WashU weekly Neuroscience publications

Gene-based polygenic risk scores analysis of alcohol use disorder in African Americans
(2022) Translational Psychiatry, 12 (1), art. no. 266, . 

Lai, D.^a , Schwantes-An, T.-H.^a , Abreu, M.^a , Chan, G.^b c , Hesselbrock, V.^b , Kamarajan, C.^d , Liu, Y.^a , Meyers, J.L.^d , Nurnberger, J.I., Jr.^a e , Plawecki, M.H.^e , Wetherill, L.^a , Schuckit, M.^f , Zhang, P.^g , Edenberg, H.J.^a h , Porjesz, B.^d , Agrawal, A.ⁱ , Foroud, T.^a

^a Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
^b Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, United States
^c Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, IA, United States
^d Henri Begleiter Neurodynamics Lab, Department of Psychiatry, State University of New York, Downstate Medical Center, Brooklyn, NY, United States
^e Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, United States
^f Department of Psychiatry, University of California, San Diego Medical School, San Diego, CA, United States
^g Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, IN, United States
^h Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
ⁱ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Genome-wide association studies (GWAS) in admixed populations such as African Americans (AA) have limited sample sizes, resulting in poor performance of polygenic risk scores (PRS). Based on the observations that many disease-causing genes are shared between AA and European ancestry (EA) populations, and some disease-causing variants are located within the boundaries of these genes, we proposed a novel gene-based PRS framework (PRSgene) by using variants located within disease-associated genes. Using the AA GWAS of alcohol use disorder (AUD) from the Million Veteran Program and the EA GWAS of problematic alcohol use as the discovery GWAS, we identified 858 variants from 410 genes that were AUD-related in both AA and EA. PRSgene calculated using these variants were significantly associated with AUD in three AA target datasets (P-values ranged from 7.61E−05 to 6.27E−03; Betas ranged from 0.15 to 0.21) and outperformed PRS calculated using all variants (P-values ranged from 7.28E−03 to 0.16; Betas ranged from 0.06 to 0.18). PRSgene were also associated with AUD in an EA target dataset (P-value = 0.02, Beta = 0.11). In AA, individuals in the highest PRSgene decile had an odds ratio of 1.76 (95% CI: 1.32–2.34) to develop AUD compared to those in the lowest decile. The 410 genes were enriched in 54 Gene Ontology biological processes, including ethanol oxidation and processes involving the synaptic system, which are known to be AUD-related. In addition, 26 genes were targets of drugs used to treat AUD or other diseases that might be considered for repurposing to treat AUD. Our study demonstrated that the gene-based PRS had improved performance in evaluating AUD risk in AA and provided new insight into AUD genetics. © 2022, The Author(s).

Funding details
K02DA032573, R01DA054869
National Institutes of HealthNIHU10AA008401
National Institute on Drug AbuseNIDA
National Institute on Alcohol Abuse and AlcoholismNIAAA
National Center for Research ResourcesNCRRRR020128
National Center for Advancing Translational SciencesNCATS
Indiana UniversityIU
Indiana Clinical and Translational Sciences InstituteCTSIUL1TR002529
Lilly Endowment
Washington University in St. LouisWUSTL
Icahn School of Medicine at Mount SinaiISMMS
University of Connecticut
University of California, San DiegoUCSD
Virginia Commonwealth UniversityVCU
Rutgers, The State University of New JerseyRU
Howard University
School of Medicine, CHA University

Document Type: Article
Publication Stage: Final
Source: Scopus

Effects of chronic cannabidiol in a mouse model of naturally occurring neuroinflammation, neurodegeneration, and spontaneous seizures
(2022) Scientific Reports, 12 (1), art. no. 11286, . 

Dearborn, J.T.^a , Nelvagal, H.R.^b , Rensing, N.R.^c , Takahashi, K.^b , Hughes, S.M.^d , Wishart, T.M.^e , Cooper, J.D.^b , Wong, M.^c , Sands, M.S.^a f

^a Department of Medicine, Washington University School of Medicine, 4444 Forest Park Blvd Ave. 05536, St. Louis, MO 63110, United States
^b Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Biochemistry, University of Otago, Dunedin, New Zealand
^e The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, United Kingdom
^f Department of Genetics, Washington University School of Medicine, 4444 Forest Park Ave. 05509, St. Louis, MO 63110, United States

Abstract
Cannabidiol (CBD) has gained attention as a therapeutic agent and is purported to have immunomodulatory, neuroprotective, and anti-seizure effects. Here, we determined the effects of chronic CBD administration in a mouse model of CLN1 disease (Cln1−/−) that simultaneously exhibits neuroinflammation, neurodegeneration, and spontaneous seizures. Proteomic analysis showed that putative CBD receptors are expressed at similar levels in the brains of Cln1−/− mice compared to normal animals. Cln1−/− mice received an oral dose (100 mg/kg/day) of CBD for six months and were evaluated for changes in pathological markers of disease and seizures. Chronic cannabidiol administration was well-tolerated, high levels of CBD were detected in the brain, and markers of astrocytosis and microgliosis were reduced. However, CBD had no apparent effect on seizure frequency or neuron survival. These data are consistent with CBD having immunomodulatory effects. It is possible that a higher dose of CBD could also reduce neurodegeneration and seizure frequency. © 2022, The Author(s).

Funding details
Batten Disease Support and Research AssociationBDSRANIH NS R21 106523, NS R01100779, P50 HD103525
Biotechnology and Biological Sciences Research CouncilBBSRCBBS/E/D/10002071

Document Type: Article
Publication Stage: Final
Source: Scopus

Multisite learning of high-dimensional heterogeneous data with applications to opioid use disorder study of 15,000 patients across 5 clinical sites
(2022) Scientific Reports, 12 (1), art. no. 11073, . 

Liu, X.^a , Duan, R.^b , Luo, C.^a c , Ogdie, A.^d , Moore, J.H.^e , Kranzler, H.R.^f , Bian, J.^g , Chen, Y.^a

^a Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, 423 Guardian Drive, Philadelphia, PA 19104, United States
^b Department of Biostatistics, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, United States
^c Division of Public Health Sciences, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^d Department of Medicine, Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^e Department of Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA 90096, United States
^f Department of Psychiatry, University of Pennsylvania Perelman School of Medicine and the VISN 4 MIRECC, Crescenz VAMC, Philadelphia, PA, United States
^g Department of Health Outcomes and Biomedical Informatics, University of Florida Health Cancer Center, Gainesville, FL, United States

Abstract
Integrating data across institutions can improve learning efficiency. To integrate data efficiently while protecting privacy, we propose A one-shot, summary-statistics-based, Distributed Algorithm for fitting Penalized (ADAP) regression models across multiple datasets. ADAP utilizes patient-level data from a lead site and incorporates the first-order (ADAP1) and second-order gradients (ADAP2) of the objective function from collaborating sites to construct a surrogate objective function at the lead site, where model fitting is then completed with proper regularizations applied. We evaluate the performance of the proposed method using both simulation and a real-world application to study risk factors for opioid use disorder (OUD) using 15,000 patient data from the OneFlorida Clinical Research Consortium. Our results show that ADAP performs nearly the same as the pooled estimator but achieves higher estimation accuracy and better variable selection than the local and average estimators. Moreover, ADAP2 successfully handles heterogeneity in covariate distributions. © 2022, The Author(s).

Funding details
National Institutes of HealthNIH1R01AG073435, 1R56AG074604, LM010098, R01AI130460, R01CA246518, R01LM012607 1R01LM013519, R56AG069880
Centers for Disease Control and PreventionCDCU18DP006512
Patient-Centered Outcomes Research InstitutePCORIME-2018C3-14899, ME-2019C3-18315
Enzon Pharmaceuticals
Pearl Therapeutics
American Society of Clinical PsychopharmacologyASCP

Document Type: Article
Publication Stage: Final
Source: Scopus

The Effects of Prenatal Exposure to Neighborhood Crime on Neonatal Functional Connectivity
(2022) Biological Psychiatry, 92 (2), pp. 139-148. Cited 1 time.

Brady, R.G.^a b , Rogers, C.E.^c d , Prochaska, T.^d , Kaplan, S.^b , Lean, R.E.^d , Smyser, T.A.^d , Shimony, J.S.^e , Slavich, G.M.^g , Warner, B.B.^c , Barch, D.M.^d e f , Luby, J.L.^c d , Smyser, C.D.^b c e

^a Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, Missouri
^b Department of Neurology, Washington University School of Medicine, St. Louis, Missouri
^c Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
^d Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri
^e Mallinckrot Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri
^f Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, Missouri
^g Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California

Abstract
Background: Maternal exposure to adversity during pregnancy has been found to affect infant brain development; however, the specific effect of prenatal crime exposure on neonatal brain connectivity remains unclear. Based on existing research, we hypothesized that living in a high-crime neighborhood during pregnancy would affect neonatal frontolimbic connectivity over and above other individual- and neighborhood-level adversity and that these associations would be mediated by maternal psychosocial stress. Methods: Participants included 399 pregnant women, recruited as part of the eLABE (Early Life Adversity, Biological Embedding, and Risk for Developmental Precursors of Mental Disorders) study. In the neonatal period, 319 healthy, nonsedated infants were scanned using resting-state functional magnetic resonance imaging (repetition time = 800 ms; echo time = 37 ms; voxel size = 2.0 × 2.0 × 2.0 mm3; multiband = 8) on a Prisma 3T scanner and had at least 10 minutes of high-quality data. Crime data at the block group level were obtained from Applied Geographic Solution. Linear regressions and mediation models tested associations between crime, frontolimbic connectivity, and psychosocial stress. Results: Living in a neighborhood with high property crime during pregnancy was related to weaker neonatal functional connectivity between the thalamus–anterior default mode network (aDMN) (β = −0.15, 95% CI = −0.25 to −0.04, p =.008). Similarly, high neighborhood violent crime was related to weaker functional connectivity between the thalamus-aDMN (β = −0.16, 95% CI = −0.29 to −0.04, p =.01) and amygdala-hippocampus (β = −0.16, 95% CI = −0.29 to −0.03, p =.02), controlling for other types of adversity. Psychosocial stress partially mediated relationships between the thalamus-aDMN and both violent and property crime. Conclusions: These findings suggest that prenatal exposure to crime is associated with weaker neonatal limbic and frontal functional brain connections, providing another reason for targeted public policy interventions to reduce crime. © 2022 Society of Biological Psychiatry

Author Keywords
Adversity;  Functional connectivity;  Neighborhood crime;  Neonates;  Pregnancy;  Stress

Funding details
P50 HD103525
National Institutes of HealthNIHF30 HD104313-01A1, R01 MH113883
University of WashingtonUWOPR21101
Children’s Discovery InstituteCDI
McDonnell Center for Systems Neuroscience

Document Type: Article
Publication Stage: Final
Source: Scopus

Theory-Based Self-Management Interventions for Community-Dwelling Stroke Survivors: A Systematic Review and Meta-Analysis
(2022) The American Journal of Occupational Therapy: Official Publication of the American Occupational Therapy Association, 76 (4), . 

Lau, S.C.L.^a , Judycki, S.^b , Mix, M.^c , DePaul, O.^d , Tomazin, R.^e , Hardi, A.^f , Wong, A.W.K.^g , Baum, C.^h

^a Stephen C. L. Lau, BS, is Student, Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO
^b Stephanie Judycki, BS, is Student, Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO
^c Mikayla Mix, BS, is Student, Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO
^d Olivia DePaul, BS, is Student, Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO
^e Rachel Tomazin, BS, is Student, Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO
^f Angela Hardi, MLIS, is Librarian, Becker Medical Library, Washington University School of Medicine, St. Louis, MO
^g Alex W. K. Wong, PhD, DPhil, is Assistant Professor, Program in Occupational Therapy, Department of Neurology, and Department of Psychiatry, Washington University School of Medicine, St. Louis, MO
^h Carolyn Baum, PhD, is Professor, Program in Occupational Therapy and Department of Neurology, Washington University School of Medicine, St. Louis, MO;

Abstract
IMPORTANCE: Self-management is a critical component of stroke rehabilitation. A better understanding of the use of theory and behavior change techniques (BCTs) informs the development of more effective stroke self-management interventions. OBJECTIVE: To examine what theories and BCTs have been applied in stroke self-management interventions; investigate the extent to which these interventions encourage implementation of behavior changes; and appraise their effectiveness to enhance self-efficacy, quality of life, and functional independence. DATA SOURCES: Ovid MEDLINE, Embase, Scopus, CINAHL, Cochrane Library, and ClinicalTrials.gov were searched from inception to May 26, 2020. STUDY SELECTION AND DATA COLLECTION: Randomized controlled trials (RCTs) in six databases were reviewed for inclusion and analysis. We included trials that involved community-dwelling adult stroke survivors, assessed the effectiveness of self-management interventions, and explicitly mentioned the use of theory in the development of the intervention. We assessed use of theory and BCTs using the Theory Coding Scheme and BCT taxonomy v1, respectively. FINDINGS: A total of 3,049 studies were screened, and 13 RCTs were included. The predominant theory and BCT categories were Social Cognitive Theory (7 studies) and goals and planning (12 studies), respectively. Significant and small effect sizes were found for self-efficacy (0.27) and functional independence (0.19). CONCLUSIONS AND RELEVANCE: Theory-based self-management interventions have the potential to enhance stroke outcomes. Systematic reporting on the use of theory and BCTs is recommended to enhance clarity and facilitate evaluations of future interventions. What This Article Adds: This review supports and guides occupational therapy practitioners to use theory-based self-management intervention as a routine part of stroke rehabilitation to improve stroke survivors’ experience in the community. Copyright © 2022 by the American Occupational Therapy Association, Inc.

Document Type: Article
Publication Stage: Final
Source: Scopus

Soft, bioresorbable coolers for reversible conduction block of peripheral nerves
(2022) Science, 377 (6601), pp. 109-115. 

Reeder, J.T.^a b c , Xie, Z.^d e , Yang, Q.^c f , Seo, M.-H.^b c g , Yan, Y.^h , Deng, Y.ⁱ , Jinkins, K.R.^c , Krishnan, S.R.^b c , Liu, C.^c j , McKay, S.^j , Patnaude, E.^j , Johnson, A.^j , Zhao, Z.^d e , Kim, M.J.^k , Xu, Y.^l , Huang, I.^b c , Avila, R.^f , Felicelli, C.^m , Ray, E.ⁿ , Guo, X.^d e , Ray, W.Z.^h n , Huang, Y.^b c f o , MacEwan, M.R.^h n , Rogers, J.A.^{b c f j p q r}

^a Knight Campus for Accelerating Scientific Impact, University of Oregon, Eugene, OR, United States
^b Department of Materials Science and Engineering, Northwestern University, Evanston, IL, United States
^c Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL, United States
^d State Key Laboratory of Structural Analysis for Industrial Equipment, Department of Engineering Mechanics, Dalian University of Technology, Dalian, China
^e Ningbo Institute of Dalian University of Technology, Ningbo, China
^f Department of Mechanical Engineering, Northwestern University, Evanston, IL, United States
^g School of Biomedical Convergence Engineering, College of Information and Biomedical Engineering, Pusan National University, Busan, South Korea
^h Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
ⁱ State Key Laboratory of Mechanical System and Vibration, Shanghai Jiao Tong University, Shanghai, China
^j Department of Biomedical Engineering, Northwestern University, Evanston, IL, United States
^k Department of Chemical Engineering, Northwestern University, Evanston, IL, United States
^l Institute of Materials Science and Engineering, Washington University, St. Louis, MO, United States
^m Department of Pathology, Northwestern University, Evanston, IL, United States
ⁿ Department of Biomedical Engineering, Washington University, St. Louis, MO, United States
^o Departments of Civil and Environmental Engineering, Northwestern University, Evanston, IL, United States
^p Department of Chemistry, Northwestern University, Evanston, IL, United States
^q Department of Electrical Engineering and Computer Science, Northwestern University, Evanston, IL, United States
^r Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Evanston, IL, United States

Abstract
Implantable devices capable of targeted and reversible blocking of peripheral nerve activity may provide alternatives to opioids for treating pain. Local cooling represents an attractive means for on-demand elimination of pain signals, but traditional technologies are limited by rigid, bulky form factors; imprecise cooling; and requirements for extraction surgeries. Here, we introduce soft, bioresorbable, microfluidic devices that enable delivery of focused, minimally invasive cooling power at arbitrary depths in living tissues with real-time temperature feedback control. Construction with water-soluble, biocompatible materials leads to dissolution and bioresorption as a mechanism to eliminate unnecessary device load and risk to the patient without additional surgeries. Multiweek in vivo trials demonstrate the ability to rapidly and precisely cool peripheral nerves to provide local, on-demand analgesia in rat models for neuropathic pain. © 2022 American Association for the Advancement of Science. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

Neuropathic pain correlates with worsening cognition in people with human immunodeficiency virus
(2022) Brain, 145 (6), pp. 2206-2213. 

Ellis, R.J.^a b , Sacktor, N.^c , Clifford, D.B.^d , Marra, C.M.^e , Collier, A.C.^f , Gelman, B.^g , Robinson-Papp, J.^h , Letendre, S.L.^b , Heaton, R.K.^b i

^a Department of Neurosciences, University of California, San Diego, CA 92103-8231, United States
^b Department of Psychiatry, University of California, San Diego, CA 92103-8231, United States
^c Department of Neurology, Johns-Hopkins University, Baltimore, MD 21224, United States
^d Department of Neurology, Washington University, St. Louis, MO 63110, United States
^e Department of Neurology, University of Washington, Seattle, WA 98104, United States
^f Department of Medicine, University of Washington, Seattle, WA 98104, United States
^g Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, United States
^h Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
ⁱ Department of Medicine, University of California, San Diego, CA 92103, United States

Abstract
Neuropathic pain and cognitive impairment are among the HIV-related conditions that have most stubbornly resisted amelioration by virally suppressive antiretroviral therapy. Overlaps between the regional brain substrates and mechanisms of neuropathic pain and cognitive disorders are increasingly recognized, yet no studies have examined the longitudinal relationship between these two disorders. Participants in the prospective, observational CNS HIV AntiRetroviral Therapy Effects Research (CHARTER) cohort underwent standardized clinical evaluations for clinical examination findings of distal sensory polyneuropathy, reporting distal neuropathic pain and neurocognitive performance at study entry (baseline) and an average of 12 years later. Change in neuropathic pain and neuropathy status from baseline to follow-up was by self-report and repeat examination, and change in neurocognitive performance was assessed using a previously published summary regression-based change score. Relationships between incident or worsened neuropathic pain and neurocognitive change were evaluated using uni- and multivariable regressions, including age at baseline and other relevant covariates. Participants were 385 people with HIV, 91 (23.6%) females, mean ± standard deviation (SD) age at baseline 43.5 (7.81) years, ethnicity 44.9% African American, 10.6% Hispanic, 42.6% non-Hispanic white and 1.82% other. Baseline median (interquartile range) nadir CD4 was 175 (34 309) cells/μl and current CD4 was 454 (279 639). Incident or worsened distal neuropathic pain occurred in 98 (25.5%) over the follow-up period. People with HIV with incident or worsened distal neuropathic pain had significantly worsened neurocognitive performance at follow-up compared to those without incident or worsened distal neuropathic pain (summary regression-based change score mean ± SD -0.408 ± 0.700 versus -0.228 ± 0.613; P = 0.0158). This effect remained significant when considering viral suppression on antiretroviral therapy, incident diabetes and other covariates as predictors. Overall neurocognitive change related to neuropathic pain was driven primarily by changes in the domains of executive function and speed of information processing. Those with incident distal neuropathy signs did not have neurocognitive worsening, nor did individuals who used opioid analgesics or other pain-modulating drugs such as amitriptyline. Worsened neurocognitive performance in people with HIV was associated with worsened neuropathic pain but not with changes in physical signs of neuropathy, and this was not attributable to therapies for pain or depression or to differences in viral suppression. This finding implies that incident or worsened pain may signal increased risk for neurocognitive impairment, and deserves more investigation, particularly if better pain management might stabilize or improve neurocognitive performance. © 2022 The Author(s) 2022

Author Keywords
biomarkers;  cerebrospinal fluid;  cognition;  HIV;  neurodegeneration

Document Type: Article
Publication Stage: Final
Source: Scopus

NeoRS: A Neonatal Resting State fMRI Data Preprocessing Pipeline
(2022) Frontiers in Neuroinformatics, 16, art. no. 843114, . 

Enguix, V.^a b c , Kenley, J.^d , Luck, D.^a c , Cohen-Adad, J.^a b e f , Lodygensky, G.A.^a c

^a Department of Pediatrics, CHU Sainte-Justine, University of Montreal, Montreal, QC, Canada
^b NeuroPoly Lab, Institute of Biomedical Engineering, Polytechnique Montreal, Montreal, QC, Canada
^c Canadian Neonatal Brain Platform, Montreal, QC, Canada
^d Washington University School of Medicine, St. Louis, MO, United States
^e Functional Neuroimaging Unit, CRIUGM, University of Montreal, Montreal, QC, Canada
^f Mila – Quebec AI Institute, Montreal, QC, Canada

Abstract
Resting state functional MRI (rsfMRI) has been shown to be a promising tool to study intrinsic brain functional connectivity and assess its integrity in cerebral development. In neonates, where functional MRI is limited to very few paradigms, rsfMRI was shown to be a relevant tool to explore regional interactions of brain networks. However, to identify the resting state networks, data needs to be carefully processed to reduce artifacts compromising the interpretation of results. Because of the non-collaborative nature of the neonates, the differences in brain size and the reversed contrast compared to adults due to myelination, neonates can’t be processed with the existing adult pipelines, as they are not adapted. Therefore, we developed NeoRS, a rsfMRI pipeline for neonates. The pipeline relies on popular neuroimaging tools (FSL, AFNI, and SPM) and is optimized for the neonatal brain. The main processing steps include image registration to an atlas, skull stripping, tissue segmentation, slice timing and head motion correction and regression of confounds which compromise functional data interpretation. To address the specificity of neonatal brain imaging, particular attention was given to registration including neonatal atlas type and parameters, such as brain size variations, and contrast differences compared to adults. Furthermore, head motion was scrutinized, and motion management optimized, as it is a major issue when processing neonatal rsfMRI data. The pipeline includes quality control using visual assessment checkpoints. To assess the effectiveness of NeoRS processing steps we used the neonatal data from the Baby Connectome Project dataset including a total of 10 neonates. NeoRS was designed to work on both multi-band and single-band acquisitions and is applicable on smaller datasets. NeoRS also includes popular functional connectivity analysis features such as seed-to-seed or seed-to-voxel correlations. Language, default mode, dorsal attention, visual, ventral attention, motor and fronto-parietal networks were evaluated. Topology found the different analyzed networks were in agreement with previously published studies in the neonate. NeoRS is coded in Matlab and allows parallel computing to reduce computational times; it is open-source and available on GitHub (https://github.com/venguix/NeoRS). NeoRS allows robust image processing of the neonatal rsfMRI data that can be readily customized to different datasets. Copyright © 2022 Enguix, Kenley, Luck, Cohen-Adad and Lodygensky.

Author Keywords
fMRI;  neonates;  pipeline;  preprocessing;  resting state

Funding details
Canadian Institutes of Health ResearchIRSCFDN-143263
Natural Sciences and Engineering Research Council of CanadaNSERCRGPIN-2019-07244
Fonds de Recherche du Québec – SantéFRQS
Canada Foundation for InnovationCFI32454, 34824
Canada Research Chairs950-230815
Canada First Research Excellence FundCFREF
Institut de Valorisation des DonnéesIVADO35450, 5886

Document Type: Article
Publication Stage: Final
Source: Scopus

Case Report: A Novel EIF2B3 Pathogenic Variant in Central Nervous System Hypomyelination/Vanishing White Matter
(2022) Frontiers in Genetics, 13, art. no. 893057, . 

Wongkittichote, P.^a , Mar, S.S.^b , McKinstry, R.C.^c , Nguyen, H.^a

^a Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St Louis, MO, United States
^b Division of Pediatric Neurology, Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^c Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, United States

Abstract
Leukodystrophies are a group of heterogeneous disorders affecting brain myelin. Among those, childhood ataxia with central nervous system hypomyelination/vanishing white matter (CACH/VWM) is one of the more common inherited leukodystrophies. Pathogenic variants in one of the genes encoding five subunits of EIF2B are associated with CACH/VWM. Herein, we presented a case of CACH/VWM who developed ataxia following a minor head injury. Brain magnetic resonance imaging showed extensive white matter signal abnormality. Diagnosis of CACH/VWM was confirmed by the presence of compound heterozygous variants in EIF2B3: the previously known pathogenic variant c c.260C>T (p.Ala87Val) and the novel variant c.673C>T (p.Arg225Trp). Based on the American College of Medical Genetics (ACMG) recommendations, we classified p.Arg225Trp as likely pathogenic. We report a novel variant in a patient with CACH/VWM and highlight the importance of genetic testing in patients with leukodystrophies. Copyright © 2022 Wongkittichote, Mar, McKinstry and Nguyen.

Author Keywords
ataxia;  childhood ataxia with central nervous system hypomyelination/vanishing white matter;  developmental regression;  EIF2B3;  leukodystrophy

Document Type: Article
Publication Stage: Final
Source: Scopus

Maternal Perceptions About Sensory Interventions in the Neonatal Intensive Care Unit: An Exploratory Qualitative Study
(2022) Frontiers in Pediatrics, 10, art. no. 884329, . 

Lisle, J.^a , Buma, K.^b , Smith, J.^c , Richter, M.^a , Satpute, P.^a , Pineda, R.^a b d e

^a Chan Division of Occupational Science and Occupational Therapy, University of Southern California, Los Angeles, CA, United States
^b Program in Occupational Therapy, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^c Department of Quality, Safety and Practice Excellence St, Louis Children’s Hospital, St. Louis, MO, United States
^d Department of Pediatrics, Keck School of Medicine, Los Angeles, CA, United States
^e Gehr Family Center for Health Systems Science and Innovation, University of Southern California, Los Angeles, CA, United States

Abstract
Background: Mothers play an important role in providing positive sensory experiences to their infants during NICU hospitalization. However, little is known regarding maternal perceptions about sensory-based interventions in the NICU. Further, understanding maternal perceptions was an important part of the process during development of the Supporting and Enhancing NICU Sensory Experiences (SENSE) program. Methods: Twenty mothers of very preterm infants were interviewed after NICU discharge and asked open-ended questions about sensory-based interventions they performed in the NICU and probed about their perceptions related to the development of a sensory-based guideline and the use of volunteers to provide sensory-based interventions when unable to be present in the NICU. Interviews were transcribed and uploaded into NVivoV.12 for content analysis. Results: Mothers reported that kangaroo care was a common sensory intervention they performed in the NICU. Of the 18 mothers who commented on the development of a sensory-based guideline, 17 (94%) said they would be accepting of one. Among 19 mothers, 18 (95%) supported volunteers conducting sensory-based interventions in their absence. Identified themes included: 1) Perceptions about development of a sensory-based guideline, 2) Perceptions of interactions with healthcare providers, 3) Maternal participation in sensory interventions, 4) Maternal experience, and 5) Emotions from mothers. Conclusion: Maternal perceptions regarding the development of a sensory-based guideline were favorable, and the SENSE program has since been finalized after incorporating important insights learned from stakeholders in this study. Mothers’ perceptions were tied to their NICU experiences, which elicited strong emotions. These findings highlight important considerations when developing family-centered interventions. Copyright © 2022 Lisle, Buma, Smith, Richter, Satpute and Pineda.

Author Keywords
development;  NICU (neonatal intensive care unit);  qualitative study;  sensory;  therapy

Funding details
Gordon and Betty Moore FoundationGBMF

Document Type: Article
Publication Stage: Final
Source: Scopus

A randomized feasibility study evaluating temozolomide circadian medicine in patients with glioma
(2022) Neuro-Oncology Practice, 9 (3), pp. 193-200. Cited 1 time.

Damato, A.R.^a c , Katumba, R.G.N.^d , Luo, J.^a b , Atluri, H.^d , Talcott, G.R.^d , Govindan, A.^d h , Slat, E.A.^g , Weilbaecher, K.N.^d , Tao, Y.^a b , Huang, J.^d , Butt, O.H.^d , Ansstas, G.^d , Johanns, T.M.^d , Chheda, M.G.^d , Herzog, E.D.^c f , Rubin, J.B.^e f , Campian, J.L.^d

^a Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States
^b Siteman Cancer Center Biostatistics Core, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Biology, Washington University, St Louis, MO, United States
^d Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO, United States
^e Department of Pediatrics, Washington University School of Medicine, St Louis, MO, United States
^f Department of Neuroscience, Washington University School of Medicine, St Louis, MO, United States
^g Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
^h John T. Milliken Department of Medicine, Washington University School of Medicine, St Louis, MO, United States

Abstract
Background: Gliomas are the most common primary brain tumor in adults. Current treatments involve surgery, radiation, and temozolomide (TMZ) chemotherapy; however, prognosis remains poor and new approaches are required. Circadian medicine aims to maximize treatment efficacy and/or minimize toxicity by timed delivery of medications in accordance with the daily rhythms of the patient. We published a retrospective study showing greater anti-tumor efficacy for the morning, relative to the evening, administration of TMZ in patients with glioblastoma. We conducted this prospective randomized trial to determine the feasibility, and potential clinical impact, of TMZ chronotherapy in patients with gliomas (NCT02781792). Methods: Adult patients with gliomas (WHO grade II-IV) were enrolled prior to initiation of monthly TMZ therapy and were randomized to receive TMZ either in the morning (AM) before 10 am or in the evening (PM) after 8 pm. Pill diaries were recorded to measure compliance and FACT-Br quality of life (QoL) surveys were completed throughout treatment. Study compliance, adverse events (AE), and overall survival were compared between the two arms. Results: A total of 35 evaluable patients, including 21 with GBM, were analyzed (18 AM patients and 17 PM patients). Compliance data demonstrated the feasibility of timed TMZ dosing. There were no significant differences in AEs, QoL, or survival between the arms. Conclusions: Chronotherapy with TMZ is feasible. A larger study is needed to validate the effect of chronotherapy on clinical efficacy. © 2022 The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved.

Author Keywords
chronotherapy;  feasibility;  gliomas;  quality of life

Document Type: Article
Publication Stage: Final
Source: Scopus

Peripheral inflammation and depressed mood independently predict neurocognitive worsening over 12 years
(2022) Brain, Behavior, and Immunity – Health, 21, art. no. 100437, . 

Tang, B.^a , Collier, A.C.^b , Morgello, S.^c , Cookson, D.^a , Sacktor, N.^d , Ellis, R.J.^a , Marra, C.M.^b , Clifford, D.B.^e , Gelman, B.B.^f , Robinson-Papp, J.^g , McCutchan, J.A.^a , Letendre, S.^a , Heaton, R.K.^a , Grant, I.^a

^a University of California San Diego, San Diego, CA, United States
^b University of Washington, Seattle, WA, United States
^c Icahn School of Medicine at Mount Sinai, New York, NY, United States
^d Johns-Hopkins University, Baltimore, MD, United States
^e Washington University, St Louis, MO, United States
^f University of Texas at Galveston, Galveston, TX, United States
^g Icahn School of Medicine at Mt. Sinai, United States

Abstract
Background: Neurocognitive (NC) impairment in people with HIV (PWH) is associated with important adverse outcomes, but no markers exist to predict long-term NC decline. We evaluated depressed mood and markers of persistent inflammation, oxidative stress and altered amyloid processing (all common in PWH) as predictors of NC worsening over 12 years. Methods: PWH were enrolled and followed longitudinally in the CNS HIV Antiretroviral Effects Research (CHARTER) study at six US sites. At entry we quantified biomarkers in blood of inflammation: (interleukin-6 [IL-6], C-reactive protein [CRP], monocyte chemoattractant protein type 1 [MCP-1], D-dimer, soluble sCD14 (sCD14), soluble tumor necrosis factor receptor – type II [sTNFR-II], neopterin, and soluble CD40 ligand [sCD40L], oxidative stress (protein carbonyls, 8-oxo-2′-deoxyguanosine [8-oxo-dG]) and altered amyloid processing [amyloid beta (Aβ)-42, soluble amyloid precursor protein-α (sAPPα)] using commercial immunoassays. The Beck Depression Inventory-II (BDI-II) assessed depressed mood at entry. NC decline over 12 years was evaluated using the published and validated summary (global) regression-based change score (sRBCS). A factor analysis reduced dimensionality of the biomarkers. Univariable and multiple regression models tested the relationship between baseline predictors and the outcome of neurocognitive decline. Results: Participants were 191 PWH, 37 (19.4%) women, 46.6% African American, 43.5% non-Hispanic white, 8.83% Hispanic, 15.7% white, 1.6% other; at study entry mean (SD) age 43.6 (8.06) years, estimated duration of HIV infection (median, IQR) 9.82 [4.44, 14.5] years, nadir CD4 104/μL (19,205), current CD4 568/μL (356, 817), and 80.1% had plasma HIV RNA <50 c/mL. Participants were enrolled between 2003 and 2007; median (IQR) duration of follow-up 12.4 [9.69, 16.2] years. Three biomarker factors were identified: Factor (F)1 (IL-6, CRP), F2 (sTNFR-II, neopterin) and F3 (sCD40L, sAPPα). Participants with higher F1, reflecting worse systemic inflammation at baseline, and higher F3, had greater decline in global neurocognition (r ​= ​−0.168, p ​= ​0.0205 and r ​= ​−0.156, p ​= ​0.0309, respectively). Of the F1 components, higher CRP levels were associated with worse decline (r ​= ​−0.154, p ​= ​0.0332), while IL-6 did not (r ​= ​−0.109, p ​= ​0.135). NC change was not significantly related to F2, nor to demographics, nadir and current CD4, viral suppression or baseline NC comorbidity ratings. Individuals with worse depressed mood at entry also experienced more NC decline (r ​= ​−0.1734, p ​= ​0.0006). Together BDI-II (p ​= ​0.0290), F1 (p ​= ​0.0484) and F3 (p ​= ​0.0309) contributed independently to NC decline (p ​= ​0.0028); their interactions were not significant. Neither CRP nor IL-6 correlated significantly with depression. Conclusions: PWH with greater systemic inflammation and more depression at entry had greater NC decline over 12 years. Understanding the basis of this inflammatory state might be particularly important. These findings raise the possibility that targeted anti-inflammatory or antidepressant therapies may help prevent NC worsening in PWH with depression and inflammation. © 2022

Document Type: Article
Publication Stage: Final
Source: Scopus

Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer’s disease
(2022) Alzheimer’s and Dementia, . 

Liu, L.^a , Lauro, B.M.^a , He, A.^a , Lee, H.^a , Bhattarai, S.^b , Wolfe, M.S.^b , Bennett, D.A.^c , Karch, C.M.^d e , Young-Pearse, T.^a , Selkoe, D.J.^a , Dominantly Inherited Alzheimer Network (DIAN)^f

^a Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
^b Department of Medicinal Chemistry, University of Kansas, Lawrence, KS, United States
^c Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, United States
^d Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
^e Hope Center for Neurologic Disorders, St. Louis, MO, United States

Abstract
Introduction: Identifying CSF-based biomarkers for the β-amyloidosis that initiates Alzheimer’s disease (AD) could provide inexpensive and dynamic tests to distinguish AD from normal aging and predict future cognitive decline. Methods: We developed immunoassays specifically detecting all C-terminal variants of secreted amyloid β-protein and identified a novel biomarker, the Aβ 37/42 ratio, that outperforms the canonical Aβ42/40 ratio as a means to evaluate the γ-secretase activity and brain Aβ accumulation. Results: We show that Aβ 37/42 can distinguish physiological and pathological status in (1) presenilin-1 mutant vs wild-type cultured cells, (2) AD vs control brain tissue, and (3) AD versus cognitively normal (CN) subjects in CSF, where 37/42 (AUC 0.9622) outperformed 42/40 (AUC 0.8651) in distinguishing CN from AD. Discussion: We conclude that the Aβ 37/42 ratio sensitively detects presenilin/γ-secretase dysfunction and better distinguishes CN from AD than Aβ42/40 in CSF. Measuring this novel ratio alongside promising phospho-tau analytes may provide highly discriminatory fluid biomarkers for AD. © 2022 the Alzheimer’s Association

Author Keywords
Alzheimer’s disease;  amyloid β-protein;  CSF biomarkers

Funding details
National Institutes of HealthNIHP30AG10161, PPG AG015379, R01 AG055909, R01 AG06173, R01 AG071865, R01AG15819, R01AG17917, R01AG30146, R01AG36836, R03AG063046, U01AG32984, U01AG46152
National Institute on AgingNIA
Alzheimer’s AssociationAA
Illinois Department of Public HealthIDPH
Fondation Brain Canada
Japan Agency for Medical Research and DevelopmentAMED
Translational Genomics Research InstituteTGEN
Canadian Institutes of Health ResearchIRSC
Fonds de Recherche du Québec – SantéFRQS
Korea Health Industry Development InstituteKHIDI
Instituto de Salud Carlos IIIISCIII
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Fleni

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

Screen for Small-Molecule Modulators of Circadian Rhythms Reveals Phenazine as a Redox-State Modifying Clockwork Tuner
(2022) ACS Chemical Biology, . 

Kelly, K.P.^a , Borsetti, H.^a , Wenzler, M.E.^b , Ustione, A.^c , Kim, K.^b d , Christov, P.P.^d , Ramirez, B.^b , Bauer, J.A.^d e , Piston, D.W.^c , Johnson, C.H.^a d , Sulikowski, G.A.^b d

^a Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235, United States
^b Department of Chemistry, Vanderbilt University, Nashville, TN 37235, United States
^c Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, United States
^e Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, United States

Abstract
A high-Throughput cell-based screen identified redox-Active small molecules that produce a period lengthening of the circadian rhythm. The strongest period lengthening phenotype was induced by a phenazine carboxamide (VU661). Comparison to two isomeric benzquinoline carboxamides (VU673 and VU164) shows the activity is associated with the redox modulating phenazine functionality. Furthermore, ex vivo cell analysis using optical redox ratio measurements shows the period lengthening phenotype to be associated with a shift to the NAD/FAD oxidation state of nicotinamide and flavine coenzymes. ©

Funding details
CHE 0850976
National Institutes of HealthNIHR21 MH082258, R21 NS054991, R37 GM067152, S10 OD028719
National Cancer InstituteNCIR50 CA211206
Vanderbilt-Ingram Cancer CenterVICCP30 CA68485
Vanderbilt Institute of Chemical Biology, School of Medicine, Vanderbilt UniversityVICB

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

Investing in Late-Life Brain Capital
(2022) Innovation in Aging, 6 (3), art. no. igac016, . 

Dawson, W.D.^a b c , Smith, E.^b d , Booi, L.^b e , Mosse, M.^d , Lavretsky, H.^f , Reynolds, C.F.^g , Cummings, J.^h , Brannally, P.ⁱ , Hynes, W.^d , Lenze, E.J.^j , Manes, F.^k l , Ayadi, R.^m , Frank, L.ⁿ , Chapman, S.B.^o , Robertson, I.H.^b o , Rubenstein, L.^p , Jraissati, J.^q , Ibáñez, A.^b r , Fillit, H.^s t , Jeste, D.V.^u v , Rao, A.^w x , Berk, M.^y z , Storch, E.A.^aa , Santuccione Chadha, A.^ab ac , Eyre, H.A.^y ad

^a Department of Neurology, School of Medicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, CR131, Portland, OR 97239, United States
^b Global Brain Health Institute at University of California, San Francisco (UCSF), San Francisco, CA, United States
^c Trinity College Dublin, Dublin, Ireland
^d Department of Medicine, Stanford Hospital, StanfordCA, United States
^e Centre for Dementia Research, School of Health, Leeds Beckett University, Leeds, United Kingdom
^f Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles (UCLA), Los Angeles, CA, United States
^g Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
^h Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada, Las Vegas, NV, United States
ⁱ Alzheimer’s Disease Data Initiative, Gates Ventures, Redwood City, CA, United States
^j Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^k Institute of Cognitive and Translational Neuroscience (INCYT), INECO Foundation, Favaloro University, Buenos Aires, Argentina
^l National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina
^m Euro-Mediterranean Economists Association, Barcelona, Spain
ⁿ RAND Corporation, Arlington, VA, United States
^o Center for BrainHealth®, University of Texas at Dallas, Dallas, TX, United States
^p Australian Research Alliance for Children and Youth (ARACY), Canberra, ACT, Australia
^q IESE Center for Public Leadership and Government, IESE Business School, Madrid, Spain
^r Latin American Brain Health Institute (BrainLat), Universidad Adolfo Ibáñez, Santiago, Chile
^s Alzheimer’s Drug Discovery Foundation (ADDF), New York City, NY, United States
^t Departments of Geriatric Medicine, Palliative Care and Neuroscience, Icahn School of Medicine at Mount Sinai, New York City, NY, United States
^u Departments of Psychiatry and Neurosciences, University of California San Diego, La JollaCA, United States
^v IBM-UC San Diego Center for Artificial Intelligence for Healthy Living, University of California San Diego, La JollaCA, United States
^w Neurocern, Chicago, IL, United States
^x Department of Neurology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States
^y IMPACT, Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, VIC, Australia
^z Department of Psychiatry, University of Melbourne, Melbourne, VIC, Australia
^aa Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, United States
^ab Biogen, Cambridge, MA, United States
^ac Women’s Brain Project, Zurich, Switzerland
^ad Neuroscience-inspired Policy Initiative, Organisation for Economic Co-operation and Development (OECD) and the PRODEO Institute, Paris, France

Abstract
Within many societies and cultures around the world, older adults are too often undervalued and underappreciated. This exacerbates many key challenges that older adults may face. It also undermines the many positive aspects of late life that are of tremendous value at both an individual and societal level. We propose a new approach to elevate health and well-being in late life by optimizing late-life Brain Capital. This form of capital prioritizes brain skills and brain health in a brain economy, which the challenges and opportunities of the 21st-century demands. This approach incorporates investing in late-life Brain Capital, developing initiatives focused on building late-life Brain Capital. © 2022 The Author(s) 2022.

Author Keywords
Aging;  Brain health;  Innovation;  Mental disorders;  Neuroscience;  Psychiatry

Funding details
159418, GBHI ALZ UK-20-640170
BPIN2018000100059
National Institutes of HealthNIH
National Institute on AgingNIAP20AG068053, R01 AG057234, R01AG053798, R35AG71476
National Institute of General Medical SciencesNIGMSP20GM109025
National Institute of Neurological Disorders and StrokeNINDSU01NS093334
Alzheimer’s AssociationAASG-20-725707
Alzheimer’s Drug Discovery FoundationADDF
American Nurses FoundationANF
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDP50HD103555
Rainwater Charitable FoundationRCF
National Health and Medical Research CouncilNHMRC1156072
Fondo Nacional de Desarrollo Científico y TecnológicoFONDECYT1210176, 1210195, ANID/FONDAP/15150012, FONCYT-PICT 2017-1820
Consejo Nacional de Investigaciones Científicas y TécnicasCONICET
Universidad del ValleUnivalleCI 5316, GBHI ALZ UK-20-639295

Document Type: Article
Publication Stage: Final
Source: Scopus

68Ga-Labeled Benzothiazole Derivatives for Imaging Aβ Plaques in Cerebral Amyloid Angiopathy
(2022) ACS Omega, 7 (23), pp. 20339-20346. 

Huynh, T.T.^a c , Wang, Y.^b , Terpstra, K.^b , Cho, H.-J.^b , Mirica, L.M.^b d , Rogers, B.E.^a

^a Department of Radiation Oncology, Washington University School of Medicine, 4511 Forest Park Avenue, St. Louis, MO 63108, United States
^b Department of Chemistry, University of Illinois at Urbana-Champaign, 600 S. Mathews Avenue, Urbana, IL 61801, United States
^c Department of Chemistry, Washington University, St. Louis, MO 63130, United States
^d Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Timely diagnostic imaging plays a crucial role in managing cerebral amyloid angiopathy (CAA)â” the condition in which amyloid β is deposited on blood vessels. To selectively map these amyloid plaques, we have designed amyloid-Targeting ligands that can effectively complex with 68Ga3+while maintaining good affinity for amyloid β. In this study, we introduced novel 1,4,7-Triazacyclononane-based bifunctional chelators (BFCs) that incorporate a benzothiazole moiety as the Aβ-binding fragment and form charged and neutral species with 68Ga3+. In vitro autoradiography using 5xFAD and WT mouse brain sections (11-month-old) suggested strong and specific binding of the 68Ga complexes to amyloid β. Biodistribution studies in CD-1 mice revealed a low brain uptake of 0.10-0.33% ID/g, thus suggesting 68Ga-labeled novel BFCs as promising candidates for detecting CAA. © 2022 American Chemical Society. All rights reserved.

Funding details
National Institutes of HealthNIHR01GM114588

Document Type: Article
Publication Stage: Final
Source: Scopus

Technological features of blast identification in the cerebrospinal fluid: A systematic review of flow cytometry and laboratory haematology methods
(2022) International Journal of Laboratory Hematology, . 

Frater, J.L., Shirai, C.L., Brestoff, J.R.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Involvement of the central nervous system (CNS) by acute leukemias (ALs) has important implications for risk stratification and disease outcome. The clinical laboratory plays an essential role in assessment of cerebrospinal fluid (CSF) specimens from patients with ALs at initial diagnosis, at the end of treatment, and when CNS involvement is clinically suspected. The two challenges for the laboratory are 1) to accurately provide a cell count of the CSF and 2) to successfully distinguish blasts from other cell types. These tasks are classically performed using manual techniques, which suffer from suboptimal turnaround time, imprecision, and inconsistent inter-operator performance. Technological innovations in flow cytometry and hematology analyzer technology have provided useful complements and/or alternatives to conventional manual techniques. Aims: We performed a PRISMA-compliant systematic review to address the medical literature regarding the development and current state of the art of CSF blast identification using flow cytometry and laboratory hematology technologies. Materials and Methods: We searched the peer reviewed medical literature using MEDLINE (PubMed interface), Web of Science, and Embase using the keywords “CSF or cerebrospinal” AND “blasts(s)”. Results: 108 articles were suitable for inclusion in our systematic review. These articles covered 1) clinical rationale for CSF blast identification; 2) morphology-based CSF blast identification; 3) the role of flow cytometry; 4) use of hematology analyzers for CSF blast identification; and 5) quality issues. 9/L, which is much lower than the original machine count and platelet transfusion was warranted. Discussion: 1) Clinical laboratory testing plays a central role in risk stratification and clinical management of patients with acute leukemias, most clearly in pediatric ALs; 2) studies focused on other patient populations, including adults and patients with AML are less prevalent in the literature; 3) improvements in instrumentation may provide better performance for the classification of CSF specimens. Conclusion: Current challenges include: 1) more precisely characterizing the natural history of AL involvement of the CNS, 2) improvements in automated cell count technology of low cellularity specimens, 3) defining the role of flow MRD testing of CSF specimens and 4) improved recognition of specimen quality by clinicians and laboratory personnel. © 2022 John Wiley & Sons Ltd.

Author Keywords
acute;  cerebrospinal fluid;  flow cytometry;  haematology analyser;  leukaemia

Funding details
National Institutes of HealthNIHDP5 OD028125
National Institute of Allergy and Infectious DiseasesNIAIDR01 AI168044
Burroughs Wellcome FundBWF1019648

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

Remote Research: Resources, Intervention Needs, and Methods in People with Diabetes and Peripheral Neuropathy
(2022) Journal of Diabetes Science and Technology, . 

Bohnert, K.L.^a , Zellers, J.A.^a b , Jeong, H.J.^c d , Chen, L.^e , York, A.^a , Hastings, M.K.^a b

^a Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO, United States
^b Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, United States
^c Orthopaedic Rehabilitation Engineering Center, Marquette University, Milwaukee, WI, United States
^d Rehabilitation Sciences Technology, Marquette University, Milwaukee, WI, United States
^e Biostatistics, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Stay-at-home orders associated with the SARS-CoV-2 (COVID-19) pandemic were particularly important for older adults with type 2 diabetes, at risk for severe COVID-19 complications. In response, research shifted to remote telehealth methodology. Study participant interests, equipment needs, and ability to adapt methods to the remote/telehealth environment were unknown. Study purposes to assess (1) resource needs (internet/devices accessibility), (2) future telehealth interests, and (3) ability to adapt common research and clinical measures of glycemic control, physical function, activity measures, and quality of life outcomes to a telehealth setting. Method: Twenty-one participants with type 2 diabetes and peripheral neuropathy were recruited from a longitudinal study (11 female; age: 66.3 ± 8.3 years; DM: 15.1 ± 8.7 years). Technology needs and future telehealth interests were assessed. A glycemic measure (HbA1c), a five-times chair rise, a one-week activity monitor, and surveys (self-efficacy, depression, and balance) were collected. All aspects of the study were completed remotely over email and video/phone call. Results: Twelve participants used computers; nine used phones for study completion. Participants had the following resource needs: connectivity (n = 3), devices (n = 6), and technical support (n = 12). Twenty people expressed interest in participating in future telehealth studies related to balance, exercise, and diabetes management. Methodological considerations were primarily the need for assistance for participants to complete the home HbA1c test, five-time chair rise, wearable activity monitoring, and surveys. Conclusions: Older adults with type 2 diabetes and peripheral neuropathy would need technological and personal assistance (connection, device, guidance) to complete a long-term telehealth intervention. Despite technology needs, participants were interested in telehealth interventions. Clinical Trial: Parent study, “Metatarsal Phalangeal Joint Deformity Progression—R01 (NCT02616263) is registered at https://clinicaltrials.gov/. © 2022 Diabetes Technology Society.

Author Keywords
COVID-19;  glycemic control;  physical activity;  quality of life;  rehabilitation;  technology

Funding details
National Institutes of HealthNIH
National Institute of Diabetes and Digestive and Kidney DiseasesNIDDKDK107809, F32 DK123916
National Center for Medical Rehabilitation ResearchNCMRR
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDT32 HD07434

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

Automated analysis of low-field brain MRI in cerebral malaria
(2022) Biometrics, . 

Tu, D.^a , Goyal, M.S.^b , Dworkin, J.D.^c , Kampondeni, S.^d , Vidal, L.^e , Biondo-Savin, E.^f , Juvvadi, S.^g , Raghavan, P.^h , Nicholas, J.ⁱ , Chetcuti, K.^j , Clark, K.^a , Robert-Fitzgerald, T.^a , Satterthwaite, T.D.^k , Yushkevich, P.^l , Davatzikos, C.^l , Erus, G.^m , Tustison, N.J.ⁿ , Postels, D.G.^o , Taylor, T.E.^d p , Small, D.S.^q , Shinohara, R.T.^a m

^a The Penn Statistics in Imaging and Visualization Endeavor (PennSIVE), Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA, United States
^b Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, United States
^d Blantyre Malaria Project, Kamuzu University of Health Sciences, Southern Region, Blantyre, Malawi
^e Department of Radiology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^f Department of Radiology, Michigan State University, East Lansing, MI, United States
^g Tenet Diagnostics, Hyderabad, India
^h Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, United States
ⁱ University Hospitals Cleveland Medical Center, Department of Radiology, Case Western Reserve University, Cleveland, OH, United States
^j Department of Paediatrics and Child Health, Kamuzu University of Health Sciences, Southern Region, Blantyre, Malawi
^k Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, United States
^l Department of Radiology, University of Pennsylvania, Philadelphia, PA, United States
^m Center for Biomedical Image Computing and Analysis (CBICA), Department of Radiology, University of Pennsylvania, Philadelphia, PA, United States
ⁿ Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA, United States
^o Division of Neurology, George Washington University/Children’s National Medical Center, Washington, DC, United States
^p College of Osteopathic Medicine, Michigan State University, East Lansing, MI, United States
^q Department of Statistics, University of Pennsylvania, Philadelphia, PA, United States

Abstract
A central challenge of medical imaging studies is to extract biomarkers that characterize disease pathology or outcomes. Modern automated approaches have found tremendous success in high-resolution, high-quality magnetic resonance images. These methods, however, may not translate to low-resolution images acquired on magnetic resonance imaging (MRI) scanners with lower magnetic field strength. In low-resource settings where low-field scanners are more common and there is a shortage of radiologists to manually interpret MRI scans, it is critical to develop automated methods that can augment or replace manual interpretation, while accommodating reduced image quality. We present a fully automated framework for translating radiological diagnostic criteria into image-based biomarkers, inspired by a project in which children with cerebral malaria (CM) were imaged using low-field 0.35 Tesla MRI. We integrate multiatlas label fusion, which leverages high-resolution images from another sample as prior spatial information, with parametric Gaussian hidden Markov models based on image intensities, to create a robust method for determining ventricular cerebrospinal fluid volume. We also propose normalized image intensity and texture measurements to determine the loss of gray-to-white matter tissue differentiation and sulcal effacement. These integrated biomarkers have excellent classification performance for determining severe brain swelling due to CM. © 2022 The International Biometric Society.

Author Keywords
brain segmentation;  data integration;  Markov random field;  MRI

Funding details
National Institutes of HealthNIHR01 AI034969, R01 MH112847, R01 NS060910, R01 NS112274

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

Anterior nucleus of the thalamus deep brain stimulation vs temporal lobe responsive neurostimulation for temporal lobe epilepsy
(2022) Epilepsia, . 

Yang, J.C.^a , Bullinger, K.L.^b , Dickey, A.S.^b , Karakis, I.^b , Alwaki, A.^b , Cabaniss, B.T.^b , Winkel, D.^b , Rodriguez-Ruiz, A.^b , Willie, J.T.^c , Gross, R.E.^a b

^a Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, United States
^b Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States
^c Departments of Neurosurgery, Neurology, and Psychiatry, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Objective: Based on the promising results of randomized controlled trials, deep brain stimulation (DBS) and responsive neurostimulation (RNS) are used increasingly in the treatment of patients with drug-resistant epilepsy. Drug-resistant temporal lobe epilepsy (TLE) is an indication for either DBS of the anterior nucleus of the thalamus (ANT) or temporal lobe (TL) RNS, but there are no studies that directly compare the seizure benefits and adverse effects associated with these therapies in this patient population. We, therefore, examined all patients who underwent ANT-DBS or TL-RNS for drug-resistant TLE at our center. Methods: We performed a retrospective review of patients who were treated with either ANT-DBS or TL-RNS for drug-resistant TLE with at least 12 months of follow-up. Along with the clinical characteristics of each patient’s epilepsy, seizure frequency was recorded throughout each patient’s postoperative clinical course. Results: Twenty-six patients underwent ANT-DBS implantation and 32 patients underwent TL-RNS for drug-resistant TLE. The epilepsy characteristics of both groups were similar. Patients who underwent ANT-DBS demonstrated a median seizure reduction of 58% at 12–15 months, compared to a median seizure reduction of 70% at 12–15 months in patients treated with TL-RNS (p >.05). The responder rate (percentage of patients with a 50% decrease or more in seizure frequency) was 54% for ANT-DBS and 56% for TL-RNS (p >.05). The incidence of complications and stimulation-related side effects did not significantly differ between therapies. Significance: We demonstrate in our single-center experience that patients with drug-resistant TLE benefit similarly from either ANT-DBS or TL-RNS. Selection of either ANT-DBS or TL-RNS may, therefore, depend more heavily on patient and provider preference, as each has unique capabilities and configurations. Future studies will consider subgroup analyses to determine if specific patients have greater seizure frequency reduction from one form of neuromodulation strategy over another. © 2022 International League Against Epilepsy.

Author Keywords
deep brain stimulation;  epilepsy;  neuromodulation;  responsive neurostimulation

Funding details
Medtronic
NeuroPace

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

Motor Network Reorganization Induced in Chronic Stroke Patients with the Use of a Contralesionally-Controlled Brain Computer Interface
(2022) Brain-Computer Interfaces, . 

Humphries, J.B.^a , Mattos, D.J.S.^b , Rutlin, J.^c , Daniel, A.G.S.^a , Rybczynski, K.^d , Notestine, T.^d , Shimony, J.S.^c , Burton, H.^e , Carter, A.^b , Leuthardt, E.C.^{a d e f g}

^a Departments of Neurosurgery, Washington University in St. Louis, St. Louis, MO, United States
^b Neurology, Washington University in St. Louis, St. Louis, MO, United States
^c Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, United States
^d Neurosurgery, Washington University in St. Louis, St. Louis, MO, United States
^e Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
^f Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Upper extremity weakness in chronic stroke remains a problem not fully addressed by current therapies. Brain–computer interfaces (BCIs) engaging the unaffected hemisphere are a promising therapy that are entering clinical application, but the mechanism underlying recovery is not well understood. We used resting state functional MRI to assess the impact a contralesionally driven EEG BCI therapy had on motor system functional organization. Patients used a therapeutic BCI for 12 weeks at home. We acquired resting-state fMRI scans and motor function data before and after the therapy period. Changes in functional connectivity (FC) strength between motor network regions of interest (ROIs) and the topographic extent of FC to specific ROIs were analyzed. Most patients achieved clinically significant improvement. Motor FC strength and topographic extent decreased following BCI therapy. Motor recovery correlated with reductions in motor FC strength across the entire motor network. These findings suggest BCI-mediated interventions may reverse pathologic strengthening of dysfunctional network interactions. © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Author Keywords
brain–computer interface;  functional MRI;  motor network;  Rehabilitation;  stroke

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

Study of “ALS reversals”: LifeTime environmental exposures (StARLiTE)
(2022) Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, . 

Crayle, J.^a , Lutz, M.^b , Raymond, J.^c , Mehta, P.^c , Bedlack, R.^b

^a Department of Neurology, Washington University in Saint Louis, Saint Louis, MO, United States
^b Department of Neurology, Duke University, Durham, NC, United States
^c Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry, National ALS Registry, Atlanta, GA, United States

Abstract
We previously reported on a series of patients diagnosed with ALS whom had an extraordinary course defined by substantial and sustained improvement in weakness and function. For this study, twenty-five of these “ALS Reversals” completed extensive environmental exposure questionnaires. These responses were then compared to a large database of prior responses from patients with typically progressive ALS (n = 6187). The results demonstrated that the “Reversal” participants have had a diverse number of exposures with substantial heterogeneity. In general, this was similar to the control group; however, there were a few specific differences that could be further explored in future research. © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Author Keywords
Amyotrophic lateral sclerosis;  epidemiology;  risk;  survival

Funding details
CytokineticsCYTK

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

Pattern and degree of individual brain atrophy predicts dementia onset in dominantly inherited Alzheimer’s disease
(2021) Alzheimer’s and Dementia: Diagnosis, Assessment and Disease Monitoring, 13 (1), art. no. e12197, . 

Keret, O.^a , Staffaroni, A.M.^b , Ringman, J.M.^c , Cobigo, Y.^b , Goh, S.-Y.M.^b , Wolf, A.^b , Allen, I.E.^a d , Salloway, S.^e , Chhatwal, J.^f , Brickman, A.M.^g , Reyes-Dumeyer, D.^g , Bateman, R.J.^{h i j k l} , Benzinger, T.L.S.^h j , Morris, J.C.^{h i j k l} , Ances, B.M.^{h i j k l} , Joseph-Mathurin, N.^{h i j k l} , Perrin, R.J.^{h i j k l} , Gordon, B.A.^{h i j k l} , Levin, J.^m n , Vöglein, J.^m n , Jucker, M.^o p , la Fougère, C.^o q , Martins, R.N.^{r s t u v} , Sohrabi, H.R.^{r s t u v} , Taddei, K.^s u , Villemagne, V.L.^w , Schofield, P.R.^x y , Brooks, W.S.^x z , Fulham, M.^aa , Masters, C.L.^ab , Ghetti, B.^ac , Saykin, A.J.^ad ae , Jack, C.R.^af , Graff-Radford, N.R.^ag , Weiner, M.^{ah ai aj ak al} , Cash, D.M.^am an , Allegri, R.F.^ao , Chrem, P.^ao , Yi, S.^ap , Miller, B.L.^a b , Rabinovici, G.D.^a , Rosen, H.J.^a b , Dominantly Inherited Alzheimer Network^aq

^a Global Brain Health Institute, University of California, San Francisco, CA, United States
^b Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, United States
^c Alzheimer’s Disease Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
^d Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, United States
^e Warren Alpert Medical School, Brown University, Providence, RI, United States
^f Massachusetts General Hospital, Harvard Medical School Boston, Boston, MA, United States
^g Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, NY, United States
^h Charles F. and Joanne Knight Alzheimer Disease Research Center, Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
ⁱ Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^j Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^k Division of Neuropathology, Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, United States
^l Division of Biostatistics, Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^m German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
ⁿ Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
^o German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
^p Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
^q Institute for Nuclear Medicine and Clinical Molecular Imaging, Eberhard Karls University, Tübingen, Germany
^r Department of Biomedical Sciences, Macquarie University, North Ryde, NSW, Australia
^s Centre of Excellence for Alzheimer’s Disease Research and Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia
^t School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, WA, Australia
^u Australian Alzheimer’s Research Foundation, Nedlands, WA, Australia
^v The Cooperative Research Centre for Mental Health, Carlton South, VIC, Australia
^w Department of Molecular Imaging and Therapy, Austin Health, Melbourne, VIC, Australia
^x Neuroscience Research Australia, Randwick, Sydney, NSW, Australia
^y School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia
^z Prince of Wales Hospital Clinical School, UNSW Sydney, Sydney, NSW, Australia
^aa Department of Molecular Imaging, Royal Prince Alfred Hospital, Sydney Medical School, University of Sydney, Camperdown, NSW, Australia
^ab The Florey Institute, University of Melbourne, Parkville, VIC, Australia
^ac Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
^ad Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, United States
^ae Department of Radiology, Indiana University School of Medicine, Indianapolis, IN, United States
^af Department of Radiology, Mayo Clinic, Rochester, MN, United States
^ag Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
^ah Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, San Francisco, CA, United States
^ai Department of Radiology, University of California, San Francisco, San Francisco, CA, United States
^aj Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
^ak Department of Psychiatry, University of California, San Francisco, San Francisco, CA, United States
^al Department of Neurology, University of California, San Francisco, San Francisco, CA, United States
^am Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
^an Centre for Medical Image Computing, Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom
^ao Department of Cognitive Neurology, Neuropsychiatry and Neuropsychology, Instituto de InvestigacionesNeurológicas FLENI, Buenos Aires, Argentina
^ap Banner Alzheimer’s Institute, Phoenix, AZ, United States

Abstract
Introduction: Asymptomatic and mildly symptomatic dominantly inherited Alzheimer’s disease mutation carriers (DIAD-MC) are ideal candidates for preventative treatment trials aimed at delaying or preventing dementia onset. Brain atrophy is an early feature of DIAD-MC and could help predict risk for dementia during trial enrollment. Methods: We created a dementia risk score by entering standardized gray-matter volumes from 231 DIAD-MC into a logistic regression to classify participants with and without dementia. The score’s predictive utility was assessed using Cox models and receiver operating curves on a separate group of 65 DIAD-MC followed longitudinally. Results: Our risk score separated asymptomatic versus demented DIAD-MC with 96.4% (standard error = 0.02) and predicted conversion to dementia at next visit (hazard ratio = 1.32, 95% confidence interval [CI: 1.15, 1.49]) and within 2 years (area under the curve = 90.3%, 95% CI [82.3%–98.2%]) and improved prediction beyond established methods based on familial age of onset. Discussion: Individualized risk scores based on brain atrophy could be useful for establishing enrollment criteria and stratifying DIAD-MC participants for prevention trials. © 2021 The Authors. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer’s Association

Author Keywords
autosomal dominant Alzheimer’s disease;  brain atrophy;  Dominantly Inherited Alzheimer Network;  preclinical Alzheimer’s disease

Funding details
P01 AG003991, P01 AG026276
National Institutes of HealthNIHK08AG022228, K24 AG045333, P30 AG010133, P30 AG066444, P50AG005142, P50AG016570, R01 AG019771, R01 AG057739, R01 AG068193, R01 LM013463, U01 AG024904, U01 AG045390, U01 AG068057, U01AG051218, U19 AG032438, U19 AG063911, U54 NS092089
U.S. Department of DefenseDOD
National Institute on AgingNIA
U.S. Department of Veterans AffairsVA
Mayo Clinic
Alzheimer’s AssociationAAAARFD‐20‐681815, UF1AG032438
Larry L. Hillblom FoundationLLHF
Eli Lilly and Company
Roche
California Department of Public HealthCDPH
Patient-Centered Outcomes Research InstitutePCORI
Alzheimer’s Disease Research Center, Emory UniversityADRCP01 AG019724, P30 AG062422, R01 AG057234, T32 AG023481
Japan Agency for Medical Research and DevelopmentAMED
Stroke FoundationSF
Buck Institute for Research on Aging
Avid Radiopharmaceuticals
Rainwater Charitable FoundationRCF
Australian Catholic UniversityACU
Korea Health Industry Development InstituteKHIDI
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Fleni
NIHR Cambridge Biomedical Research Centre

Document Type: Article
Publication Stage: Final
Source: Scopus