bluuebunny/crossref_metadata_2025_split huggingface dataset:
A randomized, placebo‐controlled, double‐blind, Phase 1b study to evaluate the safety, tolerability and pharmacodynamics of PRI‐002 in early AD
Authors: Peters Oliver , Cosma Nicoleta Carmen , Kutzsche Janine , Willbold Dieter 
Published: December 2022

AbstractBackgroundPRI‐002 is an all‐D‐enantiomeric peptide developed to disassemble Abeta oligomers, which has shown to improve cognition in animal models and which has demonstrated its safety profile in healthy young volunteers (Kutzsche et al. 2020).Method20 AD patients in early disease stages fulfilling the ATN‐criteria were recruited to participate in a single center, randomized, placebo –controlled, double‐blind study. Patients received once daily oral doses of 300 mg PRI‐002 or placebo for 28 days. Safety and efficacy assessments were executed at baseline, day 14, day 28 and day 56 (follow up). Blood sampling was carried out at each time point, EEG and CSF measurements before and at the end of treatment. Imaging (MRI) and functional tests (CERAD, CDR) were performed in parallel to EEG/CSF and additionally at follow up.Result10 patients (age 76.9±3.4, MMSE 28±1.6) received placebo and 9 patients PRI‐002 (72.4±6.9, 27.2±2.9). One patient withdraw informed consent before treatment was started. 13 patients reported in total 27 adverse events while no serious adverse event was noted. There was no statistical difference regarding adverse events between treatment and placebo. EEG and MRI revealed no changes after treatment. While no significant changes were detected in p‐TAU, Abeta1‐42 and Abeta oligomers in CSF before and after treatment, patients receiving PRI‐002 significantly performed better than those receiving placebo in the CERAD word list at follow up (p≤0.05).ConclusionPRI‐002 showed an excellent safety profile in AD patients. While no biomarker changes were detected after 4 weeks of treatment interestingly, an improvement of memory function was noted at follow up. A phase 2 study is scheduled.Kutzsche J, Jürgens D, Willuweit A, Adermann K, Fuchs C, Simons S, Windisch M, Hümpel M, Rossberg W, Wolzt M, Willbold D. Safety and pharmacokinetics of the orally available antiprionic compound PRI‐002: A single and multiple ascending dose phase I study. Alzheimers Dement (N Y). 2020 Mar 20;6(1):e12001. https://doi.org/10.1002/trc2.12001.
Reduced density of cholinergic fibers in App knock‐in mouse models of Aβ amyloidosis
Authors: Hirota Yu , Sakakibara Yasufumi , Ibaraki Kyoko , Takei Kimi , Nishijima Risa , Iijima Koichi M. , Sekiya Michiko 
Published: December 2022

AbstractBackgroundCholinergic system is critical for learning, memory, attention, and other cognitive functions. Nucleus basalis of Meynert (NBM) is a nucleus containing the cell bodies of cholinergic neurons in the brain and is severely affected by Alzheimer’s disease (AD). Significant loss of forebrain cholinergic projections is evident at prodromal stage of AD, and, along with locus coeruleus (LC), NBM neurons are among the first to display neurofibrillary tangle, suggesting that abnormality in cholinergic system is involved in the early stage of AD pathogenesis. Acetylcholinesterase inhibitors have been used for symptomatic treatment to improve cognitive function, however, mechanisms underlying neurodegeneration in cholinergic system remain elusive. We have previously reported that AppNL‐G‐F
mice, which harbor three familial AD mutations (Swedish, Beyreuther/Iberian, and Arctic) exhibited cognitive deficits, severe neuroinflammation and significant loss of LC noradrenergic fibers accompanied by massive amyloid‐β (Aβ) pathology. In this study, we asked whether and how cholinergic system is altered in AppNL‐G‐F
mice.MethodTo ask whether AppNL‐G‐F
mice exhibit cholinergic degeneration, we compared the density of vesicular acetylcholine transporter (VAChT)‐positive fibers in the cortex and hippocampus as well as the number of choline acetyltransferase (ChAT)‐positive neurons in the NBM between AppNL‐G‐F
and wild‐type (WT) C57BL/6J mice at 24 months of age. We also examined whether tau pathology occurs in the cholinergic system in these mice.ResultHistochemical analyses revealed that 24‐month‐old AppNL‐G‐F
mice exhibited significant decreases in the density of VAChT‐positive fibers in the cortex and the hippocampal CA1, the regions associated with learning and memory, compared to WT mice.ConclusionThis study demonstrates that Aβ pathology is sufficient to reduce the density of cholinergic fibers. Quantitative analyses of cell loss and tau accumulation in ChAT‐positive neurons in the NBM are currently underway, and we will present these results at the meeting.
Interactions between apolipoprotein E, sex, and amyloid‐beta on cerebrospinal fluid p‐tau levels in the European Prevention of Alzheimer’s Dementia Longitudinal Cohort Study (EPAD LCS)
Authors: Saunders Tyler S , Jenkins Natalie D , Blennow Kaj , Ritchie Craig W. , Muniz Terrera Graciela , Muniz Graciela 
Published: December 2022

AbstractBackgroundAlzheimer’s Disease, the leading cause of dementia, is over‐represented in females. The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late‐onset AD and is associated with aberrant cerebrospinal fluid levels (CSF) of total tau (t‐tau), phosphorylated tau (p‐tau), and amyloid‐β (Aβ). There is some evidence that sex may mediate the relationship between APOE status and CSF tau, however, evidence is mixed.MethodWe aimed to examine the association between sex, APOE ε4 status, CSF Aβ on t‐tau and p‐tau in 1776 mid‐to‐late life individuals without a diagnosis of dementia in the European Prevention of Alzheimer’s Dementia (EPAD) longitudinal cohort study.ResultWe found a significant interaction between APOE status, sex, and CSF Aβ on CSF p‐tau levels. Specifically, the association between CSF Aβ and CSF p‐tau was stronger in male ε4 carriers relative to female ε4 carriers. Further, in females with high Aβ levels (reflecting less cortical deposition), ε4 carriers had significantly elevated p‐tau levels relative to non‐carriers. However, there were no significant differences in p‐tau between male ε4 carriers and non‐carriers with high Aβ.ConclusionAn interaction between sex and cerebrospinal fluid Aβ may mediate the relationship between APOE status and CSF p‐tau. These data suggest tau accumulation may be independent of Aβ in females, but not males. Future work would benefit from replication in separate cohorts, longitudinal examination, and the consideration of the role of sex hormones on CSF markers.
Loneliness and subjective cognitive impairment in preclinical Alzheimer’s disease and healthy aging
Authors: Harrington Karra D , Roque Nelson A , Strenger Jennifer , Correia Stephen , Salloway Stephen P. , Sliwinski Martin J. , Thompson Louisa I 
Published: December 2022

AbstractBackgroundLoneliness is associated with increased dementia risk, and greater amyloid‐β (Aβ) and tau accumulation in cognitively normal older adults. However, the potential for loneliness to influence cognitive dysfunction during the preclinical disease stage has not yet been examined. Subjective cognitive complaints are an early indicator of cognitive dysfunction in Alzheimer’s disease, and may provide a sensitive endpoint to evaluate the influence of loneliness during the preclinical disease stage. This study evaluated the relationships between loneliness, subjective cognition, and Aβ status in cognitively unimpaired older adults.MethodParticipants were 112 older adults aged 60–81 years (68% female, 89% White) recruited from the Butler Hospital Alzheimer’s Prevention Registry (BAPR). A cut off score of ≥34 on a modified Telephone Interview for Cognitive Status (TICSm) was used to establish unimpaired cognition. All participants completed the 3‐item version of the UCLA Loneliness Scale and the Cognitive Function Index (CFI) to assess loneliness and subjective cognition respectively. At the time of this analysis, a subsample (n = 63) had also undergone PET neuroimaging for classification of Aß status, of which 40% were classified as Aß+.ResultOf the total sample, 28% reported mild‐moderate levels of loneliness, and another 8% reported severe loneliness. Subjective cognitive function was significantly associated with loneliness group, H(2) = 6.66, p = .036, with post hoc analyses indicating a significant trend for subjective cognitive complaints to increase with loneliness severity. Among the PET subsample, there was no significant difference observed between Aß groups in level of loneliness (p = .754) or subjective cognition (p = .852). However, there was a significant association between Aß status and loneliness group (p = .023), with Aß+ individuals being more likely to a be severely lonely (12%, n = 3) relative to the Aß‐ group (0%, n = 0).ConclusionThe results of this study highlight the potential for loneliness to be involved in the preclinical stages of AD by demonstrating associations with both subjective cognitive function and Aß status. Prospective investigations are needed to further disentangle whether loneliness may be an indicator of, or a risk factor for, emerging disease.
Bacteroides genus is associated with lower executive function in cognitively unimpaired participants
Authors: Forst Allison A , Heston Margo B. , González Antonio , Chin Nathaniel A. , Przybelski Robert J , Johnson Sterling C. , Asthana Sanjay , Knight Rob , Kaddurah‐Daouk Rima , Rey Federico E. , Bendlin Barbara B. 
Published: December 2022

AbstractBackgroundVitamin B1, B6, and B12 deficiencies are associated with increased prevalence of dementia due to Alzheimer’s disease (AD). Clinical trials suggest that vitamin supplementation may improve cognitive function, however the mechanisms that link these factors remain unknown. A site of vitamin metabolism and synthesis is the gut microbiome, which is compositionally altered in AD. The gut microbiota’s role in perpetuating vitamin deficiencies and subsequent cognitive decline is unclear, so here we tested the hypothesis that lower abundances of vitamin B‐modulating microbes are linked to lower cognitive testing scores.Method211 cognitively unimpaired participants were recruited from the Wisconsin Alzheimer’s Disease Research Center and Wisconsin Registry for Alzheimer’s Prevention (Table 1). Stool samples were collected at home and returned chilled, and 16S rRNA sequencing was performed to characterize gut microbiome composition. QIIME2 was used to denoise (deblur) and classify features, and phyloseq (R) was used to filter rare taxa, compute relative abundances, and agglomerate at genus rank. Literature review was used to select 10 microbial genera which synthesize/metabolize B vitamins (Table 2). The Rey Auditory Verbal Learning Test (RAVLT) long‐delay recall score and Trail Making Test (TMT) B (number‐letter switching) examined verbal memory and executive function, respectively. Multiple linear regression was conducted on each cognitive outcome to test microbial associations.ResultHigher relative abundance of the B vitamin‐synthesizing genus Bacteroides was associated with greater time to complete the TMT B. This remained significant after controlling for covariates of participant age, sex, and years of education (Table 3). No other genera were significantly associated with either the TMT B or RAVLT scores.ConclusionIn a cognitively unimpaired participant group, Bacteroides was correlated with lower performance on an executive function task. This genus was previously identified as elevated in people with AD and mild cognitive impairment; this study, therefore, indicates a relationship between Bacteroides and executive function even before cognitive decline. Bacteroides species are also linked to inflammation, which may explain the results of the current study. Future work should examine how Bacteroides relates to both biomarkers of neuroinflammation and cognitive function in unimpaired participants.
Simultaneous Mass Spectrometric quantification of multiple p‐tau species in plasma – findings along the Alzheimer´s disease continuum
Authors: Montoliu‐Gaya Laia , Benedet Andréa Lessa , Brum Wagner Scheeren , Vrillon Agathe , Ashton Nicholas J. , Rodriguez Juan Lantero , Brinkmalm Gunnar , Nilsson Johanna , Karikari Thomas K , Kern Silke , Zetterberg Henrik , Paquet Claire , Rosa‐Neto Pedro , Gobom Johan , Blennow Kaj 
Published: December 2022

AbstractBackgroundBlood phosphorylated tau (p‐tau) species at positions 181, 217 and 231 have been demonstrated accurate biomarkers of Alzheimer´s disease pathology. Comparisons to assess the performance of each phosphorylation along the Alzheimer´s disease (AD) continuum rely on the use of different immunoassays. In the current study, we simultaneously quantified the plasma concentration of six different phosphorylated (p‐tau 181, 199, 202, 205, 217 and 231), and two non‐phosphorylated, tau peptides using a targeted Mass Spectrometric (MS) method.MethodWe analysed a total of 224 samples from two centres, the TRIAD cohort (Canada) and the BioCogBank Paris Lariboisière cohort (France). Tau enrichment prior to MS analysis was performed by immunoprecipitation, using a combination of several non‐phospho‐tau antibodies, followed by tryptic digestion. A parallel reaction monitoring method with Orbitrap MS was used to measure the levels of targeted peptides. Group‐level comparisons were carried with non‐parametric tests. Cross‐sectional associations between plasma tau biomarkers and Aβ and tau PET were investigated using the locally estimated scatterplot smoothing (LOESS) method for local polynomial regression. Voxel‐wise correlations were performed between plasma and PET biomarkers using Rminc.ResultP‐tau231 levels were significantly increased in amyloid positive and tau negative (A+T‐) individuals compared to A‐T‐ (stratified by CSF biomarkers). Increases in p‐tau217 and p‐tau205 emerged later in the AD continuum, only when tau pathology was present (A+T+). Plasma p‐tau217, p‐tau231 and p‐tau205 were the site‐specific phosphorylations that showed higher correlations with Tau PET (Braak I‐VI) (R=0.7 p<0.0001; R=0.53 p<0.0001; and R=0.53 p<0.0001; respectively) and with Aβ PET (R=0.66 p<0.0001; R=0.56 p<0.0001; R=0.45 p<0.0001, respectively). LOESS analysis revealed that plasma p‐tau231 increases earlier in the disease progression, followed by p‐tau217 and p‐tau205, which showed a progressive increase along Braak stages and amyloid centiloid. Voxel‐wise analysis for tau PET were highest with p‐tau205 with associations in in the inferior, medial, and lateral temporal regions. For Aβ PET, p‐tau217 and p‐tau205 showed the highest associations with frontal, precuneus, posterior cingulate and temporal cortices.ConclusionOur results indicate that plasma p‐tau217, p‐tau231 and p‐tau205 are the site‐specific phosphorylations that better reflect amyloid and tau pathologies, although with different emergence along the AD continuum.
Tau protein profiling across brain of different tauopathies using high‐resolution mass spectrometry: quantification of isoforms and phosphorylations
Authors: Camporesi Elena , Rodriguez Juan Lantero , Montoliu‐Gaya Laia , Fox Nick C , Lashley Tammaryn , Zetterberg Henrik , Blennow Kaj , Brinkmalm Gunnar 
Published: December 2022

AbstractBackgroundThe abnormal accumulation of the microtubule‐associated protein tau in the brain is the main contributing factor of a group of diseases called tauopathies, including Alzheimer’s disease (AD). Due to similarities, it is currently problematic to chemically characterize the tau pathology in these diseases. Our aim was to develop a multiplex assay to detect and quantify isoform‐specific peptides and phospho‐tau species in brain of different tauopathies, possibly holding disease‐specificity.MethodFrontal cortices from AD (n = 10), progressive supranuclear palsy (PSP, n = 11), Pick’s disease (PiD, n = 10), corticobasal degeneration (CBD, n = 10) and controls (n = 10) were processed to obtain a soluble (tris‐buffered saline, TBS) and a sarkosyl‐insoluble (SI) fraction. Fractions were immunoprecipitated using antibodies targeting all four tau regions. Tryptic peptides corresponding to isoforms and peptides carrying one, two or three phosphorylations were monitored by liquid chromatography/high‐resolution mass spectrometry, using isotope‐labelled protein and phospho‐peptide standards for quantification.ResultIn all samples, the 0N and 1N tau isoforms were most abundant. In the AD group we observed an increase of the 0N isoform in the SI fraction. The SI fraction also showed the 3R/4R isoform predominance characteristic of the different tauopathies, with the 3R being more abundant in PiD, 4R in PSP and CBD, while in AD and controls they had similar abundance. Further, in the SI fraction, peptides from the microtubule‐binding region (MTBR) were markedly more abundant in AD, indicating aggregation of these species (Fig.1). Compared to the TBS fractions, the SI fraction was enriched in double and triple‐phospho peptides (example in Fig.2), which were markedly increased in the AD group as compared to the other non‐AD tauopathies or the control.ConclusionThe novel assay here developed can identify isoform differences across tauopathies. The parallel investigation of TBS and SI fractions showed higher abundancy of phosphorylations and MTBR region in the SI fraction, possibly reflecting this fraction to contain an interphase between small aggregates and immunohistochemical inclusions. While the measurement of multiply phosphorylated peptides could clearly differentiate AD from the other tauopathies, none of them could discriminate between the non‐AD tauopathies. This further indicate that multiply phosphorylated peptides are highly disease relevant species for AD.
Alzheimer’s Disease risk gene SORL1 affects synaptic function in hiPSC‐derived cortical neurons
Authors: Williams Charles A , Knupp Allison , Mishra Swati , Young Jessica E. 
Published: December 2022

AbstractBackgroundThe cellular endo‐lysosomal network (ELN) is implicated in Alzheimer’s Disease pathology and Sortilin‐related receptor 1 (SORL1) is important for normal function of the neuronal ELN. Loss of SORL1 in human induced pluripotent stem cell (hiPSC) derived neurons replicates early AD cytopathology, such as enlarged early endosomes. Work in our laboratory has shown that SORL1 deficiency results in decreased cell‐surface expression of glutamate receptor subunit GLUR1 and neurotrophic receptor TRKB. RNAseq of SORL1 deficient neurons revealed alterations in synaptic‐associated gene ontology transcripts. Together, these data implicate a potential functional consequence for SORL1 deletion. Here we investigate the impact of SORL1 on hiPSC‐derived neuronal synaptic function.MethodNeuronal cultures were differentiated using dual SMAD inhibition of previously generated wild‐type and SORL1 deficient hiPSCs. Following differentiation, neuronal cultures were either purified using cell surface markers CD44, CD184, and CD271 or passaged as mixed cultures for immunocytochemical (ICC) or electrophysiological experiments, respectively. For ICC, neurons were then fixed with paraformaldehyde and stained with experiment‐appropriate antibodies before imaging on a confocal scanning microscope. Mixed cultures were plated onto Axion Biosystems multiple electrode array (MEA) culture plates for electrophysiological analysis. MEA cultures were recorded twice a week for up to ten weeks post‐plating. Recordings and analysis were performed using Axion Biosystems Maestro Pro system.ResultUsing ICC, we find alterations in alterations in synaptic protein and glutamate receptor co‐localization in SORL1 deficient neuronal cultures. When cultured on MEA plates, wild‐type and SORL1 deficient neuronal cultures are active and robust. Neuronal cultures develop glutamate signaling dependent patterns of activity, or network bursting. Neural firing rates are increased in SORL1 deficient neurons. Network bursting properties in SORL1 deficient are altered in comparison to wild‐type cultures, consistent with increased neural excitability.ConclusionLoss of SORL1 alters hiPSC‐derived neuronal activity and synapse‐dependent activity. Further investigation is warranted into the alterations in neuronal physiology and will help us understand the role AD‐related ELN disruption plays in synaptic pathologies.
Brain‐targeted N‐Acetyl Cysteine‐loaded nanoparticle for AD treatment
Authors: Xu Peisheng , Wang Mingming 
Published: December 2022

AbstractBackgroundThe microglia activation‐induced neuroinflammation is one potential cause of Alzheimer’s disease (AD). N‐Acetyl cysteine (NAC), which has anti‐oxidant and anti‐inflammatory effects, has been extensively explored for the treatment of of AD. However, its therapeutic efficacy for AD is limited due to the existence of the blood‐brain barrier (BBB).MethodTo facilitate NAC cross the BBB, a brain‐targeted NAC‐loaded nanoparticle (BTN‐NAC) has been developed. The brain‐targeting efficacy and therapeutic efficacy of BTN‐NAC were evaluated in a 5xFAD transgenic mouse model through nest construction assay and Morris water maze test.ResultIn vivo study revealed that BTN‐NAC could effectively cross the BBB of AD mice. Nest construction assay found that BTN‐NAC treated AD mice exhibited better nesting score than free NAC and control treated mice. In addition, BTN‐NAC treatment significantly improved the learning and cognitive skills of AD mice. Immunohistochemical staining confirmed that BTN‐NAC effectively inhibited the activation of microglia in the brain and attenuated the deposition of Aβ plaques in the hippocampus.ConclusionBTN‐NAC can effectively cross the BBB, prevent the activation of microglia, and attenuate Aβ burden in the brain of AD mice. Consequently, BTN‐NAC slows down the progress of AD. Therefore, BTN‐NAC could be safe and effective tool for the treatment of AD.