bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cognition in the Oldest Old Using the NIH Toolbox
Authors: Mather Molly A , Ho Emily , Karpouzian‐Rogers Tatiana , Rogalski Emily J. , Gershon Richard C. , Weintraub Sandra 
Published: December 2022

AbstractBackgroundThe percentage of cognitively intact older adults living into their 80s and beyond is growing rapidly. This age group is not only one of the fastest growing segments of the population, but it is also the group most susceptible to developing dementia. Effective detection of early cognitive decline is paramount but is complicated by a dearth of normative data for older adults above the age of 85. It is well‐established that crystallized cognition remains stable into older adulthood, whereas fluid cognition tends to decrease; however, it is unknown whether the same holds true for the oldest old. We use the comprehensive NIH Toolbox Cognition Battery (NIHTB‐CB) to assess differences in cognition.MethodParticipants (age range 65 to 94) were diagnosed as having normal cognition and were either 65–85 years old (N = 175, Mage
= 73.9, SDage
= 6.06) or 86+ (N = 98, Mage
= 88.6, SDage
= 2.39). Participants completed the NIHTB‐CB, which assesses fluid reasoning, executive functioning, processing speed, episodic memory, and crystallized language abilities. A series of univariate linear models regressed age with covariates (education, gender, race/ethnicity, site) on each NIHTB‐CB domain.ResultAge was a significant predictor for all NIHTB‐CB fluid measures. The R2 for each fluid reason model ranged from 0.17 to 0.22, suggesting a medium effect size. Of the crystallized measures, Picture Vocabulary decreased with age, while oral reading ability remained constant. The effect for Picture Vocabulary appears to be at least partially driven by education levels, as more educated participants exhibited higher scores. For all statistically significant models, age remained a significant predictor after adjusting for demographic covariates and site. The fluid measure with the steepest decline was Picture Sequence Memory and Pattern Comparison, while the fluid measure with the least steep decline was Flanker.ConclusionAs expected, fluid reasoning ability decreased with age in the oldest old. Contrary to theoretical expectations of stability across crystallized abilities, scores on one crystallized measure decreased with age. This study comprehensively characterizes the oldest old across multiple facets of cognition and adds to the extant literature regarding cognitive performance in the oldest old.
Influence of Socioeconomic Opportunity Disparities on Sex/Gender Inequalities in Cognitive Decline
Authors: Avila Justina F , Seblova Dominika , Turney Indira C , Schupf Nicole , Mayeux Richard , Brickman Adam M. , Manly Jennifer J 
Published: December 2022

AbstractBackgroundState‐level socioeconomic opportunity disparities have been linked to health outcomes. We examined whether early‐life exposure to state‐level socioeconomic opportunity disparities between women and men influences the pattern of sex/gender inequalities in cognitive decline.MethodParticipants were 2,394 U.S.‐born non‐Latinx Black and non‐Latinx White women and men enrolled in the Washington Heights/Inwood Columbia Aging Project (WHICAP), who were dementia free at their baseline study visit. Age at first cognitive assessment ranged from 61‐101 and the average follow‐up time was 4.8 years. Cognitive outcomes were level and trajectory on memory and language scores. A socioeconomic opportunity disparity index (SODI) was created using census data on sex/gender disparities in labor force participation, occupational status, and educational attainment between the years 1900 to 1960 (birth year range for WHICAP participants). The SODI ranged from 0 to 1, with higher scores reflecting wider sex/gender disparities in socioeconomic opportunities. SODI values were linked to WHICAP individual data via birth year and state. Multiple‐group growth curve modeling was used to examine interactions between sex/gender and SODI on cognitive trajectories across racial groups. All models accounted for age, childhood SES, and state of birth, as well as differential study attrition due to death.ResultSmaller disparities in state‐level opportunity were associated with 1) higher baseline cognitive test performance across groups and 2) slower memory and language decline for Black women and White women and men. Women demonstrated an advantage over men on cognitive measures and we expected women’s advantage to be more pronounced in states with lower opportunity disparities. This pattern held true for Black individuals with regards to memory and language level and for memory decline among White individuals. However, White women’s advantage over White men on baseline memory was more pronounced in states with higher opportunity disparities.ConclusionBeing born in a state where socioeconomic opportunities were more equally distributed among women and men was positively linked to cognitive outcomes later in life. Our results suggest that this relationship varies across men and women depending on their race, contributing to different patterns of sex/gender inequalities in late‐life cognitive trajectories.
Effects of Eicosapentaenoic Acid Supplementation in obese Transgenic Mouse Model of Alzheimer’s Disease
Authors: Razafimanjato Fitia , Yavari Mahsa , Chavira Angela , Davis Mckenna , Ramalingam Latha , Harris Breanna N. , Zu Yujiao , Moustaid‐Moussa Naima 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is a progressive brain disease characterised by cerebral aggregation of amyloid beta (Aβ) plaques. Obesity is a chronic complex disease characterised by excessive fat accumulation, that is associated with systemic and adipose tissue inflammation, and may increase the risk for AD. Eicosapentaenoic acid (EPA) found in fish oil, is an omega‐3 polyunsaturated fatty acid with anti‐obesity and anti‐inflammatory properties. In this study, we propose that EPA supplementation will protect against AD‐associated metabolic dysfunctions in diet‐induced obese mice. We aim to determine the mechanisms mediating EPA effects in obesity‐related metabolic impairments in diet‐induced obese APPswePS1dE9 AD mouse model.MethodWild‐type (WT) and transgenic Alzheimer’s (TG) male and female mice were randomly assigned to either a low‐fat LF (10% kcal fat), a high‐fat (HF, 45% kcal fat), or a HF diet supplemented with 36 g/kg EPA (EPA) for 8 months. Body weights were measured weekly and tissues including adipose tissue were collected at the end of the intervention for analyses of genes involved in inflammation (TNF, fatty acid synthesis (ACACA), fatty acid oxidation (CPT1). Data were analysed by three‐way ANOVA using GraphPad Prism.ResultOverall, TG females gained less weight in HF and EPA groups, compared to male mice (P = 0.0075 and P < 0.0001, respectively). Moreover, TNF was lower in EPA groups compared to HF groups. Significant main effects were observed for sex in TNF, ACACA, and CPT1 (P<0.0001, P=0.0008, and P<0.0001, respectively). Main effects for genotype were observed for ACACA and CPT1 expression (P=0.0497 and P=0.0318, respectively). Main effects for diet (LF vs HF) were observed for TNF, ACACA, and CPT1 (P=<0.0001, P=0.0004, and P=0.0040, respectively). Moreover, significant main effects of HF vs EPA were observed for ACACA (P=0.0497). Interactions in sex x diet (LF vs HF and HF vs EPA) were observed for TNF (P=0.0003 and P=0.0252, respectively), also in sex x diet (LF vs HF) interactions for CPT1 (P=0.0086).ConclusionOur findings showed that EPA counteracted both inflammation and obesity induced by HF diets, especially in female mice. Further analyses are ongoing to determine mechanisms underlying potential benefits of EPA in obesity‐associated AD.
Oxidative stress biomarkers and longitudinal changes in human brain imaging across the Alzheimer’s disease continuum
Authors: Willette Auriel A , Li Tianqi , Willette Sara A , Larsen Brittany A , Pollpeter Amy , Klinedinst Brandon S , Moody Shannin , Barnett Neil , Parvin Mohammadiarvejeh , Pappas Colleen , Jonathan Mochel , Allenspach‐Jorn Karin , Wang Qian 
Published: December 2022

AbstractBackgroundOxidative stress is critical for Alzheimer’s disease (AD) pathophysiology. Brain mitochondrial function, proteins, and lipids are susceptible to oxidative damage caused by reactive oxygen species. In turn, this damage leads to key AD‐like changes in the brain, such as impaired glucose metabolism (i.e., lower fluorodeoxyglucose, or FDG‐PET) and gray matter volume atrophy in AD‐sensitive regions. It is unknown if oxidative stress biomarkers like superoxide dismutase (SOD) proteins track these changes using longitudinal brain imaging data, and what mechanisms may be at work (Figure 1).MethodUsing Alzheimer’s Disease Neuroimaging Initiative (ADNI) data, 192 aged adults (75 unimpaired, 48 MCI, 69 AD) had annual CSF and FDG data available for over 6 years. A two‐phase MRM targeted proteomics panel was used to gauge CSF SOD1 levels from serum. Standard assays in CSF determined Aβ, p‐tau‐181, and total tau. Brain glucose uptake was determined using FDG SUVR calibrated to the pons. Brain volume was examined longitudinally using FreeSurfer.ResultLongitudinally, among SOD1 quartiles (Figure 2), the lowest SOD1 group showed marked hypometabolism among older adults at baseline (R2=0.528, p<.001, “blue line”), but 6 years later instead predicted hypermetabolism (R2=0.389, p<.001). The highest SOD1 group showed no association at baseline but at 6 years later predicted hypometabolism among older adults (R2=0.151, p<.05, “dotted red line”). CSF Aβ and p‐tau‐181 fully mediated these effects (ps<.01), such that lower Aβ and higher p‐tau‐181 over time resulted in higher SOD1 predicting less glucose uptake. Similarly, higher SOD1 was not related to atrophy in AD‐sensitive regions like parahippocampus at baseline, but 5 years later was strongly related to more brain atrophy (R2=0.207,p<.001) (Figure 3), which was mediated by higher CSF total tau (p<.001).ConclusionLike previous reports, we found that SOD1 initially showed neutral or ameliorative patterns, reflecting its classical role in reducing oxidative stress. With increased Aβ or p‐tau‐181 deposition over time, however, SOD1 became a marker of the degree of oxidative damage that may have occurred in neural tissue due to Aβ or tau.
Non‐invasive brain stimulation causes anxiolytic effect in intracerebroventricular streptozotocin injected rats through prevention of serotonergic fibres in dorsal hippocampus
Authors: Roy Avishek , Sharma Binney , Nag Tapas Chandra , Gupta Yogendra Kumar , Jain Suman 
Published: December 2022

AbstractBackgroundIntracerebroventricular streptozotocin (ICV‐STZ) injection at 3mg/kg of b/w is reported to induce sporadic Alzheimer disease (sAD) like pathology, where it causes an insulin resistance brain state. Synaptic dysfunction along with glial aggravation poses major risk factor for sAD. Brain stimulation evinced to be promising in AD patients, however, mechanism of the same in the form of magnetic field (MF) stimulation are elusive.MethodTotal 55 rats were recruited and randomly divided into five groups: Control, Sham, AD, Sham+MF, AD+MF. Animals were provided with ad libitum food and water, experiments were performed under permission from IAEC (file no. 937/IAEC/2016). Rats were exposed to 17.96µT for 2hr/day for 30 days and at end elevated plus maze task was performed. Next, transmission electron microscopy(TEM), Golgi‐Cox staining was done on hippocampal sample. In addition, GPx activity and serotonin was measured in hippocampal homogenate.ResultReduction in ratio of time spent in close versus open arm in AD group as compared to Sham (p<0.001), Sham+MF (p<0.01) and AD+MF (p = 0.008). In continuation, head dipping duration was also reduced significantly in AD group as compared to control (p = 0.008), Sham+MF (p = 0.03) and AD+MF (p = 0.001). We found a loss of spine density in apical dendrite of with invasion of ramified microglia in neurovascular‐unit in dCA1 layer of AD group versus control (p<0.0001) and AD+MF(p = 0.004). TEM examination of hippocampal samples, we found invasion of ramified microglia in NVU as well as loss of synaptic density. Furthermore, GPx activity was found to be decreased in AD group (p<0.05) versus other counterparts on 30th day post‐injection of STZ. Similarly, serotonin was depleted in AD group as compared to other groups (p<0.05). In addition, results showed a strong correlation between head dipping duration and serotonin level in AD group on 30th day post‐injection of STZ (r = 0.7;p = 0.02).ConclusionHence, this work reveals that MF stimulation to have anxiolytic effect through replenishing the synaptic dysfunction and serotonin loss in dorsal CA1 pyramidal cells of hippocampus in ICV‐STZ model of sAD.
Potential Bio‐signal Links between Alzheimer’s Disease and Osteoporosis
Authors: Lee Ji‐Won , Lee In‐Hee , Iimura Tadahiro , Kong Sek Won 
Published: December 2022

AbstractBackgroundLow bone mineral density is associated with the development of Alzheimer’s disease (AD). The patients with AD have an early‐onset bone loss with a rapid progression before cognitive symptoms appear. Yet the pathophysiological relationship is not well understood between two clinical conditions. Microglia and osteoclasts share developmental origins and are commonly classified as tissue‐specific macrophages in brain and bone, and are responsible for pathological changes in AD and osteoporosis, respectively. Interestingly, Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), caused by mutations in TREM2 or DAP12 genes, present bone pathology followed by presenile dementia.MethodTo further discover genetic correlations between AD and osteoporosis, we constructed comprehensive network of signaling pathways for microglia and osteoclasts.ResultWe discovered that an intracellular kinase, Pyk2 encoded by the PTK2B gene in microglia and osteoclasts in brain and bone, respectively, is a pleiotropic mediator of shared genetic risk factor for AD and osteoporosis. Pyk2, a non‐tyrosine kinase that regulates cytoskeleton rearrangement, is one candidate that is potentially related to both the progression of both AD and osteoporosis, as it is specifically expressed within the central nervous system and in bone tissue.ConclusionOur findings indicate that Pyk2 may be eligible for horizontal pleiotropy as genetic variants in PTK2B increase the risk of two traits, and thus we suggest that Pyk2 has potential as a novel diagnostic and therapeutic biomarker for AD.
A transcriptomic study reveals beneficial effects of HsTX1[R14A] on the cognition of a mouse model of sporadic Alzheimer’s disease
Authors: Pan Yijun , Sun Jiaqi , Deveson Deanna , Mamo John CL , Takechi Ryu , Norton Raymond , Jin Liang , Nicolazzo Joseph 
Published: December 2022

AbstractBackgroundNeuroinflammation is a key pathological feature of Alzheimer’s disease (AD), which can be partly attributed to the chronic activation of microglia. The voltage‐gated potassium channel 1.3 (Kv1.3) is selectively upregulated in pro‐inflammatory microglia, making it an ideal therapeutic target to modulate microglia‐mediated neuroinflammation. A highly potent and selective Kv1.3 blocker (HsTX1[R14A]) developed in our laboratory can effectively suppress neuroinflammation. More importantly, chronic subcutaneous dosing of HsTX1[R14A] (1 mg/kg every 2 day) over 8 weeks improved cognitive function in a mouse model of sporadic AD, senescence accelerated mouse‐prone 8 (SAMP8). The current transcriptomic study is to explore the therapeutic benefits in the SAMP8 mouse brains from chronic dosing of HsTX1[R14A].MethodSubcutaneous dose of HsTX1[R14A] (1mg/kg every 2 day) or PBS was administered to 4‐month‐old SAMP8 mice for 8 weeks (n = 6 each). At the conclusion of treatment, mice were euthanized and RNA from the brains were extracted using RNeasy Lipid Tissue Mini Kit (Qiagen). RNA samples were processed using an MGI RNA Directional Library Preparation Set V2. Fastq files were processed using the Laxy tool and the NfCore/RNAseq (v3.2) pipeline. Reads were aligned to the Mus musculus GRCm38 reference using STAR aligner and quantified using Salmon producing the raw genes count matrix. Raw counts were then analyzed with Degust and functional enrichment analysis was performed using R packages.ResultFunctional enrichment analysis indicated an upregulation of genes associated with 1) synapse assembly, neuronal synaptic plasticity for biological process; 2) postsynaptic neurotransmitter receptor activity, glutamate receptor activity for molecular function; 3) presynaptic active zone, NMDA selective glutamate receptor complex for cellular component. A downregulation of genes associated with 1) oxidative phosphorylation, ATP synthesis coupled electron transport for biological process; 2) chemokine activity for molecular function; 3) mitochondrial proton transporting ATP synthase complex for cellular component have also been highlighted.ConclusionOverall, the transcriptomics data indicated beneficial effects of HsTX1[R14A] on cognition in a mouse model of sporadic AD, possibly achieved by improving synaptic function, altering cellular metabolism, and reducing inflammation. Further experiments are required to confirm the current transcriptomics study.
Prevalence of Suspected non‐Alzheimer’s disease pathophysiology across the Alzheimer’s disease clinical spectrum: a meta‐analysis
Authors: Vos Stephanie J. B. , Delvenne Aurore , Visser Pieter Jelle 
Published: December 2022

AbstractBackgroundSuspected non‐Alzheimer’s disease pathophysiology (SNAP) is a heterogeneous biomarker‐based concept that describes individuals with neurodegeneration without amyloid pathology. Our aim was to perform a meta‐analysis of all available SNAP studies to better estimate the prevalence of SNAP based on different definitions across the Alzheimer’s disease (AD) clinical spectrum.MethodA search in PubMed was performed to identify all papers on SNAP. From these papers, we extracted the prevalence of persons with SNAP, biomarker negative persons and amyloid positive persons. We performed a meta‐analysis on overall SNAP prevalence by cognitive status and compared different SNAP definitions according to ATN biomarker classifications. In persons without dementia, we examined SNAP prevalence based on imaging versus CSF definitions and investigated differences in sex and APOE‐e4 carriership. We used R packages meta and metafor.ResultWe included 47 papers with SNAP across the AD clinical spectrum. Table 1 presents SNAP prevalence by cognitive status, compared to the prevalence of other biomarker groups. Overall prevalence of SNAP was 19.6% (95% CI 16.3‐23.2) in persons with normal cognition (NC), 15.6% (12.3‐19.3) in persons with mild cognitive impairment (MCI), and 10.1% (5.5‐15.8) in persons with dementia. In persons with NC, SNAP based on tau only (A‐T+N‐) was most common (36%) and SNAP based on both tau and neurodegeneration (A‐T+N+) least common (21%). In persons with MCI or dementia, SNAP based on neurodegeneration only (A‐T‐N+) was most common (MCI 39%, dementia 34%) and SNAP based on tau only least common (MCI 20%, dementia 7%). In persons without dementia, a similar SNAP prevalence was observed between imaging and CSF biomarker definitions (NC 19 vs. 20%, MCI 18 vs. 12%). Yet, persons with NC‐SNAP using imaging‐based definitions were more often male and less often APOEe4 carrier as compared to NC‐SNAP using CSF‐based definitions (imaging: male 54% and APOEe4 16%; CSF: male 41% and APOEe4 34%).ConclusionSNAP is common across the AD clinical spectrum. In persons without dementia, CSF and imaging definitions of SNAP resulted in a similar prevalence but in differences in sex and APOE‐e4 carriership in NC‐SNAP. Findings are valuable for AD trial design and clinical diagnostics.
Developing a bioprinted scaffold‐based model of neurodegeneration for high throughput screening in Drug Development
Authors: Whitehouse Chloe Ann , Corbett Nicola J 
Published: December 2022

AbstractBackgroundA major component of the failure to bring novel drugs for Alzheimer’s disease (AD) to market is the translational gap between in vitro, animal and human studies. Using the novel technology of 3D bio‐printing, this project aims to develop a scaffold‐based 3D quad‐culture model of AD for drug screening using human induced pluripotent stem cells.MethodA cell‐hydrogel suspension is “printed” onto 96‐ and 394‐well plates using a 3D bioprinter, which uses drop‐on‐demand technology to allow high resolution placement of the cells. The culture is suspended in a hydrogel of extracellular matrix proteins, which has been modulated to mimic brain biomechanics.ResultProtocols to differentiate human neural progenitor cells into cortical neurons, astrocytes and oligodendrocytes have been established from AD mutation lines and healthy controls which express desired markers. These cell types, alongside iPSC‐derived microglia, will form the quad‐culture of cells within the model.ConclusionThis model will exercise the benefits of a 3D model, while maintaining the benefits of 2D systems, including reproducibility, reliability, and suitability for high throughput screening.
Intrathecal pseudodelivery of Ab‐mAb alleviates pathology in an Alzheimer’s disease model
Authors: Menendez‐Gonzalez Manuel , Vilcapoma Almudena Coto , Silgado Juan Castilla , Alvarez‐Vega Marco , Antuña‐Ramos Aida , Fernandez‐Garcia Benjamin , Prado Catuxa , Alvarez Gabriel , Rodriguez Maria , Perez Ester , Tomas‐Zapico Cristina 
Published: December 2022

AbstractBackgroundIntrathecal pseudodelivery is a new route of drug delivery to the CNS based on an implantable device endowed with a smart system of nanoporous membranes. We have developed a miniaturized prototype of the device for rodents. Here we present preliminary results on the use of antiAbeta mAbs intrathecally pseudodelivered in the APP/PS1 mouse model of Alzheimer’s disease.Method28‐week‐old male mice, APP/PS1 and non‐transgenic were used. The device was implanted subcutaneously in the back of the mouse and connected to one of the lateral ventricles via a catheter, also subcutaneous. The reservoir of the devices was filled with artificial CSF (aCSF) or with a solution of anti‐amyloid beta (Ab) antibody (clone 6E10, Biolegend) in aLCR. The infusion period was three weeks, during which animal welfare aspects were assessed. After this time, the mice were sacrificed for histopathological evaluation. All procedures were performed in accordance with institutional guidelines approved by the Ethical Committee in Research of Universidad de Oviedo.Result
Safety: The device was successfully implanted in a total of 18 mice. Three mice showed complications 3 days after surgery, including lethargy and significant weight loss. This could be due to the surgery itself or to the post‐operative medication. The rest of the mice recovered perfectly and returned to normal activity 4 days after surgery.Efficacy: Immunohistochemistry was performed to assess the size of Ab plaques, using a rabbit polyclonal anti‐Ab antibody (Invitrogen). The surface area occupied by the plaques in each of the APP/PS1 mice was determined. The results show a decrease in the area occupied by Ab‐positive plaques in the mice treated with the antibody. Although not statistically significant, there is a tendency for treated mice to have a smaller area occupied by plaques.ConclusionsOur results show that:• Intrathecal pseudodelivery of mAbs is a feasible route of drug delivery for neurodegenerative diseases.• Intrathecal pseudodelivery of Ab‐mAb alleviates pathology in an Alzheimer’s disease model.• Albeit preliminary efficacy and safety results are promising, further studies are needed.