bluuebunny/crossref_metadata_2025_split huggingface dataset:
Generation and screening of mouse models of ADRD with multiple genetic manipulations to model dementia with mixed brain pathologies
Authors: MacDonald Bethany , Kaur Harpreet , Tooley Andrew , Zuberi Aamir , Lutz Cathleen , O'Connell Kristen MS , Dunn Amy R , Kaczorowski Catherine C. 
Published: December 2023

AbstractBackgroundAlzheimer’s disease‐related dementias (ADRD) encompass a wide range of neurodegenerative diseases including Alzheimer’s disease, vascular dementia, frontotemporal dementia (FTD), Lewy body dementia (LBD), and mixed dementia [1‐4]. ADRDs are distinguished by the presence of pathologies including amyloid, tau, TDP‐43 inclusions, alpha‐synuclein aggregates, cerebral amyloid angiopathy, and/or hippocampal sclerosis [4‐9]. Consequently, the heterogeneity of ADRDs presents challenges for animal modeling of disease mechanisms. Our laboratory has demonstrated that genetic diversity in disease modeling is critical to recapitulate the molecular and cognitive features of AD [1,9, 10]. Here, we introduce multiple genetic manipulations to develop novel translational models of ADRD.MethodPrecision models of ADRD on multiple genetic backgrounds were generated via combinatorial CRISPR editing to knock‐in human disease‐causing mutations onto the C57BL/6J (B6) strain and crossed to either B6, DBA/2J (D2), FVB, or WSB to generate a set of 20 unique ADRD models (Fig.1). The effect of homozygous mutations were evaluated on the B6 background. Each model was assessed using a high‐capacity multi‐domain go/no‐go screen to prioritize candidate strains for future ADRD modeling of drug discovery, preclinical testing, and disease pathology.ResultAssays included frailty, open field, y‐maze, rotarod, and contextual fear conditioning. Models with one or more late‐onset behavioral deficits (12 mo) were a “go”; whereas, early behavioral deficits (6 and 9 mo), aggression, high attrition, and low fecundity and additional factors were considered unsuitable (“no‐go”). We identified several promising models of ADRD that exhibited late‐onset frailty and motor deficits as function of mutation burden and genetic background (e.g., App/Psen1/Tardbp/Mapt on the D2 background). The FVB background strain exhibited early frailty deficits (6 mo), and thus considered unsuitable (“no‐go”). The WSB background strain exhibited reserve across multiple frailty and behavioral assays up to 12 mo.ConclusionOur results demonstrate that combining ADRD mutations in genetically distinct backgrounds is a promising strategy to generate new mouse models that better model the human mid and late‐life onset of deficits associated with ADRD. The resulting model(s) will be translationally relevant and provide important insight into disease mechanisms for the future of ADRD research and drug discoveries.
Cancer Type and Dementia Diagnosis in Community Dwelling African Americans
Authors: Anderson Loretta R. , Pollack Andrew A. 
Published: December 2023

AbstractBackgroundCancer and dementia have been reported to have an inverse relationship, suggesting those with cancer may have decreased risk of subsequent dementia, and those with dementia may have a decreased risk of subsequent cancer diagnosis (Zablocka, 2021). However, emerging evidence challenges this idea. A paucity of research exists examining these associations in African Americans, who are twice as likely as whites to develop dementia (Barnes, 2022). Our objective was to examine the association between different types of cancer and dementia risk in community dwelling African Americans.MethodsUsing data from the 2011 National Health and Aging Trends Study (NHATS), a nationally representative sample of Medicare beneficiaries aged 65 and older, we examined the association between cancer type and dementia diagnosis in community dwelling African Americans (n = 1529). Multinomial logistic regression models examined the association between cancer type and dementia diagnosis, controlling for age, sex, and education, as well as anxiety, depression, diabetes, heart disease, and stroke.ResultsResults showed 2.6% of African Americans reported a kidney disease diagnosis, representing 208,107 older adults. Fully adjusted models revealed that African Americans with kidney cancer are over 5 times as likely to have a dementia diagnosis compared to African Americans without kidney cancer [OR: 5.48, p<0.05 (95% CI: 1.24, 24.20]). Other types of cancer (skin, breast, prostate, bladder, ovarian, colon, and “other”) were not significantly associated with increased odds of dementia diagnosis.ConclusionResults show a strong association between kidney cancer and dementia diagnosis in older African Americans, but not other types of cancer. Further research in this area may elucidate reasons for increased dementia risk in African Americans.
Inflammatory and metabolic responses in the aging rat brain
Authors: de Souza Débora Guerini , da Rocha Andreia Silva , Almeida Roberto Farina , Peixoto Guilherme G. Schu , Salles Giovanna Bortoluzzi , Oliveira Ana Cristina Laydner Joly , Limberger Christian , de Bastiani Marco Antônio , Greggio Samuel , Venturin Gianina Teribele , da Costa Jaderson Costa , Souza Diogo O. , Zimmer Eduardo R. 
Published: December 2023

AbstractBackgroundThe brain is an energetically demanding organ that mostly relies on glucose oxidation to sustain its sophisticated networks. Transcriptomic studies suggest metabolic‐related genes are downregulated in the aging brain but inflammation‐related genes are highly upregulated. Astrocytes are key mediators of brain inflammation and metabolism. Yet, the relationship between inflammatory signals and energy substrates consumption in the aging brain remains unclear. To address this question, we investigated the response of the young and aged rat brain metabolism to a nonsteroidal anti‐inflammatory (NSAID) drug.MethodFive young adults (4 mo), and five aged (24 mo) male Wistar rats were scanned using positron emission microtomography with 18F‐fluorodeoxyglucose ([18F]FDG‐PET). Scans were done under basal conditions or after three‐day treatment with 5mg/kg ketoprofen (i.p.), an NSAID known to cross the blood‐brain barrier. Standard uptake values ratios (SUVr, pons as reference) were calculated for the main brain regions. Synaptosome and total mitochondria preparations from the cortex had their oxygen consumption rates measured in an Oroboros Instrument, using a SUIT protocol. Results were analyzed by t‐test, with statistical significance P < 0.05.ResultUnder basal conditions, glucose uptake showed no differences between young and aged rats. After ketoprofen treatment, clusters of glucose hypermetabolism appeared in the cortex and hippocampus of the adult but not the aged brain. Synaptosomal and mitochondrial preparations did not present differences in ATP‐linked, maximal, or leak respiration between groups under basal conditions. However, aged synaptosomes (t = 3.417, p = 0.0112) and total mitochondria (t = 3.131, p = 0.0166) presented higher respiratory coupling ratios.ConclusionWe previously showed that [18F]FDG‐PET signal highly depends on astrocyte function. The lack of response to ketoprofen in aged rats may be related to astrocyte dysfunction in aging. As a counter‐response to the aging process, the brain mitochondria are highly coupled, keeping the system as efficient as necessary. Our findings indicate that brain metabolism might not be coupled to inflammation in the aged rat brain. Still, we identified a remarkable plasticity of the mitochondria, which can sustain physiological responses despite the aging process.
Sex and age dependent effects of gut microbiota manipulation in AppSAA mouse model of Alzheimer disease
Authors: Kaur Harpreet , Singh Surjeet , Tooley Andrew , O'Connell Kristen MS , Kaczorowski Catherine C. 
Published: December 2023

AbstractBackgroundPopulation based studies indicate that women are at significantly greater risk of developing Alzheimer’s disease (AD) than men. Gut microbiome is involved in the pathogenesis of AD however sex specific (/differential) effect of gut microbiome manipulation is not well understood.MethodTo determine the effect of sex and age on the impact of gut microbiota manipulation on cognitive outcomes, 3‐4 months old male and females AppSAA mice (AD) were treated with probiotics (for 8 weeks) and antibiotics for (10‐days) along with C57BL/6J and hApp as controls. Based on our previous studies, probiotic had beneficial effects on younger AD females and had no effect on males. To understand if gut bacteria are directly involved in eliciting these differential effects, we collected the stool samples from AD females treated with probiotic (VSL#3) and did fecal microbiota transplantation (FMT) in younger and older male and female AD mice. Neurobehavioral testing was performed including Open field task (OFT), Y‐Maze, Contextual fear conditioning (CFC) and Novel object recognition. Brain and intestine samples were collected for biochemical and molecular characterization.ResultIn OFT, AppSAA mice travelled more distance as compared to C57BL/6J, and treating AppSAA mice with probiotic or antibiotic resulted in increased distance traveled. Antibiotic mice also showed less freezing in CFC task when compared to controls. Overall, FMT mice had a trend towards lower mean speed and distance travelled on Y‐maze with no significant change in memory functions. That said, the AppSAA mice at 5‐6 months of age showed no significant memory deficits as assessed using CFC and Y‐maze, and will need to be aged further to assess the effect of antibiotics and FMT on cognitive deficits.ConclusionTreating AppSAA mice with probiotic or FMT (samples from probiotic treated females to AD young and old animals) had effects on motor behavior, but no effects in terms of memory functions. This lack of change is not surprising, as AD mice at early age did not demonstrate a behavioral phenotype compared to controls. Currently, we are doing biochemical analysis to elucidate if FMT influenced brain pathology (inflammation or Aβ) in AD mice.
Cognitive and muscle health, and related amino acid kinetics in older adults with Mild Cognitive Impairment, and the effect of comorbidities
Authors: De Wandel Sofie M , Deutz Nicolaas EP. , Engelen Marielle PKJ 
Published: December 2023

AbstractBackgroundRecent studies suggest cognitive decline and reduced muscle health is associated with the presence of comorbidities. Our objective is to identify whether the presence of comorbidities in older adults affects muscle health (mass and function) and related protein and amino acid (AA) kinetics differently when Mild Cognitive Impairment is present.MethodWe selected older adults (127 with comorbidities (Charlson comorbidity index (CCIS>0)) and120 without comorbidities (CCIS = 0) from the MEDIT database. These were stratified into MCI and non‐MCI based on their Montreal Cognitive Assessment (MoCA) score. Health history obtained by interview, body composition by DEXA, and habitual dietary intake by 3‐day food record, . Mood (depression) assessed by questionnaire, and cognitive function by MoCA and battery. Muscle function measured by handgrip dynamometry. Postabsorptive protein and AA kinetics analyzed by pulse administration of 18 stable isotopes of AAs and tracer enrichments/concentrations by LC‐MS/MS to calculate whole‐body production (WBP) of these AAs. Statistics by ANCOVA to examine effects of MCI, CCIS, and MCI*CCIS interaction, with covariates Sex, BMI, and Age. Significance was set as p<0.05.ResultPresence of MCI was associated with lower cognitive and muscle function and lean mass (all p<0.05). There were no differences in lean mass between CCIS and healthy counterparts (all p>0.05). CCIS subjects had higher depression score (p<0.05), performed worse on Stroop test (p = 0.0124) and had lower muscle function (p<0.05). Furthermore, CCIS subjects had higher plasma concentrations of glutamate (p = 0.0115), and isoleucine (p = 0.0071) compared to healthy counterparts. CCIS subjects had higher WBP of phenylalanine (p = 0.032), tryptophan (p = 0.0143), and isoleucine (p = 0.035), and higher net protein breakdown (PHE>>TYR) (p = 0.0758). There was no MCI*CCI interaction for lean mass, dietary intake, or mood. MCI with comorbidities had higher moca scores (p = 0.0037), stroop test performance (p = 0.0592) and muscle function compared to healthy counterparts (all P<0.05). MCI*CCI interactions showed MCI with CCIS had lower BCAA concentrations.ConclusionPresence of comorbidities affects mood, cognitive function, muscle health, and metabolism in older adults independent of MCI. The presence of comorbidities in MCI should be considered when designing nutritional based intervention trials.
A novel Caenorhabditis elegans model of Alzheimer’s Disease
Authors: Bajuszova Viktoria , Cohen Netta , Johnston Jamie 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is the most prevalent form of neurodegenerative disease, characterised by the presence of Aβ plaques and neurofibrillary tangles, mediating memory impairments due to loss of neurons and impairments in neuronal plasticity. The most common model to study the toxic effects of Aβ in AD are transgenic rodents. However, these animals develop cognitive impairments and suffer. Thus, to reduce and replace the rodent animals used to study these toxic effects, we are developing a C. elegans neuronal model of human Aβ1‐42 with a posterior co‐injection marker to allow multi‐colour neuronal imaging without interference from the fluorescence of the co‐injection marker. To achieve this we generated a transcriptional reporter of the antimicrobial peptide gene clec‐60, as the expression of this gene under normal conditions is solely in the posterior intestine.MethodConstructs containing ultra pan‐neuronal Aβ reporter and the clec‐60p::cemOrange co‐injection marker were generated via gateway cloning and micro‐injected into wild type C. elegans. To confirm expression of the co‐injection marker is restricted to posterior intestine confocal images were taken of the injected strains. To confirm presence of Aβ in the neurons, fixed C. elegans were antibody stained using the 4G8 primary and goat anti mouse 488 secondary antibody.ResultWe generated the Aβ strain with the clec‐60 fluorescent marker, however, upon expression of the human Aβ1‐42 in the C. elegans nervous system we observed expression of the fluorescently tagged clec‐60 in the neurons. The presence of the Aβ in the neurons was confirmed with the antibody staining.ConclusionExpression of human Aβ1‐42 changes and increases the expression of the innate immunity antimicrobial peptide clec‐60 indicating C. elegans perceive Aβ as a pathogen and elevate innate immune peptide upon its expression.
Differential spatial transcriptome profile of the hippocampal formation of protected PSEN1 E280A familial Alzheimer’s disease cases
Authors: Villalba‐Moreno Nelson David , Littau Jessica Lisa , Amri Yassir El , Lopera Francisco , ‐Lanau Andres Villegas , Glatzel Markus , Quiroz Yakeel T. , Arboleda‐Velasquez Joseph F , Sepulveda‐Falla Diego 
Published: December 2023

AbstractBackgroundWe have described two cases with ∼ 30 years of delayed disease onset among carriers of PSEN1 mutation E280A, suffering from familial Alzheimer’s disease (FAD). One case was homozygous for the ApoE Christchurch (hApoEch) mutation. This case showed sparse hyperphosphorylated tau (pTau) pathology in several cortical areas. The second case was heterozygous for the RELN‐COLBOS mutation and was globally affected by severe pTau and amyloid beta pathology, with evidence of localized cellular protection in the entorhinal cortex (EC). Here we used digital spatial profiling (DSP) transcriptomics to characterize the hippocampal formation of FAD protected cases and identify possible molecular mechanisms of protection.MethodsIn depth morphological characterization of the EC together with identification of thirteen different regions of interest (ROIs) were performed in Formalin‐fixed paraffinized 3 mm thick slides taken from the hippocampal formation (Fig. 1A) of the RELN‐COLBOS FAD case, the hApoEch FAD case, three FAD cases, and three sporadic Alzheimer’s cases (SAD). Slides were immunostained for NeuN and GFAP for morphological ROIs identification and processed for localized transcriptome analyses using the GeoMX DSP platform from Nanostring. Obtained data was processed for quality control, dimensionality reduction and differential gene expression (DGE) analyses.ResultsDimensionality reduction of transcriptomic data obtained from all ROIs and studied cases showed a distinctive distribution of ROIs belonging to both protected cases (Fig. 1B). Furthermore, DGE was observed in all sampled ROIs. ROIs such as hippocampal white matter or dentate gyri showed a higher number of differentially expressed genes due to a more homogeneous cellular composition of the ROIs (Fig. 1C). Also, EC and dentate gyrus from FAD protected cases showed distinctive molecular signatures compatible with excitatory neuronal pathways (Fig. 1D). Complementary morphological analyses showed increased neuronal density in the supragranular region of the EC in the RELN‐COLBOS FAD protected case, specifically in neuronal layer II.ConclusionOur results suggest that regardless of the protective gene conferring protection to FAD, the EC is one key protected structure with distinctive regional transcriptomic profiles suggesting the preservation of neuronal function in this region and hinting towards a possible therapeutic target in the protection against Alzheimer’s disease.
Palliative care in Autosomal Dominant Alzheimer’s disease due to PSEN1‐E280A genetic variant in Colombia
Authors: Márquez Isabel C , Tabares Maria Alejandra , Henao Paola Gallo , Londoño Luisa , Castaño Karen , Pabon Manuela , Upegui Maria , Gómez Manuela , Quintero Juan Felipe , Rassi Sofia , Vasquez Daniel , Zuluaga Maria , Aguillon David , Krikorian Alicia , Vargas John Jairo , Madrigal Lucia , Lopera Francisco 
Published: December 2023

AbstractBackgroundAutosomal Dominant Alzheimer’s disease (ADAD) is a subtype of AD in which the symptoms begin before age 65. ADAD is an important subtype of AD as it affects people at productive and reproductive age, has a genetic origin in most of the cases and is one of the 10 causes of years lost to disability (YDLs) (1). Colombia has the largest kindred family with ADAD due to PSEN1‐E280A genetic variant, we aimed to characterize the palliative care need in a subsample of individuals from these families.MethodsWe performed an analytical observational study with one year follow‐up, data obtained from visit 1 (V1) is shown in this first report. Carriers of PSEN1‐E280A variant and GDS/FAST score above 4 were included. NECPAL and Edmonton surveys were conducted to the main carer to assess the need for palliative care and the frequency of symptoms. A complete medical evaluation was also performed.Results36 patients were included in V1. Median age was 53, most of the individuals were women (63.89%), lived in urban areas (88.89%) and the most common level of education was elementary‐middle school (47.22%). Clinical variables are listed in Table 2. Results of the poisson regression showed that dysphagia, pressure ulcers, asthenia perceived by the main carer, not being surprised if the patient died in the following 12 months (Surprise question of NECPAL scale), functional decline, use of medical services (2 visits in the past year), PAINAD scale and GDS/FAST scale were associated with the need for palliative care when adjusted by number of persons involved in caring, type of carer, hours of care per week and caregiver training.ConclusionADAD is a neurodegenerative disease that requires follow‐up by palliative care services. The health perception of the main carer should be taken into consideration when deciding the need for palliative care in these patients.
Relationship between APOE risk score and myelin in Alzheimer’s disease
Authors: Schulz Nicholas R , Yang Kao Lee , Oh Jennifer M. , Kang Theresa J , Randall Allison M , Davenport‐Sis Nancy J , Deming Yuetiva , Van Hulle Carol A. , Betthauser Tobey J , Dean Doug C , Johnson Sterling C , Alexander Andrew L , Bendlin Barbara B 
Published: December 2023

AbstractBackgroundPostmortem brain tissue analysis suggests that apolipoprotein E (APOE) ε4 is associated with lower brain myelination (Blanchard et al. 2022). However, in vivo evidence for this association is lacking. Here, we examined the relationship between APOE genotype and myelin content in the brain using multicomponent relaxometry (mcDESPOT) imaging and an APOE neuropathologic risk score (Deming et al, 2023).Methods121 cognitively unimpaired participants from the Wisconsin Alzheimer’s Disease Research Center and the Wisconsin Registry for Alzheimer’s Prevention completed at least one mcDESPOT MRI scan and were APOE genotyped. Myelin content was quantified using mcDESPOT‐derived myelin water fraction (MWF) maps. Amyloid positivity was determined using CSF Aβ42/Aβ40 or a [C‐11]PiB PET scan. Cutoffs for amyloid positivity was a CSF Aβ42/Aβ40 ratio of <0.046 (Van Hulle et al, 2020) or a global PiB DVR threshold >1.19 (Betthauser et al, 2020). MWF maps were registered to MNI space and smoothed with an 8mm FWHM kernel. We conducted a voxel‐wise regression analysis to determine the relationship between APOE risk and myelin content. Covariates included age, age difference between MRI and amyloid acquisition, gender, race, amyloid status, APOE by amyloid status interaction, and APOE by gender interaction. We followed up these analyses examining specific brain regions implicated in AD. All analyses were corrected for multiple comparisons.ResultsParticipant characteristics are shown in Table 1. Voxel‐wise analysis indicated that MWF was negatively associated with age in the superior longitudinal fasciculus and small regions of the brainstem (Figure 1). MWF was not associated with APOE risk, gender, or race. ROI analysis showed a significant APOE by amyloid status interaction in the left (β = 0.006, p‐value = 0.035) and right cingulum (β = ‐0.013, p‐value = 0.037; Table 2). However, these interactions did not survive FDR correction.ConclusionThese findings suggest that myelin content decreases with age. Although APOE ε4 increases risk for developing AD dementia, it was not associated with brain myelin content in this cohort. In preclinical participants harboring amyloid pathology, APOE risk may impact myelin content although our findings did not survive FDR correction. More research is needed to fully elucidate this relationship.