bluuebunny/crossref_metadata_2025_split huggingface dataset:
MAC28 Attenuates Neurodegeneration and Restores Cognitive Function via Reducing Peripheral Insulin Resistance, Neuroinflammation, Brain Oxidative Stress, Amyloid‐β Deposition, and Loss of Dendritic Spines in High‐Fat Diet‐induced Obese Rats
Authors: Oo Thura Tun , Sumneang Natticha , Nawara Wichwara , Arunsak Busarin , Chunchai Titikorn , Apaijai Nattayaporn , Pratchayasakul Wasana , Liang Guang , Chattipakorn Nipon , Chattipakorn Siriporn C 
Published: June 2023

AbstractBackgroundLong‐term high‐fat diet (HFD) consumption induces not only peripheral insulin resistance with low‐grade systemic inflammation, but also neuroinflammation and subsequent brain pathologies including neurodegeneration, which can lead to cognitive impairment (1). MAC28, a novel mono‐carbonyl analogue of curcumin, was recently identified as a novel MD‐2 inhibitor, and has been shown to attenuate systemic inflammation (2). However, the effects of MAC 28 on the neuroinflammation, neurodegeneration and cognitive function in the HFD‐induced obese rats have never been studied.MethodMale Wistar rats were fed either a normal diet (ND; n = 8) or HFD (n = 40) for 16 weeks. At week 13, ND‐fed rats were orally administered a vehicle for 4 weeks, while HFD‐fed rats were randomly divided into 5 groups (n = 8/group). Each subgroup was orally administrated either vehicle, 10mg/kg/day of MAC 28, 20mg/kg/day of MAC 28, 40mg/kg/day of MAC 28 or 300 mg/kg/day of metformin for 4 weeks. At the end of experimental protocol, the novel object location (NOL) test was examined in each rat. Brains were rapidly removed to determine brain TLR4‐MD‐2 signaling pathway, inflammatory cytokines, brain oxidative stress, dendritic spine density, amyloid and tau pathology.ResultHFD‐fed rats developed obesity with peripheral insulin resistance. Neuroinflammation was observed in HFD‐fed rats, as evidenced by increased expressions of hippocampal MD‐2, TLR4 and TNF‐α levels. In addition, HFD‐fed rats not only increased the levels of brain MDA, hippocampal amyloid‐β/APP ratio, but also reduced hippocampal dendritic spine density, resulting in cognitive decline. Although all doses of MAC 28 and metformin attenuated peripheral insulin resistance, brain pathologies and cognitive impairment, MAC 28 (20mg/kg/day and 40mg/kg/day) and metformin had the highest efficacy in attenuating peripheral insulin resistance, brain inflammation, brain oxidative stress, amyloid‐β deposition and improving dendritic spines, resulting in restoring cognitive function (P < 0.05, Figure 1).ConclusionThese findings suggest that an obvious neuroprotective effect of MD‐2 inhibitor may be the potential strategy for attenuating neurodegenerative disorders in the obese‐insulin resistant condition.
Cross‐species evidence of differential expression of S100A6 and SLC11A1 in the hippocampus of Alzheimer’s disease patients and mouse models
Authors: De Bastiani Marco Antônio , Bellaver Bruna , Carello‐Collar Giovanna , Zimmermann Maria , Kunach Peter , Forner Stefania , Martini Alessandra Cadete , Lima‐Filho Ricardo A S , Lourenco Mychael V. , Rosa‐Neto Pedro , Pascoal Tharick A. , Zimmer Eduardo R. 
Published: June 2023

AbstractBackgroundThe evaluation of similarities and differences between mouse models and human Alzheimer’s disease (AD) provides invaluable insights on disease pathophysiology. We compared hippocampal transcriptomic profiles of human late‐onset AD (LOAD) and early‐onset AD (EOAD) individuals with three mouse models (hAβ‐KI, APP/PS1 and 5xFAD) in an exploratory analysis. Afterwards, we validated the intersection of genes consistently altered in all groups using hippocampal tissue from APP/PS1 mice, and EOAD and LOAD patients.MethodsFive publicly available human AD/cognitively unimpaired (CU) transcriptomic profiles were collected from GEO (https://www.ncbi.nlm.nih.gov/geo/), merged and submitted to differential expression analysis (DEA) using R. APP/PS1 mouse model RNAseq data from two datasets (GSE149661 and GSE145907) were also collected. Finally, RNAseq data of 5xFAD and hAβ‐KI mouse models were obtained from AMP‐AD Knowledge Portal (https://www.synapse.org/) using synapser and synapserutils packages. All animal models were also submitted to DEA. Validation of selected genes was performed by qRT‐PCR. Target mRNA levels were normalized using β‐actin as a housekeeper gene. The results were expressed relative to wild‐type (WT) animals or CU controls using the 2−ΔΔCt method.ResultsDEA identified 1164, 3261 and 1782 differentially expressed genes (DEGs) for the comparisons between hAβ‐KI, 5xFAD and APP/PS1 mutants versus WT controls, respectively. hAβ‐KI, APP/PS1, and 5xFAD mice exhibited more DEGs in common with LOAD than with EOAD patients. Interestingly, APP/PS1 and 5xFAD mice also presented more DEGs in common with LOAD than with EOAD patients. However, 5xFAD showed significantly higher DEGs intersection with EOAD than with hAβ‐KI and APP/PS1. Additionally, we identified S100A6, C1QB, SST, CD14, CD33, SLC11A1 and KCNK1 genes altered in both EOAD and LOAD as well as the three mouse models evaluated. qRT‐PCR analysis of these genes in EOAD, LOAD and APP/PS1 model revealed S100A6 and SLC11A1 consistently altered in human pathology and mouse model.ConclusionAnimal models seek to better simulate AD pathology, making the evaluation of their molecular overlap with human disease greatly important. S100A6, a calcium‐binding protein modulating several biological activities, and SLC11A1, a metal transporter associated with inflammatory processes, were consistently altered in our transcriptomics exploratory analyses and experimental validation, making them promising targets for further investigation.
Beta‐amyloid plaque accumulation comparison in down syndrome and non‐down syndrome cohorts
Authors: McVea Andrew K , DiFilippo Alexandra H , McLachlan Max , Murali Dhanabalan , Xin Yangchun , Johnson Sterling C. , Betthauser Tobey J , Converse Alexander K , Stone Charles K , Tudorascu Dana L. , Laymon Charles M , Klunk William E , Cohen Ann D. , Handen Benjamin L. , Christian Bradley T. 
Published: June 2023

AbstractBackgroundDown syndrome (DS) is characterized by earlier beta‐amyloid (Aβ) plaque accumulation and an increased prevalence of Alzheimer’s disease (AD) due to trisomy 21 and triplication of the amyloid precursor protein (APP) gene. While the age of AD onset is earlier in DS, AD pathology progression in non‐DS populations follows similar trends to the DS cohort. This study compares the accumulation rate of Aβ between DS and non‐DS populations measured with [C‐11]PiB at same site using the same scanning procedures.MethodsIndividuals with at least one Aβ+ [C‐11]PiB scan (Global SUVR>1.40), and at least one Aβ‐ scan from our site at the University of Wisconsin were selected for this study. 12 out of 58 DS participants in the Neurodegeneration in Aging DS (NiAD) study and 14 out of 246 non‐DS subjects from the PREDICT study fit this criteria. All images were collected on an ECAT HR+ scanner from 50‐70 minutes injection (i.d. = 15mCi). Reconstructed PET images were aligned and summed before being normalized into MNI‐152 space and converted into an SUVR image using cerebellar grey matter as a reference region. We determined rate of Aβ accumulation as the change in global SUVR per year, defined as the average of grey matter regions in the anterior cingulate, frontal cortex, parietal cortex, precuneus, temporal cortex, and striatum, and focused on the period when participants became Aβ+.ResultsPlotting global [C‐11]PiB SUVR and age (Fig 1) there is no age overlap between the two groups. The average rate of amyloid accumulation per year when becoming Aβ+ in the DS group was 0.058±0.026 compared to 0.059±0.028 for the non‐DS sample. The two groups have notably similar mean values, although when organized into box plots (Fig 2), the interquartile range of the DS subjects is 0.044 compared to a tighter 0.019 for non‐DS.ConclusionsThe pattern of Aβ accumulation in DS and non‐DS groups becoming Aβ+ have similar distributions. While we might expect a higher rate in the DS population due to the additional APP gene, our findings do not support this hypothesis. However, considerable variability in the rate of accumulation is observed requiring further investigation towards understanding this process.
Anti‐amyloid beta and anti‐acetylcholinesterase activity of Anaphalis neelgerriana leaves extract in streptozotocin induced Alzheimer rats
Authors: Malviya Dr Sapna , Malviya Dr Neelesh , Joshi Ankur 
Published: June 2023

AbstractBackgroundAlzheimer is associated with neuronal degeneration, characterized by memory loss and altered behaviour. Many pathological conditions like increased amyloid β (Aβ) plaque formation, and acetylcholinesterase neuroinflammation results in AD. Due to excess of reactive oxygen species (ROS) oxidative stress develops which overexpress Aß in the neuron which modifies the cellular function and thereby activates the neurodegeneration.MethodAD was induced by streptozotocin i.e. STZ (3 mg/kg, ICV) day 1st and 3rd day after surgery. Surgery was done on anesthetized rats by the help of stereotaxic apparatus. STZ induced AD rats were treated with ethanolic extracts of Anaphalis neelgerriana leaves (ANLE) (100 and 200 mg/kg, p.o.) for 14 days. Effects of ANLE in Alzheimer diseased rats were assessed for amyloid β peptide (Aβ) and acetylcholinesterase (AchE)ResultANLE significantly (p<0.01) decreases the Aβ1‐40, Aβ1‐42 peptides. Acetylcholinesterase level in the rat’s brain tissue reduced compared to Alzheimer diseased rats.ConclusionThe present study reveals that the ANLE produces Anti‐Alzheimer’s effect in Alzheimer diseased rats by decreasing Aβ protein level and Acetylcholinesterase level in the brain tissue.
Patterns matter: differential effects of stress‐inducing and novelty‐associated locus coeruleus firing on pretangle tau pathophysiology in a rat model
Authors: Omoluabi Tamunotonye , Torraville Sarah , Maziar Aida , Ghosh Abhinaba , Power Kyron , Rinhardt Camila , Harley Carolyn , Yuan Qi 
Published: June 2023

AbstractBackgroundThe brainstem locus coeruleus (LC), the main source of brain norepinephrine (NE), is critically involved in several functions including wakefulness, vigilance, attention, learning and memory. LC functioning is firing pattern‐dependent. Phasic pattern promotes novelty and learning, while high tonic activity associates with stress and anxiety. LC has been identified as a key structure in Alzheimer’s disease (AD) development. Braak and colleagues propose that soluble abnormally phosphorylated tau (pretangle tau) originates in the LC early in life. The spreading of pretangle tau to other neuromodulatory areas and transentorhinal cortex constitutes Braak’s pretangle AD stages. Pretangle stages appear to be universal in human, however, only a portion of us develop AD. The selective vulnerability of individuals for AD is not understood. We hypothesized that differential LC activity patterns, influence the pretangle tau pathophysiology and the development of AD.MethodIn this study, an AAV carrying pseudo‐phosphorylated human tau (AAV9‐DIO‐EGFP‐htauE14) was infused into the LC of 2‐3 month‐old TH‐CRE rats, mimicking the onset of tauopathy during puberty in humans. Another AAV containing ChR2 opsin (AAVdj‐DIO‐ChR2‐mCherry) was co‐infused with htauE14. Chronic light stimulation of the LC of either a 10 Hz phasic pattern or a 25 Hz tonic pattern was carried out for 6 weeks. The performance of ChR2 rats in a battery of behavioral assays was compared with control groups without ChR2 (AAVdj‐DIO‐mCherry), 10 months following the AAV infusion. This was followed by immunohistochemistry and Western blotting comparing different biomarkers.ResultPhasic LC activation improved spatial and olfactory discrimination of the htauE14 rats, while chronic tonic activation increased stress level of the rats and led to anhedonia. Phasic pattern rescued axonal degeneration observed in the control htauE14 rats, showing higher density of LC fibers in the piriform cortex and hippocampal dentate gyrus. Tonic LC activation did not rescue LC fiber degeneration, instead, worsened LC neuronal health indexed by elevated level of active caspase 3. The learning performance was positively correlated with the LC fiber density.ConclusionThese results argue that variations in environmental experiences associated with differing LC activity patterns may account for individual susceptibility to development of AD in humans.
A case of early‐onset familial Alzheimer’s disease caused by PSEN1 gene Y115C mutation in a Chinese pedigree
Authors: Zhang Yuan , Jia Ziyan , Suen Mengfan , Jiang Jiwei , Xu Jun 
Published: June 2023

AbstractBackgroundAlzheimer’s disease is the most common cause of dementia, with approximately 0.9% associated with known genetic mutations. Presenilin 1(PSEN1) gene is one of the most common genes associated with early‐onset familial Alzheimer’s disease (EOFAD). We reported a case of EOFAD with Y115C mutation of PSEN1 gene which was the first report in China.MethodAn early‐onset Alzheimer’s patient from Beijing Tiantan Hospital, Capital Medical University and her family were enrolled as the research object. The clinical and imaging data of the proband were collected. The genomic DNA from peripheral venous blood of the proband was screened.ResultThere were 6 members with memory and working competence loss in this pedigree. The proband, whose age of onset was 42 years old, was manifested as memory loss for more than 1year. She became apathetic, lazy in housework but without abnormal mood and behavior. She was healthy in the past, denied smoking and drinking history. Her grandmother, mother, aunt, uncle and brother all showed memory loss. Her brother is now unable to complete the driver’s work. The physical examination showed poor memory, calculation, orientation, executive functions, slow reaction and poor comprehension. The MMSE score was 11, MoCA‐Beijing score was 5, ADL‐20 score was 28, HAMD score was 2, HAMA score was 1 and PSQI score was 5. Head MRI of the proband showed whole cerebral cortical atrophy and bilateral hippocampal atrophy, obviously on the left side. The arterial spin labeling finding showed significantly reduced blood perfusion in the left cortex and hippocampus. A c.344A > G (p. Tyr115Cys) pathogenic mutation in the exon 5 of PSEN1 gene was found, proving the diagnosis.ConclusionWe reported this EOFAD case caused by Y115C mutation of PSEN1 gene in a Chinese family to enrich the genetic and clinical phenotypic characteristics in China. Gene detection plays an important role in the diagnosis of the early‐onset Alzheimer’s disease.
Determining feasibility for use of geriatric cognitive screening tools by medical case managers (MCM) serving older (50+) people living with HIV (PLWH)
Authors: Maly Monica , Burk‐Leaver Erin 
Published: June 2023

AbstractBackgroundThe advent of antiretroviral therapy (ART) has led to improved life expectancy of people living with HIV (PLWH) that is nearing that of populations living without HIV. In the United States, 51% of PLWH are 50 years or older and have unique pathophysiology contributing to accelerated and accentuated aging when compared to older adults living without HIV. Cognitive impairment (CI) is a significant age‐related risk and is exacerbated by HIV. Currently, geriatric cognitive screening tools are not calibrated for older PLWH, and have not been effectively translated for use within AIDS Service Organization (ASOs) where older PLWH often seek HIV‐related care and supportive services. In partnership with the Colorado Health Network Inc., this study examined feasibility for use of cognitive screening tools by medical case managers (MCM) working with clients aging with HIV at Colorado‐based ASOs.MethodMCMs were recruited from 11 Colorado‐based ASOs. MCMs completed an anonymous, self‐administered questionnaire measuring baseline knowledge related to risks of CI in older PLWH, and evaluated their familiarity with, screening of, and response to signs of CI within this client population. The questionnaire also evaluated perceived limitations and barriers to use of cognitive screening tools within MCM workflow.ResultData was collected from 28 MCMs who confirmed barriers and limitation to use of cognitive screening tools. While MCMs reported, on average, 50% of their clients were 50+, 71.4% of respondents reported not receiving training on complications related to aging with HIV, signs and symptoms, or on warning signs and risk factors (WS/RF) of CI. All (100%) respondents reported not screening for CI. MCMs indicated important elements of cognitive screening questions, including ease of administration, clear instructions, and information on referral. Table 1 provides a list of warning signs and Table 2 provides a list of screening questions.ConclusionMCMs working with older PLWH identified a need and desire for use and implementation of cognitive screening tools within their workflow. Training MCM on WS/RF, signs, and symptoms of CI, and implementing cognitive screening tools and referral systems will lead to improved continuity of care provided by medical case managers, and ASOs, serving older PLWH.
Effects of aerobic exercise on plasma AT(N) biomarkers
Authors: Yu Fang , Han SeungYong , Salisbury Dereck , Pruzin Jeremy J. , Geda Yonas E. , Caselli Richard J. , Li Danni 
Published: June 2023

AbstractBackgroundPhysical activity is associated with reduced risk for Alzheimer’s disease (AD). Aerobic exercise produced modest‐to‐moderate cognitive gains in older adults with mild cognitive impairment or AD dementia. In animal models, aerobic exercise modifies AD’s AT(N) biomarkers of Amyloid‐beta (Aβ), hyperphosphorylated Tau, and Neurodegeneration. However, most observational studies didn’t find significant associations between physical activity and AT(N) biomarkers. Few exercise trials included biomarkers, partially attributable to the prohibitive cost and invasiveness of cerebrospinal fluid or PET biomarkers and reported mixed effects on central AT(N) biomarkers. Plasma Aβ42/40 ratio, phosphorylated tau 181 (p‐tau181), and total tau (t‐tau) demonstrate robust correlations with central amyloid and tau levels and offer an opportunity for inclusion in exercise trials.MethodThis pilot study examined the preliminary effects of 6‐month aerobic exercise on plasma Aβ42/40 ratio, p‐tau181, and t‐tau in older adults with mild‐to‐moderate AD dementia. Twenty‐six participants were eligible, and all consented to enroll (8 in stretching, 18 in cycling). Plasma Aβ42/40 ratio, p‐tau181, and t‐tau were measured using Simoa™ assays at baseline, 3, and 6 months. Data were analyzed using Cohen’s d, multilevel model, and intention‐to‐treat.ResultThe sample averaged 77.58±6.99 years old, 15.44±3.00 years of education, 65% male, and 96.2% carrying an APOE e4 allele. The 6‐month within‐group trajectories of changes in outcomes trended differently but were not statistically significant. Aβ42/40 ratio (mean ± standard deviation) increased by 0.001±0.012, p‐tau181 increased by 0.609±1.417 pg/ml, and t‐tau decreased by 0.020±0.279 ng/ml in the stretching group, while Aβ42/40 ratio decreased by 0.001±0.010, p‐tau181 increased by 0.101±1.579 pg/ml, and t‐tau decreased by 0.075±0.215 pg/ml in the cycling group. Between‐group differences were not significant. Effect sizes for 6‐month within‐group changes were small except for p‐tau181 in stretching (d = 0.43 [‐.65, 1.45]) and t‐tau in cycling (‐0.35 [‐0.87, 0.17]). Most 6‐month between‐group effect sizes were also small except for p‐tau181 (d = .40 [‐.70, 1.51]) and t‐tau (d = .53 [‐.40, 1.46]), a trend favoring cycling.ConclusionBlood biomarkers are highly feasible and tolerable. Exercise modalities may affect AD plasma biomarkers differently. Aerobic exercise may reduce p‐tau181 levels and stretching exercise may improve Aβ42/40 ratio, which need to be validated in future trials.
Increased spatial extent of cerebral tau PET elevations in former NFL and college football players from the DIAGNOSE CTE Research Project
Authors: Chen Kewei , Reiman Eric M. , Luo Ji , Protas Hillary D. , Cummings Jeffrey , Shenton Martha E , Stern Robert A , Su Yi 
Published: June 2023

AbstractBackgroundWe previously found greater spatial extent of flortaucipir (tau) PET elevations in Arizona‐Boston (DETECT) Study of 26 former National Football League (NFL) players than in 31 normal controls—using a voxel‐based Majority Count Statistics (MCS) algorithm which enabled us to detect tau PET abnormalities in the player group free from the inflated Type 1 error associated with voxel‐wise multiple comparisons (Stern et al, NEJM 2019). We now confirm this finding in a larger group of former NFL players, former college football players and asymptomatic controls without exposure to repetitive head impacts from the DIAGNOSE CTE Research Project.MethodFlortaucipir PET images were acquired in 106 former NFL players, 51 former college players, and 53 unexposed controls, 57.71+8.37 years of age. An automated algorithm (SPM12) and co‐registered MRIs were used to spatially normalize PET images into Montreal Neurological Institute template, and compute statistical brain maps of group differences in regional cerebral‐to‐cerebellar crus1 standard uptake value ratio (SUVR), controlling for the participants’ age and race with P≤0.005, uncorrected for multiple comparisons. Our MCS was then applied with 1,000 iterations to test the hypothesis that there would be a greater number of cerebral voxels with SUVR elevations in each and combined player group versus control group, as well as between the NFL versus college player groups.ResultAs predicted, the NFL, college player and aggregate player groups each had significantly more cerebral voxels with flortaucipir SUVR elevations than in the control group (postulated vs opposite directions: 53,879 vs 79, 79,552 vs 89 and 100,837 vs 86 voxels), respectively, MCS P<0.001, but not between former NFL and former college players (482 versus 306, p = 0.305).ConclusionUsing a voxel based MCS analysis, former NFL and college football players have a greater spatial extent of elevations in tau PET measurements than asymptomatic controls. Additional work is needed to clarify the biological nature of these small but spatially extensive elevations, the extent to which they are related to symptom severity, cognitive performance, repetitive head impact exposure, and other risk or resilience factors, and the extent to which they are associated with subsequent clinical decline.