Neurosciences Commons^™

Parkinson's Disease And Other Alzheimer's Disease And Related Dementia Pathologies And The Progression Of Parkinsonism In Older Adults, Aron S Buchman, Lei Yu, Shahram Oveisgharan, Andrea R Zammit, Tianhao Wang, Joshua M Shulman, Veronique Vanderhorst, Sukrit Nag, David A Bennett

Faculty, Staff and Students Publications

BACKGROUND: The interrelationship of parkinsonism, Parkinson's disease (PD) and other Alzheimer's disease (AD) and Alzheimer's disease and related dementias (ADRD) pathologies is unclear.

OBJECTIVE: We examined the progression of parkinsonian signs in adults with and without parkinsonism, and their underlying brain pathologies.

METHODS: Annual parkinsonian signs were based on a modified Unified Parkinson's Disease Rating Scale. We used linear mixed effects models to compare the progression of parkinsonian signs in 3 groups categorized based on all available clinical evaluations: Group1 (never parkinsonism or clinical PD), Group2 (ever parkinsonism, but never clinical PD), Group3 (ever clinical PD). In decedents, we examined …

Translational Symmetry In Convolutions With Localized Kernels Causes An Implicit Bias Toward High Frequency Adversarial Examples, Josue O Caro, Yilong Ju, Ryan Pyle, Sourav Dey, Wieland Brendel, Fabio Anselmi, Ankit B Patel

Faculty, Staff and Students Publications

Adversarial attacks are still a significant challenge for neural networks. Recent efforts have shown that adversarial perturbations typically contain high-frequency features, but the root cause of this phenomenon remains unknown. Inspired by theoretical work on linear convolutional models, we hypothesize that translational symmetry in convolutional operations together with localized kernels implicitly bias the learning of high-frequency features, and that this is one of the main causes of high frequency adversarial examples. To test this hypothesis, we analyzed the impact of different choices of linear and non-linear architectures on the implicit bias of the learned features and adversarial perturbations, …

Multimodal Prediction Of Obsessive-Compulsive Disorder And Comorbid Depression Severity And Energy Delivered By Deep Brain Electrodes, Saurabh Hinduja, Ali Darzi, Itir Onal Ertugrul, Nicole Provenza, Ron Gadot, Eric A Storch, Sameer A Sheth, Wayne K Goodman, Jeffrey F Cohn

Faculty, Staff and Students Publications

To develop reliable, valid, and efficient measures of obsessive-compulsive disorder (OCD) severity, comorbid depression severity, and total electrical energy delivered (TEED) by deep brain stimulation (DBS), we trained and compared random forests regression models in a clinical trial of participants receiving DBS for refractory OCD. Six participants were recorded during open-ended interviews at pre- and post-surgery baselines and then at 3-month intervals following DBS activation. Ground-truth severity was assessed by clinical interview and self-report. Visual and auditory modalities included facial action units, head and facial landmarks, speech behavior and content, and voice acoustics. Mixed-effects random forest regression with Shapley feature …

Dolutegravir Induces Folr1 Expression During Brain Organoid Development, Carlo Donato Caiaffa, Gabriel Tukeman, Christian Zevallos Delgado, Yogeshwari S Ambekar, Taye T Mekonnen, Manmohan Singh, Victoria Rodriguez, Emily Ricco, Daniel Kraushaar, Salavat R Aglyamov, Giuliano Scarcelli, Kirill V Larin, Richard H Finnell, Robert M Cabrera

Faculty, Staff and Students Publications

During the first month of pregnancy, the brain and spinal cord are formed through a process called neurulation. However, this process can be altered by low serum levels of folic acid, environmental factors, or genetic predispositions. In 2018, a surveillance study in Botswana, a country with a high incidence of human immunodeficiency virus (HIV) and lacking mandatory food folate fortification programs, found that newborns whose mothers were taking dolutegravir (DTG) during the first trimester of pregnancy had an increased risk of neural tube defects (NTDs). As a result, the World Health Organization and the U.S. Food and Drug Administration have …

Proceedings Of The 11th Annual Deep Brain Stimulation Think Tank: Pushing The Forefront Of Neuromodulation With Functional Network Mapping, Biomarkers For Adaptive Dbs, Bioethical Dilemmas, Ai-Guided Neuromodulation, And Translational Advancements, Kara A Johnson, Nico U F Dosenbach, Evan M Gordon, Cristin G Welle, Kevin B Wilkins, Helen M Bronte-Stewart, Valerie Voon, Takashi Morishita, Yuki Sakai, Amanda R Merner, Gabriel Lázaro-Muñoz, Theresa Williamson, Andreas Horn, Ro'ee Gilron, Jonathan O'Keeffe, Aryn H Gittis, Wolf-Julian Neumann, Simon Little, Nicole R Provenza, Sameer A Sheth, Alfonso Fasano, Abbey B Holt-Becker, Robert S Raike, Lisa Moore, Yagna J Pathak, David Greene, Sara Marceglia, Lothar Krinke, Huiling Tan, Hagai Bergman, Monika Pötter-Nerger, Bomin Sun, Laura Y Cabrera, Cameron C Mcintyre, Noam Harel, Helen S Mayberg, Andrew D Krystal, Nader Pouratian, Philip A Starr, Kelly D Foote, Michael S Okun, Joshua K Wong

Faculty, Staff and Students Publications

The Deep Brain Stimulation (DBS) Think Tank XI was held on August 9-11, 2023 in Gainesville, Florida with the theme of "Pushing the Forefront of Neuromodulation". The keynote speaker was Dr. Nico Dosenbach from Washington University in St. Louis, Missouri. He presented his research recently published in Nature inn a collaboration with Dr. Evan Gordon to identify and characterize the somato-cognitive action network (SCAN), which has redefined the motor homunculus and has led to new hypotheses about the integrative networks underpinning therapeutic DBS. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers, and …

Functional Genomics And Small Molecules In Mitochondrial Neurodevelopmental Disorders, Daniel G Calame, Lisa T Emrick

Faculty, Staff and Students Publications

Mitochondria are critical for brain development and homeostasis. Therefore, pathogenic variation in the mitochondrial or nuclear genome which disrupts mitochondrial function frequently results in developmental disorders and neurodegeneration at the organismal level. Large-scale application of genome-wide technologies to individuals with mitochondrial diseases has dramatically accelerated identification of mitochondrial disease-gene associations in humans. Multi-omic and high-throughput studies involving transcriptomics, proteomics, metabolomics, and saturation genome editing are providing deeper insights into the functional consequence of mitochondrial genomic variation. Integration of deep phenotypic and genomic data through allelic series continues to uncover novel mitochondrial functions and permit mitochondrial gene function dissection on an …

Understanding The Role Of Ampa Receptors In Autism: Insights From Circuit And Synapse Dysfunction, Andres Jimenez-Gomez, Megan X Nguyen, Jason S Gill

Faculty, Staff and Students Publications

Autism spectrum disorders represent a diverse etiological spectrum that converge on a syndrome characterized by discrepant deficits in developmental domains often highlighted by concerns in socialization, sensory integration, and autonomic functioning. Importantly, the incidence and prevalence of autism spectrum disorders have seen sharp increases since the syndrome was first described in the 1940s. The wide etiological spectrum and rising number of individuals being diagnosed with the condition lend urgency to capturing a more nuanced understanding of the pathogenic mechanisms underlying the autism spectrum disorders. The current review seeks to understand how the disruption of AMPA receptor (AMPAr)-mediated neurotransmission in the …

Metabolic Bioactivation Of Antidepressants: Advance And Underlying Hepatotoxicity, Saleh M Khalil, Kevin R Mackenzie, Mirjana Maletic-Savatic, Feng Li

Faculty, Staff and Students Publications

Many drugs that serve as first-line medications for the treatment of depression are associated with severe side effects, including liver injury. Of the 34 antidepressants discussed in this review, four have been withdrawn from the market due to severe hepatotoxicity, and others carry boxed warnings for idiosyncratic liver toxicity. The clinical and economic implications of antidepressant-induced liver injury are substantial, but the underlying mechanisms remain elusive. Drug-induced liver injury may involve the host immune system, the parent drug, or its metabolites, and reactive drug metabolites are one of the most commonly referenced risk factors. Although the precise mechanism by which …

Mecp2-Related Disorders While Gene-Based Therapies Are On The Horizon, Katherine Allison, Mirjana Maletic-Savatic, Davut Pehlivan

Faculty, Staff and Students Publications

The emergence of new genetic tools has led to the discovery of the genetic bases of many intellectual and developmental disabilities. This creates exciting opportunities for research and treatment development, and a few genetic disorders (e.g., spinal muscular atrophy) have recently been treated with gene-based therapies. MECP2 is found on the X chromosome and regulates the transcription of thousands of genes. Loss of MECP2 gene product leads to Rett Syndrome, a disease found primarily in females, and is characterized by developmental regression, motor dysfunction, midline hand stereotypies, autonomic nervous system dysfunction, epilepsy, scoliosis, and autistic-like behavior. Duplication of MECP2 causes …

Nutritional Importance Of Animal-Sourced Foods In A Healthy Diet, Sydney Sheffield, Marta L Fiorotto, Teresa A Davis

Faculty, Staff and Students Publications

Animal-sourced foods, such as meats, poultry, eggs, milk, and fish are nutrient-dense foods that are rich sources of protein, essential amino acids, and micronutrients that can be challenging to obtain solely through plant-based foods. Animal-sourced protein foods provide crucial nutrients that support the growth and development in children, maintenance of muscle mass and function in adults, gain in muscle mass and strength in exercising individuals, and mitigation of sarcopenia in the elderly. The 2020–2025 Dietary Guidelines for Americans have identified the important role of animal-sourced foods in the diet at every stage of life. Animal-sourced foods are consumed worldwide and …

Citrulline And Adi-Peg20 Reduce Inflammation In A Juvenile Porcine Model Of Acute Endotoxemia, Caitlin Vonderohe, Barbara Stoll, Inka Didelija, Trung Nguyen, Mahmoud Mohammad, Yava Jones-Hall, Miguel A Cruz, Juan Marini, Douglas Burrin

Faculty, Staff and Students Publications

BACKGROUND: Arginine is a conditionally essential amino acid that is depleted in critically ill or surgical patients. In pediatric and adult patients, sepsis results in an arginine-deficient state, and the depletion of plasma arginine is associated with greater mortality. However, direct supplementation of arginine can result in the excessive production of nitric oxide (NO), which can contribute to the hypotension and macrovascular hypo-reactivity observed in septic shock. Pegylated arginine deiminase (ADI-PEG20, pegargiminase) reduces plasma arginine and generates citrulline that can be transported intracellularly to generate local arginine and NO, without resulting in hypotension, while maintaining microvascular patency. The objective of …

Association Of Circulating Ketone Bodies With Cognitive Performance And Dementia In The Multi-Ethnic Study Of Atherosclerosis (Mesa), Parag Anilkumar Chevli, Christopher L Schaich, Alexis C Wood, Luqman A Tk, Anurag Mehta, Vardhmaan Jain, Margery Connelly, Suzanne Craft, Elad Shemesh, José A Luchsinger, Kathleen M Hayden, Bonnie Colleen Sachs, Timothy M Hughes, Michael D Shapiro

Faculty, Staff and Students Publications

Introduction

Growing interest centers on the association between circulating ketone bodies (KB) and cognitive function, notably in aging and neurodegenerative diseases.

Methods

Associations of plasma KB with incident dementia and cognitive performances were examined among Multi‐Ethnic Study of Atherosclerosis (MESA) participants. KB were measured using plasma samples collected following an overnight fasting at Exam 1 (2000–02) and detailed cognitive testing at Exam 5 (2010–2012, N = 4392), Exam 6 (2016–2018, N = 1838), and in MESA‐MIND (2019–2021, N = 2060).

Results

Over 16.7 years, a doubling of total KB was associated with a greater risk of incident dementia (hazard ratio …

Polygenic Scores And Mendelian Randomization Identify Plasma Proteins Causally Implicated In Alzheimer’S Disease, Davis B Cammann, Yimei Lu, Jerome I Rotter, Alexis C Wood, Jingchun Chen

Faculty, Staff and Students Publications

BACKGROUND: An increasing body of evidence suggests that neuroinflammation is one of the key drivers of late-onset Alzheimer's disease (LOAD) pathology. Due to the increased permeability of the blood-brain barrier (BBB) in older adults, peripheral plasma proteins can infiltrate the central nervous system (CNS) and drive neuroinflammation through interactions with neurons and glial cells. Because these inflammatory factors are heritable, a greater understanding of their genetic relationship with LOAD could identify new biomarkers that contribute to LOAD pathology or offer protection against it.

METHODS: We used a genome-wide association study (GWAS) of 90 different plasma proteins (

RESULTS: We identified …

Call The Experts: Identifying Stakeholders In The Long-Term Care Of Youth With Hypospadias, Vinaya P Bhatia, Kristin Ebert, Shannon Cannon, Walid A Farhat, Heidi W Brown, Jane Mahoney, Marisa E Hilliard, Kristina L Penniston

Faculty, Staff and Students Publications

Long-term follow-up for individuals with hypospadias remains a critical area of need, yet evidence-based guidelines for such follow-up are lacking, and the role of involvement of relevant experts is not yet established. Using our hypospadias-specific health-related quality of life conceptual framework and a subsequent qualitative study of prepubertal males and parents of males with hypospadias, we identified potential priorities for long-term follow-up of youth with hypospadias. Using thematic codes from our patient and parent interviews, we searched PubMed for relevant articles and identified the specialties represented by all the authors of these articles. Our search strategy revealed consistent expertise across …

Metabolink Is A Novel Algorithm For Unveiling Cell-Specific Metabolic Pathways In Longitudinal Datasets, Jared Lichtarge, Gerarda Cappuccio, Soumya Pati, Alfred Kwabena Dei-Ampeh, Senghong Sing, Lihua Ma, Zhandong Liu, Mirjana Maletic-Savatic

Duncan NRI Faculty and Staff Publications

Introduction: In the rapidly advancing field of 'omics research, there is an increasing demand for sophisticated bioinformatic tools to enable efficient and consistent data analysis. As biological datasets, particularly metabolomics, become larger and more complex, innovative strategies are essential for deciphering the intricate molecular and cellular networks.

Methods: We introduce a pioneering analytical approach that combines Principal Component Analysis (PCA) with Graphical Lasso (GLASSO). This method is designed to reduce the dimensionality of large datasets while preserving significant variance. For the first time, we applied the PCA-GLASSO algorithm (i.e., MetaboLINK) to metabolomics data derived from Nuclear Magnetic Resonance (NMR) spectroscopy …

Rragd-Associated Autosomal Dominant Kidney Hypomagnesemia With Cardiomyopathy: A Review On The Clinical Manifestations And Therapeutic Options, Francesco Trepiccione, Irene Sambri, Barbara Ruggiero, Francesco Emma, Andrea Ballabio, Giulia Florio, Ines Vanderheyden, Anna Iervolino, François Jouret

Duncan NRI Faculty and Staff Publications

Background: A hereditary condition primarily affecting the kidneys and heart has newly been identified: the RRAGD-associated autosomal dominant kidney hypomagnesemia with cardiomyopathy (ADKH-RRAGD). This disorder is characterized by renal loss of magnesium and potassium, coupled with varying degrees of cardiac dysfunction. These range from arrhythmias to severe dilated cardiomyopathy, which may require heart transplantation. Mutations associated with RRAGD significantly disrupt the non-canonical branch of the mechanistic target of rapamycin complex 1 pathway. This disruption hinders the nuclear translocation and transcriptional activity of the transcription factor EB a crucial regulator of lysosomal and autophagic function.

Summary: All identified RRAGD variants compromise …

International Society For Pediatric And Adolescent Diabetes Clinical Practice Consensus Guidelines 2024: Diabetes Technologies - Insulin Delivery, Torben Biester, Cari Berget, Charlotte Boughton, Laura Cudizio, Laya Ekhlaspour, Marisa E Hilliard, Leenatha Reddy, Suzanne Sap Ngo Um, Melissa Schoelwer, Jennifer L Sherr, Klemen Dovc

Faculty, Staff and Students Publications

The International Society for Pediatric and Adolescent Diabetes (ISPAD) guidelines represent a rich repository that serves as the only comprehensive set of clinical recommendations for children, adolescents, and young adults living with diabetes worldwide. This chapter builds on the 2022 ISPAD guidelines, and summarizes recent advances in the technology behind insulin administration, with special emphasis on insulin pump therapy, especially on glucose-responsive integrated technology that is feasible with the use of automated insulin delivery (AID) systems in children and adolescents. The International Society for Pediatric and Adolescent Diabetes (ISPAD) guidelines represent a rich repository that serves as the only comprehensive …

5-Htp Inhibits Eosinophilia Via Intracellular Endothelial 5-Htrs; Snps In 5-Htrs Associate With Asthmatic Lung Function, Matthew T Walker, Jeffrey C Bloodworth, Timothy S Kountz, Samantha L Mccarty, Jeremy E Green, Ryan P Ferrie, Jackson A Campbell, Samantha H Averill, Kenneth B Beckman, Leslie C Grammer, Celeste Eng, Pedro C Avila, Harold J Farber, William Rodriguez-Cintron, Jose R Rodriguez-Santana, Denise Serebrisky, Shannon M Thyne, Max A Seibold, Esteban G Burchard, Rajesh Kumar, Joan M Cook-Mills

Faculty, Staff and Students Publications

BACKGROUND: Previous research showed that 5-hydroxytryptophan (5HTP), a metabolic precursor of serotonin, reduces allergic lung inflammation by inhibiting eosinophil migration across endothelial monolayers.

OBJECTIVE: It is unknown if serotonin receptors are involved in mediating this 5HTP function or if serotonin receptor (HTR) single nucleotide polymorphisms (SNPs) associate with lung function in humans.

METHODS: Serotonin receptor subtypes were assessed by qPCR, western blot, confocal microscopy, pharmacological inhibitors and siRNA knockdown. HTR SNPs were assessed in two cohorts.

RESULTS: Pharmacological inhibition or siRNA knockdown of the serotonin receptors HTR1A or HTR1B in endothelial cells abrogated the inhibitory effects of 5HTP on eosinophil …

Night-Time Neuronal Activation Of Cluster N In A North American Songbird\, Jennifer Rudolf, Natalie Philipello, Tamara Fleihan, J David Dickman, Kira E Delmore

Faculty, Staff and Students Publications

Night-migrating songbirds utilize the Earth's magnetic field to help navigate to and from their breeding sites each year. A region of the avian forebrain called Cluster N has been shown to be activated during night migratory behavior and it has been implicated in processing geomagnetic information. Previous studies with night-migratory European songbirds have shown that neuronal activity at Cluster N is higher at night than during the day. Comparable work in North American migrants has only been performed in one species of swallows, so extension of examination for Cluster N in other migratory birds is needed. In addition, it is …

Cisplatin Vestibulotoxicity: A Current Review, Tamara Fleihan, Marc Elie Nader, J David Dickman

Faculty, Staff and Students Publications

Cisplatin, a commonly used chemotherapy drug, is well-established for its ototoxic effects, primarily attributed to the damage it inflicts on cochlear hair cells. However, its impact on the vestibular system remains inadequately understood. Here, we provide a comprehensive review of existing literature concerning cisplatin-induced vestibulotoxicity. Animal studies have shown that cisplatin induces a vestibular hair cell loss that is dose-dependent, with the severity of damage also varying according to the route of administration. Notably, intratympanic and systemic injections in animal models have manifested significant damage primarily to utricular hair cells, with a lesser degree of damage observed for the other …

Scan-Less Microscopy Based On Acousto-Optic Encoded Illumination, Andrea Marchese, Pietro Ricci, Peter Saggau, Martí Duocastella

Faculty, Staff and Students Publications

Several optical microscopy methods are now available for characterizing scientific and industrial processes at sub-micron resolution. However, they are often ill-suited for imaging rapid events. Limited by the trade-off between camera frame-rate and sensitivity, or the need for mechanical scanning, current microscopes are optimized for imaging at hundreds of frames-per-second (fps), well-below what is needed in processes such as neuronal signaling or moving parts in manufacturing lines. Here, we present a scan-less technology that allows sub-micrometric imaging at thousands of fps. It is based on combining a single-pixel camera with parallelized encoded illumination. We use two acousto-optic deflectors (AODs) placed …

Activation Of Mechanoreceptor Piezo1 Inhibits Enteric Neuronal Growth And Migration, Chioma Moneme, Oluyinka O Olutoye, Michał F Sobstel, Yuwen Zhang, Xinyu Zhou, Jacob L Kaminer, Britney A Hsu, Chengli Shen, Arabinda Mandal, Hui Li, Ling Yu, Swathi Balaji, Sundeep G Keswani, Lily S Cheng

Faculty, Staff and Students Publications

INTRODUCTION: Dysfunction of the enteric nervous system (ENS) is linked to a myriad of gastrointestinal (GI) disorders. Piezo1 is a mechanosensitive ion channel found throughout the GI tract, but its role in the ENS is largely unknown. We hypothesize that Piezo1 plays an important role in the growth and development of the ENS.

METHODS: Enteric neural crest-derived progenitor cells (ENPC) were isolated from adult mouse intestine and propagated in culture as neurospheres. ENPC-derived neurons were then subject to

RESULTS: Though stretch did not cause upregulation of Piezo1 expression in enteric neurons, both stretch and Piezo1 activation produced similar alterations in …

Predictors Of Making A Referral To Child Protective Services Prior To Expert Consultation, Danielle Zamalin, Irene Hamlin, Justine Shults, M Katherine Henry, Kristine A Campbell, James D Anderst, Angela N Bachim, Rachel P Berger, Lori D Frasier, Nancy S Harper, Megan M Letson, John D Melville, Daniel M Lindberg, Joanne N Wood

Faculty, Staff and Students Publications

OBJECTIVE: Suspicion for child abuse is influenced by implicit biases. Evaluation by a Child Abuse Pediatrician (CAP) may reduce avoidable child protective services (CPS) referrals. Our objective was to investigate the association of patient demographic, social and clinical characteristics with CPS referral before consultation by a CAP (preconsultation referral).

METHODS: Children <5 years-old undergoing in-person CAP consultation for suspected physical abuse from February 2021 through April 2022 were identified in CAPNET, a multicenter child abuse research network. Marginal standardization implemented with logistic regression analysis examined hospital-level variation and identified demographic, social, and clinical factors associated with pre-consultation referral adjusting for CAP’s final assessment of abuse likelihood.

RESULTS: Among the 61% (1005/1657) of cases with preconsultation referral, the CAP consultant had low concern for abuse in 38% (384/1005). Preconsultation referrals ranged from 25% to 78% of cases across 10 hospitals (P < .001). In multivariable analyses, preconsultation referral was associated with public insurance, caregiver history of CPS involvement, history of intimate partner violence, higher CAP level of concern for abuse, hospital transfer, and near-fatality (all P < .05). The difference in preconsultation referral prevalence for children with public versus private insurance was significant for children with low CAP concern for abuse (52% vs 38%) but not those with higher concern for abuse (73% vs 73%), (P = .023 for interaction of insurance and abuse likelihood category). There were no differences in preconsultation referral based on race or ethnicity.

CONCLUSIONS: Biases based on socioeconomic status and social factors may impact decisions to refer to …

Stepped-Care Cognitive Behavioral Therapy In Children On The Autism Spectrum With Co-Occurring Anxiety, Eric A Storch, Sophie C Schneider, Sean M Olsen, Ana C Ramirez, Leandra N Berry, Robin P Goin-Kochel, Morgan Mcneel, Abigail E Candelari, Andrew G Guzick, Sandra L Cepeda, Saira Weinzimmer, Robert G Voigt, Troy Quast, Wayne K Goodman, Alison Salloum

Faculty, Staff and Students Publications

This trial examined stepped-care cognitive-behavioral treatment (CBT) among 96 autistic youth with co-occurring anxiety. Step 1 included an open trial of parent-led, therapist-guided bibliotherapy. Step 2 was family-based CBT for those who did not respond to Step 1 or maintenance for those who did. Eighteen participants (28%) who completed Step 1 responded. Responders reported significantly lower pre-treatment anxiety, internalizing symptoms, and functional impairment than non-responders. After Steps 1 and 2, 80% of completers (55% intent-to-treat) were responders. Anxiety, impairment, and ASD-related impairments significantly improved. Youth in maintenance experienced faster improvement through post-treatment, though there were no group differences at 3-month-follow-up. …

Branched-Chain Amino Acid Accumulation Fuels The Senescence-Associated Secretory Phenotype, Yaosi Liang, Christopher Pan, Tao Yin, Lu Wang, Xia Gao, Ergang Wang, Holly Quang, De Huang, Lianmei Tan, Kun Xiang, Yu Wang, Peter B Alexander, Qi-Jing Li, Tso-Pang Yao, Zhao Zhang, Xiao-Fan Wang

Faculty, Staff and Students Publications

The essential branched-chain amino acids (BCAAs) leucine, isoleucine, and valine play critical roles in protein synthesis and energy metabolism. Despite their widespread use as nutritional supplements, BCAAs' full effects on mammalian physiology remain uncertain due to the complexities of BCAA metabolic regulation. Here a novel mechanism linking intrinsic alterations in BCAA metabolism is identified to cellular senescence and the senescence-associated secretory phenotype (SASP), both of which contribute to organismal aging and inflammation-related diseases. Altered BCAA metabolism driving the SASP is mediated by robust activation of the BCAA transporters Solute Carrier Family 6 Members 14 and 15 as well as downregulation …

De Novo Missense Variants In Zbtb47 Are Associated With Developmental Delays, Hypotonia, Seizures, Gait Abnormalities, And Variable Movement Abnormalities, Scott K Ward, Alexandrea Wadley, Chun-Hui Anne Tsai, Paul J Benke, Lisa Emrick, Kristen Fisher, Kimberly M Houck, Hongzheng Dai, Undiagnosed Diseases Network, Maria J Guillen Sacoto, William Craigen, Kimberly Glaser, David R Murdock, Luis Rohena, Karin E M Diderich, Hennie T Bruggenwirth, Brendan Lee, Carlos Bacino, Lindsay C Burrage, Jill A Rosenfeld

Faculty, Staff and Students Publications

The collection of known genetic etiologies of neurodevelopmental disorders continues to increase, including several syndromes associated with defects in zinc finger protein transcription factors (ZNFs) that vary in clinical severity from mild learning disabilities and developmental delay to refractory seizures and severe autism spectrum disorder. Here we describe a new neurodevelopmental disorder associated with variants in ZBTB47 (also known as ZNF651), which encodes zinc finger and BTB domain-containing protein 47. Exome sequencing (ES) was performed for five unrelated patients with neurodevelopmental disorders. All five patients are heterozygous for a de novo missense variant in ZBTB47, with p.(Glu680Gly) (c.2039A>G) detected …

A Dual Target Molecular Magnetic Resonance Imaging Probe For Noninvasive Profiling Of Pathologic Alpha-Synuclein And Microgliosis In A Mouse Model Of Parkinson’S Disease, Xianwei Sun, Andrew Badachhape, Prajwal Bhandari, Jeannie Chin, Ananth Annapragada, Eric Tanifum

Faculty, Staff and Students Publications

The pathogenesis of Parkinson’s disease (PD) is characterized by progressive deposition of alpha-synuclein (α-syn) aggregates in dopaminergic neurons and neuroinflammation. Noninvasive in vivo imaging of α-syn aggregate accumulation and neuroinflammation can elicit the underlying mechanisms involved in disease progression and facilitate the development of effective treatment as well as disease diagnosis and prognosis. Here we present a novel approach to simultaneously profile α-syn aggregation and reactive microgliosis in vivo, by targeting oligomeric α-syn in cerebrospinal fluid with nanoparticle bearing a magnetic resonance imaging (MRI), contrast payload. In this proof-of-concept report we demonstrate, in vitro, that microglia and neuroblastoma …

Thrombectomy In Stroke Patients With Low Alberta Stroke Program Early Computed Tomography Score: Is Modified Thrombolysis In Cerebral Infarction (Mtici) 2c/3 Superior To Mtici 2b?, Sameh Samir Elawady, Brian Fabian Saway, Hidetoshi Matsukawa, Kazutaka Uchida, Steven Lin, Ilko Maier, Pascal Jabbour, Joon-Tae Kim, Stacey Quintero Wolfe, Ansaar Rai, Robert M Starke, Marios-Nikos Psychogios, Edgar A Samaniego, Adam Arthur, Shinichi Yoshimura, Hugo Cuellar, Jonathan A Grossberg, Ali Alawieh, Daniele G Romano, Omar Tanweer, Justin Mascitelli, Isabel Fragata, Adam Polifka, Joshua Osbun, Roberto Crosa, Charles Matouk, Min S Park, Michael R Levitt, Waleed Brinjikji, Mark Moss, Travis Dumont, Richard Williamson, Pedro Navia, Peter Kan, Reade De Leacy, Shakeel Chowdhry, Mohamad Ezzeldin, Alejandro M Spiotta, Sami Al Kasab

Faculty, Staff and Students Publications

BACKGROUND AND PURPOSE: Outcomes following mechanical thrombectomy (MT) are strongly correlated with successful recanalization, traditionally defined as modified Thrombolysis in Cerebral Infarction (mTICI) ≥2b. This retrospective cohort study aimed to compare the outcomes of patients with low Alberta Stroke Program Early Computed Tomography Score (ASPECTS; 2-5) who achieved mTICI 2b versus those who achieved mTICI 2c/3 after MT.

METHODS: This study utilized data from the Stroke Thrombectomy and Aneurysm Registry (STAR), which combined databases from 32 thrombectomy-capable stroke centers between 2013 and 2023. The study included only patients with low ASPECTS who achieved mTICI 2b, 2c, or 3 after MT …

Role Of Short Chain Fatty Acids On Astrocytes And Microglia In Alzheimer's Disease Brain, Rathnayaka Mudiyanselage Uththara Sachinthanie Senarath, Matthew Burton, Welisarage Mary Kendrea Thiasangee Fernando, Vijay Jayasena, Charles Brennan, Wanakulasuriya Mary Ann Dipika Binosha Fernando

Research outputs 2022 to 2026

Short-chain fatty acids (SCFAs) hold exert many nutritional benefits on both physiological and pathological processes, including host metabolism, immune modulation, and appetite control. Originating from the microbial fermentation of resistant starches and dietary fibre in the colon, SCFAs have the capability to traverse the blood–brain barrier (BBB). It is evident that SCFAs play a critical role in the development of neurodegenerative disorders such as Alzheimer's disease (AD). AD is the most common form of dementia and is characterised by the deposition of amyloid β peptides (Aβ) and tau hyperphosphorylation. SCFAs have demonstrated the potential to interfere with the protein–protein interactions …

A Comprehensive Multi-Omics Analysis Reveals Unique Signatures To Predict Alzheimer’S Disease, Michael Vacher, Rodrigo Canovas, Simon M. Laws, James D. Doecke

Research outputs 2022 to 2026

Background: Complex disorders, such as Alzheimer’s disease (AD), result from the combined influence of multiple biological and environmental factors. The integration of high-throughput data from multiple omics platforms can provide system overviews, improving our understanding of complex biological processes underlying human disease. In this study, integrated data from four omics platforms were used to characterise biological signatures of AD. Method: The study cohort consists of 455 participants (Control:148, Cases:307) from the Religious Orders Study and Memory and Aging Project (ROSMAP). Genotype (SNP), methylation (CpG), RNA and proteomics data were collected, quality-controlled and pre-processed (SNP = 130; CpG = 83; RNA …