Neurosciences Commons^™

Diagnostic Yield Of Exome Sequencing For Pregnancies With And Without Fetal Anomalies And For Stillbirth, Roni Zemet, Christian M Parobek, April D Adams, Mohamad Ali Maktabi, Lena Shay, Linyan Meng, Pengfei Liu, Hongzheng Dai, Fan Xia, Christine Eng, Ignatia B Van Den Veyver, Liesbeth Vossaert

Duncan NRI Faculty and Staff Publications

Objective: Exome sequencing (ES) benefits the genetic work-up for fetuses with structural anomalies, but data on its utility for fetuses without anomalies and stillbirths is more limited. We report our experience with prenatal ES for all three indications.

Method: We retrospectively reviewed results from 344 trio-ES performed for fetuses with structural anomalies (N = 262), stillbirths (N = 39), and fetuses without anomalies (N = 43), many of which had a relevant family history. We classified pathogenic variants (P), likely pathogenic variants (LP), or variants of uncertain significance (VUS) favoring pathogenicity in a gene consistent with the fetal phenotype as …

Coenzyme Q Headgroup Intermediates Can Ameliorate A Mitochondrial Encephalopathy, Guangbin Shi, Claire Miller, Sota Kuno, Alejandro G Rey Hipolito, Salsabiel El Nagar, Giulietta M Riboldi, Megan Korn, Wyatt C Tran, Zixuan Wang, Lia Ficaro, Tao Lin, Quentin Spillier, Begoña Gamallo-Lana, Drew R Jones, Matija Snuderl, Soomin C Song, Adam C Mar, Alexandra L Joyner, Roy V Sillitoe, Robert S Banh, Michael E Pacold

Duncan NRI Faculty and Staff Publications

Decreased brain levels of coenzyme Q10 (CoQ10), an endogenously synthesized lipophilic antioxidant1,2, underpin encephalopathy in primary CoQ10 deficiencies3,4 and are associated with common neurodegenerative diseases and the ageing process5,6. CoQ10 supplementation does not increase CoQ10 pools in the brain or in other tissues. The recent discovery of the mammalian CoQ10 headgroup synthesis pathway, in which 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL) makes 4-hydroxymandelate (4-HMA) to synthesize the CoQ10 headgroup precursor 4-hydroxybenzoate (4-HB)7, offers an opportunity to pharmacologically restore CoQ10 synthesis and mechanistically treat CoQ10 deficiencies. To test whether 4-HMA …

High-Resolution Mapping Of Alcohol-Related Brain Connectivity In Adults Using 7t Fmri And Multivoxel Pattern Classification, Alan N. Francis, Ihsan Salloum

School of Medicine Publications

Background: Emerging evidence suggests that alcohol use disrupts large-scale brain network interactions, particularly within the triple network model-comprising the Salience Network (SN), Default Mode Network (DMN), and Frontoparietal Network (FPN). However, few studies have examined how these connectivity alterations vary across the full spectrum of alcohol consumption, especially using ultra-high-field imaging and data-driven approaches. This study leverages 7 Tesla resting-state fMRI and multivariate pattern analysis (MVPA) to characterize distinct brain connectivity patterns across heavy, moderate, and non-drinking adults, aiming to identify neural signatures that differentiate alcohol use severity levels.

Methods: We analyzed resting-state functional connectivity data from 69 adults (Mean …

Systematic Review And Evidence Gap Mapping Of Alzheimer's Disease Biomarker Studies In Those With Intellectual And Developmental Disability, Lubnaa B. Abdullah, Ney Alex Alliey, Emma Elizondo, Ney Alliey Rodriguez, Gladys Maestre, James Hall

School of Medicine Publications

There are a relatively small number of investigations into brain aging in those with intellectual and developmental disability (I/DD). This project seeks to (1) characterize the internationally available multi-omics Alzheimer's disease (AD) biomarker studies including those with I/DD, and (2) discuss future research directions. PubMed, Web of Science, and Scopus were searched under the following criteria: cross-sectional or longitudinal AD-omics studies on adults (18 +) with I/DD. 532 studies were identified, 186 studies were evaluated for full-text, 79 studies were excluded, and 117 studies were extracted. Most biological specimens were analyzed in blood, plasma, or serum. Metabolomics, hormonomics, and transcriptomics …

Moderate Coffee And Tea Consumption Is Associated With Slower Cognitive Decline, Stephanie R. Rainey-Smith, Kelsey R. Sewell, Belinda M. Brown, Hamid R. Sohrabi, Ralph N. Martins, Samantha L. Gardener

Research outputs 2022 to 2026

Background: Globally, coffee and tea are consumed extensively, potentially providing neuroprotection through anti-inflammatory and antioxidative stress effects. Objective: This study aimed to investigate associations between coffee and tea intake and cognitive function. Methods: In a longitudinal prospective cohort study, dementia-free (n = 8715; age range 60.0–85.2 years) older adults from the UK Biobank self-reported coffee and tea intake over the previous year; ‘never’, ‘moderate’ (1–3 cups/day), or ‘high’ (≥4 cups/day). Participants completed cognitive assessments at ≥2 timepoints (mean of 9.11 years). Results: Those ‘never’ consuming coffee and ‘moderate’ coffee consumers (β = 0.06, p = 0.005; β = 0.07, p <  0.001, respectively), as well as ‘moderate’ tea consumers and ‘high’ tea consumers (β = 0.06, p = 0.009; β = 0.06, p = 0.003, respectively) had slower fluid intelligence decline. Additionally, those ‘never’ consuming coffee and ‘moderate’ coffee consumers had a slower increase in pairs matching errors (β = −0.05, p = 0.022; β = 0.05, p = 0.013) compared to ‘high’ consumers. Conclusions: ‘Moderate’ coffee, and ‘moderate’ and ‘high’ tea intake may be a protective factor against cognitive decline. Randomized controlled trials are required to establish causal relationships leading to evidence-based recommendations regarding benefits of coffee and tea intake.

Heightened Risk: Childhood Trauma And Anticipatory Grief Exacerbate The Impact Of Loneliness On Depressive Symptoms And Lps-Stimulated Cytokines In Dementia Caregivers, Kelly N Brice, Jensine Paoletti-Hatcher, E Lydia Wu-Chung, Vincent D Lai, Daniel L Argueta, Michelle A Chen, Itee Mahant, Bryan T Denny, Charles Green, Luis D Medina, Paul Schulz, Jennifer Stinson, Samantha K Henry, Cobi Heijnen, Christopher P Fagundes

Faculty, Staff and Student Publications

Dementia spousal caregivers are at a disproportionate risk for adverse mental and physical health outcomes. Loneliness is associated with depressive symptoms and proinflammatory cytokine production among caregivers. Additionally, childhood trauma, anticipatory grief, and poor sleep quality are all associated with enhanced stress reactivity. This study used a cross-sectional design to investigate whether loneliness is associated with proinflammatory cytokine production and depressive symptoms in caregivers, and whether these relationships are strongest among caregivers who report high levels of childhood trauma, high amounts of anticipatory grief, or poor sleep quality. A sample of 111 dementia spousal caregivers provided blood samples and completed …

A Large-Scale Multi-Centre Study Characterising Atrophy Heterogeneity In Alzheimer's Disease, Vikram Venkatraghavan, Damiano Archetti, Pierrick Bourgeat, Chenyang Jiang, Mara Ten Kate, Anna C. Van Loenhoud, Rik Ossenkoppele, Charlotte E. Teunissen, Elsmarieke Van De Giessen, Yolande A.L. Pijnenburg, Giovanni B. Frisoni, Béla Weiss, Zoltán Vidnyánszky, Tibor Auer, Stanley Durrleman, Alberto Redolfi, Simon M. Laws, Paul Maruff, Neil P. Oxtoby, Andre Altmann, Daniel C. Alexander, Wiesje M. Van Der Flier, Frederik Barkhof, Betty M. Tijms

Research outputs 2022 to 2026

Previous studies identified atrophy-based Alzheimer's disease(AD) subtypes linked to distinct clinical symptoms, but their consistency across subtyping approaches remains unclear. This large-scale study evaluates subtype concordance using two data-driven approaches. In this work, we analyzed data from n=10,011 patients across 10 AD cohorts spanning Europe, the US, and Australia, extracting regional volumes using Freesurfer. To characterize atrophy heterogeneity in the AD continuum, we developed a two-step approach, Snowphlake (Staging NeurOdegeneration With PHenotype informed progression timeLine of biomarKErs), to identify subtypes and atrophy-event sequences within each subtype. Results were compared with SuStaIn (Subtype and Stage Inference), which jointly estimates subtypes and …

Risk Of Major Depression In Partners Of People With Alzheimer's Disease: A National Cohort Study, Casey Crump, Jingkai Wei, Barbara G Vickrey, Alexis C Edwards, Paul E Schulz, Weiva Sieh, Jan Sundquist, Kristina Sundquist

Faculty, Staff and Student Publications

Background: Alzheimer's disease (AD) may cause significant psychosocial distress not only in the patient but also their partner. However, long-term risks of major depression in partners of AD patients are largely unknown.

Methods: A national cohort study was conducted of all 145 289 partners of people diagnosed with all-cause dementia, including 57 113 partners of people diagnosed with AD, in Sweden during 1998-2017, and 1 300 561 population-based controls. Cox regression was used to compute hazard ratios (HRs) for subsequent risk of major depression identified from nationwide outpatient and inpatient diagnoses through 2018, adjusting for sociodemographic factors and prior mental …

Heterozygous Variants In Plcg1 Affect Hearing, Vision, Cardiac, And Immune Function, Mengqi Ma, Yiming Zheng, Mingxi Deng, Shenzhao Lu, Xueyang Pan, Xi Luo, Michelle Etoundi, David Li-Kroeger, Kim C Worley, Lindsay C Burrage, Lauren S Blieden, Aimee Allworth, Wei-Liang Chen, Giuseppe Merla, Barbara Mandriani, Catherine E Otten, Pierre Blanc, Jill A Rosenfeld, Debdeep Dutta, Shinya Yamamoto, Michael F Wangler, Ian A Glass, Jingheng Chen, Elizabeth Blue, Paolo Prontera, Jeremie Rosain, Sandrine Marlin, Seema R Lalani, Hugo J Bellen, Undiagnosed Diseases Network

Duncan NRI Faculty and Staff Publications

Phospholipase C isozymes (PLCs) hydrolyze phosphatidylinositol 4,5-bisphosphate (PIP₂) into inositol 1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG), important signaling molecules involved in many cellular processes including Ca²⁺ release from the endoplasmic reticulum (ER). PLCG1 encodes the PLCγ1 isozyme that is broadly expressed. Hyperactive somatic mutations of PLCG1 are observed in multiple cancers, but only one germline variant has been reported. Here, we describe seven individuals with heterozygous missense variants in PLCG1 [p.(Asp1019Gly), p.(His380Arg), p.(Asp1165Gly), and p.(Leu597Phe)] who present with hearing impairment (5/7), ocular pathology (4/7), cardiac septal defects (3/6), and various immunological issues (5/7). To model these …

A Protective Role Of Src-1 Against Aging Associated Cognitive Decline, Hesong Liu, Yongjie Yang, Jonathan C Bean, Yang He, Hailan Liu, Rambabu Majji, Chen Liang, Nan Zhang, Meng Yu, Longlong Tu, Qingzhuo Liu, Yue Deng, Kristine M Conde, Na Yin, Mengjie Wang, Yongxiang Li, Junying Han, Sanika Vattakuzhiyil Jossy, Megan Elyse Burt, Hari Krishna Yalamanchili, Chunmei Wang

Duncan NRI Faculty and Staff Publications

Introduction: Research indicates a strong correlation between obesity and the risk of dementia, both are linked to steroid receptor coactivator-1 (SRC-1), a transcriptional coactivator.

Methods: We used RNA sequencing analysis (RNA-Seq) to investigate the transcriptome of SRC-1-KO mice, and identified S100 calcium-binding protein A6 (S100A6), an AD associated gene, as one target of SRC-1. We tested cognitive behaviors in SRC-1-KO mice and mice with a humanized SRC-1 mutation (SRC-1L1376P), and performed promoter luciferase assays on S100A6.

Results: Loss of SRC-1 caused alterations in gene signatures that are commonly associated with neurodegenerative diseases, including AD, and diminished the neural plasticity of …

The 9th Annual Lafora Science Symposium: A Rare Epilepsy Community Makes Progress Towards Clinical Readiness, Meredith I. Williams, Katherine J. Donahue, Pascual Sanz, Souad Messahel, Jose M. Serratosa, Jordi Duran, Roberto Michelucci, Lorenzo Muccioli, Antonio Delgado-Escueta, Viet-Hong Nguyen, Berge A. Minassian, Matthew S. Gentry

Pharmacy Faculty Articles and Research

Lafora disease (LD) is a fatal childhood progressive myoclonus epilepsy and glycogen storage disease that is caused by recessive mutations in either EPM2A or EPM2B. The hallmarks of LD are cytoplasmic, aberrant glycogen-like aggregates, called Lafora bodies (LBs), that drive disease progression. The 9th Annual Lafora Science Symposium was held in San Diego, California and brought together over 70 researchers, clinicians, academic trainees, and friends and family members of patients with LD and 80 attendees joined virtually. This symposium focused primarily on international collaborations for therapeutic development and biomarker identification and strategies for preparing the Lafora community for upcoming …

Signaling By Intracellular Β2-Adrenergic Receptors Regulates Ampa Receptor Trafficking And Synaptic Plasticity, Boram Lee, Xiaomin Xing, Kyle E. Ireton, Bing Xu, Paul J. Gasser, Johannes W. Hell

Biomedical Sciences Faculty Research and Publications

Signaling by norepinephrine (NE) via adrenergic receptors (ARs) mediates attention, yet the underlying molecular mechanisms are largely unknown. AMPA receptors (AMPARs) form a complex with β2ARs, Gs, adenylyl cyclase, and protein kinase A (PKA) to augment AMPAR phosphorylation and, thereby, surface expression. We show that signaling by intracellular β2ARs is required for these effects and two different forms of long-term potentiation (LTP) that depend on β2AR signaling and phosphorylation of the AMPAR GluA1 subunit on S845. Inhibition of two NE transporters, the organic cation transporter 3 (OCT3) and the plasma membrane monoamine transporter (PMAT), impairs phosphorylation of the AMPAR GluA1 …

Current Practices In The Study Of Biomolecular Acondensates: A Community Comment, Simon Alberti, Paolo Arosio, Robert B Best, Steven Boeynaems, Danfeng Cai, Rosana Collepardo-Guevara, Gregory L Dignon, Rumiana Dimova, Shana Elbaum-Garfinkle, Nicolas L Fawzi, Monika Fuxreiter, Amy S Gladfelter, Alf Honigmann, Ankur Jain, Jerelle A Joseph, Tuomas P J Knowles, Keren Lasker, Edward A Lemke, Kresten Lindorff-Larsen, Reinhard Lipowsky, Jeetain Mittal, Samrat Mukhopadhyay, Sua Myong, Rohit V Pappu, Karsten Rippe, Tatyana A Shelkovnikova, Anthony G Vecchiarelli, Susanne Wegmann, Huaiying Zhang, Mingjie Zhang, Chloe Zubieta, Markus Zweckstetter, Dorothee Dormann, Tanja Mittag

Duncan NRI Faculty and Staff Publications

The realization that the cell is abundantly compartmentalized into biomolecular condensates has opened new opportunities for understanding the physics and chemistry underlying many cellular processes, fundamentally changing the study of biology. The term biomolecular condensate refers to non-stoichiometric assemblies that are composed of multiple types of macromolecules in cells, occur through phase transitions, and can be investigated by using concepts from soft matter physics. As such, they are intimately related to aqueous two-phase systems and water-in-water emulsions. Condensates possess tunable emergent properties such as interfaces, interfacial tension, viscoelasticity, network structure, dielectric permittivity, and sometimes interphase pH gradients and electric potentials–. …

Prior Adolescent Oxycodone Exposure Enhances Pain Sensitivity Following Chronic Intermittent Ethanol In Adult Female Mice, Lisa L. Wilson, Lucas Albrechet-Souza, Linh Ha, Nicholas W. Gilpin, Tiffany A. Wills

School of Graduate Studies Faculty Publications

The opioid crisis remains a critical public health concern, with rising rates of overdose and opioid use disorder. While opioids are effective for managing pain, both chronic use and withdrawal are associated with increased pain sensitivity. Although most prior research has focused on adults, opioid use during adolescence is common and linked to a heightened risk for developing alcohol use disorder and other forms of substance misuse. Like opioids, acute alcohol use can be analgesic, but chronic alcohol exposure and withdrawal lead to increased pain sensitivity. However, the interactive effects of adolescent opioid and adult alcohol exposure on pain remain …

Transcriptomic And Epigenomic Profiling Of Immune Cells Responses To Simian Immunodeficiency Virus Infection In The Brain, Xiaoke Xu

Theses & Dissertations

Human immunodeficiency virus type 1 (HIV-1) is an enveloped retrovirus that significantly impairs the human immune system. A common complication of HIV-1 infection is HIV-associated neurocognitive disorder (HAND), which, prior to the introduction of antiretroviral therapy (ART), led to considerable morbidity and mortality due to untreated neuropsychiatric manifestations. Although ART has substantially reduced the incidence of HIV-associated dementia (HAD), approximately 50% of people living with HIV (PLWH) continue to experience milder forms of HAND. The CNS is seeded by HIV during the acute phase of infection. Once in the brain, HIV targets and activates resident immune cells, primarily microglia and …

The Speech-To-Song Illusion Across Development And The Effects Of High-Level Expectations, Rodica R. Constantine

UNLV Theses, Dissertations, Professional Papers, and Capstones

The typical listener can readily categorize auditory stimuli as either speech or song even though these structures share many acoustic similarities. These musical and linguistic categories may nevertheless take time to develop as children acquire language- and music-specific knowledge. In the Speech-to-Song (STS) illusion, multiple repetitions of a natural spoken utterance can give rise to a perceptual switch wherein the stimulus begins to sound song-like to the listener. While the STS illusion has been well-researched in adult listeners, it had yet to be investigated in children. In our study, we examined whether children experience the STS illusion by presenting participants …

Exploring The Processing Of Objects, Settings, And Global Properties In Natural Auditory Scenes, Margaret A. Mcmullin

UNLV Theses, Dissertations, Professional Papers, and Capstones

Our auditory system has a remarkable ability to make sense of complex environments, allowing us to identify what we are hearing and where sounds come from. This process of auditory scene analysis is essential for situational awareness, decision-making, and effective communication in daily life. While much is known about how listeners segregate and identify individual sound sources (e.g., voices), less is understood about how global properties of a scene (e.g., openness, naturalness) contribute to perception. This dissertation examined how object- and setting-level information in natural auditory scenes are processed, and whether they rely on distinct or overlapping mechanisms. In Experiment …

A Multi-Measurement Study Of The Relation Between Deliberation And Volition, Guillaume P. Pech, Emilie A. Caspar, Elisabeth Pacherie, Axel Cleeremans, Uri Maoz

Psychology Faculty Articles and Research

Historically, voluntary action and volition more generally have been investigated through the lens of meaningless decisions. Importantly, these findings have been used in the debate about key notions like free will and moral responsibility. However, more recent claims have challenged the possibility of generalizing findings from a meaningless context to a more meaningful one. The current study investigates the markers of volition, specifically comparing meaningful and meaningless decisions. In an effort to maximize their monetary gain, 50 participants repeatedly deliberated between two options, making either rewarded choices—hard-deliberation decisions (where the options differed along two dimensions) or easy-deliberation decisions (where the …

Rare Variants In Bmal1 Are Associated With A Neurodevelopmental Syndrome, Vishnu Anand Cuddapah, Dechun Chen, Bumsik Cho, Rebecca Moore, Mohnish Suri, Hana Safraou, Frederic Tran-Mau-Them, Ashley Wilson, Jacqueline Odgis, Atteeq U Rehman, Carol Saunders, Shiva Ganesan, Vaidehi Jobanputra, Stephen W Scherer, Ingo Helbig, Amita Sehgal

Duncan NRI Faculty and Staff Publications

Children with neurodevelopmental disorders exhibit highly penetrant sleep and circadian dysfunction, but the underlying mechanisms are unclear. We asked whether a subset of individuals with neurodevelopmental disorders might have genetic variants in genes known to drive circadian rhythms. Through international collaboration, we identified ten individuals with very rare genetic variants in BMAL1, a core component of the molecular clock. These individuals exhibited overlapping signs and symptoms including developmental delay, autism spectrum disorder, and variably penetrant marfanoid features. We functionally tested the identified BMAL1 variants in cell culture and in vivo and found disrupted BMAL1 function. These findings demonstrate that …

Upregulating Ankhd1 In Ps19 Mice Reduces Tau Phosphorylation And Mitigates Tau Toxicity-Induced Cognitive Deficits, Xiaolin Tian, Nathan Le, Yuhai Zhao, Dina Alawamleh, Andrew Schwartz, Lauren Meyer, Elizabeth Helm, Chunlai Wu

School of Graduate Studies Faculty Publications

Using the fly eye as a model system, we previously demonstrated that upregulation of the fly gene mask protects against FUS- and Tau-induced photoreceptor degeneration. Building upon this finding, we investigated whether the protective role of mask is conserved in mammals. To this end, we generated a transgenic mouse line carrying Cre-inducible ANKHD1, the human homolog of mask. Utilizing the TauP301S-PS19 mouse model for Tau-related dementia, we found that expressing ANKHD1 driven by CamK2a-Cre reduced hyperphosphorylated human Tau in 6-month-old mice. Additionally, ANKHD1 expression was associated with a trend toward reduced gliosis and preservation of the presynaptic marker Synaptophysin, suggesting …