bluuebunny/crossref_metadata_2025_split huggingface dataset:
Susceptibility of aged pericytes to Aβ1‐42 oligomers
Authors: Randall Ryleigh B. , Bauman Allison J. , Bobinger Hanna V. , Saiyasit Napatsorn , Nelson Amy R. 
Published: December 2022

AbstractBackgroundAging is associated with increased incidence of Alzheimer’s disease, blood brain barrier breakdown, and increased cellular senescence (Saez‐Atienzar et. al, 2020). Senescence is the permanent arrest of the proliferative state of the cell and is initiated as a result of aging and cellular stress (Martínez‐Cué et.al, 2020). Senescent cells induce production of proinflammatory cytokines. In the brain, chronic inflammation leads to synapse damage and cognitive decline (Saez‐Atienzar et. al, 2020). The objective of this study is to examine the impact of cellular senescence on brain vascular pericytes, which contribute to the regulation of cerebral blood flow.MethodFor this study, both in vitro as well as in vivo experiments were performed. To induce senescence by oxidative stress in vitro in a culture of mouse brain vascular pericytes, 100 uM of hydrogen peroxide was added to culture flasks. Senescence was confirmed in the treated cells via staining for β‐galactosidase, a known biomarker of senescent cells. The next steps for the in vitro aspects of this study include performing western blotting on senescent pericytes to determine if there is a differential expression of pericyte p75 neurotrophin receptor (p75NTR), which has a potential role in the impaired hemodynamic response and cell death in pericytes. Finally, cranial window procedures were performed on 18‐month‐old C57BL/6 mice followed by imaging the live brain tissue with a multiphoton microscope. While imaging, artificial cerebral spinal fluid (control animals) or 72 nM amyloid‐beta (Aβ)1‐42 oligomers were topically delivered to the brain surface to determine if Aβ1‐42 oligomers cause a significant reduction in erythrocyte flow through pericyte covered capillaries.ResultPreliminary data from the β‐galactosidase staining suggest that the hydrogen peroxide is an effective method for inducing senescence in mouse brain vascular pericytes. We have observed a decreased growth rate in cells treated with the hydrogen peroxide, further suggesting senescence in these cells.ConclusionThese findings characterize the impact of Aβ on pericyte contractility and could illuminate the role of senescence and aging on impaired hemodynamic responses because of dysfunctional pericytes.
Chronic FK506 treatment reduces amyloid β and tau levels in the hippocampus and cortex of 3xTg‐AD mice
Authors: Fracassi Anna , Marcatti Michela , Saieva Salvatore , Taglialatela Giulio 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is the most common form of neurodegenerative dementia. While major histopathological hallmarks of AD are amyloid‐β (Aβ) plaques and neurofibrillary tau tangles, soluble oligomeric forms of Aβ and tau (TauO) have been identified as the most neurotoxic species involved in synaptic degeneration. Previous studies associate alterations of the phosphatase calcineurin (CaN) to AβO‐driven toxicity. We previously have shown that CaN mediates both the neurotoxic and cognitive effects of AβO and elevated CaN levels have been also shown in AD patients, suggesting a central role of CaN in AD onset and/or clinical progression. Our previous studies in mouse models demonstrated that an acute treatment with the CaN inhibitor FK506/Tacrolimus in Tg2576 acutely injected intracerebroventricularly with AβO restores memory function in these cognitively impaired animals. Moreover, we reported absence of AD in aging human chronically treated with KF506 following solid organ transplant. To deeper investigate the involvement of CaN in AD onset and progression, we used a 3xTgAD mouse model presenting both Aβ and Tau aggregates.Method7 month‐old 3xTg‐AD mice were chronically treated for two weeks with intraperitoneal administration of either FK506 (1mg/kg) or PBS. Using immunofluorescence and western blot analyses we analyzed the levels of CaN, total Tau and Aβ in hippocampal (dentate gyrus‐DG, CA1 and CA3) and cortical areas (frontal and parietal‐occipital cortex) in our experimental groups.ResultWe found significantly decreased levels of CaN in DG, CA1 and CA3 and cortical areas in FK506 treated 3xTg‐AD mice as compared to 3xTg‐AD mice injected with PBS. Furthermore, performing double staining for Aβ and total Tau, FK506 treated mice displayed significant lower levels of Aβ and Tau in all the considered areas as compared to PBS‐treated 3xTg‐AD mice. These data suggest that the treatment with FK506 might trigger some mechanisms involved in the elimination of Tau and Aβ, i.e. autophagy.ConclusionOur data confirm the role of CaN as a key player in AD. The reduced key AD pathology following CaN inhibition with FK506 suggests the use of an FDA approved drug as a potential treatment with rapid clinical translation to slow the progression of the disease.
Next Generation Sequencing analysis of late‐onset dementia patients with a strong family history
Authors: Gómez‐Tortosa Estrella , Agüero Pablo , Sainz María José , Pérez‐Pérez Julián 
Published: December 2022

AbstractBackgroundNext‐generation sequencing (NGS) techniques allow for efficient screening of potentially pathogenic variants by using gene panels that target the genes known to underlie neurodegenerative dementias. Most NGS studies are focused on cases with early‐onset disease, which have a higher genetic burden. The objective of this study is to identify known and/or novel rare variants in major candidate genes associated with neurodegenerative dementias in cases with a strong family history, including patients with late‐onset disease.MethodWe studied 53 patients (25 early‐ and 28 late‐onset) with a strong family history of dementia (Goldman scale 1 and 2) and phenotypes including dementia of the Alzheimer type (DAT), frontotemporal variants (FTD) and Lewy body type dementia. Presence of the C9Orf72 hexanucleotide repeat expansion had been ruled out and all cases had plasma progranulin levels within the normal range. The NGS panel included 20 genes. Variants identified were reviewed in genomic databases and analyzed for potential pathogenicity using prediction programs. Segregation was evaluated in available siblings.ResultPotentially pathogenic mutations (CADD >20 and/or M‐CAP > 0.025) were found in 20 cases (38%, 11 early‐onset and 9 late‐onset), with two cases carrying mutations in two different genes. We detected known pathogenic mutations in two cases with the SQSTM1 P392L variant, manifesting as bv‐FTD and Paget disease. Six cases had non‐described variants in the PSEN1, ADAM10, SORL1, UBQLN2, and TIROBP genes that were likely disease‐related, as further supported by segregation patterns. We also found rare, potentially pathogenic variants in the SORL1, SQSTM1, and FUS genes in four cases. Finally, ten cases carried variants of unknown‐impact in the following genes: MAPT, CSF1R, ADAM10, SORL1, and SERPINI1. In the late‐onset cases, frontotemporal phenotypes were more likely to have positive results and the potentially pathogenic variants were found in the PSEN1, ADAM10, SQSTM1, FUS, and CSF1R genes.ConclusionIt is worthwhile to screen for the genetic causes of the disease in cases with late‐onset dementia if there is a strong family history. Positive results are more likely obtained in frontotemporal phenotypes.
SINGLE AND COMBINED EFFECTS OF 5GHZ FREQUENCY WAVES AND COMPUTED TOMOGRAPHY(CT) SCAN DOSES ON WHOLE BLOOD PARAMETRES, MEMORY AND P53 GENE EXPRESSION IN RATS
Authors: Obajuluwa Adejoke Olukayode , Danlami Amina , Onwuka Chidiogo Chukwunweike , Bolarinwa Rahman Ayodele , Lech James , Obajuluwa Tiwalola Madoc , Anish Abel 
Published: December 2022

AbstractBackgroundExponential increase has emerged globally in the use of non‐ionizing and ionizing radio‐frequency electromagnetic fields(Rf‐emfs) for a wide range of applications, daily activities, communication, diagnostics , therapeutics to mention but a few. However, a significant public concern is how these technologies interacts and affects the biota as electromagnetic field (EMF) emissions is linked to dysregulation of genes involved in neurotransmission,oxidative stress and normal cellular function.MethodsStandard methods (y‐maze, novel object recognition tests, automated hematology analyzer, PCR etc), were used to study how the combination of EM waves from 5Ghz radio and CT irradiation affects whole blood parameters, neurobehavioural profiles (memory and cognition), DNA fragmentation and p53 gene expression in Wistar rats which were grouped into five namely: I‐Negative control, II‐sham, III‐5Ghz only , IV‐ 5Ghz+CT, V‐CT only for fourteen days. Genomic DNA was isolated from rats’ cerebral cortex while target gene and internal control primers (GAPDH) were synthesized for p53 gene exons expression and electrophoresed on a 2.5% agarose gel.ResultsWe found that CT irradiation had higher modulatory effects on platelets, white blood cell counts and memory impairments compared to 5GHz only group. However, there was gross DNA damage and complete loss of p53 (exons 5‐7) gene expression profiles in the 5GHz while the CT irradiated rats expressed mutant p53 gene. The effect of CT irradiation in pre‐exposed 5GHz rats revealed mutant p53(exons 5‐7), elevated memory and cognition impairments amongst others .ConclusionDeleterious single effects of 5GHz was observed in p53 gene expression profiles and cognition with an interferential interaction in its combination with CT irradiation leading to mutant p53 gene expression . The impaired neurobehavioural and p53 gene profiles as a result of the single and combined 5GHz and CT exposure predicts functional radiation waves emission effects, changes in resultant protein and dysregulated cellular functions.
The role of the Locus Coeruleus in depression in Alzheimer’s disease
Authors: Sedgwick Katie Sarah , Dwyer Dominic , Good Mark A , Saito Takashi 
Published: December 2022

AbstractBackgroundDepression, one of many common neuropsychiatric symptoms (NPS) seen in Alzheimer’s disease (AD), frequently predisposes the onset of cognitive deficits. NPS are often reported to cause the most suffering in patients and their loved ones so understanding their cause could lead to treatments that afford a better quality of life. The Locus coeruleus (LC) has strong links to depression and, being one of the first areas to show AD pathology, could be integral to understanding this NPS‐AD link. Alongside a natural LC neuron loss with age, AD causes its neurodegeneration reducing the LC’s neuroprotective capabilities and control of inflammatory pathways. Examination of the LC, inflammation and depressive phenotype could offer insights into future treatments.MethodBehavioural testing was done using a novel, knock‐in mouse model, AppNL‐G‐F
, to assess depressive phenotype at an early and old time point. This included tests for anxiety (open field, elevated plus maze), social deficits (social preference test) and anhedonia (lick cluster analysis) all common NPS symptoms. Brains extracted from these animals were used to stain for LC neurons, plaques and microglia as well as assess astrocytes and inflammatory markers using western blotting technique.ResultAn anxiolytic phenotype was prominent but no social deficits or anhedonia suggesting a lack of depressive phenotype. There was also no loss of LC neurons with age or genotype. Western blotting revealed a large increase in astrocytes within the AppNL‐G‐F
but no differences in inflammatory markers.ConclusionOverall, without the loss of LC neurons, it is difficult to draw firm conclusions on its role in NPS onset. Hence, the AppNL‐G‐F
mice are insufficient at modelling affective deficits seen in human AD due to the lack of neurodegeneration of the LC. It may be concluded that, as this is a model of amyloid beta pathology, that plaques and inflammation play a minimal role in NPS without LC loss. Future testing could lesion the LC to better understand its role.
Retromer‐dependent mechanisms of tau dysregulation in Down syndrome
Authors: Curtis Mary Elizabeth , Smith Tiffany , Yu Daohai , Pratico Domenico 
Published: December 2022

AbstractBackgroundDeficiencies in the retromer complex are reported in brains of Down syndrome subjects, and retromer protein levels inversely correlate with amyloidosis. The complex is also proposed to influence tau levels, however, the relationship between tau neuropathology and retromer deficiency in Down syndrome remains unclear. In the current study, we examine the relationship between pathological tau and retromer deficiency and explore potential mechanisms involved.MethodsPost‐mortem brain tissues from Down syndrome and control subjects were evaluated for retromer proteins, pathological tau and proteins relevant to its post‐translational modification. To explore potential mechanisms of retromer‐dependent effects on tau, neuro‐2A cells overexpressing human tau were treated with the pharmacological chaperone, TPT‐172, with or without the CDK5 inhibitor, roscovitine.ResultsPhosphorylated epitopes and insoluble forms tau were elevated in brain tissues of subjects with Down syndrome and inversely correlated with retromer proteins and the activity of cathepsin D. In vitro pharmacological stabilization of the retromer complex with TPT‐172 resulted in decreased levels of phosphorylated tau and the CDK5 activating protein, p25. The effect on tau phosphorylation was neutralized by incubation with the CDK5 inhibitor, roscovitine. Furthermore, CDK5‐p25 immunoprecipitated from cells treated with TPT‐172 caused significantly less histone phosphorylation, indicating that the treatment reduced CDK5 activity.ConclusionWe conclude that in Down syndrome deficiency of retromer proteins is involved in the development of tau neuropathology. We propose that retromer dysfunction contributes to the development of tau pathology by decreasing the degradative lysosomal pathway and by increasing phosphorylation via CDK5. Because pharmacological stabilization of the retromer complex decreases tau phosphorylation, we propose this could represent a novel therapy against tau pathology in Down syndrome.
Efficacy and safety of pimavanserin in patients with Alzheimer’s dementia psychosis in the HARMONY phase 3, randomized discontinuation study: a post hoc subgroup analysis
Authors: Cummings Jeffrey , Devanand Davangere P , Ballard Clive G , Tariot Pierre N. , Hendrix Suzanne B. , Dickson Samuel P. , Li Caiyan , Abler Victor , Pathak Sanjeev , Stankovic Srdjan 
Published: December 2022

AbstractBackgroundPimavanserin was investigated for the treatment of dementia‐related psychosis (DRP) in HARMONY (NCT03325556), a phase 3 randomized discontinuation study. As the study met the primary endpoint (one‐sided P = 0.0023), we evaluated the consistency of the efficacy for reducing the risk of relapse in the largest dementia patient subgroup (ie, Alzheimer’s dementia psychosis [ADP] patients) treated with pimavanserin 34mg.MethodEnrolled DRP patients (N = 392) entered the 12‐week open‐label (OL) period and received pimavanserin 34mg daily. During weeks 1‐4, dose could be adjusted to 20mg at investigator discretion. Patients meeting prespecified response criteria at weeks 8 and 12 were randomized to continue pimavanserin or receive placebo for up to 26 weeks in the double‐blind (DB) period. The primary endpoint was time from randomization to adjudicated relapse. Efficacy analyses included patients at the interim analysis (IA); safety analyses included all dosed patients.ResultOf 260 ADP patients, 243 stayed on pimavanserin 34mg throughout the OL period; 17 patients received pimavanserin 20mg beyond OL week 4. At baseline, mean age in the pimavanserin 34mg group was 75.7 years; mean MMSE score was 16.0. Twenty‐nine patients were terminated with sponsor termination of the study; of the remaining 214 patients, 130 (60.7%) met response criteria at weeks 8 and 12 and were randomized. At the IA, 116 ADP patients were randomized to pimavanserin 34mg (N = 57) or placebo (N = 59). Hazard ratio for psychosis relapse risk with pimavanserin 34mg versus placebo was 0.466 (95% CI: 0.179, 1.214); 6/57 (10.5%) pimavanserin‐treated and 14/59 (23.7%) placebo‐treated patients met relapse criteria. Treatment‐emergent adverse events incidence rates were: OL, 29.6% (72/243); DB‐pimavanserin 34mg, 39.7% (25/63); DB‐placebo, 34.3% (23/67). Pimavanserin did not have a negative effect on Mini‐Mental State Examination or Extrapyramidal Symptom Rating Scale‐Abbreviated score change from baseline versus placebo in the DB period.ConclusionIn a study that met its primary endpoint, a post‐hoc subgroup analysis in ADP, although not statistically significant, demonstrated a clinically meaningful reduction in the risk of relapse was observed in patients treated with pimavanserin 34mg versus placebo. Pimavanserin was not associated with an adverse impact on cognition or motor function.
Neuropathological Validation of the Alzheimer’s Questionnaire
Authors: Mohebpour Ida , Malek‐Ahmadi Michael H. , Virden Thomas , Breitmeyer Angela , Sue Lucia I , Serrano Geidy E , Sabbagh Marwan N. , Beach Thomas G 
Published: December 2022

AbstractBackgroundThe Alzheimer’s Questionnaire (AQ) is a brief, informant‐based screening tool that has demonstrated good diagnostic accuracy in identifying clinical Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI). The AQ has been further validated by its correlations with established informant‐ and performance‐based cognitive assessments as well as with standard neuropsychological tests. Recent evidence has also demonstrated that the AQ correlates well with PET‐based measures of amyloid plaque. The aim of this study is to validate the AQ with the hallmark neuritic plaque (NP) and neurofibrillary tangle (NFT) pathology of AD.MethodData from 205 prospectively‐followed autopsy cases classified as AD (n=90), aMCI (n=42), or cognitively unimpaired (CU, n=73) were used in this analysis. The average age at death was 87.07±7.84 years with the average interval between the last clinical assessment and death of 16.48±14.32 months. Semi‐quantitative measures of NP and NFT pathology from five brain regions were used to assess total plaque and total tangle loads which were then correlated with the AQ, Clinical Dementia Rating Sum of Boxes (CDR‐SOB), and the Mini‐Mental State Exam (MMSE). Spearman correlations were used in the primary analyses and were followed up with robust regression models that adjusted for age at death, sex, education, and APOE ε4 carrier status.ResultThe AQ correlated significantly with NP load (r=0.37, p<0.001) and NFT load (r=0.57, p<0.001). These associations remained significant after covariate adjustment (NP: β=0.28, 95% CI: (0.21, 0.34), p<0.001; NFT: β=0.22, 95% CI: (0.17, 0.28), p<0.001). The MMSE and CDR‐SOB showed similar correlations with NP load (r=‐0.37, r=0.35, respectively) and NFT load (r=‐0.58, r=0.55, respectively).ConclusionThese findings extend previous clinical and neuroimaging findings of the AQ showing that it correlates well with the hallmark NP and NFT pathology of AD and provide additional confidence to clinicians who use the AQ to screen for AD‐related cognitive impairment.
Cognitive impairment is associated with increased central arterial stiffness in an animal model of chronic kidney disease.
Authors: Grigorova Yulia N , Fox Shanaya , Long Jeffrey M , Santos Carla Rocha Dos , McDevitt Ross A , Zernetkina Valentina , Haghkar Mahdi , Wei Wen , Morrell Christopher H , Juhasz Ondrej , Sodhi Komal , Rapp Peter R. , Lakatta Edward G , Fedorova Olga V 
Published: December 2022

AbstractBackgroundThe prevalence of cognitive impairment (CI) and dementia in end‐stage chronic kidney disease (CKD) has been estimated at 30‐60%. Cardiovascular diseases (CVD) including increased central arterial stiffness (CAS) accompany CKD development and contribute to CI. Elevated pulse wave velocity (PWV) is associated with higher mortality in CVD and CKD independently of blood pressure (BP). Marinobufagenin (MBG) is a pro‐fibrotic factor, which increases in CKD and contributes to CAS. The aim of this study was to determine whether CKD potentiates CI development via CAS and cardiovascular remodeling in a rat model of CKD.MethodFour months old male Sprague‐Dawley rats were fed with 0.25% adenine (n=19; CKD group) diet to induce CKD or regular diet (n=16; CTRL group) for 8 weeks. Body weight (BW), BP, heart rate (HR), aortic PWV (aPWV), and behavioral tests were conducted at the end of the study. The level of anxiety was tested in an open field test (OFT). Morris water maze (MWM) was used to test spatial memory. Blood was collected for measurements of plasma sodium, potassium, blood urea nitrogen (BUN), hematocrit and MBG. The data were analyzed using two‐tailed unpaired t‐test and linear regression.ResultAnimals in the CKD group had higher levels of plasma creatinine and BUN, which indicate the development of CKD, higher plasma sodium, potassium, and MBG, and higher aPWV, lower hemoglobin, hematocrit, BW, HR, enlarged hearts, aortae, and kidneys, vs. CTRL group (Table 1). BP was similar in both groups. .Rats in CKD group spent less time in the center of open field compared to their CTRL counterparts, indicating increased anxiety‐like behavior (Figure 1 A, B). Although there was no difference in performance in MWM between the groups, there was a positive correlation between aortic weight and ability to find a hidden platform in the CKD group (Figure 1C).ConclusionWe demonstrated that CKD development in young Sprague‐Dawley rats was accompanied by increased CAS, estimated as aPWV, which developed in blood pressure‐independent manner. Higher PWV was associated with a higher level of anxiety, and aortic tissue remodeling was associated with spatial memory in CKD model.Supported by NIH/NIA IRP