bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of RAA7 treatment in TG4510 mouse model of Alzheimer's disease
Authors: Tai Chin‐Yin , Jang Ming‐Kuei , Stenius Taina‐Kaisa , Paldanius Kaisa , Puoliväli Jukka , Rytkönen Jussi , Oksman Juho , Parkkari Teija , Huhtala Tuulia , Rauhala Leena , Miszczuk Diana , Nurmi Antti 
Published: December 2020

AbstractBackgroundTauopathies are neurodegenerative characterized by the accumulation of abnormal phosphorylated and aggregated forms of Tau protein in the brain. rTg4510 (MAPT*P301L) mouse model is a widely used tauopathy model for studying therapeutic intervention that target neurodegeneration and tau pathology.MethodIn this study rTg4510 mice (n=13‐15/group) were treated with RAA7 (10 mg/kg and 50 mg/kg) or vehicle (PBS). At 7 months of age tau pathology and neurodegeneration was characterized using cresyl fast violet staining (CFV) and NeuN for neurodegeneration, total human Tau (HT7) and phosphorylated human Tau (AT8). Sections were analyzed as % of area of positive signal. Four regions of interest were examined: cortex, CA1 and dentate gyrus regions and whole hippocampus.ResultOur results showed that RAA7 treatment diminish neurodegeneration and affect tau pathology. In CFV and NeuN staining, RAA7 10 mg/kg increased % of stained area in all analyzed brain regions, whereas RAA7 50 mg/kg in the CA1 region when compared to PBS group. In addition, high dose treatment showed neuroprotective effect in the DG regions of hippocampus as well. NeuN/CFV ratio was decreased by RAA7 10 mg/kg treatment in all analyzed areas. Assessment of tau expression revealed that RAA7 10 mg/kg decreased level of total Tau in CA1 region and phosphorylated Tau in cortex when compared to PBS group. Unexpectedly, RAA7 50 mg/kg showed significantly higher total tau level in the whole hippocampus when compared to PBS group, and no effect on the tau phosphorylation level.ConclusionIn conclusion, RAA7 treatment showed neuroprotective in Tg4510 mice demonstrated by reduced Tau accumulation and phosphorylation driven inhibition of neuronal cell death.
Albumin glycation in Alzheimer’s disease patients: Results from the AMBAR trial
Authors: Ortiz Ana Maria , Minguet Carla , Mestre Anna , Orellana Adelina , Núñez Laura , Boada Mercè , Ruiz Agustín , Páez Antonio , Costa Montserrat 
Published: December 2020

AbstractBackgroundA novel therapeutic approach that includes therapeutic plasma exchange (TPE) plus albumin replacement has shown to slow cognitive and functional decline in mild‐to‐moderate Alzheimer’s disease (AD) patients (AMBAR Trial, NCT01561053). We previously described higher levels of early glycated albumin (eGA) in baseline AD plasma samples from a Phase II clinical trial using TPE with albumin replacement (EudraCT#2007‐000414‐36), compared to age‐matched healthy controls. Moreover, treatment showed a positive but transient effect in lowering eGA. Glycated albumin is known to have impaired binding capacity and to be less effective in preventing amyloid beta peptide aggregation (Ramos‐Fernández et al, 2014.JAD;643). In the present study, eGA in samples from AMBAR trial has been evaluated to confirm previous findings.MethodWe measured eGA in AMBAR baseline serum samples (n=318) from mild‐moderate AD patients (MMSE:16‐26) and compared with serum samples from age‐matched healthy controls (HC) (n=25, MMSE:28‐30). Samples collected throughout the two intervention regimens in AMBAR were also analyzed: conventional TPE period for 6 weeks (processing 1 plasma volume [2500‐3000mL]; 1TPE/week); and low volume plasma exchange [LVPE] period for 12 moths (removing approximately 1/3 plasma volume [similar to a plasma donation]; 1LVPE/month) in comparison to non‐treated AD controls. QuantiLab Glycated Albumin assay (Werfen) on Beckman‐Coulter AU5800 was used. Values are expressed as %eGA, median‐IQR.ResultResults of eGA in AMBAR baseline samples was similar to those from HC (13.0% [12.2%‐14.0%] vs 12.6% [12.1%‐13.8%], respectively). Of note, percentage of patients with eGA above the normal reference range (9%‐16%) in AMBAR AD patients was higher than in HC (10% vs 0%). A transient effect in lowering eGA after each intervention period in AMBAR was observed: change from baseline eGA after conventional TPE and after LVPE periods were ‐4.2% (‐5.3% to ‐2.8%) and ‐1.2% (‐1.8% to ‐0.5%) respectively. Interestingly, when considering only patients with hyperglycated albumin baseline levels (eGA≥16%; n=29), all patients except one reached the normal reference range after the first TPE intervention (11.2% [10.5%‐13.0%]).ConclusionPE with albumin replacement, in particular conventional TPE regime, caused a transient but noticeable effect in lowering eGA levels in AD patients, which allowed patients with hyperglycated albumin to reach normal reference values.
Mild cognitive impairment and rheumatoid arthritis
Authors: McDowell Bethany , Holmes Clive , Edwards Christopher , Cardwell Christopher , McHenry Michelle , Meenagh Gary , McGuinness Bernadette 
Published: December 2020

AbstractBackgroundIncreasing evidence from the last ten years suggests that systemic inflammation may be associated with an increased risk of developing Alzheimer’s disease (AD). Some studies have found an association between rheumatoid arthritis (RA) and neurodegeneration with several finding increased incidence of mild cognitive impairment (MCI) in those with RA compared to healthy controls. This study aims to use preliminary data from the Rheumatoid arthritis, medication and memory study (RESIST) to investigate the prevalence of MCI in a population of patients with RA and explore the relationship between MCI and specific demographic and clinical characteristics.MethodThe Montreal Cognitive Assessment (MoCA) was used as a cognitive screening tool and was administered to subjects who were ≥55 years of age and had been diagnosed with RA according to the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria. Demographic and clinical data was recorded at screening in face‐to‐face interviews and included age, gender, type of RA medication and date of RA diagnosis. 260 participants completed both screening and baseline visits as part of the RESIST longitudinal study, MoCA scores from baseline were analysed for these participants. Statistical analysis was used to provide descriptive statistics for our population and determine predictors of cognitive impairment.ResultA total of 636 participants (mean age 68.1, 67.5% female) were screened between May 2018 and December 2019. The mean MoCA for screened participants was 25.4, 45.3% of our population scored <26 in the MoCA and were considered cognitively impaired. Age was negatively correlated to MoCA score and was the only significant predictor of cognitive impairment (p<0.001). Gender, type of RA medication and duration of disease did not contribute to the regression model. The mean MoCA score was found to differ by 0.404 points between screening and baseline.ConclusionA large proportion of our participants scored below the proposed cut‐off for normal cognition in the MoCA suggesting at the high prevalence of MCI in older adults with RA. This may provide further support for the role of chronic inflammation in AD and questions whether it would be worthwhile introducing routine screening for MCI in rheumatology clinics.
Different response of hypothalamus and temporal cortex to intranasal insulin in rat model of sporadic Alzheimer's disease
Authors: Knezovic Ana , Budisa Stjepan , Andrilovic Ana , Homolak Jan , Perhoc Ana Babic , Barilar Jelena Osmanovic , Salkovic‐Petrisic Melita 
Published: December 2020

AbstractBackgroundSporadic Alzheimer’s disease (sAD) is the most common form of dementia. Central administration of streptozotocin (STZ‐icv) has been shown to induce Alzheimer‐like changes and has been proposed as a non‐transgenic sAD animal model. Intranasal insulin administration is being investigated as a possible pharmacological treatment in order to reverse and ameliorate brain insulin dysfunction, but exact mechanism is not yet clear.MethodMale Wistar rats were given icv vehicle or STZ (3 mg/kg). Activation of c‐fos co‐localized with neuronal, astrocytic and microglial markers was evaluated in the brain 2 hours after intranasal insulin administration (2 IU), which was given 1 month after STZ. Western blot analysis of insulin receptor (IR) and postsynaptic marker (PSD95) were performed in hypothalamus (HPT) and temporal cortex (TC) 2h after intranasal insulin administration in STZ‐icv rat model. Spectrophotometry was used to measure glucose and β‐amyloid in plasma and CSF and glutamate and insulin concentration in brain tissue samples.ResultIntranasal insulin significantly increases c‐fos expression in TC only. C‐fos expression in TC was co‐localized with neuron marker, while in HPT was co‐localized also with microglial marker, especially with activated microglia in STZ‐icv rats. Glucose levels were found unaltered in plasma and CSF, while β‐amyloid concentration was found slightly increased after STZ and insulin administration. Increment of insulin concentration was found most pronounced in HPT of control animals after intranasal insulin (+289% vs CTR). Both insulin and STZ significantly decreases glutamate concentration in HPT (∼−92% vs CTR). treatments mostly s. At the level of IR and PSD95 expression STZ and insulin have opposite effects in HPT compared to TC.ConclusionIn this research, we have shown that STZ and insulin have different and opposite effects in the brain, showing distinct cell response to insulin depending on brain region in rat model of sAD. Financed by CSF projects IP‐09‐2014‐4639 and IP‐01‐2018‐8938. This publication was co‐financed by the Scientific Centre of Excellence for Basic, Clinical and Translational Neuroscience (project “Experimental and clinical research of hypoxic‐ischemic damage in perinatal and adult brain”; GA KK01.1.1.01.0007 funded by the European Union through the European Regional Development Fund).
SEC24 isoform specificity regulates the assembly of γ‐secretase from dimeric subcomplexes
Authors: Wouters Rosanne , Michiels Christine , Kleizen Bertrand , Dillen Katleen , Vermeire Wendy , Demedts David , Sannerud Ragna , Schekman Randy , Annaert Wim 
Published: December 2020

AbstractBackgroundγ‐Secretase is a diaspartyl protease with presenilin (PSEN) as the catalytic subunit. It targets a plethora of type I transmembrane proteins and, as such, affects a broad range of physiological processes. Because of this, aberrant functioning of γ‐secretase is linked to several diseases including cancer and Alzheimer’s disease (AD). Herein, mutations in the PSEN genes are associated with rare cases of familial AD and shift the production to longer, more aggregation prone amyloid β peptides. γ‐Secretase consists, besides the catalytic component PSEN, of nicastrin, APH1 and PEN‐2 that are co‐translationally translocated in the endoplasmic reticulum (ER). As γ‐secretase has a stoichiometry of 1:1:1:1, the assembly process is spatially and temporally regulated. Although it is generally agreed that this occurs in early biosynthetic compartments, it remains far from understood whether full assembly occurs already in the ER and to what extent Golgi‐to‐ER recycling is involved.MethodWe used advanced cell fractionation protocols and an in vitro reconstituted ER budding assay to explore in detail the stepwise assembly process of γ‐secretase in early biosynthetic compartments.ResultCell fractionation combined with blue native electrophoresis shows that subcomplexes are mainly present in ER‐enriched fractions while full complexes appear in the ER‐Golgi intermediate compartment, indicating that final assembly occurs beyond the ER. In vitro reconstitution of ER export reveals that none of the γ‐secretase subunits is required for ER‐exit of the others. However, knock‐out of any subunit induces the accumulation of preceding subcomplexes in de novo formed COPII vesicles. Mutating a motif in the cytosolic loop domain of PSEN1, which is lost in the familial AD‐associated PSEN1∆E9 mutant, abrogates ER‐exit of PSEN1 as well as PEN‐2, but not of nicastrin. This is explained molecularly by the selectivity of Sec24A/B and Sec24C/D in packaging PSEN1 and nicastrin, respectively, and further argues against full complex assembly prior to ER‐exit.ConclusionIn conclusion, our data support a model wherein individual subunits and dimeric subcomplexes preferentially exit the ER. Full assembly likely occurs in intermediate compartment/cis‐Golgi allowing complexes to escape active Golgi‐to‐ER recycling as part of a secondary quality control mechanism in controlling cellular γ‐secretase levels and activity.
CSF and plasma biomarkers for DLB
Authors: Galasko Doug R. , Caughey Byron , Mollenhauer Brit , Leverenz James B. 
Published: December 2020

AbstractBackgroundCSF biomarkers of amyloid and tau provide components of the A/T/N classification for AD and hold clinical prognostic value. They can help to identify how AD co‐pathology contributes to DLB. Alpha‐synuclein (a‐Syn) aggregation is a key pathogenic process in DLB, proposed to follow a staging system for spread of pathology. We review existing CSF markers in DLB and evaluate how well RT‐QuIC, a protein misfolding amplification assay for a‐Syn, detects DLB and different degrees of a‐Syn pathology at autopsy, and performs in RBD, a prodromal stage of DLB. We discuss the potential for plasma biomarkers for diagnosis and progression in DLB.Method1) selected studies of CSF biomarker data from RBD subjects and from published data for DLB on A/T/N biomarkers and on a‐Syn RT‐QuIC and other a‐Syn biomarkers; 2) analysis of different parameters of a‐synuclein RT‐QuIC and clinical‐pathological correlations for RT‐QuIC; 3) data on plasma neurofilament light as a progression biomarker.Result1) AD biomarkers in CSF support AD co‐pathology in a substantial percentage of cases of DLB, which is associated with faster cognitive progression. Data on RBD and prodromal DLB are limited. 2) RT‐QUiC has high sensitivity and specificity for PD and DLB diagnosis, including RBD. RT‐QuIC parameters (time to 50% of maximal fluorescence or peak fluorescence) do not correlate with measures of movement or cognition. Limiting dilution may provide an index of seeding burden, but in preliminary analyses shows a weak relationship to clinical progression; 3) longitudinal Nfl plasma levels in the PPMI cohort show a slight increase in early PD and RBD, to a greater extent than in aging alone, with much overlap. Concomitant AD pathology may drive plasma Nfl changes.ConclusionCSF biomarkers related to neurodegeneration may provide value in early DLB. CSF Aβ1‐42/Tau has prognostic value for cognitive decline in DLB. RT‐QuIC for a‐synuclein in CSF has diagnostic but not predictive value. Plasma biomarkers for diagnosis of pathology are emerging, but prognostic markers will need extensive additional research.
From diagnosis to rehabilitation: Report of a clinical case of Alzheimer's disease
Authors: Avila Renata , Porto Fabio Henrique de Gobbi 
Published: December 2020

AbstractBackgroundA thorough investigation is necessary for the diagnosis of Alzheimer’s disease (AD). An ideal treatment is composed of drug treatment and neuropsychological rehabilitation (NR). AD still has no cure, but its adequate treatment can delay the evolution of the disease and make the patient and family live with more quality. The purpose of this case report is to describe the NR of a mild AD patient, his participation in the decision about rehabilitation objectives and his growing awareness about his difficulties. Male client, a 73‐year‐old retired electrical engineer, married, 3 sons and 4 grandsons. The neuropsychological assessment confirmed the cognitive deficits, as well as MRI showed hippocampal atrophy and PET showed typical pattern of AD. His main cognitive changes included mild memory problems, important inattention, wordy speech, and lack of planning. Disinhibition, rigidity and impulsivity where the behavior change observed, added to a lack of awareness of his difficulties in daily activities. He started individual NR sessions twice a week with a neuropsychologist. In parallel family was oriented and received support with the same professional about how to cope with the changes. He was also accompanied by a psychiatrist, neurologist, and a clinical psychologist. Four months after the RN had started, he became much more aware about his difficulties, managed to define with the therapist three goals for the treatment, stopped driving and agreed to hire a driver, and the wife reported attention, language and behavior improvement. After 8 months he said: “I am recovering from my eccentricities, the left and the right brain seem to be OK, and my wife and I are meeting again”, and the wife said, “now I think about which fights to pick. Our relationship is much better. He’s calmer, more alert, and speaking better. He himself is organizing his weekly medicine box and its working.” This single case study illustrates the importance of a team of experts working together with a person with AD and his family for maintenance of autonomy, enhancement of the behavior and cognitive changes, as well as improving the quality of life of families and their loved ones.
Extracellular vesicles derived from postmortem human brain tissue contain seed‐competent C‐terminal tau fragments, and provide proteomic clues to the identity of selectively vulnerable cell populations in human tauopathies
Authors: Fowler Stephanie L. , Bez Sumi , Gaur Pallavi , Miller Chelsea , Turkes Emir , Schaler Ari , Hernandez Villegas Nancy E. , Perez‐Gonzalez Rocio , Levy Efrat , Duff Karen E. 
Published: December 2020

AbstractBackgroundPathological tau is spread along anatomically connected networks, originating in areas containing particularly vulnerable cell populations. It is hypothesized that tau is released and spread as free tau, or via extracellular vesicles (EVs) that include exosomes (30‐150 nm), microvesicles (100‐1000 nm), and apoptotic bodies (1000‐5000 nM). While a variety of different EV tau species have been identified in tissue, cells, and bio‐fluids, EV tau has not yet been described from human post‐mortem tauopathy brain tissue.MethodUsing a differential centrifugation and sucrose flotation method described by Perez‐Gonzalez et al., EVs were isolated from post‐mortem human frontal cortex tissue blocks from Alzheimer’s Disease (AD), Corticobasal Degeneration (CBD), and Control cases (BA9, n=4/group).ResultElectron microscopy (EM) confirmed the presence of vesicles with characteristic shape and size of exosomes and microvesicles. As demonstrated by immunoblotting, EV tau from tauopathy cases contains very little full‐length tau, but is specifically enriched in tau fragments of 10‐15 and 30‐35 kDa. EVs from control cases contain low levels of full‐length tau, and no tau fragments. EV tau fragments are sarkosyl‐insoluble, protected by the lipid membrane of the vesicle, and are seed‐competent (RD‐tau biosensor FRET seeding assay, seeding of primary neurons, and significant spread of AT8+ tau in EV‐injected PS19 mouse hippocampi). Epitope mapping and mass spectrometry sequencing confirm the presence of C‐terminal tau fragments, and further proteomic analyses confirm the identity of EVs as secreted vesicles. Together, these data provide the first clues to tauopathy‐specific proteomic signatures of EVs, and identify exosome components derived from the most vulnerable cell populations. This work complements the biomarker literature showing that N‐terminal regions of tau are secreted into the cerebral spinal fluid, while C‐terminal regions are retained in the brain.ConclusionThe identification of a seed‐competent species encased in a vesicle that readily fuses with cell membranes confirms that EVs are likely a significant mediator of pathological tau spread in the human brain. Our continued investigation of EV tau cryo‐EM structure, and of EV tau‐containing vesicles will focus on identifying novel immunological targets for pathological tau, and the vesicles that facilitate its spread.
Data‐driven full‐resolution model of amyloid, hypometabolism and atrophy changes over Alzheimer's disease progression
Authors: Nader Clement Abi , Ayache Nicholas , Robert Philippe , Lorenzi Marco 
Published: December 2020

AbstractBackgroundNeurodegenerative disorders such as Alzheimer’s disease (AD) are characterized by morphological and molecular changes of the brain, ultimately leading to cognitive and behavioral decline. A comprehensive model of the brain’s spatio‐temporal changes in AD would be a valuable instrument for improving our understanding of the disease dynamics, and for tracking disease progression in clinical trials.MethodWe propose a spatio‐temporal generative model of disease progression, aimed at disentangling and quantifying the independent dynamics of changes observed in datasets of multi‐modal imaging data. Our data consists of AV45‐PET, FDG‐PET, and structural magnetic resonance images (MRI), representing respectively amyloid deposition, glucose metabolism and gray matter atrophy for 544 individuals (137 healthy, 293 affected by mild cognitive impairment, and 114 AD patients). The model is based on a monotonicity constraint, which forces the spatio‐temporal image trajectories to evolve from a normal to a pathological stage. Moreover, we aim at automatically inferring the disease severity of a patient with respect to the estimated trajectory.ResultsThe estimated spatio‐temporal processes at stake in AD are shown in Figure 1. The model identifies specific brain areas and their evolution in time in terms of gray matter atrophy, glucose metabolism, and amyloid concentration. The model describes a gray matter loss encompassing a large extent of the brain with a focus on cortical areas, but also targets subcortical areas such as the hippocampi. Concerning the glucose metabolism, the model identifies a pattern of hypometabolism involving most of the brain regions that tends to plateau, while also detecting a linear pattern of hypometabolism targeting areas such as the precuneus and the parietal lobe. Finally, the model highlights an increase of amyloid deposition mapping most of brain regions, such as the parietal and frontal lobes, while exhibiting a differential pattern of amyloid deposition targeting mostly frontal, temporal, occipital areas and precuneus. Moreover, the time‐scale associated with these spatio‐temporal processes strongly correlates with the clinical evolution of the disease (Figure 2).ConclusionThe presented disease progression allows to disentangle differential temporal progression patterns mapping brain regions key to neurodegeneration, while revealing a disease‐specific time scale associated to the clinical diagnosis.