Neurosciences Commons^™

Dark And Camouflaged Genomic Regions Remain Challenging In Chm13, Mark E. Wadsworth, Madeline L. Page, Bernardo Aguzzoli Heberle, Justin B. Miller, Cody J. Steely, Mark T. W. Ebbert

Sanders-Brown Center on Aging Faculty Publications

Comprehensive genomic analysis is essential for advancing our understanding of human genetics and disease. However, short-read sequencing technologies are inherently limited in their ability to resolve highly repetitive, structurally complex, and low-mappability genomic regions, previously coined as “dark” regions. Long-read sequencing technologies, such as PacBio and Oxford Nanopore Technologies (ONT), offer improved resolution of these regions, yet they are not perfect. With the advent of the new Telomere-to-Telomere (T2T) CHM13 reference genome, exploring its effect on dark regions is prudent. In this study, we systematically analyze dark regions across four human genome references—HG19, HG38 (with and without alternate contigs), and …

Data-Driven Thresholds For Standardized Classification Of Severe Alzheimer’S Disease Neuropathology Using Digital Neuropathology, Ryan K. Shahidehpour, Allison M. Neltner, Mitchell A. Klusty, Cole Corbett, Angelique D. Gonzalez, David A. Gutman, David W. Fardo, Adam D. Bachstetter, Cody Bumgardner, Margaret E. Flanagan, Peter T. Nelson

Sanders-Brown Center on Aging Faculty Publications

Alzheimer's disease neuropathological changes (ADNC)—operationalized with semi-quantitative parameters—represent the consensus-based gold standard for diagnostic evaluation of disease severity. Although useful, ADNC diagnostic frameworks have limitations, particularly in advanced disease stages where pathological severity varies widely within a given diagnostic category. Further, some individuals lacking cognitive impairment are inappropriately categorized as having severe ADNC. In this study, quantitative pathology metrics and alternative tissue sampling schemes were integrated with data about premortem cognitive status, in order to derive clinically informed neuropathologic diagnostic thresholds. Specific goals of the current study were to generate data-driven, standardized diagnostic cut-points, with the most severe stages of …

Clonal Expansion Of Cytotoxic Cd8⁺ T Cells In Lecanemab-Associated Aria, Lance A. Johnson, Kai Saito, Akhil V. Pallerla, Jessica L. Funnell, Ashley R. Ezzo, Chelsea M. Song, Douglas A. Harrison, Noah J. Norton, Lauren C. Moore, Linda J. Van Eldik, David W. Fardo, Greg E. Cooper, Josh M. Morganti

Sanders-Brown Center on Aging Faculty Publications

Amyloid-related imaging abnormalities (ARIA) are the principal safety concern limiting anti-amyloid therapies for Alzheimer’s disease, yet their biology remains unclear. Here we show, through multi-omic profiling of peripheral blood from three ARIA+ patients and matched controls, that ARIA is associated with coordinated reprogramming of CD8 + T cells. CD8+ effector memory (TEM) and terminally differentiated (TEMRA) subsets were expanded, clonally enriched, and transcriptionally primed for cytotoxicity and vascular trafficking. Transcription factor inference and metabolomics converged on glycolytic reprogramming favoring short-lived effector function. Ligand-receptor modeling revealed enhanced monocyte-to-T cell signaling through antigen presentation, adhesion, and chemokine axes, while integration with a …

Apoe4 Drives Maladaptive Heterogeneity And Immunometabolic Responses Of Astrocytes, Danielle S. Goulding, Holden C. Williams, Amy A. Gorman, Nicholas A. Devanney, Douglas A. Harrison, Adeline E. Walsh, Tony Tuck, Diana J. Zajac, Shannon L. Macauley, Steven Estus, Julia Tcw, Lance A. Johnson, Josh M. Morganti

Sanders-Brown Center on Aging Faculty Publications

Apolipoprotein E4 (APOE4) is the strongest risk allele associated with the development of late onset Alzheimer’s disease (AD). Across the CNS, astrocytes are the predominant expressor of APOE while also being critical mediators of neuroinflammation and cerebral metabolism. APOE4 has been consistently linked with dysfunctional inflammation and metabolic processes, yet insights into the molecular constituents driving these responses remain unclear. Utilizing complementary approaches across humanized APOE mice and isogenic human iPSC astrocytes, we demonstrate that ApoE4 alters the astrocyte immunometabolic response to pro-inflammatory stimuli. Our findings show that ApoE4-expressing astrocytes acquire distinct transcriptional repertoires at single-cell and spatially-resolved domains, which …

Dual Orexin Receptor Antagonism With Lemborexant Enhances Microglial Clearance Of Β-Amyloid In Mice, Ashish Sharma, Emiko Segawa, Xiaoying Chen, Sohui Park, Shoutang Wang, Riley E. Irmen, Nicholas J. Constantino, Chanung Wang, Michael F. Kanan, Marco Colonna, Shannon L. Macauley, Jocelyn Y. Cheng, Ken Hatanaka, Margaret Moline, Erik S. Musiek

Sanders-Brown Center on Aging Faculty Publications

Background: Sleep disturbances elevate brain amyloid-beta (Aβ) levels and represent a modifiable risk factor for Alzheimer’s disease (AD). The orexin/hypocretin system regulates sleep–wake behavior and has emerged as a therapeutic target in AD; however, the effects of FDA-approved dual orexin receptor antagonists (DORAs) on amyloid pathology remain unclear. We compared lemborexant, an FDA-approved DORA, to doxepin, an antihistaminergic sleep medication, on amyloid pathology and microglial responses in PSAPP mice.

Methods: PSAPP mice received lemborexant (10 or 30 mg/kg/day), doxepin (35 mg/kg/day), or vehicle for 6 weeks beginning prior to plaque onset or 4 weeks after established pathology. Sleep was assessed …

Early Changes In Inflammation-Related Proteins In The Cerebrospinal Fluid And Plasma Of Patients With Aneurysmal Subarachnoid Hemorrhage, David J. Braun, Kevin W. Hatton, Justin F. Fraser, Robert M. Flight, Hunter N. B. Moseley, Caleb S. Bailey, Josh M. Morganti, Bingqing Zhang, Ishara S. Ariyapala, Tae K. Kim, Linda J. Van Eldik

Sanders-Brown Center on Aging Faculty Publications

Background

Aneurysmal subarachnoid hemorrhage (aSAH) is a relatively uncommon but high mortality form of stroke that can result in long-lasting disability. A better understanding of key neuroinflammatory changes during the early phase (< 72 h) may provide potential avenues of treatment.

Methods

In an attempt to understand these early changes, we recruited 7 aSAH patients for profiling of longitudinal plasma and cerebrospinal fluid (CSF) proteins at up to 72 h post injury. We additionally compared this to control plasma obtained previously from healthy elderly volunteers. Using the Alamar Biosciences NULISAseq platform, we obtained a comprehensive picture of early peripheral and central inflammatory changes after injury.

Results

This study …

Nicorandil Treatment Improves Survival And Spatial Learning In Aged Granulin Knockout Mice, Dana M. Niedowicz, Wang-Xia Wang, Paresh Prajapati, Yu Zhong, Shuling X. Fister, Colin B. Rogers, Pradoldej Sompol, David K. Powell, Indumati Patel, Christopher M. Norris, Kathryn E. Saatman, Peter T. Nelson

Sanders-Brown Center on Aging Faculty Publications

Mutations in the human granulin (GRN) gene are associated with multiple diseases, including dementia disorders such as frontotemporal dementia (FTD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). We studied a Grn knockout (Grn-KO) mouse model in order to evaluate a potential therapeutic strategy for these diseases using nicorandil, a commercially available agonist for the ABCC9/Abcc9-encoded regulatory subunit of the “K⁺ATP” channel that is well-tolerated in humans. Aged (13 months) Grn-KO and wild-type (WT) mice were treated as controls or with nicorandil (15 mg/kg/day) in drinking water for 7 months, then tested for neurobehavioral …

Gait Variability As A Marker Of White Matter Integrity In Individuals With Down Syndrome, Elizabeth M. Leach, David K. Powell, Amanda C. Glueck, Elizabeth Head, Moaz W. Ibrahim, Amelia J. Anderson-Mooney, Kathryn L. Van Pelt, Jordan P. Harp, Frederick A. Schmitt, Ahmed A. Bahrani

Sanders-Brown Center on Aging Faculty Publications

Introduction: Individuals with Down syndrome (DS) face a significant risk of neurodegeneration, and gait variability may serve as a clinical biomarker of neurological health. This longitudinal parent substudy aimed to explore relationships between gait, white matter (WM) integrity, and cognitive function in DS.

Methods: The associations were investigated between magnetic resonance imaging diffusion tensor imaging (DTI), cognition, and self-paced gait data from 22 DS participants (mean age ± SD 37 ± 7.5 years).

Results: DTI measures, such as lower fractional anisotropy (FA) and higher mean diffusivity, were correlated with greater step time variability but not normalized velocities. Lower cognitive scores …

Disrupted Calcium Dynamics In Reactive Astrocytes Occur With End Feet–Arteriole Decoupling In An Amyloid Mouse Model Of Alzheimer’S Disease, Blaine Weiss, John C. Gant, Ruei-Lung Lin, Jenna L. Gollihue, Colin B. Rogers, Susan D. Kraner, Edmund B. Rucker, Yuriko Katsumata, Yang Jiang, Peter T. Nelson, Donna M. Wilcock, Pradoldej Sompol, Olivier Thibault, Christopher M. Norris

Sanders-Brown Center on Aging Faculty Publications

While cerebrovascular dysfunction and reactive astrocytosis are extensively characterized hallmarks of Alzheimer's disease (AD) and related dementias, the dynamic relationship between reactive astrocytes and cerebral vessels remains poorly understood. Here, we used jGCaMP8f and two-photon microscopy to investigate calcium signaling in multiple astrocyte subcompartments, concurrent with changes in cerebral arteriole activity, in fully awake 7- to 8-month-old male and female 5xFAD mice, a model for AD-like pathology, and wild-type (WT) littermates. In the absence of movement, spontaneous calcium transients in barrel cortex occurred more frequently in astrocyte somata, processes, and perivascular regions of 5xFAD mice. However, evoked arteriole dilations (in …

Rna Editing Of Microtubule-Associated Protein Tau Circular Rnas Promotes Their Translation And Tau Tangle Formation, Justin Ralph Welden, Giorgi Margvelani, Karol Andrea Arizaca Maquera, Bhavani Gudlavalleti, Sandra C. Miranda Sardón, Alexandre Rosa Campos, Noémie Robil, Daniel C. Lee, Alvaro G. Hernandez, Wang-Xia Wang, Jing Di, Pierre De La Grange, Peter T. Nelson, Stefan Stamm

Sanders-Brown Center on Aging Faculty Publications

Aggregation of the microtubule-associated protein tau characterizes tauopathies, including Alzheimer’s disease and frontotemporal lobar degeneration (FTLD-Tau). Gene expression regulation of tau is complex and incompletely understood. Here we report that the human tau gene (MAPT) generates two circular RNAs (circRNAs) through backsplicing of exon 12 to either exon 7 (12→7 circRNA) or exon 10 (12→10 circRNA). Both circRNAs lack stop codons. The 12→7 circRNA contains one start codon and is translated in a rolling circle, generating a protein consisting of multimers of the microtubule-binding repeats R1–R4. For the 12→10 circRNA, a start codon can be introduced by two …

Genetic Expression Changes And Pathologic Findings Associated With Hyperhomocysteinemia In Human Autopsy Brain Tissue, Erica M. Weekman, Zachary Winder, Colin B. Rogers, Erin L. Abner, Tiffany L. Sudduth, Ela Patel, Adam J. Dugan, Shuling X. Fister, Brandi Wasek, Peter T. Nelson, Gregory A. Jicha, Teodoro Bottiglieri, David W. Fardo, Donna M. Wilcock

Sanders-Brown Center on Aging Faculty Publications

Introduction: Vascular contributions to cognitive impairment and dementia (VCID) are a leading cause of dementia. An underappreciated, modifiable risk factor for VCID is hyperhomocysteinemia (HHcy), defined by elevated levels of plasma homocysteine, most often due to impaired B vitamin absorption in aged persons. Studies aimed at identifying neuropathologic features and gene expression profiles associated with HHcy have been lacking.

Methods: A subset of research volunteers from the University of Kentucky Alzheimer’s Disease Research Center longitudinal cohort came to autopsy and had ante mortem plasma homocysteine levels available. Brain tissue and blood plasma drawn closest to death were used to measure …

Apoe Genetics Influence Murine Gut Microbiome, Diana J. Zajac, Stefan J. Green, Lance A. Johnson, Steven Estus

Sanders-Brown Center on Aging Faculty Publications

Apolipoprotein E (APOE) alleles impact pathogenesis and risk for multiple human diseases, making them primary targets for disease treatment and prevention. Previously, we and others reported an association between APOE alleles and the gut microbiome. Here, we evaluated effects of APOE heterozygosity and tested whether these overall results extended to mice maintained under ideal conditions for microbiome analyses. To model human APOE alleles, this study used APOE targeted replacement (TR) mice on a C57Bl/6 background. To minimize genetic drift, homozygous APOE3 mice were crossed to homozygous APOE2 or homozygous APOE4 mice prior to the study, and the resulting …

Single Low-Dose Targeted Bevacizumab Infusion In Adult Patients With Steroid-Refractory Radiation Necrosis Of The Brain: A Phase Ii Open-Label Prospective Clinical Trial, Shervin R. Dashti, Robert J. Kadner, Bradley S. Folley, Jason P. Sheehan, Dong Y. Han, Richard J. Kryscio, Mary B. Carter, Lisa B. E. Shields, Brian M. Plato, Renato V. La Rocca, Aaron C. Spalding, Tom L. Yao, Justin F. Fraser

Sanders-Brown Center on Aging Faculty Publications

OBJECTIVE There is an unmet need for safe and rapidly effective therapies for refractory brain radiation necrosis (RN). The aim of this prospective single-arm phase II trial was to evaluate the safety and efficacy of a single low-dose targeted bevacizumab infusion after blood-brain barrier disruption (BBBD) in adult patients with steroid-refractory brain RN.

METHODS Ten adults with steroid-refractory, imaging-confirmed brain RN were enrolled between November 2016 and January 2018 and followed for 12 months after treatment. Bevacizumab 2.5 mg/kg was administered as a one-time targeted intra-arterial infusion immediately after BBBD. Primary outcomes included safety and > 25% decrease in lesion volume. …

The Association Of Gabapentin Initiation And Neurocognitive Changes In Older Adults With Normal Cognition, Gyeon Oh, Daniela Claudia Moga, David W. Fardo, Erin L. Abner

Sanders-Brown Center on Aging Faculty Publications

Background: Gabapentin is increasingly prescribed to older adults, which raises concerns about its potential to cause neurocognitive changes. Therefore, we aimed to examine the association of gabapentin use with neurocognitive changes (i.e., cognitive decline, functional status decline, and motor function change) in older adults.

Methods: We conducted a retrospective cohort study using the National Alzheimer’s Coordinating Center Uniform Data Set (UDS; September 2005-March 2021 data freeze). From the eligible sample (≥age 65 years), we identified cognitively normal new-users of gabapentin and the visit they initiated gabapentin (i.e., index visit). Initiators were matched to randomly selected nonusers on year …

Deep Learning Algorithm Reveals Probabilities Of Stage-Specific Time To Conversion In Individuals With Neurodegenerative Disease Late, Xinxing Wu, Chong Peng, Peter T. Nelson, Qiang Cheng

Sanders-Brown Center on Aging Faculty Publications

Introduction: Limbic-predominant age-related TAR DNA-binding protein 43 (TDP-43) encephalopathy (LATE) is a recently defined neurodegenerative disease. Currently, there is no effective way to make a prognosis of time to stage-specific future conversions at an individual level.

Methods: After using the Kaplan–Meier estimation and log-rank test to confirm the heterogeneity of LATE progression, we developed a deep learning–based approach to assess the stage-specific probabilities of time to LATE conversions for different subjects.

Results: Our approach could accurately estimate the disease incidence and transition to next stages: the concordance index was at least 82% and the integrated Brier score …

Examining The Effects Of Formal Education Level On The Montreal Cognitive Assessment, Renee S. White, Justin M. Barber, Jordan P. Harp, Gregory A. Jicha

Sanders-Brown Center on Aging Faculty Publications

Background: Brief, global assessments such as the Montreal Cognitive Assessment (MoCA) are widely used in primary care for assessing cognition in older adults. Like other neuropsychological instruments, lower formal education can influence MoCA interpretation.

Methods: Data from 2 large studies of cognitive aging were used—Alzheimer’s Disease Neuroimaging Initiative (ADNI) and National Alzheimer’s Coordinating Center (NACC). Both use comprehensive examinations to determine cognitive status and have brain amyloid status for many participants. Mixed models were used to account for random variation due to data source.

Results: Cognitively intact participants with lower education (≤12 years) were more likely than …

Multiple Gene Variants Linked To Alzheimer's-Type Clinical Dementia Via Gwas Are Also Associated With Non-Alzheimer's Neuropathologic Entities, Yuriko Katsumata, Lincoln M. P. Shade, Timothy J. Hohman, Julie A. Schneider, David A. Bennett, Jose M. Farfel, Walter A. Kukull, David W. Fardo, Peter T. Nelson

Sanders-Brown Center on Aging Faculty Publications

The classic pathologic hallmarks of Alzheimer’s disease (AD) are amyloid plaques and neurofibrillary tangles (AD neuropathologic changes, or ADNC). However, brains from individuals clinically diagnosed with “AD-type” (amnestic) dementia usually harbor heterogeneous neuropathologies in addition to, or other than, ADNC. We hypothesized that some AD-type dementia associated genetic single nucleotide variants (SNVs) identified from large genomewide association studies (GWAS) were associated with non-ADNC neuropathologies. To test this hypothesis, we analyzed data from multiple studies with available genotype and neuropathologic phenotype information. Clinical AD/dementia risk alleles of interest were derived from the very large GWAS by Bellenguez et al. (2022) who …

Role Of Sympathetic Pathway In Light-Phase Time-Restricted Feeding-Induced Blood Pressure Circadian Rhythm Alteration, Tianfei Hou, Aaron Chacon, Wen Su, Yuriko Katsumata, Zhenheng Guo, Ming Gong

Sanders-Brown Center on Aging Faculty Publications

Disruption of blood pressure (BP) circadian rhythm, independent of hypertension, is emerging as an index for future target organ damage and is associated with a higher risk of cardiovascular events. Previous studies showed that changing food availability time alters BP rhythm in several mammalian species. However, the underlying mechanisms remain largely unknown. To address this, the current study specifically investigates (1) the relationship between rhythms of food intake and BP in wild-type mice; (2) effects of light-phase time-restricted feeding (TRF, food only available during light-phase) on BP circadian rhythm in wild-type and diabetic db/db mice; (3) the roles of the …

The Trend Of Disruption In The Functional Brain Network Topology Of Alzheimer’S Disease, Alireza Fathian, Yousef Jamali, Mohammad Reza Raoufy, The Alzheimer's Disease Neuroimaging Initiative, Michael W. Weiner, Norbert Schuf, Howard J. Rosen, Bruce L. Miller, Thomas Neylan, Jacqueline Hayess, Shannon Finley, Paul Aisen, Zaven Khachaturian, Ronald G. Thomas, Charles D. Smith, Gregory A. Jicha, Peter A. Hardy, Partha Sinha, Elizabeth Oates, Gary Conrad

Sanders-Brown Center on Aging Faculty Publications

Alzheimer’s disease (AD) is a progressive disorder associated with cognitive dysfunction that alters the brain’s functional connectivity. Assessing these alterations has become a topic of increasing interest. However, a few studies have examined different stages of AD from a complex network perspective that cover different topological scales. This study used resting state fMRI data to analyze the trend of functional connectivity alterations from a cognitively normal (CN) state through early and late mild cognitive impairment (EMCI and LMCI) and to Alzheimer’s disease. The analyses had been done at the local (hubs and activated links and areas), meso (clustering, assortativity, and …

Patients’ Attitudes Toward Deprescribing And Their Experiences Communicating With Clinicians And Pharmacists, Kaylee Marie Lukacena, James W. Keck, Patricia R. Freeman, Nancy Grant Harrington, Mark Huffmyer, Daniela C. Moga

Sanders-Brown Center on Aging Faculty Publications

Purpose: Developing effective deprescribing interventions relies on understanding attitudes, beliefs, and communication challenges of those involved in the deprescribing decision-making process, including the patient, the primary care clinician, and the pharmacist. The objective of this study was to assess patients’ beliefs and attitudes and identify facilitators of and barriers to deprescribing.

Methods: As part of a larger study, we recruited patients ⩾18years of age taking ⩾3 chronic medications. Participants were recruited from retail pharmacies associated with the University of Kentucky HealthCare system. They completed an electronic survey that included demographic information, questions about communication with their primary care clinician and …

Characterization And Comparison Of Human Glioblastoma Models, Julia A. Schulz, Louis T. Rogers, Richard J. Kryscio, Anika M. S. Hartz, Björn Bauer

Sanders-Brown Center on Aging Faculty Publications

Abstract
Glioblastoma (GBM) is one of the deadliest cancers. Treatment options are limited, and median patient survival is only several months. Translation of new therapies is hindered by a lack of GBM models that fully recapitulate disease heterogeneity. Here, we characterize two human GBM models (U87-luc2, U251-RedFLuc). In vitro, both cell lines express similar levels of luciferase and show comparable sensitivity to temozolomide and lapatinib exposure. In vivo, however, the two GBM models recapitulate diferent aspects of the disease. U87-luc2 cells quickly grow into large, well-demarcated tumors; U251-RedFLuc cells form small, highly invasive tumors. Using a new method to assess …

An Il1rl1 Genetic Variant Lowers Soluble St2 Levels And The Risk Effects Of Apoe-Ε4 In Female Patients With Alzheimer’S Disease, Yuanbing Jiang, Xiaopu Zhou, Hui Yi Wong, Li Ouyang, Fanny C. F. Ip, Vicky M. N. Chau, Shun-Fat Lau, Wei Wu, Daniel Y. K. Wong, Heukjin Seo, Wing-Yu Fu, Nicole C. H. Lai, Yuewen Chen, Alzheimer’S Disease Neuroimaging Initiative, Charles D. Smith, Gregory A. Jicha, Peter A. Hardy, Partha Sinha, Elizabeth Oates, Gary Conrad

Sanders-Brown Center on Aging Faculty Publications

Changes in the levels of circulating proteins are associated with Alzheimer’s disease (AD), whereas their pathogenic roles in AD are unclear. Here, we identified soluble ST2 (sST2), a decoy receptor of interleukin-33–ST2 signaling, as a new disease-causing factor in AD. Increased circulating sST2 level is associated with more severe pathological changes in female individuals with AD. Genome-wide association analysis and CRISPR–Cas9 genome editing identified rs1921622, a genetic variant in an enhancer element of IL1RL1, which downregulates gene and protein levels of sST2. Mendelian randomization analysis using genetic variants, including rs1921622, demonstrated that decreased sST2 levels lower AD …

Exogenous Short Chain Fatty Acid Effects In App/Ps1 Mice, Diana J. Zajac, Benjamin C. Shaw, David J. Braun, Stefan J. Green, Joshua M. Morganti, Steven Estus

Sanders-Brown Center on Aging Faculty Publications

Elucidating the impact of the gut microbiome on Alzheimer’s Disease (AD) is an area of intense interest. Short chain fatty acids (SCFAs) are major microbiota metabolites that have been implicated as a mediator of gut microbiome effects in the brain. Here, we tested the effects of SCFA-treated water vs. saline-treated water on APPswe/PSEN1dE9 mice maintained under standard laboratory conditions. Mice were treated with SCFAs from five months of age until ten months of age, when they were evaluated for microbiome profile, impaired spatial memory as evaluated with the radial arm water maze, astrocyte activation as measured by Gfap expression and …

Enlarged Perivascular Spaces Are Negatively Associated With Montreal Cognitive Assessment Scores In Older Adults, Timothy J. Libecap, Valentinos Zachariou, Christopher E. Bauer, Donna M. Wilcock, Gregory A. Jicha, Flavius D. Raslau, Brian T. Gold

Sanders-Brown Center on Aging Faculty Publications

Emerging evidence suggests that enlarged perivascular spaces (ePVS) may be a clinically significant neuroimaging marker of global cognitive function related to cerebral small vessel disease (cSVD). We tested this possibility by assessing the relationship between ePVS and both a standardized measure of global cognitive function, the Montreal Cognitive Assessment (MoCA), and an established marker of cSVD, white matter hyperintensity volume (WMH) volume. One hundred and eleven community-dwelling older adults (56–86) underwent neuroimaging and MoCA testing. Quantification of region-specific ePVS burden was performed using a previously validated visual rating method and WMH volumes were computed using the standard ADNI pipeline. Separate …

Impact Of The Covid-19 Pandemic On Daily Life, Mood, And Behavior Of Adults With Down Syndrome, Sigan L. Hartley, Victoria Fleming, Brianna Piro-Gambetti, Annie Cohen, Beau M. Ances, Michael A. Yassa, Adam M. Brickman, Benjamin L. Handen, Elizabeth Head, Mark Mapstone, Bradley T. Christian, Ira T. Lott, Eric Doran, Shahid Zaman, Sharon Krinsky-Mchale, Frederick A. Schmitt, Christy L. Hom, Nicole Schupf

Sanders-Brown Center on Aging Faculty Publications

Background: The Down syndrome population has been disproportionately affected by Coronavirus 2019 (COVID-19) in terms of experiencing severe illness and death. Societal efforts to curb the spread of COVID-19 may also have taken a heavy toll on the daily lives of individuals with Down syndrome.

Objective/hypothesis: The goal of the study was to understand how the COVID-19 pandemic has altered daily life (including residence, employment, and participation in adult disability day programs) and influenced the mood and behavior of adults with Down syndrome.

Methods: Between September 2020 and February 2021, caregivers of 171 adults with Down syndrome (aged …

Sex Differences In The Genetic Architecture Of Cognitive Resilience To Alzheimer’S Disease, Jaclyn M. Eissman, Logan Dumitrescu, Emily R. Mahoney, Alexandra N. Smith, Shubhabrata Mukherjee, Michael L. Lee, Phoebe Scollard, Seo Eun Choi, William S. Bush, Corinne D. Engelman, Qiongshi Lu, David W. Fardo, Emily H. Trittschuh, Jesse Mez, Catherine C. Kaczorowski, Hector Hernandez Saucedo, Keith F. Widaman, Rachel F. Buckley, Michael J. Properzi, Elizabeth C. Mormino, Hyun Sik Yang, Theresa M. Harrison, Trey Hedden, Kwangsik Nho, Shea J. Andrews, Douglas Tommet, Niran Hadad, R. Elizabeth Sanders, Douglas M. Ruderfer, Katherine A. Gifford, Xiaoyuan Zhong, Neha S. Raghavan, Badri Vardarajan, Margaret A. Pericak-Vance, Lindsay A. Farrer, Li San Wang, Carlos Cruchaga, Gerard D. Schellenberg, Nancy J. Cox, Jonathan L. Haines, C. Dirk Keene, Andrew J. Saykin, Eric B. Larson, Reisa A. Sperling, Richard Mayeux, Michael L. Cuccaro, David A. Bennett, Julie A. Schneider, Paul K. Crane, Angela L. Jefferson, Timothy J. Hohman

Sanders-Brown Center on Aging Faculty Publications

Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer's disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer's disease neuropathology may uncover novel therapeutic targets to treat Alzheimer's disease. It is well established that there are sex differences in response to Alzheimer's disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience.

We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts …

Extracellular Vesicles Released After Cranial Radiation: An Insight Into An Early Mechanism Of Brain Injury, Suriyan Sukati, Jenni Ho, Luksana Chaiswing, Pradoldej Sompol, Harshul Shreekant Pandit, Wendy Wei, Tadahide Izumi, Quan Chen, Heidi Weiss, Teresa Noel, Subbarao Bondada, D. Allan Butterfield, Daret K. St. Clair

Sanders-Brown Center on Aging Faculty Publications

Cranial radiation is important for treating both primary brain tumors and brain metastases. A potential delayed side effect of cranial radiation is neurocognitive function decline. Early detection of CNS injury might prevent further neuronal damage. Extracellular vesicles (EVs) have emerged as a potential diagnostic tool because of their unique membranous characteristics and cargos. We investigated whether EVs can be an early indicator of CNS injury by giving C57BJ/6 mice 10 Gy cranial IR. EVs were isolated from sera to quantify: 1) number of EVs using nanoparticle tracking analysis (NTA); 2) Glial fibrillary acidic protein (GFAP), an astrocyte marker; and 3) …

Association Between Concussions And Suicidality In High School Students In The United States, Grant L. Iverson, Justin E. Karr

Sanders-Brown Center on Aging Faculty Publications

Importance: Prior research has shown a statistically significant association between sustaining a concussion and suicidality in adolescents, but this prior research controlled for relatively few variables predictive of suicidality.

Objective: To examine whether sustaining a concussion remained a significant predictor of suicidality after controlling for relevant covariates (e.g., sexual abuse/assault, bullying, substance use, depression), hypothesizing that the relationship between concussion and suicidality would become non-significant after controlling for these variables.

Design: This study involved secondary data analysis of the 2019 Youth Risk Behavior Surveillance (YRBS) System, a national cross-sectional study of adolescents. Analyses were stratified by gender. …

Manifestations Of Alzheimer’S Disease Genetic Risk In The Blood Are Evident In A Multiomic Analysis In Healthy Adults Aged 18 To 90, Laura Heath, John C. Earls, Andrew T. Magis, Sergey A. Kornilov, Jennifer C. Lovejoy, Cory C. Funk, Noa Rappaport, Benjamin A. Logsdon, Lara M. Mangravite, Brian W. Kunkle, Eden R. Martin, Adam C. Naj, Nilüfer Ertekin-Taner, Todd E. Golde, Leroy Hood, Nathan D. Price, Erin Abner, David W. Fardo, Linda J. Van Eldik, Alzheimer’S Disease Genetics Consortium

Sanders-Brown Center on Aging Faculty Publications

Genetics play an important role in late-onset Alzheimer’s Disease (AD) etiology and dozens of genetic variants have been implicated in AD risk through large-scale GWAS meta-analyses. However, the precise mechanistic effects of most of these variants have yet to be determined. Deeply phenotyped cohort data can reveal physiological changes associated with genetic risk for AD across an age spectrum that may provide clues to the biology of the disease. We utilized over 2000 high-quality quantitative measurements obtained from blood of 2831 cognitively normal adult clients of a consumer-based scientific wellness company, each with CLIA-certified whole-genome sequencing data. Measurements included: clinical …

Patterns Of Amygdala Region Pathology In Late-Nc: Subtypes That Differ With Regard To Tdp-43 Histopathology, Genetic Risk Factors, And Comorbid Pathologies, Matthew D. Cykowski, Anithachristy S. Arumanayagam, Suzanne Z. Powell, Andreana L. Rivera, Erin L. Abner, Gustavo C. Roman, Joseph C. Masdeu, Peter T. Nelson

Sanders-Brown Center on Aging Faculty Publications

Transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) pathology is a hallmark of limbic-predominant agerelated TDP-43 encephalopathy (LATE). The amygdala is afected early in the evolution of LATE neuropathologic change (LATE-NC), and heterogeneity of LATE-NC in amygdala has previously been observed. However, much remains to be learned about how LATE-NC originates and progresses in the brain. To address this, we assessed TDP-43 and other pathologies in the amygdala region of 184 autopsied subjects (median age=85 years), blinded to clinical diagnoses, other neuropathologic diagnoses, and risk genotype information. As previously described, LATE-NC was associated with older age at death, cognitive impairment, …