WashU weekly Neuroscience publications: November 26, 2023

Increasing Energetic Demands on Photoreceptors in Diabetes Corrects Retinal Lipid Dysmetabolism and Reduces Subsequent Microvascular Damage
(2023) American Journal of Pathology, 193 (12), pp. 2144-2155. 

Zhang, S.^a , Wei, X.^b , Bowers, M.^c , Jessberger, S.^c , Golczak, M.^d , Semenkovich, C.F.^b e , Rajagopal, R.^a

^a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, United States
^b Division of Endocrinology, Metabolism, Lipid Research, Washington University School of Medicine, St. Louis, Missouri, United States
^c Faculties of Medicine and Science, Laboratory of Neural Plasticity, Brain Research Institute, University of Zurich, Zurich, Switzerland
^d Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States
^e Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, United States

Abstract
Mechanisms responsible for the pathogenesis of diabetic retinal disease remain incompletely understood, but they likely involve multiple cellular targets, including photoreceptors. Evidence suggests that dysregulated de novo lipogenesis in photoreceptors is a critical early target of diabetes. Following on this observation, the present study aimed to determine whether two interventions shown to improve diabetic retinopathy in mice—pharmacologic visual cycle inhibition and prolonged dark adaptation—reduce photoreceptor anabolic lipid metabolism. Elevated retinal lipid biosynthetic signaling was observed in two mouse models of diabetes, with both models showing reduced retinal AMP-activated kinase (AMPK) signaling, elevated acetyl CoA carboxylase (ACC) signaling, and increased activity of fatty acid synthase, which promotes lipotoxicity in photoreceptors. Although retinal AMPK-ACC axis signaling was dependent on systemic glucose fluctuations in healthy animals, mice with diabetes lacked such regulation. Visual cycle inhibition and prolonged dark adaptation reversed abnormal retinal AMPK-ACC signaling in mice with diabetes. Although visual cycle inhibition reduced the severity of diabetic retinopathy in control mice, as assessed by retinal capillary atrophy, this intervention was ineffective in fatty acid synthase gain-of-function mice. These results suggest that early diabetic retinopathy is characterized by glucose-driven elevations in retinal lipid biosynthetic activity, and that two interventions known to increase photoreceptor glucose demands alleviate disease by reversing these signals. © 2023 American Society for Investigative Pathology

Funding details
National Institutes of HealthNIHEY023948, EY034172, P30 EY002687
Research to Prevent BlindnessRPB
Horncrest Foundation
Diabetes Research Center, University of WashingtonDRC, UWDK020579

Document Type: Article
Publication Stage: Final
Source: Scopus

Effects of chronotype-tailored bright light intervention on post-treatment symptoms and quality of life in breast cancer survivors
(2023) Supportive Care in Cancer, 31 (12), art. no. 705, . 

Wu, H.-S.^a , Gao, F.^b , Davis, J.E.^c , Given, C.W.^a

^a Michigan State University College of Nursing, C347 Bott Building, 1355 Bogue Street, East Lansing, MI 48824, United States
^b Division of Public Health Sciences, Washington University School of Medicine, St. Louis, MO, United States
^c University of South Carolina College of Nursing, Columbia, SC, United States

Abstract
Purpose: Bright light therapy holds promise for reducing common symptoms, e.g., fatigue, experienced by individuals with cancer. This study aimed to examine the effects of a chronotype-tailored bright light intervention on sleep disturbance, fatigue, depressive mood, cognitive dysfunction, and quality of life among post-treatment breast cancer survivors. Methods: In this two-group randomized controlled trial (NCT03304587), participants were randomized to receive 30-min daily bright blue-green light (12,000 lx) or dim red light (5 lx) either between 19:00 and 20:00 h or within 30 min of waking in the morning. Self-reported outcomes and in-lab overnight polysomnography sleep study were assessed before (pre-test) and after the 14-day light intervention (post-test). Results: The sample included 30 women 1–3 years post-completion of chemotherapy and/or radiation for stage I to III breast cancer (mean age = 52.5 ± 8.4 years). There were no significant between-group differences in any of the symptoms or quality of life (all p > 0.05). However, within each group, self-reported sleep disturbance, fatigue, depressive mood, cognitive dysfunction, and quality of life-related functioning showed significant improvements over time (all p < 0.05); the extent of improvement for fatigue and depressive mood was clinically relevant. Polysomnography sleep findings showed that a number of awakenings significantly decreased (p = 0.011) among participants who received bright light, while stage 2 sleep significantly increased (p = 0.015) among participants who received dim-red light. Conclusion: The findings support using light therapy to manage post-treatment symptoms in breast cancer survivors. The unexpected symptom improvements among dim-red light controls remain unexplained and require further investigation. Trial registration: ClinicalTrials.gov Identifier: NCT03304587, October 19, 2017. © 2023, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Author Keywords
Bright light;  Cancer symptom;  Chronotype;  Polysomnography;  Quality of life;  Survivorship

Funding details
National Institutes of HealthNIH
National Institute of Nursing ResearchNINRR15NR016828

Document Type: Article
Publication Stage: Final
Source: Scopus

COMPRESSED SPECTRAL SCREENING FOR LARGE-SCALE DIFFERENTIAL CORRELATION ANALYSIS WITH APPLICATION IN SELECTING GLIOBLASTOMA GENE MODULES
(2023) Annals of Applied Statistics, 17 (4), pp. 3450-3475. Cited 1 time.

Li, T.^a , Tang, X.^a , Chatrath, A.^b

^a Department of Statistics, University of Virginia, United States
^b Department of Neurosurgery, Washington University School of Medicine in St. Louis, United States

Abstract
Differential coexpression analysis has been widely applied by scientists in understanding the biological mechanisms of diseases. However, the unknown differential patterns are often complicated; thus, models based on simplified parametric assumptions can be ineffective in identifying the dif-ferences. Meanwhile, the gene expression data involved in such analysis are in extremely high dimensions by nature, whose correlation matrices may not even be computable. Such a large scale seriously limits the application of most well-studied statistical methods. This paper introduces a simple yet powerful approach to the differential correlation analysis problem called compressed spectral screening. By leveraging spectral structures and random sampling techniques, our approach could achieve a highly accurate screening of features with complicated differential patterns while maintaining the scalability to analyze correlation matrices of 104 –105 variables within a few minutes on a standard personal computer. We have applied this screening approach in comparing a TCGA data set about Glioblastoma with normal subjects. Our analysis successfully identifies multiple functional modules of genes that exhibit different coexpression patterns. The findings reveal new insights about Glioblastoma’s evolving mechanism. The validity of our approach is also justified by a theoretical analysis, showing that the compressed spectral analysis can achieve variable screening consistency. © Institute of Mathematical Statistics, 2023.

Author Keywords
Differential correlation analysis;  gene coexpression;  high-dimensional correlation matrices;  spectral methods

Funding details
National Science FoundationNSFDMS-2015298
National Institutes of HealthNIHT32 GM007267
University of VirginiaUVDMS-2113467

Document Type: Article
Publication Stage: Final
Source: Scopus

Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations
(2023) Nature Communications, 14 (1), art. no. 7452, . 

Zhao, S.^a b , Mekbib, K.Y.^b c , van der Ent, M.A.^d , Allington, G.^b e , Prendergast, A.^f , Chau, J.E.^g , Smith, H.^b c , Shohfi, J.^b c , Ocken, J.^c , Duran, D.^h , Furey, C.G.^c i j , Hao, L.T.^b , Duy, P.Q.^k , Reeves, B.C.^c , Zhang, J.^l , Nelson-Williams, C.^l , Chen, D.^d , Li, B.^m , Nottoli, T.ⁿ , Bai, S.ⁿ , Rolle, M.^b , Zeng, X.^g o , Dong, W.^l o , Fu, P.-Y.^a , Wang, Y.-C.^a , Mane, S.^l , Piwowarczyk, P.^p , Fehnel, K.P.^p , See, A.P.^p , Iskandar, B.J.^q , Aagaard-Kienitz, B.^q r , Moyer, Q.J.^b , Dennis, E.^b , Kiziltug, E.^b , Kundishora, A.J.^c , DeSpenza, T., Jr.^c , Greenberg, A.B.W.^b , Kidanemariam, S.M.^s , Hale, A.T.^t , Johnston, J.M.^t , Jackson, E.M.^u , Storm, P.B.^v w , Lang, S.-S.^v w , Butler, W.E.^b , Carter, B.S.^b , Chapman, P.^b , Stapleton, C.J.^b , Patel, A.B.^b , Rodesch, G.^x y , Smajda, S.^y , Berenstein, A.^z , Barak, T.^c , Erson-Omay, E.Z.^c , Zhao, H.^l m , Moreno-De-Luca, A.^aa , Proctor, M.R.^p , Smith, E.R.^p , Orbach, D.B.^p ab , Alper, S.L.^ac , Nicoli, S.^l ad ae , Boggon, T.J.^g ad , Lifton, R.P.^o , Gunel, M.^c , King, P.D.^d , Jin, S.C.^a af , Kahle, K.T.^b c ag ah

^a Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^c Department of Neurosurgery, Yale School of Medicine, New Haven, CT, United States
^d Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, United States
^e Department of Pathology, Yale School of Medicine, New Haven, CT, United States
^f Yale Zebrafish Research Core, Yale School of Medicine, New Haven, CT, United States
^g Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, New Haven, CT, United States
^h Department of Neurosurgery, University of Mississippi Medical Center, Jackson, MS, United States
ⁱ Department of Neurosurgery, Barrow Neurological Institute, Phoenix, AZ, United States
^j Ivy Brain Tumor Center, Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ, United States
^k Department of Neurosurgery, University of Virginia School of Medicine, Charlottesville, VA, United States
^l Department of Genetics, Yale School of Medicine, New Haven, CT, United States
^m Department of Biostatistics, Yale School of Public Health, New Haven, CT, United States
ⁿ Yale Genome Editing Center, Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, United States
^o Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, United States
^p Department of Neurosurgery, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
^q Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
^r Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
^s Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
^t Department of Neurosurgery, University of Alabama School of Medicine, Birmingham, AL, United States
^u Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^v Department of Neurosurgery, Hospital of the University of Pennsylvania, Philadelphia, PA, United States
^w Division of Neurosurgery, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^x Service de Neuroradiologie Diagnostique et Thérapeutique, Hôpital Foch, Suresnes, France
^y Department of Interventional Neuroradiology, Hôpital Fondation A. de Rothschild, Paris, France
^z Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^aa Department of Radiology, Autism & Developmental Medicine Institute, Genomic Medicine Institute, Geisinger, Danville, PA, United States
^ab Department of Neurointerventional Radiology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
^ac Division of Nephrology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, MA, United States
^ad Department of Pharmacology, Yale School of Medicine, New Haven, CT, United States
^ae Yale Cardiovascular Research Center, Department of Internal Medicine, Section of Cardiology, Yale School of Medicine, New Haven, CT, United States
^af Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^ag Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, United States
^ah Broad Institute of MIT and Harvard, Cambridge, MA, United States

Abstract
To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and most severe of congenital brain arteriovenous malformations, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-function de novo variants (2042.5-fold, p = 4.79 x 10−7). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 (EPHB4) (17.5-fold, p = 1.22 x 10−5), which cooperates with p120 RasGAP to regulate vascular development. Additional probands had damaging variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomic analysis defined developing endothelial cells as a likely spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant (Phe867Leu) exhibited disrupted developmental angiogenesis and impaired hierarchical development of arterial-capillary-venous networks, but only in the presence of a “second-hit” allele. These results illuminate human arterio-venous development and VOGM pathobiology and have implications for patients and their families. © 2023, The Author(s).

Funding details
CTSA1405
National Institutes of HealthNIH5U54HG006504, K12 228168, R01 NS109358, R01 NS111029-01A1
Howard Hughes Medical InstituteHHMI2R01 HL120888, R01 HL146352
National Institute of General Medical SciencesNIGMST32GM007205
March of Dimes FoundationMDF
National Center for Advancing Translational SciencesNCATSR00HL143036-02, TL1 TR001864
Children’s Discovery InstituteCDICDI-FR-2021-926
Rudi Schulte Research InstituteRSRIR01 117609

Document Type: Article
Publication Stage: Final
Source: Scopus

Association between microbiome and the development of adverse posttraumatic neuropsychiatric sequelae after traumatic stress exposure
(2023) Translational Psychiatry, 13 (1), art. no. 354, . 

Zeamer, A.L.^a , Salive, M.-C.^b , An, X.^c , Beaudoin, F.L.^d e , House, S.L.^f , Stevens, J.S.^g , Zeng, D.^h , Neylan, T.C.ⁱ , Clifford, G.D.^j k , Linnstaedt, S.D.^c l m , Rauch, S.L.^m n o , Storrow, A.B.^p , Lewandowski, C.^q , Musey, P.I., Jr.^r , Hendry, P.L.^s , Sheikh, S.^s , Jones, C.W.^t , Punches, B.E.^u v , Swor, R.A.^w , Hudak, L.A.^x , Pascual, J.L.^y z , Seamon, M.J.^y z , Harris, E.^aa , Pearson, C.^ab , Peak, D.A.^ac , Merchant, R.C.^ad , Domeier, R.M.^ae , Rathlev, N.K.^af , O’Neil, B.J.^ag , Sergot, P.^ah , Sanchez, L.D.^ad ai , Bruce, S.E.^aj , Kessler, R.C.^ak , Koenen, K.C.^al , McLean, S.A.^am , Bucci, V.^a an , Haran, J.P.^a b an

^a Department of Microbiology and Physiologic Systems, University of Massachusetts Chan Medical School, Worcester, MA, United States
^b Department of Emergency Medicine, University of Massachusetts Chan Medical School, Worcester, MA, United States
^c Institute for Trauma Recovery, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^d Department of Epidemiology, Brown University, Providence, RI, United States
^e Department of Emergency Medicine, Brown University, Providence, RI, United States
^f Department of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
^h Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, United States
ⁱ Departments of Psychiatry and Neurology, University of California San Francisco, San Francisco, CA, United States
^j Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA, United States
^k Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, United States
^l The Many Brains Project, Belmont, MA, United States
^m Department of Psychiatry, Harvard Medical School, Boston, MA, United States
ⁿ Institute for Technology in Psychiatry, McLean Hospital, Belmont, MA, United States
^o Department of Psychiatry, McLean Hospital, Belmont, MA, United States
^p Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
^q Department of Emergency Medicine, Henry Ford Health System, Detroit, MI, United States
^r Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
^s Department of Emergency Medicine, University of Florida College of Medicine-Jacksonville, Jacksonville, FL, United States
^t Department of Emergency Medicine, Cooper Medical School of Rowan University, Camden, NJ, United States
^u Department of Emergency Medicine, Ohio State University College of Medicine, Columbus, OH, United States
^v Ohio State University College of Nursing, Columbus, OH, United States
^w Department of Emergency Medicine, Oakland University William Beaumont School of Medicine, Rochester, MI, United States
^x Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA, United States
^y Department of Surgery, University of Pennsylvania, Philadelphia, PA, United States
^z Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^aa Department of Emergency Medicine, Einstein Medical Center, Philadelphia, PA, United States
^ab Department of Emergency Medicine, Wayne State University, Ascension St. John Hospital, Detroit, MI, United States
^ac Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, United States
^ad Department of Emergency Medicine, Brigham and Women’s Hospital, Boston, MA, United States
^ae Department of Emergency Medicine, Trinity Health-Ann Arbor, Ypsilanti, MI, United States
^af Department of Emergency Medicine, University of Massachusetts Medical School-Baystate, Springfield, MA, United States
^ag Department of Emergency Medicine, Wayne State University, Detroit Receiving Hospital, Detroit, MI, United States
^ah Department of Emergency Medicine, McGovern Medical School at UTHealth, Houston, TX, United States
^ai Department of Emergency Medicine, Harvard Medical School, Boston, MA, United States
^aj Department of Psychological Sciences, University of Missouri – St. Louis, St. Louis, MO, United States
^ak Department of Health Care Policy, Harvard Medical School, Boston, MA, United States
^al Department of Epidemiology, Harvard University, Boston, MA, United States
^am Department of Emergency Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^an Program in Microbiome Dynamics, University of Massachusetts Chan Medical School, Worcester, MA, United States

Abstract
Patients exposed to trauma often experience high rates of adverse post-traumatic neuropsychiatric sequelae (APNS). The biological mechanisms promoting APNS are currently unknown, but the microbiota-gut-brain axis offers an avenue to understanding mechanisms as well as possibilities for intervention. Microbiome composition after trauma exposure has been poorly examined regarding neuropsychiatric outcomes. We aimed to determine whether the gut microbiomes of trauma-exposed emergency department patients who develop APNS have dysfunctional gut microbiome profiles and discover potential associated mechanisms. We performed metagenomic analysis on stool samples (n = 51) from a subset of adults enrolled in the Advancing Understanding of RecOvery afteR traumA (AURORA) study. Two-, eight- and twelve-week post-trauma outcomes for post-traumatic stress disorder (PTSD) (PTSD checklist for DSM-5), normalized depression scores (PROMIS Depression Short Form 8b) and somatic symptom counts were collected. Generalized linear models were created for each outcome using microbial abundances and relevant demographics. Mixed-effect random forest machine learning models were used to identify associations between APNS outcomes and microbial features and encoded metabolic pathways from stool metagenomics. Microbial species, including Flavonifractor plautii, Ruminococcus gnavus and, Bifidobacterium species, which are prevalent commensal gut microbes, were found to be important in predicting worse APNS outcomes from microbial abundance data. Notably, through APNS outcome modeling using microbial metabolic pathways, worse APNS outcomes were highly predicted by decreased L-arginine related pathway genes and increased citrulline and ornithine pathways. Common commensal microbial species are enriched in individuals who develop APNS. More notably, we identified a biological mechanism through which the gut microbiome reduces global arginine bioavailability, a metabolic change that has also been demonstrated in the plasma of patients with PTSD. © 2023, The Author(s).

Funding details
National Institutes of HealthNIH
National Institute of Mental HealthNIMH
Congressionally Directed Medical Research ProgramsCDMRPU01MH110925, W81XWH2020013
MAYDAY Fund

Document Type: Article
Publication Stage: Final
Source: Scopus

Contribution of macrophages to neural survival and intracochlear tissue remodeling responses following cochlear implantation
(2023) Journal of Neuroinflammation, 20 (1), art. no. 266, . 

Rahman, M.T.^a , Mostaert, B.J.^a , Hunger, B.^a , Saha, U.^a , Claussen, A.D.^a , Razu, I.^a , Nasrin, F.^a , Khan, N.A.^a , Eckard, P.^a , Coleman, S.^b , Oleson, J.^b , Kirk, J.R.^c , Hirose, K.^d , Hansen, M.R.^a

^a Department of Otolaryngology-Head and Neck Surgery, The University of Iowa, Iowa City, IA 52242, United States
^b Department of Biostatistics, The University of Iowa, Iowa City, IA, United States
^c Cochlear Limited, Sydney, Australia
^d Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Cochlear implants (CIs) restore hearing to deafened patients. The foreign body response (FBR) following cochlear implantation (post-CI) comprises an infiltration of macrophages, other immune and non-immune cells, and fibrosis into the scala tympani, a space that is normally devoid of cells. This FBR is associated with negative effects on CI outcomes including increased electrode impedances and loss of residual acoustic hearing. This study investigates the extent to which macrophage depletion by an orally administered CSF-1R specific kinase (c-FMS) inhibitor, PLX-5622, modulates the tissue response to CI and neural health. Main text: 10- to 12-week-old CX3CR1 + /GFP Thy1 + /YFP mice on C57BL/6J/B6 background was fed chow containing 1200 mg/kg PLX5622 or control chow for the duration of the study. 7 days after starting the diet, 3-channel cochlear implants were implanted in the ear via the round window. Serial impedance and neural response telemetry (NRT) measurements were acquired throughout the study. Electric stimulation began 7 days post-CI until 28 days post-CI for 5 h/day, 5 days/week, with programming guided by NRT and behavioral responses. Cochleae harvested at 10, 28 or 56 days post-CI were cryosectioned and labeled with an antibody against α-smooth muscle actin (α-SMA) to identify myofibroblasts and quantify the fibrotic response. Using IMARIS image analysis software, the outlines of scala tympani, Rosenthal canal, modiolus, and lateral wall for each turn were traced manually to measure region volume. The density of nuclei, CX3CR1 + macrophages, Thy1 + spiral ganglion neuron (SGN) numbers, and the ratio of the α-SMA + volume/scala tympani volume were calculated. Cochlear implantation in control diet subjects caused infiltration of cells, including macrophages, into the cochlea. Fibrosis was evident in the scala tympani adjacent to the electrode array. Mice fed PLX5622 chow showed reduced macrophage infiltration throughout the implanted cochleae across all time points. However, scala tympani fibrosis was not reduced relative to control diet subjects. Further, mice treated with PLX5622 showed increased electrode impedances compared to controls. Finally, treatment with PLX5622 decreased SGN survival in implanted and contralateral cochleae. Conclusion: The data suggest that macrophages play an important role in modulating the intracochlear tissue response following CI and neural survival. © 2023, The Author(s).

Author Keywords
Biomaterials;  Cochlear implant;  Fibrosis;  Foreign body response;  Inflammation

Document Type: Article
Publication Stage: Final
Source: Scopus

Dimerization mechanism of an inverted-topology ion channel in membranes
(2023) Proceedings of the National Academy of Sciences of the United States of America, 120 (47), pp. e2308454120. 

Ernst, M.^a , Orabi, E.A.^b , Stockbridge, R.B.^c , Faraldo-Gómez, J.D.^b , Robertson, J.L.^a

^a Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Theoretical Molecular Biophysics Section, National Heart, Lung, Blood Institute, NIH, Bethesda, United States
^c Department of Molecular, Cellular, Developmental Biology, University of Michigan, Ann Arbor, MI 48109, United States

Abstract
Many ion channels are multisubunit complexes where oligomerization is an obligatory requirement for function as the binding axis forms the charged permeation pathway. However, the mechanisms of in-membrane assembly of thermodynamically stable channels are largely unknown. Here, we demonstrate a key advance by reporting the dimerization equilibrium reaction of an inverted-topology, homodimeric fluoride channel Fluc in lipid bilayers. While the wild-type channel is a long-lived dimer, we leverage a known mutation, N43S, that weakens Na+ binding in a buried site at the interface, thereby unlocking the complex for reversible association in lipid bilayers. Single-channel recordings show that Na+ binding is required for fluoride conduction while single-molecule microscopy experiments demonstrate that N43S Fluc exists in a dynamic monomer-dimer equilibrium in the membrane, even following removal of Na+. Quantifying the thermodynamic stability while titrating Na+ indicates that dimerization occurs first, providing a membrane-embedded binding site where Na+ binding weakly stabilizes the complex. To understand how these subunits form stable assemblies while presenting charged surfaces to the membrane, we carried out molecular dynamics simulations, which show the formation of a thinned membrane defect around the exposed dimerization interface. In simulations where subunits are permitted to encounter each other while preventing protein contacts, we observe spontaneous and selective association at the native interface, where stability is achieved by mitigation of the membrane defect. These results suggest a model wherein membrane-associated forces drive channel assembly in the native orientation while subsequent factors, such as Na+ binding, result in channel activation.

Author Keywords
computational modeling;  dimerization;  Fluc;  ion channel;  single-molecule microscopy

Document Type: Article
Publication Stage: Final
Source: Scopus

Quantitative Analysis of S1PR1 Expression in the Postmortem Multiple Sclerosis Central Nervous System
(2023) ACS Chemical Neuroscience, 14 (22), pp. 4039-4050. 

Jiang, H.^a , Zhou, C.^a , Qiu, L.^a , Gropler, R.J.^a , Brier, M.R.^a b , Wu, G.F.^b , Cross, A.H.^b , Perlmutter, J.S.^a b , Benzinger, T.L.S.^a c , Tu, Z.^a

^a Department of Radiology, Washington University School of Medicine, St Louis, MO 63110, United States
^b Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, United States
^c Department of Neurological Surgery, Washington University School of Medicine, St Louis, MO 63110, United States

Abstract
Multiple sclerosis (MS) is an immune-mediated disease that is characterized by demyelination and inflammation in the central nervous system (CNS). Previous studies demonstrated that sphingosine-1-phosphate receptor (S1PR) modulators effectively inhibit S1PR1 in immune cell trafficking and reduce entry of pathogenic cells into the CNS. Studies have also implicated a nonimmune, inflammatory role of S1PR1 within the CNS in MS. In this study, we explored the expression of S1PR1 in the development and progression of demyelinating pathology of MS by quantitative assessment of S1PR1 expression using our S1PR1-specific radioligand, [3H]CS1P1, in the postmortem human CNS tissues including cortex, cerebellum, and spinal cord of MS cases and age- and sex-matched healthy cases. Immunohistochemistry with whole slide scanning for S1PR1 and various myelin proteins was also performed. Autoradiographic analysis using [3H]CS1P1 showed that the expression of S1PR1 was statistically significantly elevated in lesions compared to nonlesion regions in the MS cases, as well as normal healthy controls. The uptake of [3H]CS1P1 in the gray matter and nonlesion white matter did not significantly differ between healthy and MS CNS tissues. Saturation autoradiography analysis showed an increased binding affinity (Kd) of [3H]CS1P1 to S1PR1 in both gray matter and white matter of MS brains compared to healthy brains. Our blocking study using NIBR-0213, a S1PR1 antagonist, indicated [3H]CS1P1 is highly specific to S1PR1. Our findings demonstrated the activation of S1PR1 and an increased uptake of [3H]CS1P1 in the lesions of MS CNS. In summary, our quantitative autoradiography analysis using [3H]CS1P1 on human postmortem tissues shows the feasibility of novel imaging strategies for MS by targeting S1PR1.

Author Keywords
autoradiograph;  central nervous system;  lesion;  multiple sclerosis;  S1PR1;  [3H]CS1P1

Document Type: Article
Publication Stage: Final
Source: Scopus

Heterogeneity in Measures and Rates of Reported Dementia and Subjective Memory Complaints Across U.S. National Surveys
(2023) The Journals of Gerontology. Series B, Psychological Sciences and Social Sciences, 78 (11), pp. 1854-1859. 

Picchiello, M.C., Carpenter, B.D.

Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States

Abstract
OBJECTIVES: Several U.S. health surveillance surveys contain items related to self- and proxy reports of dementia and subjective memory complaints (SMC). Despite their similar content, these items differ in terminology, item specificity, and time frame. The goal of this study was to analyze whether item features might influence endorsement rates for dementia and SMC. METHODS: We calculated design-appropriate estimates for the endorsement of dementia and SMC across U.S.-based national surveys and employed pairwise comparisons to evaluate endorsement rates across surveys. We also examined item characteristics to explore possible effects on endorsement rates. RESULTS: Endorsement rates were wide-ranging for dementia (ranging from 2.7% to 9.9%) and SMC (5.6% to 46.6%). Pairwise comparisons revealed statistically significant differences on most dementia-related items (76%), and all SMC comparisons (100%). Items varied substantially in the terminology used to assess dementia and SMC (e.g., “dementia” vs “Alzheimer’s disease”) and used different time frames (e.g., “past month” vs “5 years”). DISCUSSION: National survey data on reported dementia and SMC can have important research, training, and policy implications, yet endorsement rates vary widely across surveys. That variability could emerge from subtle but influential item characteristics, and our findings highlight the need for item harmonization, in even their most basic characteristics. Standardizing items across national surveillance surveys facilitates comparison across surveys so that we can better understand the true burden of these conditions to inform public health initiatives. © The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
Dementia;  Measurement;  Research methods and issues;  Subjective memory complaints

Document Type: Article
Publication Stage: Final
Source: Scopus

Dementia Attributable Healthcare Utilizations in the Caribbean versus United States
(2023) Journal of Alzheimer’s Disease, 96 (2), pp. 801-811. 

Li, J.^a , Weiss, J.^b , Rajadhyaksha, A.^c , Acosta, D.^d , Harrati, A.^e , Jiménez Velázquez, I.Z.^f , Liu, M.-M.^g , Guerra, J.J.L.^h , Rodriguez, J.D.J.L.ⁱ , Dow, W.H.^g j

^a The Comparative Health Outcomes Policy and Economics (CHOICE) Institute, Department of Pharmacy, University of Washington, Seattle, WA, United States
^b Stanford Center on Longevity, Stanford University, Stanford, CA, United States
^c New York-Presbyterian Hospital, New York, NY, United States
^d Universidad Nacional Pedro Henriquez Ureña (UNPHU), Santo Domingo, Dominican Republic
^e Mathematica Policy Research, Oakland, CA, United States
^f Department of Medicine, Medical Sciences Campus, University of Puerto Rico, San Juan, PR, United States
^g Department of Demography, University of California at Berkeley, Berkeley, CA, United States
^h Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
ⁱ Medical University of Havana, Havana, Cuba
^j School of Public Health, University of California at Berkeley, Berkeley, CA, United States

Abstract
Background: Despite the high burden of Alzheimer’s disease and other dementias among the Hispanic population worldwide, little is known about how dementia affects healthcare utilizations among this population outside of the US, in particular among those in the Caribbean region. Objective: This study examines healthcare utilization associated with Alzheimer’s disease and other dementias among older adults in the Caribbean as compared to the US. Methods: We conducted harmonized analyses of two population-based surveys, the 10/66 Dementia Group Research data collected in Dominican Republic, Cuba, and Puerto Rico, and the US-based Health and Retirement Study. We examined changes in hospital nights and physician visits in response to incident and ongoing dementias. Results: Incident dementia significantly increased the risk of hospitalization and number of hospital nights in both populations. Ongoing dementia increased the risk of hospitalization and hospital nights in the US, with imprecise estimates for the Caribbean. The number of physician visits was elevated in the US but not in the Caribbean. Conclusions: The concentration of increased healthcare utilization on hospital care and among patients with incident dementia suggests an opportunity for improved outpatient management of new and existing dementia patients in the Caribbean. © 2023 – IOS Press. All rights reserved.

Author Keywords
Alzheimer’s disease;  Caribbean;  dementia;  healthcare utilization;  Hispanics

Funding details
National Institutes of HealthNIH
National Institute on AgingNIA
Alzheimer’s AssociationAA

Document Type: Article
Publication Stage: Final
Source: Scopus

PIGO-CDG: A case study with a new genotype, expansion of the phenotype, literature review, and nosological considerations
(2023) JIMD Reports, 64 (6), pp. 424-433. 

Starosta, R.T.^a , Kerashvili, N.^b , Pruitt, C.^c , Schultz, M.J.^d , Boyer, S.W.^e , Morava, E.^e , Lasio, M.L.D.^a f , Grange, D.K.^a

^a Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University in St. Louis, Clayton, MO, United States
^b Division of Pediatric Neurology, Department of Neurology, Washington University in St. Louis, Clayton, MO, United States
^c Division of Academic Pediatrics, Department of Pediatrics, Washington University in St. Louis, Clayton, MO, United States
^d Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
^e Department of Clinical Genomics, Mayo Clinic, Rochester, MN, United States
^f Division of Laboratory and Genomic Medicine, Department of Pathology and Immunology, Washington University in St. Louis, Clayton, MO, United States

Abstract
The phosphatidylinositol glycan anchor biosynthesis class O protein (PIGO) enzyme is an important step in the biosynthesis of glycosylphosphatidylinositol (GPI), which is essential for the membrane anchoring of several proteins. Bi-allelic pathogenic variants in PIGO lead to a congenital disorder of glycosylation (CDG) characterized by global developmental delay, an increase in serum alkaline phosphatase levels, congenital anomalies including anorectal, genitourinary, and limb malformations in most patients; this phenotype has been alternately called “Mabry syndrome” or “hyperphosphatasia with impaired intellectual development syndrome 2.” We report a 22-month-old female with PIGO deficiency caused by novel PIGO variants. In addition to the Mabry syndrome phenotype, our patient’s clinical picture was complicated by intermittent hypoglycemia with signs of functional hyperinsulinism, severe secretory diarrhea, and osteopenia with a pathological fracture, thus, potentially expanding the known phenotype of this disorder, although more studies are necessary to confirm these associations. We also provide an updated review of the literature, and propose unifying the nomenclature of PIGO deficiency as “PIGO-CDG,” which reflects its pathophysiology and position in the broad scope of metabolic disorders and congenital disorders of glycosylation. © 2023 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.

Author Keywords
congenital disorder of glycosylation;  diarrhea;  glycophosphatidylinositol;  hyperphosphatasia;  hypoglycemia;  Mabry syndrome

Funding details
National Institute of Neurological Disorders and StrokeNINDS1U54NS115198-01
National Center for Advancing Translational SciencesNCATS

Document Type: Article
Publication Stage: Final
Source: Scopus

Amyloid Positron Emission Tomography and Subsequent Health Care Use Among Medicare Beneficiaries With Mild Cognitive Impairment or Dementia
(2023) JAMA Neurology, 80 (11), pp. 1166-1173. 

Rabinovici, G.D.^a b c , Carrillo, M.C.^d , Apgar, C.^e , Gareen, I.F.^f g , Gutman, R.^f h , Hanna, L.^f , Hillner, B.E.ⁱ , March, A.^e , Romanoff, J.^f , Siegel, B.A.^j , Smith, K.^a , Song, Y.^f g h , Weber, C.^d , Whitmer, R.A.^k , Gatsonis, C.^f h

^a Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, Mexico
^b JAMA Neurology
^c Department of Radiology and Biomedical Imaging, University of California, San Francisco, Mexico
^d Alzheimer’s Association, Chicago, IL, United States
^e Center for Research and Innovation, American College of Radiology, Reston, VA, United States
^f Center for Statistical Sciences, Brown University School of Public Health, Providence, RI, United States
^g Department of Epidemiology, Brown University School of Public Health, Providence, RI, United States
^h Department of Biostatistics, Brown University School of Public Health, Providence, RI, United States
ⁱ Department of Medicine, Virginia Commonwealth University, Richmond, United Kingdom
^j Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, United States
^k Department of Public Health Sciences and Neurology, University of California, Davis, United States

Abstract
Importance: Results of amyloid positron emission tomography (PET) have been shown to change the management of patients with mild cognitive impairment (MCI) or dementia who meet Appropriate Use Criteria (AUC). Objective: To determine if amyloid PET is associated with reduced hospitalizations and emergency department (ED) visits over 12 months in patients with MCI or dementia. Design, Setting, and Participants: This nonrandomized controlled trial analyzed participants in the Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) study, an open-label, multisite, longitudinal study that enrolled participants between February 2016 and December 2017 and followed up through December 2018. These participants were recruited at 595 clinical sites that provide specialty memory care across the US. Eligible participants were Medicare beneficiaries 65 years or older with a diagnosis of MCI or dementia within the past 24 months who met published AUC for amyloid PET. Each IDEAS study participant was matched to a control Medicare beneficiary who had not undergone amyloid PET. Data analysis was conducted on December 13, 2022. Exposure: Participants underwent amyloid PET at imaging centers. Main Outcomes and Measures: The primary end points were the proportions of patients with 12-month inpatient hospital admissions and ED visits. One of 4 secondary end points was the rate of hospitalizations and rate of ED visits in participants with positive vs negative amyloid PET results. Health care use was ascertained from Medicare claims data. Results: The 2 cohorts (IDEAS study participants and controls) each comprised 12 684 adults, including 6467 females (51.0%) with a median (IQR) age of 77 (73-81) years. Over 12 months, 24.0% of the IDEAS study participants were hospitalized, compared with 25.1% of the matched control cohort, for a relative reduction of -4.49% (97.5% CI, -9.09% to 0.34%). The 12-month ED visit rates were nearly identical between the 2 cohorts (44.8% in both IDEAS study and control cohorts) for a relative reduction of -0.12% (97.5% CI, -3.19% to 3.05%). Both outcomes fell short of the prespecified effect size of 10% or greater relative reduction. Overall, 1467 of 6848 participants (21.4%) with positive amyloid PET scans were hospitalized within 12 months compared with 1081 of 4209 participants (25.7%) with negative amyloid PET scans (adjusted odds ratio, 0.83; 95% CI, 0.78-0.89). Conclusions and Relevance: Results of this nonrandomized controlled trial showed that use of amyloid PET was not associated with a significant reduction in 12-month hospitalizations or ED visits. Rates of hospitalization were lower in patients with positive vs negative amyloid PET results.

Document Type: Article
Publication Stage: Final
Source: Scopus

Regional Vulnerability Indices in Youth With Persistent and Distressing Psychoticlike Experiences
(2023) JAMA Network Open, 6 (11), p. e2343081. 

Karcher, N.R.^a , Modi, H.^b , Kochunov, P.^c d , Gao, S.^c d , Barch, D.M.^a

^a Washington University in St Louis School of Medicine, St Louis, MO, United States
^b Washington University in St Louis, St Louis, MO, United States
^c Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, Liberia
^d Department of Psychiatry, University of Texas Health Science Center, Houston, United States

Abstract
Importance: Distressing and persistent psychoticlike experiences (PLEs) in youth are associated with greater odds of developing psychiatric conditions in adulthood. Despite this risk, it is unclear whether early PLEs show similar brain patterns compared with adults with psychiatric and neurologic conditions. Objective: To examine the degree to which persistent and distressing PLEs exhibit neural metrics that show similarity to adults with chronic psychiatric and neurologic conditions. Design, Setting, and Participants: This cohort study used Adolescent Brain Cognitive Development (ABCD) Study examining the persistence and distress associated with PLEs across the first 3 waves of data with baseline structural magnetic resonance imaging data. Analyzed data were collected between September 1, 2016, and September 27, 2021. Children were recruited from 21 research sites across the US. Exposures: Psychoticlike experiences were assessed using the Prodromal Questionnaire-Brief Child Version, and participants were categorized into groups based on the persistence and distress associated with PLEs. Main Outcomes and Measures: Cortical and subcortical regional vulnerability indices (RVIs) were created by quantifying the similarity of participants’ baseline neuroimaging measures to the expected patterns found in adult neuropsychiatric samples. The PLE groups were compared on the following RVI cortical and subcortical metrics: schizophrenia spectrum disorders, bipolar disorder, major depressive disorder, Parkinson disease, Alzheimer disease, and metabolic diseases. Results: Analyses examined PLE groups created from 8242 children in the ABCD sample (52.5% male; mean [SD] age, 9.93 [0.63] years; and 56.3% White), including persistent distressing PLEs (n = 329), transient distressing PLEs (n = 396), persistent nondistressing PLEs (n = 234), transient nondistressing PLEs (n = 390), and low distressing PLEs (n = 6893) groups. Participants with persistent or transient distressing PLEs broadly showed increased subcortical RVI scores across most RVI metrics, with persistent distressing PLEs additionally showing increased scores for cortical RVI metrics. The greatest effect sizes were found for persistent distressing PLEs with cortical RVI-schizophrenia spectrum disorders (β estimate, 1.055; 95% CI, 0.326-1.786) and RVI-Alzheimer disease (β estimate, 2.473; 95% CI, 0.930-4.018). Conclusions and Relevance: In this cohort study of ABCD participants, the findings suggest that especially the persistent distressing PLEs in children were associated with neural metrics resembling those observed in adults with severe psychiatric and neurologic conditions. These findings support the potential use of brain-based risk scores for early identification and precision medicine approaches in the assessment of PLEs.

Document Type: Article
Publication Stage: Final
Source: Scopus

Princeton RAtlas: A Common Coordinate Framework for Fully cleared, Whole Rattus norvegicus Brains
(2023) Bio-protocol, 13 (20), art. no. e4854, . 

Dennis, E.J.^a b c , Bibawi, P.^a d , Dhanerawala, Z.M.^a e , Lynch, L.A.^a , Wang, S.S.-H.^a , Brody, C.D.^a c

^a Princeton Neuroscience Institute, Princeton University, Princeton, NJ, United States
^b Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, United States
^c Howard Hughes Medical Institute, Princeton University, Princeton, United States
^d Neurology Department, University of Pennsylvania, Philadelphia, PA, United States
^e Washington University School of Medicine, St. Louis, MO, United States

Abstract
Whole-brain clearing and imaging methods are becoming more common in mice but have yet to become standard in rats, at least partially due to inadequate clearing from most available protocols. Here, we build on recent mouse-tissue clearing and light-sheet imaging methods and develop and adapt them to rats. We first used cleared rat brains to create an open-source, 3D rat atlas at 25 μm resolution. We then registered and imported other existing labeled volumes and made all of the code and data available for the community (https://github.com/emilyjanedennis/PRA) to further enable modern, whole-brain neuroscience in the rat. © 2023 The Author(s).

Author Keywords
iDISCO;  Image registration;  Light-sheet imaging;  Neuroscience;  Rat;  Rattus norvegicus;  Tissue clearing;  uDISCO

Funding details
National Institutes of HealthNIHR01 MH128775, R01 NS045193
Howard Hughes Medical InstituteHHMI
Helen Hay Whitney FoundationHHWF

Document Type: Article
Publication Stage: Final
Source: Scopus

Enzymatic vitamin A2 production enables red-shifted optogenetics
(2023) Pflugers Archiv European Journal of Physiology, . 

Gerhards, J.^a , Volkov, L.I.^b , Corbo, J.C.^b , Malan, D.^a , Sasse, P.^a

^a Institute of Physiology I, Medical Faculty, University of Bonn, Bonn, 53125, Germany
^b Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Optogenetics is a technology using light-sensitive proteins to control signaling pathways and physiological processes in cells and organs and has been applied in neuroscience, cardiovascular sciences, and many other research fields. Most commonly used optogenetic actuators are sensitive to blue and green light, but red-light activation would allow better tissue penetration and less phototoxicity. Cyp27c1 is a recently deorphanized cytochrome P450 enzyme that converts vitamin A1 to vitamin A2, thereby red-shifting the spectral sensitivity of visual pigments and enabling near-infrared vision in some aquatic species. Here, we investigated the ability of Cyp27c1-generated vitamin A2 to induce a shift in spectral sensitivity of the light-gated ion channel Channelrhodopsin-2 (ChR2) and its red-shifted homolog ReaChR. We used patch clamp to measure photocurrents at specific wavelengths in HEK 293 cells expressing ChR2 or ReaChR. Vitamin A2 incubation red-shifted the wavelength for half-maximal currents (λ50%) by 6.8 nm for ChR2 and 12.4 nm for ReaChR. Overexpression of Cyp27c1 in HEK 293 cells showed mitochondrial localization, and HPLC analysis showed conversion of vitamin A1 to vitamin A2. Notably, the λ50% of ChR2 photocurrents was red-shifted by 10.5 nm, and normalized photocurrents at 550 nm were about twofold larger with Cyp27c1 expression. Similarly, Cyp27c1 shifted the λ50% of ReaChR photocurrents by 14.3 nm and increased normalized photocurrents at 650 nm almost threefold. Since vitamin A2 incubation is not a realistic option for in vivo applications and expression of Cyp27c1 leads to a greater red-shift in spectral sensitivity, we propose co-expression of this enzyme as a novel strategy for red-shifted optogenetics. © 2023, The Author(s).

Author Keywords
ChR2;  Cyp27c1;  Optogenetics;  ReaChR;  Vitamin A2

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Sex-specific genetic architecture of late-life memory performance
(2023) Alzheimer’s and Dementia, . 

Eissman, J.M.^a b , Archer, D.B.^a b , Mukherjee, S.^c , Lee, M.L.^c , Choi, S.-E.^c , Scollard, P.^c , Trittschuh, E.H.^d e , Mez, J.B.^f , Bush, W.S.^g , Kunkle, B.W.^h , Naj, A.C.^i j , Gifford, K.A.^a , Cuccaro, M.L.^h , Cruchaga, C.^k l , Pericak-Vance, M.A.^h , Farrer, L.A.^f m n , Wang, L.-S.^j , Schellenberg, G.D.^j , Mayeux, R.P.^o p q , Haines, J.L.^g , Jefferson, A.L.^a , Kukull, W.A.^r , Keene, C.D.^s , Saykin, A.J.^t u , Thompson, P.M.^v , Martin, E.R.^h , Bennett, D.A.^w , Barnes, L.L.^w , Schneider, J.A.^w , Crane, P.K.^c , Hohman, T.J.^a b , Dumitrescu, L.^a b

^a Vanderbilt Memory & Alzheimer’s Center, Vanderbilt University Medical Center, Nashville, TN, United States
^b Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, United States
^c Department of Medicine, University of Washington, Seattle, WA, United States
^d Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, United States
^e VA Puget Sound Health Care System, GRECC, Seattle, WA, United States
^f Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, United States
^g Cleveland Institute for Computational Biology, Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, United States
^h John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, United States
ⁱ Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^j Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^k Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
^l NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
^m Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States
ⁿ Department of Medicine (Biomedical Genetics), Boston University Chobanian & Avedisian School of Medicine, Boston, MA, United States
^o Columbia University, New York, NY, United States
^p The Taub Institute for Research on Alzheimer’s Disease and The Aging Brain, Columbia University, New York, NY, United States
^q The Institute for Genomic Medicine, Columbia University Medical Center and The New York Presbyterian Hospital, New York, NY, United States
^r Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, United States
^s Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, United States
^t Department of Radiology and Imaging Services, Indiana University School of Medicine, Indianapolis, IN, United States
^u Department of Medical and Molecular Genetics, School of Medicine, Indiana University, Indianapolis, IN, United States
^v Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
^w Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, United States

Abstract
BACKGROUND: Women demonstrate a memory advantage when cognitively healthy yet lose this advantage to men in Alzheimer’s disease. However, the genetic underpinnings of this sex difference in memory performance remain unclear. METHODS: We conducted the largest sex-aware genetic study on late-life memory to date (Nmales = 11,942; Nfemales = 15,641). Leveraging harmonized memory composite scores from four cohorts of cognitive aging and AD, we performed sex-stratified and sex-interaction genome-wide association studies in 24,216 non-Hispanic White and 3367 non-Hispanic Black participants. RESULTS: We identified three sex-specific loci (rs67099044—CBLN2, rs719070—SCHIP1/IQCJ-SCHIP), including an X-chromosome locus (rs5935633—EGL6/TCEANC/OFD1), that associated with memory. Additionally, we identified heparan sulfate signaling as a sex-specific pathway and found sex-specific genetic correlations between memory and cardiovascular, immune, and education traits. DISCUSSION: This study showed memory is highly and comparably heritable across sexes, as well as highlighted novel sex-specific genes, pathways, and genetic correlations that related to late-life memory. Highlights: Demonstrated the heritable component of late-life memory is similar across sexes. Identified two genetic loci with a sex-interaction with baseline memory. Identified an X-chromosome locus associated with memory decline in females. Highlighted sex-specific candidate genes and pathways associated with memory. Revealed sex-specific shared genetic architecture between memory and complex traits. © 2023 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.

Author Keywords
aging;  Alzheimer’s disease;  cognition;  endophenotypes;  Genomics;  GWAS;  memory;  sex differences;  sex-specific

Funding details
R01AG36836, R01AG48015, RC2AG036547, RF1AG57473, U01AG32984, U01AG46152, U01AG46161, U01AG61356
P20 AG068024, P20 AG068053, P20 AG068077, P20 AG068082, P30 AG062421, P30 AG062422, P30 AG062429, P30 AG062677, P30 AG062715, P30 AG066444, P30 AG066462, P30 AG066468, P30 AG066506, P30 AG066507, P30 AG066508, P30 AG066509, P30 AG066511, P30 AG066512, P30 AG066514, P30 AG066515, P30 AG066518, P30 AG066519, P30 AG066530, P30 AG066546, P30 AG072931, P30 AG072946, P30 AG072947, P30 AG072958, P30 AG072959, P30 AG072972, P30 AG072973, P30 AG072975, P30 AG072976, P30 AG072977, P30 AG072978, P30 AG072979, P30 AG079280
R01 AG22018, R01 AG42210
U54AG052427
P30 AG010161, R01 AG01101, R01 AG019085, R01 AG030146, R01 AG17917, RC2 AG036650, U01 AG06781, U01 HG004610, U24 AG21886
U24AG041689
R01 AG017917
National Institutes of HealthNIHP01AG026276, P01AG03991, P30AG066444, P30AG066462, R01AG044546, R01AG064614, R01AG064877, RF1AG053303, RF1AG054080, RF1AG058501, U01AG052410, U01AG058922, U01‐AG024904, U24 AG072122
U.S. Department of DefenseDODW81XWH‐12‐2‐0012
National Institute on AgingNIAP30 AG10161, P30AG72975, R01 AG059716, R01 AG15819, R01AG17917, R01AG22018, R01AG30146, R01AG36042, RC2AG036528, U01 AG006781, U01 AG068057, U01AG032984, U19 AG066567, U24 AG056270, U24 AG074855
National Institute of Biomedical Imaging and BioengineeringNIBIB
Alzheimer’s AssociationAA
Alzheimer’s Drug Discovery FoundationADDF
Illinois Department of Public HealthIDPH
Biogen
AbbVie
University of Pennsylvania
Alzheimer’s Disease Neuroimaging InitiativeADNIU01 AG024904
BioClinica
Hope Center for Neurological Disorders
Translational Genomics Research InstituteTGEN
National Alzheimer’s Coordinating CenterNACCU01 AG016976

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Multi-ancestry genome-wide association study of cannabis use disorder yields insight into disease biology and public health implications
(2023) Nature Genetics, . 

Levey, D.F.^a b , Galimberti, M.^a b , Deak, J.D.^a b , Wendt, F.R.^a b c d , Bhattacharya, A.^e , Koller, D.^a b f , Harrington, K.M.^g h , Quaden, R.^g h , Johnson, E.C.ⁱ , Gupta, P.^a b , Biradar, M.^j , Lam, M.^k l m , Cooke, M.^n o , Rajagopal, V.M.^p q , Empke, S.L.L.^a b , Zhou, H.^a b , Nunez, Y.Z.^a b , Kranzler, H.R.^r , Edenberg, H.J.^s , Agrawal, A.ⁱ , Smoller, J.W.^t u , Lencz, T.^m , Hougaard, D.M.^q v , Børglum, A.D.^p q w , Demontis, D.^p q w x , Gaziano, J.M.^o y z , Gandal, M.J.^aa ab , Polimanti, R.^a b , Stein, M.B.^ac ad , Gelernter, J.^a b

^a Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
^b Department of Psychiatry, Veterans Affairs Connecticut Healthcare Center, West Haven, CT, United States
^c Department of Anthropology, University of Toronto, Mississauga, ON, Canada
^d Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
^e Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
^f Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, Catalonia, Spain
^g VA Boston Healthcare System, Massachusetts Veterans Epidemiology Research and Information Center, Boston, MA, United States
^h Department of Psychiatry, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, United States
ⁱ Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
^j NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, United Kingdom
^k Research Division, Institute of Mental Health, Singapore, Singapore
^l Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, United States
^m Department of Psychiatry and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
ⁿ Center for Addiction Medicine, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, United States
^o Harvard Medical School, Boston, MA, United States
^p Department of Biomedicine, Aarhus University, Aarhus, Denmark
^q The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark
^r Mental Illness Research, Education and Clinical Center, Crescenz VAMC and Center for Studies of Addiction, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^s Departments of Biochemistry and Molecular Biology and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
^t Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States
^u Center for Precision Psychiatry, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, United States
^v Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
^w Center for Genomics and Personalized Medicine, Aarhus, Denmark
^x The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, United States
^y Million Veteran Program Coordinating Center, VA Boston Healthcare System, Boston, MA, United States
^z Department of Medicine, Division of Aging, Brigham and Women’s Hospital, Boston, MA, United States
^aa Departments of Psychiatry and Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^ab The Lifespan Brain Institute, Penn Medicine and the Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^ac Psychiatry Service, VA San Diego Healthcare System, San Diego, CA, United States
^ad Department of Psychiatry and Herbert Wertheim School of Public Health, University of California San Diego, La Jolla, CA, United States

Abstract
As recreational use of cannabis is being decriminalized in many places and medical use widely sanctioned, there are growing concerns about increases in cannabis use disorder (CanUD), which is associated with numerous medical comorbidities. Here we performed a genome-wide association study of CanUD in the Million Veteran Program (MVP), followed by meta-analysis in 1,054,365 individuals (n cases = 64,314) from four broad ancestries designated by the reference panel used for assignment (European n = 886,025, African n = 123,208, admixed American n = 38,289 and East Asian n = 6,843). Population-specific methods were applied to calculate single nucleotide polymorphism-based heritability within each ancestry. Statistically significant single nucleotide polymorphism-based heritability for CanUD was observed in all but the smallest population (East Asian). We discovered genome-wide significant loci unique to each ancestry: 22 in European, 2 each in African and East Asian, and 1 in admixed American ancestries. A genetically informed causal relationship analysis indicated a possible effect of genetic liability for CanUD on lung cancer risk, suggesting potential unanticipated future medical and psychiatric public health consequences that require further study to disentangle from other known risk factors such as cigarette smoking. © 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

Funding details
I01CX001849
575B
1IK2BX005058-01A2
K01DA051759
National Institutes of HealthNIHR01 AA026364, R01DA054869
National Institute of Mental HealthNIMH1R01MH124851-01
U.S. Department of Veterans AffairsVAI01 BX004820, R01MH117646, R01MH118233, R21DC018098, R33DA047527
Brain and Behavior Research FoundationBBRF
Enzon Pharmaceuticals
Aarhus UniversitetAUNNF20OC0065561, NNF21SA0072102, R344-2020-1060
National Alliance for Research on Schizophrenia and DepressionNARSAD
American Society of Clinical PsychopharmacologyASCP
European CommissionEC101028810, 27835, F32MH122058, R01MH121521, R01MH123922, T32 AA028259
Lundbeck FoundationR102-A9118, R155-2014-1724, R248-2017-2003
Horizon 2020
Novo Nordisk FondenNNF

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Trajectories of therapeutic skills use and their dynamic relations to symptom change during cognitive-behavioral therapy for bulimia nervosa
(2023) International Journal of Eating Disorders, . 

D’Adamo, L.^a b , Linardon, J.^c , Manasse, S.M.^a , Juarascio, A.S.^a

^a Department of Psychological and Brain Sciences and Center for Weight, Eating, and Lifestyle Science (WELL Center), Drexel University, Philadelphia, PA, United States
^b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^c School of Psychology, Deakin University, Geelong, VIC, Australia

Abstract
Objective: To examine trajectories of therapeutic skills use and weekly relations between skills use and symptom change during the enhanced version of cognitive-behavioral therapy (CBT-E) for bulimia nervosa (BN). Method: Fifty-five adults (M age: 39.0 ± 14.1; 83.9% female; 64.3% White, 93.6% non-Hispanic/Latino) receiving CBT-E for BN-spectrum eating disorders (EDs) self-monitored their use of five therapeutic skills (i.e., regular eating, eating enough to prevent excessive hunger and eating a range of macronutrients, breaking dietary rules, urge management strategies, and mood management strategies) several times per day during treatment. Patients also self-reported their ED symptoms (i.e., frequency of binge eating, compensatory behaviors, and dietary restraint) weekly. We examined trajectories of use of each CBT-E skill and temporal relations between skills use and ED symptoms from week-to-week during treatment. Results: Participants showed significant increases in eating enough to prevent excessive hunger and eating a range of macronutrients from week-to-week (p <.05). Regular eating, eating enough to prevent excessive hunger, and eating a range of macronutrients 1 week predicted lower binge eating and compensatory behaviors the same week and the following week, and urge management strategy use predicted greater binge eating the same week and the following week (p <.05). Conclusions: Results showed temporal relationships between therapeutic skills use and symptom change on a weekly level, with evidence that using skills targeting dietary restraint was associated with lower BN symptoms. Findings highlight the promise of future work to elucidate the most potent CBT-E skills for symptom improvement and inform more targeted interventions. Public Significance: Findings showed weekly relationships between therapeutic skills use and symptom change during treatment, with evidence that using CBT-E skills aimed to reduce dietary restraint (i.e., regular eating, eating enough to prevent excessive hunger, and eating a range of macronutrients) was associated with lower BN symptoms. Future work has the potential to identify the most potent CBT-E skills for symptom improvement and inform more targeted interventions. © 2023 Wiley Periodicals LLC.

Author Keywords
bulimia nervosa;  cognitive-behavioral therapy;  eating disorder;  therapeutic skills;  treatment

Funding details
National Institutes of HealthNIHK23 DK124514, R34 MH116021, T32 HL130357

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Greater socioenvironmental risk factors and higher chronic pain stage are associated with thinner bilateral temporal lobes
(2023) Brain and Behavior, . 

Antoine, L.H.^a , Tanner, J.J.^b , Mickle, A.M.^c d , Gonzalez, C.E.^a , Kusko, D.A.^a , Watts, K.A.^e , Rumble, D.D.^f , Buchanan, T.L.^g , Sims, A.M.^h , Staud, R.ⁱ , Lai, S.^j , Deshpande, H.^k , Phillips, B.^l , Buford, T.W.^m n , Aroke, E.N.^o , Redden, D.T.^h , Fillingim, R.B.^c p , Goodin, B.R.^a q , Sibille, K.T.^c d

^a Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, United States
^b Department of Clinical and Health Psychology, University of Florida, Gainesville, FL, United States
^c Pain Research & Intervention Center of Excellence, University of Florida, Gainesville, FL, United States
^d Department of Physical Medicine & Rehabilitation, University of Florida, Gainesville, FL, United States
^e Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
^f Department of Psychology and Counseling, University of Central Arkansas, Conway, AR, United States
^g Center for Exercise Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
^h Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, United States
ⁱ Department of Medicine, University of Florida, Gainesville, FL, United States
^j Department of Radiation Oncology, University of Florida, Gainesville, FL, United States
^k Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, United States
^l Department of Accounting & Finance, North Carolina A&T State University, Greensboro, NC, United States
^m Department of Medicine − Division of Gerontology, Geriatrics, and Palliative Care, University of Alabama at Birmingham, Birmingham, AL, United States
ⁿ Birmingham/Atlanta Geriatric Research, Education, and Clinical Center, Birmingham VA Medical Center, Birmingham, AL, United States
^o School of Nursing, University of Alabama at Birmingham, Birmingham, AL, United States
^p Department of Community of Dentistry and Behavioral Sciences, University of Florida, Gainesville, FL, United States
^q Department of Anesthesiology, Washington University, Washington University Pain Center, St. Louis, MO, United States

Abstract
Introduction: Previous research indicates ethnic/race group differences in pain and neurodegenerative diseases. Accounting for socioenvironmental factors reduces ethnic/race group differences in clinical and experimental pain. In the current study sample, we previously reported that in individuals with knee pain, ethnic/race group differences were observed in bilateral temporal lobe thickness, areas of the brain associated with risk for Alzheimer’s disease, and related dementias. The purpose of the study was to determine if socioenvironmental factors reduce or account for previously observed ethnic/race group differences and explore if a combined effect of socioenvironmental risk and chronic pain severity on temporal lobe cortices is evident. Methods: Consistent with the prior study, the sample was consisted of 147 adults (95 women, 52 men), 45–85 years of age, who self-identified as non-Hispanic Black (n = 72) and non-Hispanic White (n = 75), with knee pain with/at risk for osteoarthritis. Measures included demographics, health history, pain questionnaires, cognitive screening, body mass index, individual- and community-level socioenvironmental factors (education, income, household size, marital and insurance status, and area deprivation index), and brain imaging. We computed a summative socioenvironmental risk index. Results: Regression analyses showed that with the inclusion of socioenvironmental factors, the model was significant (p <.001), and sociodemographic (ethnic/race) group differences were not significant (p =.118). Additionally, findings revealed an additive stress load pattern indicating thinner temporal lobe cortices with greater socioenvironmental risk and chronic pain severity (p =.048). Implications: Although individual socioenvironmental factors were not independent predictors, when collectively combined in models, ethnic/race group differences in bilateral temporal lobe structures were not replicated. Further, combined socioenvironmental risk factors and higher chronic pain severity were associated with thinner bilateral temporal lobes. © 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.

Author Keywords
Alzheimer’s disease risk;  brain imaging;  chronic pain;  health disparities;  osteoarthritis

Funding details
UL1TR001417, UL1TR001427
National Institutes of HealthNIH
National Institute on AgingNIA5K02AG062498, R01AG054370, R37AG033906
National Institute of General Medical SciencesNIGMS5K12GM088010‐12
National Center for Advancing Translational SciencesNCATSNSF DMR‐164479, UL1 TR000064
State of Florida

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

TFEB–vacuolar ATPase signaling regulates lysosomal function and microglial activation in tauopathy
(2023) Nature Neuroscience, . 

Wang, B.^a b , Martini-Stoica, H.^a c f , Qi, C.^a , Lu, T.-C.^a , Wang, S.^a , Xiong, W.^a , Qi, Y.^a , Xu, Y.^a g , Sardiello, M.^b d h , Li, H.^a b , Zheng, H.^a b e

^a Huffington Center on Aging, Baylor College of Medicine, Houston, TX, United States
^b Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
^c Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, United States
^d Dan and Jan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, TX, United States
^e Department of Neuroscience, Baylor College of Medicine, Houston, TX, United States
^f Department of Otolaryngology, University of North Carolina School of Medicine, Chapel Hill, NC, United States
^g School of Mental Health and Psychological Sciences, Anhui Medical University, Anhui, China
^h Department of Pediatrics, Washington University School of Medicine, St Louis, MO, United States

Abstract
Transcription factor EB (TFEB) mediates gene expression through binding to the coordinated lysosome expression and regulation (CLEAR) sequence. TFEB targets include subunits of the vacuolar ATPase (v-ATPase), which are essential for lysosome acidification. Single-nucleus RNA sequencing of wild-type and PS19 (Tau) transgenic mice expressing the P301S mutant tau identified three unique microglia subclusters in Tau mice that were associated with heightened lysosome and immune pathway genes. To explore the lysosome–immune relationship, we specifically disrupted the TFEB–v-ATPase signaling by creating a knock-in mouse line in which the CLEAR sequence of one of the v-ATPase subunits, Atp6v1h, was mutated. CLEAR mutant exhibited a muted response to TFEB, resulting in impaired lysosomal acidification and activity. Crossing the CLEAR mutant with Tau mice led to higher tau pathology but diminished microglia response. These microglia were enriched in a subcluster low in mTOR and HIF-1 pathways and were locked in a homeostatic state. Our studies demonstrate a physiological function of TFEB–v-ATPase signaling in maintaining lysosomal homeostasis and a critical role of the lysosome in mounting a microglia and immune response in tauopathy and Alzheimer’s disease. © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

The Negative Effects of Travel on Student Athletes Through Sleep and Circadian Disruption
(2023) Journal of Biological Rhythms, . 

Heller, H.C.^a , Herzog, E.^b , Brager, A.^c , Poe, G.^d , Allada, R.^e , Scheer, F.^f , Carskadon, M.^g , de la Iglesia, H.O.^h , Jang, R.^d , Montero, A.ⁱ , Wright, K.^j , Mouraine, P.^k , Walker, M.P.^l , Goel, N.^m , Hogenesch, J.ⁿ , Van Gelder, R.N.^o , Kriegsfeld, L.^l , Mah, C.^k , Colwell, C.^p , Zeitzer, J.^k , Grandner, M.^q , Jackson, C.L.^r s , Roxanne Prichard, J.^t , Kay, S.A.^u , Paul, K.^v

^a Department of Biology, Stanford University, StanfordCA, United States
^b Department of Biology, Washington University, St. Louis, MO, United States
^c U.S. Army John F. Kennedy Special Warfare Center and School, Fort Bragg, NC, United States
^d UCLA Brain Research Institute, Los Angeles, CA, United States
^e Department of Neurobiology, Northwestern University, Chicago, IL, United States
^f Medical Chronobiology Program, Brigham and Women’s Hospital, Boston, MA, United States
^g Department of Psychiatry and Human Behavior, Bradley Hospital, Brown University, Providence, RI, United States
^h Department of Biology, University of Washington, Seattle, WA, United States
ⁱ Department of Psychology, Flinders University, Adelaide, SA, Australia
^j Integrative Physiology, University of Colorado, Boulder, CO, United States
^k Department of Psychiatry and Behavioral Sciences, Stanford University, StanfordCA, United States
^l Department of Psychology, University of California, Berkeley, CA, United States
^m Department of Psychiatry and Behavioral Sciences, Rush University, Chicago, IL, United States
ⁿ Department of Genetics, Cincinnati University, Cincinnati, OH, United States
^o Department of Ophthalmology, University of Washington, Seattle, WA, United States
^p Department of Psychiatry and Behavioral Sciences, University of California, Los Angeles, CA, United States
^q University of Arizona College of Medicine, Tucson, AZ, United States
^r Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle ParkNC, United States
^s Division of Intramural Research, National Institute on Minority Health and Health Disparities, National Institutes of Health, BethesdaMD, United States
^t Department of Psychology, University of St. Thomas, St Paul, MN, United States
^u Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
^v Integrative Biology and Physiology, University of California, Los Angeles, CA, United States

Abstract
Collegiate athletes must satisfy the academic obligations common to all undergraduates, but they have the additional structural and social stressors of extensive practice time, competition schedules, and frequent travel away from their home campus. Clearly such stressors can have negative impacts on both their academic and athletic performances as well as on their health. These concerns are made more acute by recent proposals and decisions to reorganize major collegiate athletic conferences. These rearrangements will require more multi-day travel that interferes with the academic work and personal schedules of athletes. Of particular concern is additional east-west travel that results in circadian rhythm disruptions commonly called jet lag that contribute to the loss of amount as well as quality of sleep. Circadian misalignment and sleep deprivation and/or sleep disturbances have profound effects on physical and mental health and performance. We, as concerned scientists and physicians with relevant expertise, developed this white paper to raise awareness of these challenges to the wellbeing of our student-athletes and their co-travelers. We also offer practical steps to mitigate the negative consequences of collegiate travel schedules. We discuss the importance of bedtime protocols, the availability of early afternoon naps, and adherence to scheduled lighting exposure protocols before, during, and after travel, with support from wearables and apps. We call upon departments of athletics to engage with sleep and circadian experts to advise and help design tailored implementation of these mitigating practices that could contribute to the current and long-term health and wellbeing of their students and their staff members. © 2023 The Author(s).

Author Keywords
academic and athletic performance;  chronic jet lag;  circadian misalignment;  sleep and circadian health;  student mental health

Funding details
National Institutes of HealthNIH
National Institute of Environmental Health SciencesNIEHSZ1AES103325

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Cognitive Self-Efficacy in Parkinson’s Disease
(2023) OTJR: Occupational Therapy Journal of Research, . 

Jethani, P.M.^a , Toglia, J.^b , Foster, E.R.^c

^a Louisiana State University of Health Sciences, Shreveport, LA, United States
^b Mercy University, Dobbs FerryNY, United States
^c Washington University, St. Louis, MO, United States

Abstract
Cognitive self-efficacy (CSE), one’s belief in their ability to control their cognitive performance, is important for participation in daily activities and rehabilitation. This study aims to understand how Parkinson’s disease (PD) affects CSE. The Cognitive Self-Efficacy Questionnaire (CSEQ) was administered to 47 non-demented PD and 52 healthy comparison (HC) participants. Groups were compared on their self-reported ability to recognize (Part 1) and manage (Part 2) cognitive symptoms and to perform cognitively complex functional activities (Part 4). Relationships between CSEQ scores and individual characteristics were assessed within PD. The PD group had lower CSEQ scores than the HC group for all Parts. Within PD, Part 2 scores were lower than Parts 1 and 4, and worse depressive symptoms and higher medication dosage correlated with lower CSE. People with PD may have low CSE, which can contribute to participation restrictions and reduced engagement in treatment. Occupational therapists should consider CSE with clients with PD. © The Author(s) 2023.

Author Keywords
cognition;  occupational engagement;  occupational therapy;  Parkinson’s disease;  rehabilitation

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

The Pace of Biological Aging Predicts Nonspecific Chronic Low Back Pain Severity
(2023) Journal of Pain, . 

Aroke, E.N.^a , Srinivasasainagendra, V.^b , Kottae, P.^c , Quinn, T.L.^d , Wiggins, A.M.^d , Hobson, J.^d , Kinnie, K.^a , Stoudmire, T.^a , Tiwari, H.K.^b , Goodin, B.R.^e

^a School of Nursing, University of Alabama at Birmingham, Birmingham, Alabama, United States
^b Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, United States
^c Department of Computer Science, College of Arts and Sciences, University of Alabama at Birmingham, Birmingham, Alabama, United States
^d Department of Psychology, College of Arts and Sciences, University of Alabama at Birmingham, Birmingham, Alabama, United States
^e Department of Anesthesiology, School of Medicine, Washington University, St Louis, Missouri, United States

Abstract
This study aimed to determine if and how the pace of biological aging was associated with nonspecific chronic low back pain (cLBP) and compare what measure of epigenetic age acceleration most strongly predicts cLBP outcomes. We used the Dunedin Pace of Aging from the Epigenome (DunedinPACE), Horvath’s, Hannum’s, and PhenoAge clocks to determine the pace of biological aging in 69 cLBP, and 49 pain-free controls (PFCs) adults, ages 18 to 85 years. On average, participants with cLBP had higher DunedinPACE (P &lt; .001) but lower Horvath (P = .04) and Hannum (P = .02) accelerated epigenetic age than PFCs. There was no significant difference in PhenoAge acceleration between the cLBP and PFC groups (P = .97). DunedinPACE had the largest effect size (Cohen’s d = .78) on group differences. In univariate regressions, a unit increase in DunedinPACE score was associated with 265.98 times higher odds of cLBP than the PFC group (P &lt; .001). After controlling for sex, race, and body mass index (BMI), the odds ratio of cLBP to PFC group was 149.62 (P &lt; .001). Furthermore, among participants with cLBP, DunedinPACE scores positively correlated with pain severity (rs = .385, P = .001) and interference (rs = .338, P = .005). Epigenetic age acceleration from Horvath, Hannum, and PhenoAge clocks were not significant predictors of cLBP. The odds of a faster pace of biological aging are higher among adults with cLBP, and this was associated with greater pain severity and disability. Future interventions to slow the pace of biological aging may improve cLBP outcomes. Perspectives: Accelerated epigenetic aging is common among adults with nonspecific cLBP. Higher DunedinPACE scores positively correlate with pain severity and interference, and better predict cLBP than other DNA methylation clocks. Interventions to slow the pace of biological aging may be viable targets for improving pain outcomes. © 2023 United States Association for the Study of Pain, Inc.

Author Keywords
Dunedin Pace of Aging from the Epigenome (DunedinPACE);  epigenetic age acceleration;  epigenetic clocks;  nonspecific chronic low back pain;  pace of biological aging

Funding details
National Institutes of HealthNIHR01AR079178, R01MD010441

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Baseline Characteristics From a New Longitudinal Cohort of Patients With Noncancer Pain and Chronic Opioid Use in the United States
(2023) Journal of Pain, . 

Secrest, S.^a , Miller-Matero, L.R.^b , Chrusciel, T.^a c d , Salas, J.^a c , Sullivan, M.D.^e , Zabel, C.^b , Lustman, P.^f , Ahmedani, B.^b , Carpenter, R.W.^g , Scherrer, J.F.^a c h

^a Department of Family and Community Medicine, Saint Louis University School of Medicine, St. Louis, Missouri, United States
^b Center for Health Policy and Health Services Research and Behavioral Health Services, Henry Ford Health, One Ford Place, Detroit, MI, United States
^c Advanced HEAlth Data (AHEAD) Research Institute, Saint Louis University School of Medicine, St. Louis, Missouri, United States
^d Department of Health and Clinical Outcomes Research, Saint Louis University School of Medicine, St. Louis, Missouri, United States
^e Department of Psychiatry and Behavioral Science, University of Washington School of Medicine, Seattle, WA, United States
^f Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, United States
^g Department of Psychological Sciences, University of Missouri—St. Louis, St. Louis, Missouri, United States
^h Department of Psychiatry and Behavioral Neuroscience, Saint Louis University School of Medicine, St. Louis, Missouri, United States

Abstract
Retrospective cohort studies have consistently observed that long-term prescription opioid use is a risk factor for new major depressive episodes. However, prospective studies are needed to confirm these findings and establish evidence for causation. The Prescription Opioids and Depression Pathways cohort study is designed for this purpose. The present report describes the baseline sample and associations between participant characteristics and odds of daily versus nondaily opioid use. Second, we report associations between participant characteristics and odds of depression, dysthymia, anhedonia, and vital exhaustion. Patients with noncancer pain were eligible if they started a new period of prescription opioid use lasting 30 to 90 days. Participants were 54.8 (standard deviation ± 11.3) years of age, 57.3% female and 73% White race. Less than college education was more common among daily versus nondaily opioid users (32.4% vs 27.3%; P = .0008), as was back pain (64.2% vs 51.3%; P < .0001), any nonopioid substance use disorder (12.8% vs 4.8%; P < .0001), and current smoking (30.7% vs 18.4% P < .0001). High pain interference (50.9% vs 28.4%; P < .0001) was significantly associated with depression, as was having more pain sites (6.9 ± 3.6 vs 5.7 ± 3.6; P < .0001), and benzodiazepine comedication (38.2% vs 23.4%; P < .0001). High pain interference was significantly more common among those with anhedonia (46.8% vs 27.4%; P < .0001), and more pain sites (7.0 ± 3.7 vs 5.6 ± 3.6; P < .0001) were associated with anhedonia. Having more pain sites (7.9 ± 3.6 vs 5.5 ± 3.50; P < .0001) was associated with vital exhaustion, as was back pain (71.9% vs 56.8%; P = .0001) and benzodiazepine comedication (42.8% vs 22.8%; P < .0001). Patients using prescription opioids for noncancer pain have complex pain, psychiatric, and substance use disorder comorbidities. Longitudinal data will reveal whether long-term opioid therapy leads to depression or other mood disturbances such as anhedonia and vital exhaustion. Perspective: This study reports baseline characteristics of a new prospective, noncancer pain cohort study. Risk factors for adverse opioid outcomes were most common in those with depression and vital exhaustion and less common in dysthymia and anhedonia. Baseline data highlight the complexity of patients receiving long-term opioid therapy for noncancer pain. © 2023 United States Association for the Study of Pain, Inc.

Author Keywords
cohort;  epidemiology;  mood;  Opioid;  pain

Funding details
National Institute on Drug AbuseNIDAR01DA043811

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial
(2023) Nature Medicine, . 

Kilburn, L.B.^a , Khuong-Quang, D.-A.^b , Hansford, J.R.^c d , Landi, D.^e , van der Lugt, J.^f , Leary, S.E.S.^g , Driever, P.H.^h , Bailey, S.ⁱ , Perreault, S.^j , McCowage, G.^k , Waanders, A.J.^l , Ziegler, D.S.^m n o , Witt, O.^{p q r s t} , Baxter, P.A.^u , Kang, H.J.^v , Hassall, T.E.^w , Han, J.W.^x , Hargrave, D.^y , Franson, A.T.^z , Yalon Oren, M.^aa , Toledano, H.^ab , Larouche, V.^ac , Kline, C.^ad , Abdelbaki, M.S.^ae , Jabado, N.^af , Gottardo, N.G.^ag , Gerber, N.U.^ah , Whipple, N.S.^ai , Segal, D.^aj , Chi, S.N.^ak , Oren, L.^al , Tan, E.E.K.^am , Mueller, S.^an , Cornelio, I.^ao , McLeod, L.^ao , Zhao, X.^ao , Walter, A.^ao , Da Costa, D.^ao , Manley, P.^ao , Blackman, S.C.^ao , Packer, R.J.^ap , Nysom, K.^aq

^a Children’s National Hospital, Washington, DC, United States
^b Children’s Cancer Centre, Royal Children’s Hospital Melbourne, Melbourne, VIC, Australia
^c Michael Rice Centre for Hematology and Oncology, Women’s and Children’s Hospital, Adelaide, SA, Australia
^d South Australia Health and Medical Research Institute, Adelaide, Australia; South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, SA, Australia
^e Duke University, Durham, NC, United States
^f Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
^g Cancer and Blood Disorders Center, Seattle Children’s, Seattle, WA, United States
^h Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität Berlin, German HIT-LOGGIC-Registry for LGG in Children and Adolescents, Berlin, Germany
ⁱ Great North Children’s Hospital and Newcastle University Centre for Cancer, Newcastle-upon-Tyne, United Kingdom
^j CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada
^k Sydney Children’s Hospitals Network, Westmead, NSW, Australia
^l Ann & Robert H. Lurie Children’s Hospital, Chicago, IL, United States
^m Kids Cancer Centre, Sydney Children’s Hospital, Randwick, NSW, Australia
ⁿ Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia
^o School of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia
^p Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
^q Clinical Cooperation Unit, Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
^r Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany
^s German Cancer Consortium (DKTK), Heidelberg, Germany
^t National Center for Tumor Diseases (NCT), Heidelberg, Germany
^u Texas Children’s Cancer Center, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, United States
^v Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul National University Children’s Hospital, Seoul, South Korea
^w Children’s Health Queensland Hospital and Health Service, South Brisbane, QLD, Australia
^x Severance Hospital, Yonsei University Health System, Seoul, South Korea
^y UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital for Children, London, United Kingdom
^z C.S. Mott Children’s Hospital, University of Michigan Medical School, Ann Arbor, MI, United States
^aa Pediatric Hemato-Oncology, Sheba Medical Center, Ramat Gan, Israel
^ab Department of Pediatric Oncology, Schneider Children’s Medical Center, Petach Tikva, and Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
^ac Department of Pediatrics, Centre Mère-Enfant Soleil du CHU de Québec-Université Laval, Quebec City, QC, Canada
^ad Division of Oncology, Department of Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^ae Division of Hematology and Oncology, Department of Pediatrics, School of Medicine, Washington University, St. Louis, MO, United States
^af McGill University Health Centre (MUHC), Montreal Children’s Hospital (MCH), Montreal, QC, Canada
^ag Department of Pediatric and Adolescent Oncology and Hematology, Perth Children’s Hospital, Perth, Australia, and Brain Tumor Research Program, Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia, Perth, WA, Australia
^ah Department of Oncology, University Children’s Hospital, Zurich, Switzerland
^ai Primary Children’s Hospital and University of Utah, Salt Lake City, UT, United States
^aj NYU Langone Health, New York, NY, United States
^ak Pediatric Neuro-Oncology, Department of Pediatrics, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, MA, United States
^al Department of Hematology & Oncology, Rambam Healthcare Campus, Haifa, Israel
^am Haematology/Oncology Service, KK Women’s and Children’s Hospital, Singapore, Singapore
^an Department of Neurology, Neurosurgery and Pediatrics, University of California, San Francisco, San Francisco, CA, United States
^ao Day One Biopharmaceuticals, Brisbane, CA, United States
^ap Division of Neurology, Brain Tumor Institute, Center for Neuroscience and Behavioral Medicine, Children’s National Hospital, Washington, DC, United States
^aq Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark

Abstract
BRAF genomic alterations are the most common oncogenic drivers in pediatric low-grade glioma (pLGG). Arm 1 (n = 77) of the ongoing phase 2 FIREFLY-1 (PNOC026) trial investigated the efficacy of the oral, selective, central nervous system–penetrant, type II RAF inhibitor tovorafenib (420 mg m−2 once weekly; 600 mg maximum) in patients with BRAF-altered, relapsed/refractory pLGG. Arm 2 (n = 60) is an extension cohort, which provided treatment access for patients with RAF-altered pLGG after arm 1 closure. Based on independent review, according to Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, the overall response rate (ORR) of 67% met the arm 1 prespecified primary endpoint; median duration of response (DOR) was 16.6 months; and median time to response (TTR) was 3.0 months (secondary endpoints). Other select arm 1 secondary endpoints included ORR, DOR and TTR as assessed by Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO) criteria and safety (assessed in all treated patients and the primary endpoint for arm 2, n = 137). The ORR according to RAPNO criteria (including minor responses) was 51%; median DOR was 13.8 months; and median TTR was 5.3 months. The most common treatment-related adverse events (TRAEs) were hair color changes (76%), elevated creatine phosphokinase (56%) and anemia (49%). Grade ≥3 TRAEs occurred in 42% of patients. Nine (7%) patients had TRAEs leading to discontinuation of tovorafenib. These data indicate that tovorafenib could be an effective therapy for BRAF-altered, relapsed/refractory pLGG. ClinicalTrials.gov registration: NCT04775485 . © 2023, The Author(s).

Funding details
TPG2037
AstraZeneca
National Institute for Health and Care ResearchNIHR
National Health and Medical Research CouncilNHMRC2019056, APP2017898
NIHR Great Ormond Street Hospital Biomedical Research CentreNIHR GOSH BRC

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Cognitive Control in Schizophrenia: Advances in Computational Approaches
(2023) Current Directions in Psychological Science, . 

Barch, D.M.^a b c , Culbreth, A.J.^d , Sheffield, J.M.^e

^a Department of Psychological and Brain Sciences, Washington University, St. Louis, United States
^b Department of Psychiatry, Washington University School of Medicine, United States
^c Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, United States
^d Maryland Psychiatric Research Center Department of Psychiatry, University of Maryland, Baltimore, United States
^e Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical School, United States

Abstract
Psychiatric research is undergoing significant advances in an emerging subspeciality of computational psychiatry, building on cognitive neuroscience research by expanding to neurocomputational modeling. Here, we illustrate some research trends in this domain using work on proactive cognitive control deficits in schizophrenia as an example. We provide a selective review of formal modeling approaches to understanding cognitive control deficits in psychopathology, focusing primarily on biologically plausible connectionist-level models as well as mathematical models that generate parameter estimates of putatively dissociable psychological or neural processes. We illustrate some of the advantages of these models in terms of understanding both cognitive control deficits in schizophrenia and the potential roles of effort and motivation. Further, we highlight critical future directions for this work, including a focus on establishing psychometric properties, additional work modeling psychotic symptoms and their interaction with cognitive control, and the need to expand both behavioral and neural modeling to samples that include individuals with different mental health conditions, allowing for the examination of dissociable neural or psychological substrates for seemingly similar cognitive impairments across disorders. © The Author(s) 2023.

Author Keywords
cognitive control;  computation;  motivation;  psychosis;  schizophrenia

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Post-stroke Depressive Symptoms and Cognitive Performances: A Network Analysis
(2023) Archives of Physical Medicine and Rehabilitation, . 

Shi, Y.^a b , Lenze, E.J.^c , Mohr, D.C.^d e , Lee, J.-M.^f , Hu, L.^a b , Metts, C.L.^g , Fong, M.W.M.^h i , Wong, A.W.K.^h j k

^a Center for Healthful Behavior Change, Institute for Excellence in Health Equity, NYU Langone Health, New York, NY, United States
^b Department of Population Health, New York University Grossman School of Medicine, New York, NY, United States
^c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^d Center for Behavioral Intervention Technologies, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
^e Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
^f Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, United States
^h Department of Physical Medicine and Rehabilitation, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
ⁱ Michigan Avenue Neuropsychologists, Chicago, IL, United States
^j Center for Rehabilitation Outcomes Research, Shirley Ryan AbilityLab, Chicago, IL, United States
^k Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, United States

Abstract
Objective: To examine the relationships between post-stroke depression and cognition using network analysis. In particular, we identified central depressive symptoms, central cognitive performances, and bridge components that connect these 2 constructs. Design: An observational study. We applied network analysis to analyze baseline data to visualize and quantify the relationships between depression and cognition. Setting: Home and Community. Participants: 202 participants with mild-to-moderate stroke (N=202; mean age: 59.7 years; 55% men; 55% Whites; 90% ischemic stroke). Intervention: Not applicable. Main Outcome Measures: Patient Health Questionnaire (PHQ-8) for depressive symptoms and the NIH Toolbox Cognitive Battery for cognitive performances. Results: Depressive symptoms were positively intercorrelated with the network, with symptoms from similar domains clustered together. Mood (expected influence=1.58), concentration (expected influence=0.67), and guilt (expected influence=0.63) were the top 3 central depressive symptoms. Cognitive performances also showed similar network patterns, with executive function (expected influence=0.89), expressive language (expected influence=0.68), and processing speed (expected influence=0.48) identified as the top 3 central cognitive performances. Psychomotor functioning (bridge expected influence=2.49) and attention (bridge expected influence=1.10) were the components connecting depression and cognition. Conclusions: The central and bridge components identified in this study might serve as targets for interventions against these deficits. Future trials are needed to compare the effectiveness of interventions targeting the central and bridge components vs general interventions treating depression and cognitive impairment as a homogenous clinical syndrome. © 2023 American Congress of Rehabilitation Medicine

Author Keywords
Cognition;  Depression;  Network analysis;  Neuropsychiatry;  Stroke

Funding details
P2CHD101899
National Institutes of HealthNIH
American Diabetes AssociationADA
National Institute of Neurological Disorders and StrokeNINDS
Craig H. Neilsen FoundationCHNF
Patient-Centered Outcomes Research InstitutePCORI
National Center for Medical Rehabilitation ResearchNCMRRK01HD095388
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Diagnostic Utility of Cerebrospinal Fluid Biomarkers in Patients with Rapidly Progressive Dementia
(2023) Annals of Neurology, . 

Kuchenbecker, L.A.^a , Tipton, P.W.^b , Martens, Y.^a , Brier, M.R.^c , Satyadev, N.^b , Dunham, S.R.^c , Lazar, E.B.^b d , Dacquel, M.V.^a , Henson, R.L.^c , Bu, G.^a , Geschwind, M.D.^e , Morris, J.C.^c , Schindler, S.E.^c , Herries, E.^c , Graff-Radford, N.R.^b , Day, G.S.^b

^a Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, United States
^b Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, United States
^c Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
^d Hackensack Meridian JFK University Medical Center, Edison, NJ, United States
^e Department of Neurology, University of California, San Francisco, San Francisco, CA, United States

Abstract
Objective: This study was undertaken to apply established and emerging cerebrospinal fluid (CSF) biomarkers to improve diagnostic accuracy in patients with rapidly progressive dementia (RPD). Overlap in clinical presentation and results of diagnostic tests confounds etiologic diagnosis in patients with RPD. Objective measures are needed to improve diagnostic accuracy and to recognize patients with potentially treatment-responsive causes of RPD. Methods: Biomarkers of Alzheimer disease neuropathology (amyloid-β 42/40 ratio, phosphorylated tau [p-tau181, p-tau231]), neuroaxonal/neuronal injury (neurofilament light chain [NfL], visinin-like protein-1 [VILIP-1], total tau), neuroinflammation (chitinase-3-like protein [YKL-40], soluble triggering receptor expressed on myeloid cells 2 [sTREM2], glial fibrillary acidic protein [GFAP], monocyte chemoattractant protein-1 [MCP-1]), and synaptic dysfunction (synaptosomal-associated protein 25kDa, neurogranin) were measured in CSF obtained at presentation from 78 prospectively accrued patients with RPD due to neurodegenerative, vascular, and autoimmune/inflammatory diseases; 35 age- and sex-matched patients with typically progressive neurodegenerative disease; and 72 cognitively normal controls. Biomarker levels were compared across etiologic diagnoses, by potential treatment responsiveness, and between patients with typical and rapidly progressive presentations of neurodegenerative disease. Results: Alzheimer disease biomarkers were associated with neurodegenerative causes of RPD. High NfL, sTREM2, and YKL-40 and low VILIP-1 identified patients with autoimmune/inflammatory diseases. MCP-1 levels were highest in patients with vascular causes of RPD. A multivariate model including GFAP, MCP-1, p-tau181, and sTREM2 identified the 44 patients with treatment-responsive causes of RPD with 89% accuracy. Minimal differences were observed between typical and rapidly progressive presentations of neurodegenerative disease. Interpretation: Selected CSF biomarkers at presentation were associated with etiologic diagnoses and treatment responsiveness in patients with heterogeneous causes of RPD. The ability of cross-sectional biomarkers to inform upon mechanisms that drive rapidly progressive neurodegenerative disease is less clear. ANN NEUROL 2023. © 2023 American Neurological Association.

Funding details
National Institute on AgingNIAK23AG064029, P30AG062677, P30AG066444

Document Type: Article
Publication Stage: Article in Press
Source: Scopus