bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of altered nitric oxide bioavailability on the interaction of obesity and Alzheimer’s disease. Exploration of whether a high fat diet produces early cognitive decline in an Alzheimer’s mouse model.
Authors: White Ginger L 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) can be predicted by obesity and vascular risk factors. Obesity and AD are associated with vascular dysfunction, resulting in reduced peripheral and cerebral blood flow. Obesity is associated with reduced nitric oxide (NO) bioavailability, which contributes to reduced blood flow, the accumulation of β‐amyloid (Aβ), and eventual cognitive decline in AD. In animal models of AD, obesity or high fat diet exacerbates cognitive decline. The APPswe/PS1dE9 (APP/PS1) mouse, a model of beta amyloid neuropathology, demonstrates significant NO substrate dysfunction. NO substrate dysfunction and obesity potentially initiates metabolic and vascular dysfunction that can accelerate cognitive function decline. We investigated the impact of a high‐fat diet (HFD) on cognitive performance (discrimination reversal) in transgenic (Tg) and non‐transgenic (Non‐Tg) APP/PS1 mice prior to evaluating the role of NO in AD and obesity.MethodFemale APP/PS1 mice were split into four groups: Non‐Tg Chow (n = 9), Non‐Tg HFD (n = 5), Tg Chow (n = 9), and Tg HFD (n = 14). Mouse operant chambers with two nose poke ports and a dipper for delivering sucrose solution (15%) were used. Discrimination reversal procedure involved nose pokes in the left or right nose poke port produced access to 15% sucrose under a fixed ratio (FR) 1 schedule of reinforcement. Once the performance met criteria, the “correct” nose poke port was switched.ResultTg mice averaged fewer sessions to meet criteria in training. Non‐Tg and Tg mice on HFD failed to learn the discrimination to criteria and never experienced reversals. Non‐Tg mice on chow learned the discrimination multiple times. Only one Tg mice fed chow learned. Mice fed the chow diet received more sucrose reinforcers compared to mice fed the HFD.ConclusionAlthough HFD‐fed mice responded at lower rates, on average, they still made substantial numbers of responses suggesting that the failure to obtain the discrimination was not simply a result of a motivational deficit. Non‐Tg chow‐fed subjects made fewer errors than Tg chow‐fed subjects. Tg HFD‐fed mice originally made as many errors as their chow‐fed littermates but made more errors over the course of the study. Future research will investigate the impacts of decreased NO bioavailability.
Understanding characteristics of persons with early onset dementia in the UCLA Alzheimer’s and Dementia Care Program
Authors: Lee David R , Romero Tahmineh , Serrano Katherine , Panlilio Michelle , Rojas‐Parra Abel , Matsuno Lauren , Mendez Mario F. , Reuben David 
Published: December 2022

AbstractBackgroundAlthough early onset dementia (EOD) accounts for approximately 5% of persons living with dementia (PLWD), there is limited understanding of their demographic characteristics, behavioral symptoms, and caregiver measures, especially in comparison to persons with older onset dementia (OOD).MethodThe UCLA Alzheimer’s and Dementia Care Program is a comprehensive dementia care management program that has served over 3450 PLWD since 2012. This retrospective study compares baseline visit characteristics of participants with EOD (≤ 65 years of age) to participants with OOD (≥ 80 years of age). Variables include patient and caregiver demographics, Neuropsychiatric Inventory Questionnaire (NPI‐Q) scores, Mini Mental State Exam (MMSE), Modified Caregiver Strain Index (MCSI), caregiver PHQ‐9, and insurance status. Fisher exact tests were used to test differences between age groups.ResultThe attached table presents comparisons of the 177 participants with EOD and 731 with OOD. Compared to OOD, persons with EOD were more likely to be men, college graduates, dually insured, have unpaid caregivers, live alone, and be married. Caregivers for persons with EOD were most often spouses, whereas caregivers for persons with OOD were more often children. Although participants had similar MMSE scores, NPI‐Q severity and NPI‐Q distress scores were higher among persons with OOD compared to EOD.ConclusionThere are important differences in demographic characteristics, caregiving status, and behavioral symptoms among persons with EOD compared to those with OOD. Understanding the unique challenges, needs, and resources of persons with EOD may provide valuable insight to adapt dementia care to better meet their needs.
Analytical performance of the Lumipulse® G β‐Amyloid 1‐40 Plasma and Lumipulse® G β‐Amyloid 1‐42 Plasma RUO assays
Authors: Vandijck Manu , Degrieck Rosina , Denoyette Mario , Delanote Jarne , De Jonge Maarten , De Decker Bart , Bastard Nathalie Le , Vandenbroucke Ina 
Published: December 2022

AbstractBackgroundCurrent research indicates that plasma β‐amyloid1‐42/β‐amyloid1‐40 ratio has the potential for application in clinical settings and clinical trials to predict brain β‐amyloid burden. It could reduce the number of lumbar punctures (for CSF biomarker testing) or Aβ‐PET scans in light of clinical trial recruitment and could serve as a tool to evaluate target engagement and efficacy of disease‐modifying drugs. The aim of the current study was to demonstrate the analytical performance of the newly developed Lumipulse G β‐Amyloid 1‐40 Plasma and Lumipulse G β‐Amyloid 1‐42 Plasma RUO assays.MethodThe LUMIPULSE G system is a chemiluminescent enzyme immunoassay platform enabling fully automated processing of samples using ready‐to‐use immunoreaction cartridges. Time to result in these single use test cartridges takes about 30 minutes. The analytical performance of the newly developed Lumipulse G β‐Amyloid 1‐40 Plasma and Lumipulse G β‐Amyloid 1‐42 Plasma RUO assays (using respectively 2G3 and 21F12 antibody for capturing and 3D6 antibody ALP‐conjugate for detection; two‐step immunoassay method) was determined. Parameters analysed were precision, sensitivity, linearity, and potential impact of interfering substances. The studies included a series of buffer‐ and K2EDTA plasma‐based samples at different concentration levels, each tested in several replicates (70 µL/replicate (Aβ1‐40); 110 µL/replicate (Aβ1‐42)) sized to the different parameters tested.ResultThe total within‐lab variability of both assays was ≤6 % CV confirming high precision of the LUMIPULSE G system. Using low β‐amyloid concentrated plasma samples, the observed LoD was 0.44 pg/mL (Aβ1‐40) and 0.37 pg/mL (Aβ1‐42), and the LoQ was 0.44 pg/mL (Aβ1‐40) and 0.43 pg/mL (Aβ1‐42). Linearity was shown across the assay range (0 – 5000 pg/mL (Aβ1‐40); 0 – 1000 pg/mL (Aβ1‐42)). No significant impact of commonly tested endogenous substances (bilirubin, chyle, triglycerides, rheumatoid factor (RF) and human anti‐mouse antibodies (HAMA)) was observed, except for haemoglobin.ConclusionThe analytical performance studies demonstrate – amongst other characteristics – low variability and high sensitivity enabling measurement of Aβ1‐40 and Aβ1‐42 in plasma. The Lumipulse G β‐Amyloid 1‐40 Plasma and Lumipulse G β‐Amyloid 1‐42 Plasma RUO assays are now ready to be explored further for clinical utility in various contexts of use.
Long‐read sequencing and complete telomere to telomere human reference genome provide deeper insight into human brain transcriptomics
Authors: Heberle Bernardo Aguzzoli , Brandon Jason A , Nations Kayla , Page Madeline L , Wadsworth Mark E , Dickson Dennis W. , Miller Justin B , Fryer John D. , Ebbert Mark T.W. 
Published: December 2022

AbstractBackgroundRNA‐seq experiments have traditionally been done with short‐read sequencing technologies that, by nature, collapse all RNA isoforms for a given gene into a single expression measurement—a major oversimplification of the underlying biology. Collapsing all RNA isoforms for a single gene severely limits our ability to characterize all RNA isoforms and determine their individual downstream functions. While computational approaches for assembling short reads into full transcripts exist, these methods are inherently structurally inaccurate, especially when compared to full‐length sequencing possible with long‐read sequencing technologies. In contrast, long‐read sequencing technologies can sequence entire RNA molecules, allowing researchers to accurately quantify expression for the complete set of RNA isoform species, including de novo RNA isoforms. Long‐read sequencing is especially well suited for discovering novel isoforms in the recently released telomere‐to‐telomere (T2T) human reference genome (CHM13). The new CHM13 genome assembly resolved highly homologous regions that are challenging to study with short‐reads. Here we sequenced post‐mortem human brain tissue with long‐reads and aligned them to CHM13 to explore novel gene bodies and transcript isoforms.MethodsWe sequenced pre‐frontal cortex tissue from four post‐mortem human brain samples using Oxford Nanopore Technologies long‐read sequencing for PCR amplified cDNA. Data were basecalled using Guppy, reads were aligned to the CHM13 human reference genome using minimap2, and transcripts were assembled and quantified with the Bambu package in R.ResultsAmong other findings, we discovered 84 new, high‐confidence gene bodies expressed in all four samples with at least 5 reads in each sample. We also found 223 novel RNA isoforms in previously annotated gene bodies. Of these 223 novel isoforms, 29 aligned to medically relevant genes such as MAOB, HLA‐DRB1, and ABO.ConclusionsOur results suggest long‐reads aligned to the CHM13 reference genome have the potential to reveal novel gene bodies and transcript isoforms that were missed in previous studies. These methods can provide a more complete picture of the transcriptomic landscape of diseases, including Alzheimer’s disease—hopefully generating information with potential to help inform future treatment and/or early diagnostic efforts.
PFF induced striatal neurodegeneration model for preclinical proof of concept studies targeting alpha‐synuclein pathology
Authors: Cornelissen Tom 
Published: December 2022

AbstractBackgroundParkinson’s disease (PD) is the most common neurodegenerative movement disorder with more than half of the patients developing dementia about 10 years later, and is characterized by the accumulation of alpha‐synuclein protein aggregates in the PD brain. These inclusions, also called Lewy bodies, accompanied with the degeneration of dopaminergic neurons are the neuropathological hallmark of this devastating incurable disease. Currently a lot of effort is put in studying the involvement of different forms of alpha‐synuclein, i.e. monomeric, oligomeric, fibrillar and aggregated forms or different post translational modifications of the protein, and their contribution to disease progression. Targeting alpha‐synuclein might thus be of potential therapeutic value. Since the research field lacks good and consistent animal models for preclinical research, we’ve set up a mouse model based on the striatal administration of sonicated preformed fibrils (PFF).MethodIn brief, we performed unilateral stereotactical injections in the dorsal striatum of young wild type mice with sonicated PFF’s (n = 8/group). PFF injected mice were sacrificed after 5, 9 and 13 weeks, a control group of vehicle injected mice (n = 7) was sacrificed after 9 weeks. Phosphorylated alpha‐synuclein (pSer129) seed and spread and dopaminergic neurodegeneration was visualized by IHC in different brain regions both ipsilateral and contralateral.ResultPhosphorylated alpha‐synuclein (pSer129) positive inclusions were shown to be present in Striatum, substantia nigra (SN) and amygdala in the ipsilateral hemisphere already after 5 weeks, indicating clear spreading of pathology. Interestingly, in the contralateral hemisphere we were able to detect clear pSer129 alpha‐synuclein in the amygdala and striatum 5 and 9 weeks after injection respectively, demonstrating the progressive nature of this model. To assess whether the observed pathology also affected the dopaminergic circuitry we quantified the loss of synaptic tyrosine hydroxylase positive terminals in the striatum and found a significant decrease already 5 weeks after PFF administration.ConclusionThis alpha‐synuclein preformed fibril based model, which shows clear progressive seed and spread pathology and a clear decrease in dopaminergic nerve terminals in the striatum, can be of great importance to the research field to assess in vivo therapeutic interventions based on targeting alpha‐synuclein pathology.
Age‐dependent effects of the p75 neurotrophin receptor modulator LM11A‐31 on Alzheimer’s disease biomarkers in a 26‐week safety and exploratory endpoint trial
Authors: Shanks Hayley R. C. , Börjesson‐Hanson Anne , Windisch Manfred , Massa Stephen M. , Longo Frank M. , Schmitz Taylor W. 
Published: December 2022

AbstractBackgroundThe p75 neurotrophin receptor (p75NTR) modulates pro‐ and anti‐apoptotic pathways as well as neurite and neuritic spine integrity. This receptor is expressed in cells vulnerable to aging and disease, including basal forebrain cholinergic neurons and hippocampal pyramidal neurons. It is also expressed by glial cells under pathological conditions. Pharmacological modulation of the p75NTR with LM11A‐31 alters both age‐ and disease‐related neuronal dysfunction. For example, LM11A‐31 reverses neuritic pathology in aged mice and reduces amyloid‐induced tau phosphorylation in mouse models of Alzheimer’s disease (AD). In this proof‐of‐concept study, we examined the effects of LM11A‐31 treatment on longitudinal neuroimaging and CSF biomarkers in humans with mild to moderate Alzheimer’s disease. Based on our preclinical work, we hypothesized that age and disease may interact to predict response to LM11A‐31 treatment in humans. Therefore, we additionally conducted subgroup analyses of drug effect in older and younger individuals.MethodParticipants with mild to moderate AD (MMSE score = 18‐26; age 55‐85 years) were enrolled in a 26‐week placebo‐controlled phase 2a safety and exploratory endpoint trial of LM11A‐31. Exploratory outcome measures included structural MRI, CSF AD core biomarkers, and CSF biomarkers related to pathological processes affected in mouse studies including synaptic integrity and inflammation. For placebo and drug, age subgroups were defined using a median‐split: younger (<72 years) and older (> = 72 years).ResultWhole brain structural MRI analyses revealed that 26‐week treatment with LM11A‐31 reduced longitudinal grey matter degeneration in AD‐vulnerable brain regions including the inferior temporal gyrus, insula, frontal operculum and retrosplenial cortex. Furthermore, drug treatment, compared to placebo, prevented longitudinal increases of CSF tau, the presynaptic biomarker SNAP25, and the inflammatory biomarker YKL‐40. Median split analyses demonstrated that drug effects for structural MRI and CSF measures were consistently stronger in younger individuals.ConclusionThis investigation highlights that biomarkers may demonstrate age‐dependency in response to therapeutic interventions in the context of mild‐moderate AD. Our results may inform biomarker selection and design of future studies of LM11A‐31 in human AD.
An M1/sigma‐1 receptor agonist prevents cognitive deficits, reduces amyloid plaques and neuroinflammation in a transgenic rat model of Alzheimer’s amyloid pathology.
Authors: Orciani Chiara , Carmo Sonia Do , Foret Morgan K , Hall Hélène , Bonomo Quentin , Lavagna Agustina , Huang Chunwei , Cuello Claudio A 
Published: December 2022

AbstractBackgroundAcetylcholinesterase inhibitors represent four out of six drugs for treating Alzheimer’s disease (AD), with time‐limited efficacy likely due to the progressive loss of cholinergic neurons. The selective allosteric M1 muscarinic and sigma‐1 receptor agonist Anavex 3‐71 (aka AF710B) [1] takes advantage of the fact that acetylcholine postsynaptic M1 muscarinic brain receptor levels remain unchanged in AD. Previously, Anavex 3‐71 treatment attenuated AD hallmarks in McGill‐R‐Thy1‐APP transgenic rats when administered at advanced stages of the AD‐like pathology [2]. However, preventive strategies instead of late treatment should be more effective in AD. Therefore, we tested whether Anavex 3‐71 administration during early amyloid pathology stages could prevent cognitive impairment, plaque deposition and neuroinflammation.MethodPre‐plaque, seven‐month‐old McGill‐R‐Thy1‐APP rats were subjected to daily oral administration of Anavex 3‐71 (10 µg/kg) for seven months. After one month of drug interruption (wash‐out), we performed Novel Object Recognition (NOR), Morris Water Maze (MWM) and Social Preference (SP) behavioural tests. Subsequently, brains were extracted, fixed and analyzed by histochemistry and immunohistochemistry.ResultMcGill‐APP rats had deficits in discriminating the novel object in the NOR and locating the hidden platform in the MWM compared to wild‐type littermates. Anavex 3‐71 restored the abilities of McGill‐APP rats in the NOR task to wild‐type levels and partially rescued the deficits in the MWM. In the SP task, Anavex 3‐71‐treated McGill‐APP rats exhibited diminished deficits in SP interaction time with a “stranger rat”. Treatment significantly reduced the number of mature Thioflavin‐S positive plaques in the subiculum compared to vehicle‐treated McGill‐APP rats and diminished the number of diffuse plaques in the cortex and hippocampus. Furthermore, Anavex 3‐71 treatment significantly reduced microglia and astrocyte recruitment towards CA1 hippocampal Aβ‐burdened neurons compared to untreated McGill‐APP rats.ConclusionThe long‐lasting effect of Anavex 3‐71 in preventing cognitive decline of McGill‐R‐Thy1‐APP rats, even after a wash‐out period would suggest some preventative, disease‐modifying, properties of the compound over the AD‐like amyloid pathology. This is supported by the attenuation of extracellular Aβ deposition and reduced glial cell recruitment towards hippocampal neurons. [1] Fisher et al., 2016; Neurodegenerative Diseases. https://doi.org/10.1159/000440864 [2] Hall et al., 2018; Alzheimer’s & Dementia. https://doi.org/10.1016/j.jalz.2017.11.009
Clinical Profiles of Persons Who Progress to Cognitive Impairment in the Alzheimer’s Prevention Initiative (API) ADAD Colombia Trial
Authors: Giraldo‐Chica Margarita , Acosta‐Baena Natalia , Espinosa Alejandro , Ramos Claudia , Langbaum Jessica B. , Sink Kaycee M. , Tariot Pierre N. , Reiman Eric M. , Lopera Francisco , Ríos‐Romenets Silvia 
Published: December 2022

AbstractBackgroundIn Colombia, 13 pathogenic variants of presenilin 1 (PSEN1) causing Autosomal Dominant Alzheimer’s Disease (ADAD) have been identified. Some cases have atypical presentations, with variability in the age of onset and course of the disease. We characterized clinical profiles of cognitively unimpaired PSEN1 E280A mutation carriers who progress to MCI or dementia in the API ADAD Colombia Trial.MethodThe API ADAD Colombia Trial enrolled 252 cognitively unimpaired 30–60 year‐old participants into a 5‐8‐year double‐blind placebo controlled randomized prevention trial with a common close design. About 1/3 of participants were PSEN1 E280A mutation carriers who were randomized to the investigational anti‐oligomeric amyloid‐β antibody therapy crenezumab, 1/3 were mutation carriers who were randomized to placebo, and 1/3 were non‐carriers from the same kindred who were randomized to placebo. Trial results are pending. We used standardized procedures to blindly assess clinical features of participants who progressed to MCI and/or dementia during the trial, reviewed by an independent progression adjudication committee (PAC), to confirm the first instance of clinical progression.ResultDuring the trial 45 participants had an initial progression to MCI due to AD and 2 to dementia due to AD confirmed by the PAC. Among the 45 adjudicated with MCI due to AD, 32 subsequently progressed to dementia (30 due to AD and 2 due to other causes as determined by the site clinicians by consensus). The mean age onset of MCI was 45 (range 36–60 years) and of dementia was 47 (range 36–62 years). Three participants developed dementia before 40 years and one participant at 62 years. At the time of MCI, 43 participants had a predominantly amnesic profile, one had a predominantly behavioral disinhibition, and one had a Capgras syndrome, severe aggression and myoclonus. One participant developed severe global aphasia two years after the onset of dementia; two of the participant’s first‐degree relatives had language impairment in conjunction with MCI; one developed primary progressive logopenic aphasia.ConclusionSome persons with ADAD have an atypical clinical presentation. Additional studies are needed to clarify the biological changes, genetic/environmental risk factors, clinical course and response to treatment in these individuals.
A Phase 3 Clinical Trial Protocol to Evaluate the Efficacy and Safety of NA‐831 in Subjects with Early Onset of Alzheimer’s Disease
Authors: Tran Lloyd , Vu Fern , Kurkinen Markku 
Published: December 2022

AbstractBackgroundThis phase 3 study consists of a Core and Open Label Extension (OLE) Phase in 465 participants with Early Alzheimer’s Disease (EAD), and is being conducted to evaluate the efficacy and safety of NA‐ 831. The Core is a 52‐week treatment, multicenter, double blind, placebo controlled parallel group study.MethodCore Study: Participants will receive one capsule of 30 milligram (mg) NA‐831 orally once a day in the morning. The core study will be double blinded. Placebo Comparator: The core study will be double blinded. Experimental: Open Label Extension Phase: Participants completing the core study will receive one 30 milligram (mg) NA‐31 capsule orally once a day in the morning.ResultKey Outcome Measures:1. Core Study: Change from Baseline in the Clinical Dementia Rating and Sum of Boxes (CDR‐SB) Score at 48 Weeks [ Time Frame: Baseline, Week 52]2.Open‐Label Extension Phase: Number of Participants With Treatment‐Emergent Adverse Events (AEs) [ Time Frame: Up to Week 52 of Extension Phase] Secondary Outcome Measures: Cognition‐13 (ADAS‐Cog‐13) at Weeks 24, 52 [ Time Frame: Baseline, Week 24, Week 52 of Extension Phase] CORE STUDY: Mild cognitive impairment due to AD or mild AD dementia including 1. MMSE score equal to or greater than 243. CDR global score of 0.5 3. CDR Memory Box score of 0.5 or greaterConclusionThe Phase 3 clinical trial of NA‐831 is being conducted in multicenters in the US and several countries. The details of the Phase 3 methodology and protocol will be presented and discussed.