bluuebunny/crossref_metadata_2025 huggingface dataset:
Brain region‐specific metabolic signatures of Alzheimer’s disease
Authors: Batra Richa , Krumsiek Jan , Wang Xue , Allen Mariet , Wörheide Maria A. , Blach Colette , Bennett David A , Kastenmüller Gabi , Arnold Matthias , Ertekin‐Taner Nilufer , Kaddurah‐Daouk Rima
Published: December 2022

Background

Metabolic dysregulation is one of the hallmarks of Alzheimer’s disease (AD). Alterations in metabolism have been associated with AD‐related comorbidities, cognitive decline, and AD brain pathology. Brain regions are differentially affected with AD neuropathology and exhibit metabolic heterogeneity. Therefore, to build a more comprehensive picture of metabolic impact of AD, region‐specific AD‐associated metabolic changes need to be determined.

Method

We profiled 344 brain samples from the Mayo Clinic brain bank using Metabolon’s untargeted metabolomics platform, covering 182 samples from the cerebellum (CER) and 162 samples from the temporal cortex (TCX). Generalized linear models were used to assess the association of metabolic profiles with AD. Models included confounder correction for age at death, sex, and number of APOE‐ε4 alleles. To extend this study to four more brain regions, we included results from previously published brain metabolomics studies based on samples from three independent cohorts, including dorsolateral prefrontal cortex (DLPFC) from ROS/MAP, parietal lobe (PTL) from Washington University School of Medicine (WUSM), inferior temporal gyrus (ITG) and middle frontal gyrus (MFG) from Baltimore Longitudinal Study of Aging (BLSA).

Result

In the Mayo cohort, a total of 190 out of the 658 metabolites were significantly associated with AD. Out of the 190, 127 metabolites associated only in the CER region, 37 metabolites associated only in the TCX region, and 26 metabolites were associated in both brain regions. There were no metabolites commonly regulated in all the 6 brain regions under investigation. DLPFC and CER had the highest overlap of 70 metabolites, followed by DLPFC and PTL with 64 metabolites, and CER and PTL with 47 metabolites. For functional interpretation of our findings, each metabolite was further categorized with a sub‐pathway annotation provided by Metabolon. 3 of the 88 pathways including methionine cycle, phospholipid metabolism, and glutathione metabolism, were commonly regulated in the six brain regions under investigation.

Conclusion

We present a first global perspective on AD‐associated metabolic alterations across six brain regions. This study will pave the way to fill the gap in our understanding of region‐specific metabolic deregulations associated with AD pathophysiology.
Evaluation of A Direct Regional Reprojection Reconstruction Method to Improve Quantitation of Amyloid and Tau PET Images using 3D Printed Phantoms
Authors: Meehan Emily , Minhas Davneet S , Gogola Alexandra , Ghodadra Anish , Cohen Ann D , Tudorascu Dana L , Lopresti Brian J , Aizenstein Howard J , Kendro Steve , Mason Neale S , Klunk William E , Laymon Charles M
Published: December 2022

Background

Image reconstruction and partial volume correction (PVC) techniques designed to account for the limited spatial resolution of PET are used inconsistently in amyloid and tau PET imaging, likely due to a lack of characterization of the techniques and their unknown effect on reliability. In this study, we aimed to test the accuracy and reliability of a variety of reconstruction and image‐based correction methods using 3D‐printed PET phantoms.

Method

Two phantoms modeled on the lateral temporal brain region of two human subjects (67‐year‐old male and 69‐year‐old female, both cognitively normal) were created using 3D‐printing technology (Formlabs Form 3). The phantoms had six thin‐walled chambers corresponding to inferior, middle, and superior temporal grey matter (GM) and white matter (WM). Phantoms were scanned (Siemens Biograph mCT) multiple times as chambers were filled with F‐18 solution to mimic various distributions of activity seen in amyloid‐positive, amyloid‐negative, or tau‐positive subjects. 16 scans were completed in total. Data from each 3‐hour scan were binned into 16 statistically equivalent frames and reconstructed with three techniques: FBP, OSEM, and TrueX, a manufacturer‐supplied method including point spread function modeling (Figure 1). Two image‐based correction techniques were also applied and evaluated: Geometric Mean Transfer Matrix (GTM) PVC and a novel Direct Regional Reprojection Reconstruction (DRRR) method, an iterative algorithm that reprojects images directly into regions‐of‐interest. To evaluate accuracy, fractional error of each region (F = M/T ‐ 1, where M is the measured regional value averaged over 16 frames and T is the true regional value) was calculated. To evaluate reliability, the coefficient of variation (CV) of M over all 16 frames in each scan was assessed for every region of the phantoms.

Result

Fractional errors (Figure 2) and CVs (Figure 3) are shown for each reconstruction and image‐based correction method. Uncorrected TrueX fractional error was not apparently improved relative to uncorrected FBP and OSEM fractional error. For all reconstructions, GTM and DRRR improved accuracy relative to uncorrected. For the FBP and OSEM reconstructions, GTM was more accurate than DRRR, but DRRR was more reliable than GTM.

Conclusion

DRRR is a promising novel method for PET quantification that improves accuracy without compromising reliability.
Higher cortical myelin is associated with worse performance on cognitive tests: Findings from the Alzheimer’s Disease Connectome Project
Authors: Kohli Akshay , Kecskemeti Steven R , Yang Kao Lee , Oh Jennifer M. , Nair Veena A. , Pasquesi Mary‐Elizabeth , Okonkwo Ozioma C. , Alexander Andrew L , Prabhakaran Vivek , Li Shi‐Jiang , Bendlin Barbara B.
Published: December 2022

Background

Brain myelin is known to play an important role in maintaining optimal neuronal function, with deficits in myelin leading to worse performance on cognitive tests. The extent to which cortex‐specific myelin is associated with other cognitive domains, or is impacted by disease processes such as Alzheimer’s disease (AD), is unknown. Here we leverage MPnRAGE‐derived quantitative R1 (Kecskemeti et al., 2016; 2018), a metric sensitive to brain myelin, to assess the role of intracortical myelin in performance on tests of executive function (exec_func), working memory (working_mem), and processing speed (process_speed) in older adults who ranged from cognitively unimpaired to those with dementia.

Method

143 older adults (N=75 cognitively unimpaired, N=44 mild cognitive impairment, N=24 dementia) enrolled in the Alzheimer’s Disease Connectome Project underwent T1‐weighted (T1w) MPnRAGE MRI with motion‐correction and testing via the NIH Toolbox Cognitive Battery. Inherently registered quantitative R1 maps and T1w images were reconstructed at 1mm isotropic resolution. The image processing pipeline and composite regions of interest (ROIs) used for analysis can be viewed in Figure 1. Uncorrected standard scores were computed by the NIH Toolbox for each measure of exec_func (dimensional change card sort), working_mem (list sorting), and process_speed (pattern comparison). Multiple linear regression models were employed in R with test scores as the dependent variable, regional R1 as the predictor of interest, and age, sex, and education as covariates.

Result

Higher R1 was associated with worse exec_func in regions that are affected in AD, including posterior cingulate (ß = ‐62.47, t(1,138) = ‐2.42, p = 0.017) and temporal cortices(ß = ‐123.05, t(1,138) = ‐2.77, p = 0.0064) ROIs. Additionally, higher R1 in temporal cortices was associated with worse working_mem (ß = ‐158.16, t(1,133) = ‐2.84, p = 0.0053) (Figure 2). There were no significant associations between process_speed and regional cortical R1.

Conclusion

Unexpectedly, higher regional cortical myelin (as indexed by R1) was associated with worse exec_func and working_mem, suggesting higher R1 may be indicative of a regional pathologic process. Future work will test the interactive relationships between amyloid and/or tau pathology and cortical myelin on cognitive performance.
GENE REPLACEMENT OF MUTANT PRESENILIN1 NORMALIZES GAMMA‐SECRETASE FUNCTION IN MODELS OF AUTOSOMAL DOMINANT ALZHEIMER'S DISEASE
Authors: Moore Ben David , Schaeffer Eric
Published: December 2022

Background

Paros Bio is developing an AAV gene therapy for the treatment of Autosomal Dominant Alzheimer’s Disease (ADAD), an early onset form of AD (onset at <65 years of age). ADAD is mainly caused by mutations in the presenilin 1 (PSEN1) gene, which encodes the catalytic subunit of γ‐secretase complex and is responsible for the cleavage of amyloid precursor protein (APP). This cleavage produces Aβ of varying lengths, with longer peptides like Aβ42 being more prone to aggregation than shorter peptides such as Aβ40. Of the >150 distinct, 100% penetrant PSEN1 mutations associated with ADAD, most lead to a partial or nearly complete loss of g‐secretase function, resulting in decreased production of Aβ40 and an increase in the ratio of Aβ42:Aβ40. Aggregation of Aβ peptides into amyloid plaques in the brain is a hallmark of ADAD.

Method

Paros Bio is employing a gene replacement approach to normalize g‐secretase function. Using an AAV vector, Paros has successfully expressed a functional copy of PSEN1 in mouse and patient‐derived cellular models of presenilin dysfunction.

Result

We have demonstrated that introduction of wildtype PSEN1 in mouse models and patient‐derived cell lines effectively normalizes g‐secretase function. Our AAV vector can be broadly distributed in brain tissue and provides attractive expression of PSEN1.

Conclusion

Paros Bio has developed a vector that enables broad expression of WT PSEN1 and is capable of normalizing g‐secretase function in in vitro and in vivo models of ADAD.
Harmonizing machine learning imaging biomarkers – CDESH and the case for harmonization in both MR image and low‐dimensional (scalar) output space
Authors: Gunter Jeffrey L. , Cogswell Petrice M , Senjem Matthew L. , Kantarci Kejal , Knopman David S. , Petersen Ronald C. , Graff‐Radford Neill R. , Graff‐Radford Jonathan , Jack Clifford R.
Published: December 2022

Background

In 2018 we presented the Computational DESH (CDESH) metric (DOI:10.1016/j.nicl.2018.11.015), a machine learning measure of abnormal CSF space patterns commonly observed on MRI in Disproportionately Enlarged Subarachnoid‐space Hydrocephalus (DESH‐type) NPH. We have shown that CDESH positive individuals often have discordant CSF and PET amyloid measures (DOI:10.1016/j.jalz.2019.06.4921). Positive CDESH scores are predictive of cognitive decline (DOI:10.1016/j.neuroimage.2021.117899, DOI: 10.1212/WNL.0000000000008616). The score is calculated from regional CSF volumes in a sulcal atlas and within the ventricles using a support vector machine (SVM). The Mayo Clinic Study of Aging (MCSA) changed scanner platforms (GE to Siemens) and T1‐weighted image resolution (1.2mm x 1.05mm x 1.05mm to 0.8mm isotropic) in 2017. We refer to these as “isotropic” or “anisotropic” scans. Our objective was to assess the dependence of a machine learning method (specifically CDESH) to image input variation and, if necessary, determine what needed corrections.

Method

All data considered is from the MCSA or Mayo Clinic ADRC. The SVM was trained on anisotropic images with laboriously labelled ground truth. We resampled the isotropic data from a crossover study (N=112, typically scanned same‐day with both platforms/resolutions) to match the anisotropic resolution. Two approaches to correction were evaluated (Figure 1). In Figure 2 we compare of the score with and without correction cross‐sectionally in 998 MCSA participants. In Figure 3 we present longitudinal series from 23 participants with multiple scans using the isotropic resolution protocol and at least one prior anisotropic image.

Results

Comparisons of data from the crossover study are presented in Figure 1. Matching voxel resolution to the data used to train the SVM is critical and a subsequent mild linear score adjustment may be warranted. Cross‐sectional comparisons (Figure 2) confirm improvement matching voxel resolution with a possible mild linear score adjustment. After matching voxel resolution CDESH score trajectories (Figure 3) are markedly more stable across this scanner/protocol change.

Conclusion

The SVM‐based CDESH score is sensitive to voxel resolution. Corrections are needed in image processing and possibly in the scalar output score to achieve stability across protocol and scanner changes. The resulting correction supports coherent long timeseries data and longitudinal extension of previous work.
Characterization of a diverse Frontotemporal Dementia cohort, enriched for Caribbean Hispanic patients.
Authors: Martinez Anisley , Rajabli Farid , Gu Esther , Tejada Sergio , Acosta Heriberto , Baumel Bernard , Camargo Christian J , Sun Xiaoyan , Vance Jeffery M. , Cuccaro Michael L. , Pericak‐Vance Margaret A. , Nuytemans Karen
Published: December 2022

Background

The vast majority of biomedical data currently available for any disease is derived from studies in non‐Hispanic white (NHW) populations. Specifically, clinical information, genetic factors as well as biomarkers for frontotemporal dementia (FTD) have been studied predominantly in those NHW populations. To increase representation in biomedical research, we set out to enroll and characterize a diverse FTD patient cohort enriched for Caribbean Hispanic patients.

Method

Our current cohort consists of 89 FTD patients (30% NHW, 67% Hispanic), with continuing enrollment from the University of Miami Hospital Neurology Department in Miami, FL and the Caribbean Center for the Study of Memory and Cognition in San Juan, PR. All patients were evaluated using NACC approved Uniform DataSet (UDS) or equivalent in their preferred language. For ∼65% of the cohort we also completed the NACC FTD module forms. We generated genotyping data (Illumina GDA+Neurobooster array) as well as whole genome sequencing and plasma biomarker data (Quanterix Simoa Neuroplex‐3; Ab40, Ab42, and total tau) for a subset of the cohort.

Result

Initial genetic analyses showed none of the Hispanic patients are carriers of known FTD mutations originally identified in NHW patients, including the C9orf72 repeat expansion and reported pathogenic variants in MAPT or GRN. We did not identify a significant difference in age‐at‐onset or Clinical Dementia Rating scores at time of enrollment between NHW and Hispanic patients. Additionally, biomarker data on Aβ40/Aβ42 ratio and total tau levels in a subset of 22 FTD patients (∼12/10 Hispanic/NHW) did not show significantly different levels between patients of both ethnicities.

Conclusion

Genetic analyses of FTD in underrepresented population groups is necessary as genetic information from research in NHW is not always generalizable across race/ethnicity. We are currently working to expand our efforts to include identification of novel genetic risk factors for FTD in the Hispanic patients using whole genome sequencing, full evaluation of the Neuroplex as well as p‐tau181 and NfL biomarkers in the complete cohort and comparison of clinical presentations between ethnicities. The biomedical characterization of FTD across race/ethnicity will help the understanding of disease mechanisms in all patients ultimately preventing further health disparities.
The Collaboration and Harmonization of Digital Biomarkers for Alzheimer’s Research
Authors: Beattie Zachary T , Gothard Sarah , Barnes Lisa L. , Calloway Shayla , Gonzales Mitzi M , Jones Brian D , Kautz Tiffany F , Levey Allan I. , Mathews Julia J , Mulavelil Rachel , Phelps Brenna , Rosen Howard J. , Rozga Agata , Seshadri Sudha , Staffaroni Adam M. , Wasserman Dara K , Wise Amy B , Kaye Jeffrey A
Published: December 2022

Background

Among prominent unmet needs of the Alzheimer’s disease and related dementia (ADRD) research community is the ability to leverage opportunities to improve the assessments of persons with and at risk for ADRD. This vision can be realized by providing the tools and infrastructure to transform dementia assessment using remote sensing and digital technologies, pervasive computing, and wireless communications, all in concert with high dimensional data analytics. The Collaborative Aging Research using Technology (CART) initiative (carthome.org), a non‐proprietary, sharable end‐to‐end system for capturing and handling diverse kinds of digital data has been developed. The CART technology platform offers the opportunity to bring new assessment methodology and data types to NIA Alzheimer’s Disease Research Centers (ADRC) and related centers and transform the clinical research enterprise. Herein we report on progress in capturing digital data across multiple ADRC’s.

Method

Participants were recruited from affiliated studies at five NIA ADRC’s (Digital Technology Core at Oregon Health & Science University, Minority Aging Research Study at Rush University, Cognitive Empowerment Program at Emory University and Georgia Institute of Technology, ALLFTD study at University of California San Francisco, and a pilot study of Mexican Americans at University of Texas Health Science Center at San Antonio). Field technicians at each center installed the CART technology platform in the home of each participant.

Result

A total of 195 research participants have been enrolled across the 5 centers and followed for a median of 19 months (range 1‐46). A summary of the center cohorts is provided in the table. The flexibility of the platform and its components has allowed it to successfully be adapted for research in each of these studies with diverse cohorts, use cases, and research aims. Attrition due to technology concerns has been very low (0.5%).

Conclusion

Digital biomarker and related data can be readily captured across diverse cohorts, research teams, and settings using a common platform. The largely passive, continuous, and objective data generated with this approach promises to improve the opportunity to create more quantitative and ecologically valid measurements for ADRD phenotypes within the ADRD research community and related research settings.
Exploring Inflammasome/Cytokine/Insulin cascade as converging landscape for AD, Schizophrenia(SCHIZO), and COVID‐19 syndrome: synthesis of evidence and Post‐hoc analysis of Ginsans‐115 RCT in treatment‐resistant‐schizophrenia
Authors: Carriere Autumn
Published: December 2022

Background

Amid COVID‐19 pandemic, issue is raised: 1) whether AD and Very‐late‐onset‐schizophrenia‐like psychosis(VLOSL): “dementia praecox” have higher COVID‐19 risk;2)whether dysregulated cross‐talk of immunity and inflammation, in Inflammasome‐Cytokine‐insulin signaling cascade (IFCI) is the missing link for AD, VLOSL and COVID‐19.

Method

Our objective is : 1) to conduct Pub‐med search for crucial role of inflammasome‐cytokine‐insulin cascade(IFCI) in AD, VLOSL and COVID‐10 burden; 2a)to examine using RCT data whether in schizophrenia, cognitive impairment correlates with insulin resistance(IR) and cardio‐metabolic risks (CMR);2b)whether Panax Ginseng, as prime executioner of IFCI, modifies IR,CMR in TRS.

Result

In Part1: our Pubmed search concludes Dementia syndrome carries higher mortality risk. A meta‐analysis of 634,338 COVID‐19 patients from 16 studies reveals that schizophrenia, and dementia, significantly increased risk of COVID‐19 mortality and severity. Cardio‐metabolic risk factors modify the link. A large Swedish cohort study and systematic review of 17studies found evidence of VLOSL carries higher risk of dementia. Aberrant IFCI correlated with COVID‐19 severity, but very few data is available for Long‐COVID‐19 syndrome. Effect sizes cannot be calculated due to sample heterogeneity. In Part 2: post‐hoc analysis of Ginsana‐115 (Boehringer‐Ingelheim‐Pharmaton,Switzerland) of 8‐week placebo‐controlled parallel group design in TRS subjects . Log‐IR(insulin resistance) scores significantly correlated with spatial processing (p = 0.017). Framingham‐Risk‐score correlated inversely with visual perception p = 0.040) and spatial processing (p = 0.029) and neurocognitive index (p = 0.090). Systolic blood pressure (sBP) correlated significantly and inversely with visual perception (p = 0.032),speed (p = 0.010),and spatial processing (p = 0.034), HDL correlated with memory score:p = 0.008. Brief‐Psychiatric‐Rating‐Scale:BPRS correlated significantly with executive reasoning (p = 0.047),memory (p = 0.021), and mental inflexibility (p = 0.026). Ginsana‐115 at 100‐mg/200‐mg significantly reduced FRS by 24.1% compared with 16.1%(P<0.05) and systolic blood pressure (P<0.05) and significantly improved lipid profile in raising HDL and lowering LDL. Ginsana‐115 : 100 mg and 200 mg oral dosage, significantly improved negative symptom of apathy akin to AD.

Conclusion

Inflammasome‐Cytokine‐Insulin signaling (IFCI) appears to be the heuristic model integrating COVID‐19 syndrome, late‐onset schizophrenia overlapping with AD. Longitudinal studies are warranted to validate IFCI as the prime driver. The positive findings of Ginsana‐115 in TRS highlight the therapeutic Pandora box of Diet, drug leads and Exercise targeting specifically the IFCI landscape in COVID‐19 syndrome, AD and VLOSL.
A more natural context: Variation in mouse background improves models of vascular contributions to Alzheimer’s disease
Authors: Onos Kristen D , Keezer Kelly J , Uyar Asli , Yang Hongtian Stanley , Carter Gregory W , Territo Paul R , Walker Ashley E , Patel Hemal H , Sasner Michael , Howell Gareth R
Published: December 2022

Background

Initial research focused on vascular contributions to dementia often categorized these pathologies as not relevant to Alzheimer’s disease (AD). Patients that presented with vascular pathologies would commonly be excluded from clinical studies and trials of AD. Recently, these vascular contributions have become more appreciated. A number of studies have identified vascular factors either contribute to, or result from central AD hallmarks such as amyloid and tau pathology, and glial cell dysregulation. A number of genetic risk factors for AD are also centered on vascular cells and function. Unfortunately, current mouse models are limited in their presentation of vascular pathologies, and require introduction of other interventions such as diet‐induced obesity or middle cerebral artery occlusion.

Method

Our group performed a strain survey using amyloid drivers. APP/PS1 transgenes were backcrossed from C57BL/6J to nine strains including wild‐derived WSB/EiJ, PWK/PhJ and CAST/EiJ. All strains were assessed for cerebral amyloid angiopathy (CAA) as this vascular pathology is common in AD cases.

Result

WSB/EiJ showed the highest incidence of CAA, accompanied by indications of vascular leakage and damage. Male and female WSB.APP/PS1 and WSB mice were then aged from 4 to 18 months. Amyloid deposits co‐localized with astrocyte processes, but were devoid of microglia and collagen. Brain transcriptional profiling comparing differences between WSB and B6 context identified significant differences in gene expression relating to vascular health including basement membrane, endothelial function and blood vessel formation. Furthermore, upon examination of aged WSB, microbleeds were present even in the absence of amyloid. Single‐cell sequencing of WSB‐microglia states identified a signification proportion of homeostatic microglia enriched for expression of P2ry12 present in WSB but not WSB.APP/PS1. As P2RY12‐mediated chemotaxis is critical for closure of the blood brain barrier (BBB) after injury, these microglia may be central to BBB health in the WSB context. Further work is being performed to determine whether differences in microglia states, vascular integrity or metabolic dysfunction contribute to significant development of CAA present in WSB/EiJ.

Conclusion

The WSB genetic context provides a new platform to dissect vascular contributions to AD. Other factors such as humanized amyloid, tau, and apolipoprotein E are also being examined.
Racial Differences in the Association of MIND Diet/Physical Activity Combinations and Cognition in older adults
Authors: Holland Thomas Monroe , Agarwal Puja , Dhana Klodian , Desai Pankaja , Liu Xiaoran , Krueger Kristin R , Beck Todd , Cherian Laurel J , Schneider Julie A , Aggarwal Neelum T. , Barnes Lisa L. , Rajan Kumar B
Published: December 2022

Background

Diet and physical activity (PA) are important factors associated with improved cognition. Few studies have investigated the synergistic association with cognitive decline and further, whether the association differs by race. In this study, we investigate whether the observed association of high MIND diet score/high self‐reported PA and cognitive decline is different between African Americans (AA’s) and European Americans (EA’s).

Method

We examined the association of baseline MIND diet and PA combinations on cognition in 3,657 participants (2206 AAs and 1451 EAs; mean age = 73.2±SD5.8 years) from the Chicago Health and Aging Project. Diet was assessed using a validated 144‐item food frequency questionnaire; self‐reported PA was measured by frequency of engagement in six activities. Cognition was evaluated using a four‐test cognitive battery from which a global composite score and two domains were derived. Participants were followed on average 8.5±SD4.8 years and separated into 9 combinations of MIND diet score and PA (high, moderate, low for MIND diet and high, moderate, low, for PA). Using linear mixed models we examined the rate of cognitive decline; adjusting for age, sex, education, race, ApoE‐4, smoking, and caloric intake. Subsequent models were stratified by race to investigate potential differences in the association of diet and PA combinations with cognitive decline.

Result

Participants who reported high MIND/high PA had a slower rate of decline in global cognition (β = 0.015, 24.87% slower, p = 0.007), memory score (β = 0.014, 31.86% slower, p = 0.042) and improved MMSE (β = 0.023, 33.62% improvement, p<0.001) when compared to participants with low MIND/low PA. In race stratified models, we found that in European Americans, high MIND/high PA was associated with slower rates of decline in global cognition (β = 0.028, 37.1% slower, p = 0.007), memory score (β = 0.026, 48.59% slower, p = 0.033) and improved MMSE (β = 0.050, 50.0% improvement, p<0.0001) versus low MIND diet/low PA. However, only an improved MMSE (β = 0.017, 27.11% improvement, p = 0.033) was observed to be associated in African Americans.

Conclusion

High adherence to MIND diet/physical activity is associated with slower cognitive decline, regardless of race. However, the breadth of these associations may differ by race. Additional studies are required to elucidate the potential racial differences observed and determine which interventions are most impactful.
Complement C3 Lowering in Adult Inducible Conditional Knockout Mice: Long‐Lasting Effects
Authors: Batista Andre Felipe , Schroeder Maren K , Khan Khyrul , Yalcin Esra , Mei Michelle , Presumey Jessy , Li Shaomin A , Carroll Michael , Lemere Cynthia A.
Published: December 2022

Background

Complement C3, a central component of the complement cascade, participates in synaptic elimination during brain development and is elevated in the brain with aging and Alzheimer’s disease (AD). Germline C3 knockout (KO) protects against age‐ and AD‐related hippocampal synapse loss and functional decline (Shi Q et al., J Neurosci 2015; Shi Q et al., Sci Transl Med 2017). We crossed C3fl/fl mice with Rosa26‐Cre‐ERT2 mice to generate global C3 inducible conditional KO mice (C3iKO). Previously, we reported that 5 daily TAM treatments in C3iKO mice at 4‐5 mo of age led to sustained C3 reductions of ∼95% in serum and ∼80% in brain, and protected mice against age‐related cognitive decline at 16‐17 months. In addition, TAM treatment at 3‐4 mo of age protected long‐term potentiation (LTP) in hippocampal slices exposed to toxic Aβ dimers (S26C) obtained at 7‐8 mo of age. Here, we extend our analyses to include changes in complement, cytokine and ApoE expression in these same C3iKO mice and provide confirmatory results in a second cohort of mice.

Method

qRT‐PCR was used to quantify brain gene expression in the first cohort. In the second cohort, C3iKO, C3fl/fl and C3KO mice were treated with TAM or corn oil (CO) at 7‐8 mo of age. Cognitive testing commenced at 17‐18 mo and included the Spatial Novelty Y Maze (SPNY), Novel Object Recognition (NOR) and Displaced Object Recognition (DOR). Mice were euthanized and hippocampal synaptosomes isolated for Western blot analysis.

Result

One‐year post‐treatment, C1qa, C1qb, C1qc, C3, CD11b, CD18, IL‐1β, IFNα, IFNβ, and APOE mRNAs were reduced, and TGFβ and TGFβR1 mRNAs were elevated in brains of TAM‐treated C3iKO and C3KO mice compared to CO‐treated C3iKO mice. In the second cohort, C3 protein levels were reduced ∼92% in serum and ∼77% in hippocampal synaptosomes in TAM‐treated C3iKO mice. TAM‐treated C3iKO mice and both C3KO groups showed significantly better performance in SNYM, LOR and DOR tests compared to controls, consistent with our first study. Pre‐ and post‐synaptic markers were elevated in TAM‐treated vs. CO‐treated C3iKO hippocampal synaptosomes.

Conclusion

Global C3 lowering in adulthood has long‐lasting effects on immune signaling and hippocampal function. (NIH RF1 AG060057‐CAL)
Development of Assistive Technology for Instrumental Activities of Daily Living for Dementia Homecare Environments
Authors: Roberts Emily , Fan Guoliang , Chen Xiaowei
Published: December 2022

This presentation describes preliminary National Institute of Health (NIH) funded user‐centered research into Cognitive Assistive Technology (CAT) for dementia homecare and the subsequent development of a lab for testing the CAT. Caregivers face on‐going significant risk throughout the ebb and flow of providing care, as individuals with dementia may lose grasp of their understanding of their circumstances, relying heavily on caregivers for all aspects of their physical and emotional support, as well as prompting and cueing through the multi‐step IADLs. Difficulty with IADL tasks such as cooking meals and housekeeping is one feature of early‐stage dementia, as these tasks require complex cognitive processing and are cognitively demanding. The goal of this research is to improve caregiver resilience and sustainability of dementia homecare via a low‐cost wearable CAT system which can support the IADL task cueing intervention for care recipients called IADL/CAT. IADLs are highly personalized set of needs, requiring a flexible and versatile approach that can be customized and adapted for each individual in a specific setting. Smart‐home technologies and assistive technology tools of specific functionalities have been previously developed to partially address those challenges, however, there is currently a lack of low‐cost, portable, versatile and programmable interventions that can relieve the physical and emotional burden from caregivers by automatically providing timely, needed and individualized IADL task cueing to care recipients Our working hypothesis is that environmental cueing for an individual with dementia can be recorded and replayed to enable timely feedback and assistance through a IADL/CAT wearable device. This presentation will describe the initial research conducted to not only develop an environmental testing lab for the IADL/CAT project, but the initial system navigation cueing through the 3D model retrieval. Through the development of a lab‐based replication/mock‐up of environmental relationships which would be found in a home (i.e. connection between a kitchen and dining room) we have been begun to evaluate the IADL/CAT programming features and system usability.
Building an EEG‐based Alzheimer’s Diagnostic: What is the Optimal Cross‐Validation Method?
Authors: Quirk Colin , Brookshire Geoffrey , Wu Yunan "Charles" , Lucero Ché
Published: December 2022

Background

Alzheimer's disease lacks a fast, easy, reliable method of diagnosis. Attempts to create classifiers based on brain activity in resting‐state electroencephalography (rsEEG) are promising but require state‐of‐the‐art machine learning models to leverage the available information. Typically, single‐pass cross‐validation (SPCV) is used to select a model, despite work suggesting SPCV introduces bias when many models are considered. Recently, nested cross‐validation (NCV) has been introduced to correct this bias. Here we report which of these two processes yields the most accurate Alzheimer's classifiers in held‐out data.

Method

We simulated data to investigate the problem of detecting Alzheimer's Disease. We drew 225 weakly‐related coefficients from a normal distribution to represent features extracted from rsEEG. To increase the difficulty of the classification problem, highly correlated values were then generated for each of these causally meaningful features. Each iteration, 200 training cases were generated along with 1,000,000 test cases. SPCV and NCV were then employed to choose between over 1000 possible combinations of algorithm, optimization type, and hyperparameter set. Performance was assessed by examining the average AUC of the chosen model on the test data over all iterations of data generation and model selection.

Result

Comparing generalization performance on holdout data, NCV selected better models than standard SPCV (mean difference = 0.021 AUC, t(64) = 2.19, p < 0.05). SPCV overestimated generalization performance numerically, but non‐significantly (mean difference = ‐0.012 AUC, t(64) = ‐1.11, p > 0.05). In contrast, NCV showed better performance on holdout data compared to training data (mean difference = 0.025 AUC, t(64) = 3.59, p < 0.05). Furthermore, NCV produced significantly different patterns for holdout performance estimates compared to SPCV (mean difference = 0.037 AUC, t(64) = 3.48, p < 0.05).

Conclusion

Advanced machine learning models are necessary to take advantage of the large amount of information available in rsEEG activity. These results show that traditional single‐pass cross‐validation may overestimate how well model performance will generalize in the real world. Nested cross‐validation allows us to select models with better diagnostic performance, ultimately leading to better outcomes for patients, even when limited to a small number of training cases.
Assessment of ccf‐Mitochondrial DNA Damage in Cognitive Impairment via NGS: Health Disparities in Mexican Americans
Authors: Reid Danielle M , Barber Robert , Thorpe Roland J. , Sun Jie , Zhou Zhengyang , Phillips Nicole
Published: December 2022

Background

Mexican Americans (MAs) are the fastest growing subpopulation in the US. As this population ages, age‐related diseases such as Alzheimer’s disease (AD) will disproportionately affect MAs. MAs have a unique AD pathogenesis signature when compared to their non‐Hispanic White (NHW) counterparts. MtDNA damage may be implicated in the elevated AD burden among MAs due to the high prevalence of common risk factors for cognitive impairment (CI) including metabolic comorbidities. Mitochondrial dysfunction, oxidative damage to guanosine (8oxoG), and 5kb deletions are well‐documented in AD. MtDNA is particularly vulnerable to damage, which can affect mitochondrial function as well as act as a damage associated molecular pattern when released into the cell‐free space (ccf‐mtDNA), stimulating inflammatory responses. We hypothesize that MAs incur mtDNA damage at an elevated rate due to increased comorbidity burden altering mitochondrial function resulting in increased levels of 8oxoG and the common 5kb deletion.

Method

MtDNA from buffy coat and plasma samples of participants enrolled in the Texas Alzheimer’s Research Care and Consortium were amplified using the RepliG mtDNA Amplification kit and were sequenced via NexteraXT on Illumina NextSeq. Somatic oxidative variants and the commonly observed 5kb deletion were quantified in both the buffy coat mtDNA and ccf‐mtDNA. These data were analyzed for association with CI and T2D in both the NHW and MA populations. Further, haplogroup‐associated risk for mtDNA damage and ccf‐mtDNA status was assessed.

Result

Thus far, we found mtDNA 8oxoG mutations in buffy coat are significantly higher in MAs (females are more affected) compared to NHWs and suggestive evidence indicating CI is related to 8oxoG mutations. Further, we identified specific mtDNA haplotypes conferring increased risk for oxidative damage. Analysis of ccf‐mtDNA indicate an elevated level of oxidative damage.

Conclusion

Our preliminary findings suggest clinical implications of oxidative mtDNA damage as a risk factor for CI specifically in MA females. These data highlight ethnic/racial differences in oxidative burden potentially elucidating sex‐specific mechanisms contributing to the manifestation of age‐related disease etiology. Such results may ultimately inform precision‐based approaches to design therapeutics for mitigating AD disparities in MAs.
Impact of meningeal and age‐related off‐target binding on longitudinal [18F]MK6240 quantification.
Authors: Tissot Cécile , Lussier Firoza Z , Ferrari‐Souza João Pedro , Servaes Stijn , Bezgin Gleb , Ferreira Pamela C.L. , Bellaver Bruna , Leffa Douglas Teixeira , Therriault Joseph , Vermeiren Marie , Kunach Peter , Stevenson Jenna , Rahmouni Nesrine , Chamoun Mira , Benedet Andréa Lessa , Wang Yi‐Ting , Arias Jaime Fernandez , Kang Min Su , Villemagne Victor L , Tudorascu Dana L , Cohen Ann D , Klunk William E , Baker Suzanne L. , Gauthier Serge , Rosa‐Neto Pedro , Pascoal Tharick A
Published: December 2022

Background

[18F]MK6240 tau‐PET can detect changes in the early and late stages of tau tangles accumulation. However, off‐target binding, often observed in the meninges and neuromelanin‐containing cells, can interfere with longitudinal tracer quantification. Here, we investigated the association of longitudinal changes in off‐target and target signals using [18F]MK6240.

Method

We assessed individuals from the TRIAD cohort with [18F]MK6240 tau‐PET and clinical evaluation. Longitudinal analyses included 83 cognitively unimpaired (CU) and 37 cognitively impaired (CI) individuals. Age‐related off‐target binding was estimated comparing 36 CU young individuals (<25 y.o) and 28 CU elderly amyloid/tau negative (40‐65 y.o). A t‐test was used to compare both groups. The ratio between baseline and follow‐up SUVR measured changes in off‐target and target regions. Pearson correlations tested the associations between regions, and Bonferroni analysis corrected for multiple comparisons.

Result

Although averaged images did not present a striking visual difference in [18F]MK6240 uptake between CU young and elderlies, t‐test revealed significant differences between groups in the cerebellar white matter and subcortical regions (Figure1). Table 1 depicts the percentage of area of selected regions overlapping with the age‐related off‐target binding. Notably, we did not observe a significant association between longitudinal changes in age‐related or meningeal off‐target binding with longitudinal change in target regions (Braak‐II, BraakIII‐IV, BraakV‐VI), whereas changes in target regions were highly correlated (Figure2).

Conclusion

Despite not being visually perceptible, [18F]MK6240 presents age‐related off‐target binding in subcortical regions, similar to regions reported using [18F]Flortaupicir. The overlap between age‐related off‐target and Braak IV region (∼3%) may lead to the confounding results in quantifying this region. The lack of correlation between off‐target and target [18F]MK6240 changes suggests little influence of the off‐target binding on longitudinal tracer quantification. Our results suggest that although off‐target uptake appears to have a modest influence on longitudinal quantification, it is necessary to consider both age‐related and meningeal off‐target signals for an accurate tracer assessment.
Strong effects of the ABCA1 agonist CS6253 on Amyloidβ42/40 ratio and lipoproteins in cynomolgus monkeys
Authors: Kerman Bilal E. , Noveir Sassan D , Xian Haotian , Meuret Cristiana , Smadi Sabrina , Martinez Ashley E. , Johansson Johannes , Zetterberg Henrik , Parks Bryan A , Kuklenyik Zsuzsanna , Johansson Jan O. , Yassine Hussein N.
Published: December 2022

Background

ATI has discovered a novel molecule, CS6253, for hereditary Apolipoprotein E4 (ApoE4) associated Alzheimer’s disease (AD), which is highly differentiated from other molecules in development by its focus on cholesterol transport. CS6253 is a 26mer peptide optimized for ATP binding cassette transporter A1 (ABCA1) mediated cholesterol efflux, in the brain a rate‐limiting step in cholesterol transport from cells to ApoE. ABCA1 activity, as well as CS6253 in AD mouse models, is associated with improvement in AD pathology.

In preparation for human studies, we investigated the effects of the ABCA1 agonist peptide CS6253 on amyloid‐β peptides (Aβ) and lipoproteins in plasma and cerebrospinal fluid (CSF) of cynomolgus monkeys, a species with amyloid and lipoprotein metabolism similar to humans.

Methods

CS6253 peptide was injected intravenously to cynomolgus monkeys at various doses in three different studies, 1) a pharmacokinetics (PK) study, 2) a dose‐range finding (DRF) study, and 3) a 30‐day Good Laboratory Practice (GLP) toxicology study. Plasma and CSF samples were collected at several time points before and after treatment. Levels of cholesterol, triglyceride (TG), lipoprotein particles, apolipoproteins, and Aβ were measured using ELISA, ion‐mobility analysis, and asymmetric flow field flow fractionation (AF4). The relationship between the change in levels of these biomarkers was analyzed using multiple linear regression models and linear mixed‐effects models.

Results

CS6253 intravenous injection, within minutes, induced an increase in small, plasma high‐density lipoprotein (HDL) particles. Plasma TG, ApoE, and Aβ42/40 ratio were transiently increased following CS‐6253 intravenous injection, and a non‐significant decrease in CSF APP and Aβ42 was observed. CS‐6253 in plasma displaced ApoE from HDL to intermediate‐density‐ and low density‐lipoprotein (IDL/LDL) sized particles paralleled by transient reductions in total cholesterol and HDL‐cholesterol. In contrast to plasma, CS6253 had no effect on the assessed CSF apolipoproteins or lipids.

Conclusions

In cynomolgus monkeys administration of the ABCA1 agonist CS6253 transiently increased plasma ApoE and TGs which was paralleled by plasma Aβ42/40 ratio increase, providing a strong rationale for following these markers in ensuing human studies.
Characterization of a mouse model as a predictive tool for human Post‐Acute Sequelae of Covid‐19
Authors: Pasinetti Giulio Maria , Trageser Kyle J , Griggs Elizabeth
Published: December 2022

Background

While initial effects of Covid‐19 are concentrated in the respiratory system, numerous neurological symptoms and complications have been documented both during the acute disease course, as well as lingering symptoms following infection. Emerging reports have documented a multitude of transcriptional, proteomic, and homeostatic changes following acute infection. Here, we systematically evaluate a transgenic mouse model, a 5xFAD x hACE2, for its ability to recapitulate key underlying PASC‐pathologies.

Method

Five month hACE2 x 5xFAD double transgenic mice were intranasally inoculated with SARS‐CoV‐2 and sacrificed seven days post infection. Murine brain samples from the parietotemporal cortex and hippocampus, and matched postmortem SARS‐CoV‐2 infected, AD, healthy control, and AD + SARS‐CoV‐2 infected brain samples were submitted for RNA‐sequencing. Congruency analyses with upset plots and immunohistochemistry were performed to evaluate the ability of the murine model to recapitulate human findings.

Result

5xFAD x hACE2 mice exhibited key overlapping transcriptional changes common to humans, including BBB dysfunction, impaired synaptogenesis, and leukocyte dysfunction. Glial activation and distribution of virus was also recapitulated in our mouse model. Through dimensionality reduction and the integration of multimodal data, this model exhibits a similar etiopathogenesis to our findings in human.

Conclusion

These studies provide a strong evidentiary basis for the utilization of a 5xFAD x hACE2 mouse model for modelling human PASC. Additional future studies utilizing this model to elucidate mechanisms underlying neuropathogenesis and the investigation of novel therapeutics is warranted.
Single‐nucleus RNAseq‐derived pseudo‐temporal modeling of neurodegeneration in astrocytes of older brains
Authors: Heath Laura M , Wiley Jesse C , Cary Gregory A. , Poehlman William L. , Gockley Jake , Carter Gregory W , Greenwood Anna K , Mangravite Lara M
Published: December 2022

Background

We previously developed a temporal model for unobserved molecular changes occurring during late‐onset Alzheimer’s Disease (AD) for bulk RNA‐Seq and proteomic data. Here we apply this method to single‐nucleus RNAseq data from an AD case‐control cohort and identify Alzheimer’s‐related pathway changes at specific stages of trajectories derived from astrocytes to better understand celltype‐specific gene expression across a continuum.

Method

Manifold learning defines an order across samples based on their similarity of expression. This ordering estimates pseudotime, an inference of molecular disease progression, quantitatively measured as the distance of each sample from the start of the inferred trajectory. We applied this approach to available snRNAseq data from human postmortem brain samples from the ROS/MAP study (N = 48) (Mathys et al., 2019). We identified a cluster of cells expressing astrocyte‐specific markers. Sex‐specific trajectories were calculated after applying a mutual nearest‐neighbors function to correct the expression matrix values for within‐donor variability. We examined associations between pseudotime and AD case/control status. For each tree branch relative to the root (i.e. the branch with the highest proportion of control cells), we performed differential expression analysis, using a method to account for the hierarchical nature of multi‐subject snRNAseq data (NEBULA, He et al., 2021). We then used gene set enrichment analysis to identify state‐specific significant GO terms from a set that have been curated into 16 distinct AD‐relevant biological domains.

Result

Pseudotime estimates were significantly associated with LOAD status (females, p = 0.0110; males, p = 0.0011), such that “early” (low pseudotime) samples are enriched for controls, and “late” (high pseudotime) samples are enriched for cases. Genes involved in synapse function and structural stabilization were upregulated, while proteostasis and immune response were downregulated, consistently across pseudotime in males, and later in females. Genes involved in the RNA spliceosome were upregulated at earlier stages but not the latest stage in pseudotime in both sexes. We also observed differences between branches in biological domains encompassing mitochondrial metabolism, vasculature, and apoptosis.

Conclusion

This approach to identifying AD‐related gene expression changes across a continuum provides an opportunity to glean new insights about celltype‐specific genetic drivers of AD in the brain.