‐male than HC‐female. EOAD‐female showed higher T‐Tau and P‐Tau levels than EOAD‐male (all p<0.05; Table1). Comparing EOAD vs. HC, differences were found in volume of all subfields and hippocampus (p<0.05, Bonferroni corrected), except for bilateral parasubiculum and right cornu ammonis (CA) 2/3. No differences were found between EOAD‐female and EOAD‐male (p>0.05). When compared to HC of the same sex, EOAD‐female showed differences in the same regions as the whole sample, while EOAD‐male showed differences in bilateral hippocampal tail and left presubiculum and hippocampus (all p<0.05, Bonferroni corrected, Figure 1). We observed larger effect sizes than in women in these regions, except for left hippocampus (Figure 2).In EOAD, higher volume in left CA2/3 predicted higher memory z‐scores, including free and total learning and delayed total recall (p<0.05 Bonferroni corrected; Figure 3). No associations were found in EOAD‐female nor EOAD‐male.ConclusionIn EOAD, the pattern of volume loss in hippocampal subfields was similar between sexes. However, females showed more marked differences from HC, except for bilateral hippocampal tail and left presubiculum. Further studies are necessary to elucidate the existence of sex differences in EOAD and their implication for cognitive impairment.
Asiatic improves brain mitochondrial function, activates antioxidant response and attenuates cognitive deficits in beta amyloid overexpressing mice
Authors: Gray Nora E , Chamberlin Steven R , Bui Lillie E , Brandes Mikah S , Brumbach Barbara H , Quinn Joseph F 
Published: June 2023

AbstractBackgroundThe plant Centella asiatica can enhance mitochondrial function, promote antioxidant activity and improve cognitive deficits in mouse models of aging and Alzheimer’s disease. Asiatic acid (AA) is one of the constituent triterpene compounds present in the plant. In this study we explore the effects of increasing concentrations of AA on mitochondrial function and antioxidant response in healthy mice and investigate whether high doses of AA can elicit beneficial effects on mitochondrial function, antioxidant response and cognitive function in the 5xFAD mouse model of beta‐amyloid accumulation.MethodsNine month old female CF1 mice were treated with 0, 5mg, 50mg or 1000 mg of AA per 1kg of AIN‐93M diet for four weeks. Toxicity was also monitored. Hippocampal mitochondrial bioenergetics and the expression of mitochondrial and antioxidant response genes was determined. Results were compared to animals treated with 1000mg/kg of a water extract of Centella asiatica (CAW) incorporated into their diet. Additionally, six month old male and female 5xFAD mice were treated with 0 or 1000 mg/kg AA in their diet for four weeks. In the third week mice underwent cognitive testing. Hippocampal mitochondrial bioenergetics and expression of synaptic, mitochondrial and antioxidant response genes was assessed.ResultsIn the healthy mice increasing concentrations of AA resulted in a dose dependent increase in basal and maximal mitochondrial respiration, mitochondrial gene expression and antioxidant gene expression. Results from the 1000mg/kg AA dose were similar to what was observed with CAW. No evidence of toxicity was observed at any concentration of AA. In the 5xFAD mice 1000mg/kg AA attenuated deficits in cognitive and mitochondrial function and induced the expression of antioxidant genes. Interestingly, there was not a consistent effect of AA on mitochondrial or synaptic gene expression.ConclusionThese data show that high concentrations of AA can improve mitochondrial function and antioxidant response in the brains of treated animals. Consistent with the fact that mitochondrial dysfunction and oxidative stress are known to contribute to cognitive impairments this improvement was accompanied by improved cognitive function in the 5xFAD mice. Taken together these results suggest that AA is a promising cognitive enhancing therapy to develop for use in AD.
Brain regions with higher noradrenergic innervation show greater vulnerability to degeneration in preclinicial Alzheimer’s disease
Authors: Haag Lena , Lancini Elisa , Ziegler Gabriel , Yakupov Renat , Heneka Michael T. , Wagner Michael , Peters Oliver , Priller Josef , Schneider Anja , Wiltfang Jens , Buerger Katharina , Perneczky Robert , Teipel Stefan , Laske Christoph , Spottke Annika , Fliessbach Klaus , Jessen Frank , Duzel Emrah , Betts Matthew , Hämmerer Dorothea 
Published: June 2023

AbstractBackgroundThe noradrenergic (NA) system comprises several cortical and subcortical brain areas with differential densities of NA transporters and receptors. A decline in the NA system, together with additional risk factors such as ApoE4‐status, gender, age, vascular changes and years of education may contribute to the development of Alzheimer’s disease (AD). The aim of this study was to examine whether brain areas known to be rich in NA receptors and transporters are particularly vulnerable to degeneration in preclinical AD.MethodWe examined interindividual differences in volumes of specific brain areas grouped into high and low NA density regions (NA‐high/NA‐low) for healthy controls (HC) and AD relatives (n = 122), individuals with subjective cognitive decline (SCD) (n = 152) and mild cognitive impairment (MCI) (n = 78). Structural equation modeling (SEM) was used to simultaneously examine associations between NA‐high and NA‐low regions across clinical groups. We investigated whether brain volumes in NA‐high and NA‐low areas were differentially related to known AD risk factors (ApoE4 status, CSF amyloid‐ß (Aß) 42/40 and phosphorylated tau (pTau)), and whether these links differed in HC, SCD and MCI.ResultEstimating a two‐factor model with NA‐high and NA‐low revealed a better model fit than estimating one general factor. ApoE4‐carriers were associated with a lower ratio of Aß42/40 (‐0.472***) and a higher level of pTau (0.263***). In the whole sample, a low ratio of Aß42/40 was associated with lower brain volume in NA‐high (0.157***), but not NA‐low areas. pTau showed no significant association to NA‐high or NA‐low areas.The group analysis revealed an increasing association between ApoE4, pTau and Aß42/40 in HC, SCD and MCI. An association between Aß42/40 and NA‐high areas was observed in all groups, whilst for an additional positive association to NA‐low in HC (0.125*), but negative association in SCD (‐0.184*). Finally, the negative association between pTau and Aß42/40 is true for SCD and MCI, but not for HC.ConclusionSEM can be used to separate brain regions into NA‐high and NA‐low areas. Higher risk status Aß42/40 is linked to lower brain volume in high NA density areas, suggesting a particular vulnerability of brain areas likely more affected by NA decline in AD.
Relation of modifiable lifestyle and mood factors to subjective cognitive concerns among participants and their study partners in the A4 screen data
Authors: Reynolds Gretchen , Buckley Rachel F. , Papp Kathryn V. , Schultz Stephanie A. , Rentz Dorene M. , Sperling Reisa A. , Amariglio Rebecca E. 
Published: June 2023

AbstractBackgroundSubjective cognitive decline (SCD) is associated with future cognitive decline, elevated amyloid levels, and non‐specific variables, including mood. Participants often endorse higher cognitive concerns than their study partners (SPs), raising the possibility that participant complaints reflect multiple factors, including mood, lifestyle variables, and amyloid status. To determine the predictive value of modifiable factors, we examined the relation between SCD, lifestyle habits, amyloid, and mood among cognitively unimpaired older adults from a multi‐site secondary prevention trial (A4 screen data).MethodParticipants were 6943 individuals from A4 assessed pre‐randomization [mean(SD): age = 71.6(4.9), education = 16.4(3.0); 58% women, 95% non‐Hispanic or Latino, 90% white)]. Using descriptive analyses and linear regression models, we examined whether amyloid status (amyloid+: n = 1329/4492) and self‐reported mood (Geriatric Depression Scale [GDS]) or lifestyle habits (exercise, sleep) predicted subjective cognitive concerns (CFI; participant‐ and SP‐reported).ResultParticipants endorsed healthy lifestyle habits (mean hours of aerobic exercise/week = 2.9; mean hours of sleep/night = 7.1), minimal mood symptoms (mean GDS = 1.1), and higher cognitive concerns than SPs (t(5996) = ‐25.08, p<.001). Lower mood (t = 29.49, p<.001), older age (t = 5.75, p<.001), and lower education (t = ‐3.92, p<.001) predicted participant concerns on the CFI, with additive predictive value of lower self‐reported exercise (t = ‐2.90, p = .004) and sleep duration (t = ‐2.12, p = .035); however, only lower participant‐reported mood (t = 12.90, p<.001) and older participant age (t = 6.54, p<.001) predicted SP concerns. Adding amyloid to the model in a subset, all predictors for participant concerns remained except sleep, while only amyloid status (t = 4.59, p<.001), lower mood (t = 11.53, p<.001), and older age (t = 4.72, p<.001) predicted SP concerns.ConclusionCognitively unimpaired participants endorsed higher cognitive concerns on the CFI compared to their SPs. Participant concerns were associated with multiple predictors (age, education, mood, amyloid status, exercise, sleep), while SP concerns were only associated with age, mood, and amyloid status. Participants may be more aware of early changes and endorse concerns reflecting various factors, including personal lifestyle habits, while SP report may be more specific to cognitive changes due to age and amyloid burden. These findings expand understanding of how various factors (e.g., biomarkers, mood, lifestyle habits) may contribute differently to participant and SP cognitive concerns, which may inform research recruitment and clinical care.
Identification of novel genetic variants and biomarkers for cognitive decline in Alzheimer’s disease
Authors: Ali Muhammad , Wang Fengxian , Mafimoghaddam Samira , Euesden Jack , Robins Chloe , Pulford David J. , Cruchaga Carlos 
Published: June 2023

AbstractBackgroundAlzheimer’s disease (AD) is a complex, multifactorial disease that is incurable in the aging population. The success of genome‐wide association studies (GWAS), as a cross sectional design, to identify novel genetic risk factors for AD in recent years is well known; however, case‐control studies are less likely to uncover genetic factors that influence other aspects of the disease, such as progression and onset.MethodIn order to identify common and rare genetic variants associated with rates of cognitive decline in AD, we aim at systematically analyzing the largest collection of longitudinal and GWAS data (N = 7,241), across non‐Hispanic white individuals from multicenter cohorts (Knight‐ADRC, ADNI, NACC, and GSK) with at least 1.5 years of follow up after being diagnosed with AD. We also aim at exploring if genetic risk factors, alone or interacting with other genetic factors, are associated rate of cognitive decline in patients with AD when aggregated together into a single Polygenic Risk Score (PRS). Furthermore, external proteomics data will be combined with the genetics data for Mendelian Randomization (MR) analyses in order to discover causal biomarkers for cognitive decline and AD risk.ResultPreliminary results found a suggestive signal in chr21 (min P = 8.7e‐8) approaching close to the genome‐wide significance threshold. Moreover, some other suggestive signals were detected in chr2 (min P = 3.8e‐06) and chr1 (min P = 3.7e‐06) that warrant further investigation. Further results and key findings of the post‐GWAS analyses will be presented during the AAIC meeting.ConclusionWe have leveraged these datasets to generate prediction models for rate of cognitive decline in AD. The identification of AD‐specific genetic variants and biomarkers will enable the characterization of appropriate therapeutic targets for slowing or halting the AD progression.
E2511, a novel small compound TrkA biased positive allosteric modulator, reinnervates cholinergic neuron and activates cholinergic functions in non‐clinical studies
Authors: Tomioka Takeyasu , Hiramatsu Naoki , Moriyama Yoshiyuki , Kosasa Takashi 
Published: June 2023

AbstractBackgroundCholinergic innervation is particularly vulnerable in many neurodegenerative diseases associated with cognitive dysfunction, and loss of cholinergic neurons in Alzheimer’s disease (AD) is pathogenic event observed from early stage correlated with cognitive impairment. Nerve growth factor (NGF) plays a major role in the maintenance and function of cholinergic neurons, and a decrease in trophic signalling by NGF‐Tropomyosin receptor kinase A (TrkA) contributes to cholinergic neurodegeneration and cognitive decline during the course of AD. The activation of NGF‐induced trophic signal could be a promising therapy for the neurodegenerative diseases including AD, reinnervating and maintaining cholinergic neurons to functional status. E2511 was identified as a novel small compound TrkA biased positive allosteric modulator that can enhance specific trophic signal of NGF signal without induction of NGF‐like adverse effect via direct binding to TrkA in primary neuron culture and animal model. We present evidence that E2511 induced functional restoration of cholinergic neuron in animal model and rats.MethodThe trophic effect of E2511 on cholinergic neurons was assessed by biochemical studies such as western blotting and immunohistochemistry in human Tau P301S transgenic mice (Tau tg mice) following once‐daily oral administrations of E2511 for 3 months. E2511 TrkA downstream trophic effects on acetylcholine (ACh) were evaluated in cerebrospinal fluid (CSF) collected from cisterna magna in normal SD rats treated with once‐daily oral E2511 for 14 days, using an original LCMS method.ResultChronic administration of E2511 demonstrated reinnervative effects on cholinergic presynapses as well as a correlation with improvement of the number of cholinergic neurons in Tau tg mice. In SD rats, CSF ACh increased in a dose‐dependent manner at exposures associated with cholinergic reinnervation, with changes also correlating with increases in choline acetyltransferase mRNA level. These results suggest that CSF ACh may be a useful marker to establish the E2511 effective dose in humans.ConclusionE2511 functionally reinnervates cholinergic neuronal network in the Tau tg mice. CSF ACh increased in a dose‐related manner in SD rats. CSF ACh may be used as a pharmacodynamic marker to establish the dose showing the reinnervative effect of E2511 in clinical studies.
Donanemab exposure‐efficacy relationship in patients with early symptomatic Alzheimer’s disease
Authors: Gueorguieva Ivelina , Chua Laiyi , Chow Kay Hoong , Ernest C Steven , Willis Brian A. , Shcherbinin Sergey , Sims John R. , Chigutsa Emmanuel 
Published: June 2023

AbstractBackgroundDonanemab is an IgG1 antibody targeting N3pG (a modified beta amyloid present solely in brain plaques). A population pharmacokinetic/amyloid positron emission tomography (PET) imaging model described donanemab’s effect on amyloid plaque measurements and associated treatment‐effect with maintaining median (95%CI) threshold concentration of 4.43 (0.96 to 10.4 mg/mL). The extent to which exposure exceeded this threshold did not influence degree of amyloid removal. The current analysis aimed to quantify treatment effect on change in clinical decline (integrated AD Rating Scale, iADRS); evaluate the relationship of donanemab‐mediated changes in amyloid plaque on iADRS; and evaluate patient factors potentially affecting response to donanemab treatment.MethodAnalyses included patients with early symptomatic Alzheimer’s disease (AD, including prodromal AD and mild AD dementia) randomized to donanemab monotherapy versus placebo in a phase 2 study (TRAILBLAZER‐ALZ; N = 256; NCT03367403). Exposure‐response modeling employed a non‐linear mixed effects modeling approach. The treatment‐efficacy model utilized a Richard’s logistic function to fit the time course of all available iADRS data and characterize clinical decline. The impact of absolute or relative change from baseline in amyloid PET measurements (centiloids) was evaluated as a predictor of clinical decline.ResultDisease progression model‐based analyses showed donanemab significantly reduced rate of clinical decline by 28% in the overall population and 42% in APOE ε4 carriers (iADRS, p<.001 for both). No clear treatment‐effect was identified in the smaller APOE ε4 noncarrier population (27% of study participants). Overall, serum concentrations of donanemab were not correlated with clinical decline. Antidrug antibody titer did not affect donanemab’s efficacy. Model simulations showed patients would benefit from donanemab treatment regardless of baseline disease severity, and patients with worse iADRS score at baseline had a greater absolute drug effect (difference between donanemab and placebo at 76 weeks). APOE ε4 carriers who had a 100% decrease in amyloid level from baseline with donanemab treatment are predicted to achieve, on average, a 43.5% slowing of clinical decline rate versus placebo‐treated patients (Figure).ConclusionFindings show donanemab treatment would benefit patients regardless of baseline disease severity. Both exposure‐efficacy and amyloid plaque biomarker models showed donanemab reduces rate of clinical decline and produces better patient outcomes than placebo.