WashU weekly Neuroscience publications

Bacterial sepsis increases hippocampal fibrillar amyloid plaque load and neuroinflammation in a mouse model of Alzheimer’s disease
(2021) Neurobiology of Disease, 152, art. no. 105292, . 

Basak, J.M.^a , Ferreiro, A.^b , Cohen, L.S.^c d , Sheehan, P.W.^c d , Nadarajah, C.J.^c d , Kanan, M.F.^c d , Sukhum, K.V.^b e , Dantas, G.^b e f g , Musiek, E.S.^c d h

^a Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
^b Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
^c Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
^d Hope Center for Neurological Disorders, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
^e Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
^f Department of Molecular Microbiology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
^g Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
^h Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States

Abstract
Background: Sepsis, a leading cause for intensive care unit admissions, causes both an acute encephalopathy and chronic brain dysfunction in survivors. A history of sepsis is also a risk factor for future development of dementia symptoms. Similar neuropathologic changes are associated with the cognitive decline of sepsis and Alzheimer’s disease (AD), including neuroinflammation, neuronal death, and synaptic loss. Amyloid plaque pathology is the earliest pathological hallmark of AD, appearing 10 to 20 years prior to cognitive decline, and is present in 30% of people over 65. As sepsis is also more common in older adults, we hypothesized that sepsis might exacerbate amyloid plaque deposition and plaque-related injury, promoting the progression of AD-related pathology. Methods: We evaluated whether the brain’s response to sepsis modulates AD-related neurodegenerative changes by driving amyloid deposition and neuroinflammation in mice. We induced polymicrobial sepsis by cecal ligation and puncture (CLP) in APP/PS1–21 mice, a model of AD-related β-amyloidosis. We performed CLP or sham surgery at plaque onset (2 months of age) and examined pathology 2 months after CLP in surviving mice. Results: Sepsis significantly increased fibrillar amyloid plaque formation in the hippocampus of APP/PS1–21 mice. Sepsis enhanced plaque-related astrocyte activation and complement C4b gene expression in the brain, both of which may play a role in modulating amyloid formation. CLP also caused large scale changes in the gut microbiome of APP/PS1 mice, which have been associated with a pro-amyloidogenic and neuroinflammatory state. Conclusions: Our results suggest that experimental sepsis can exacerbate amyloid plaque deposition and plaque-related inflammation, providing a potential mechanism for increased dementia in older sepsis survivors. © 2021 The Author(s)

Author Keywords
Alzheimer’s disease;  Amyloid-beta;  Complement;  Microbiome;  Neuroinflammation;  Sepsis

Funding details
National Institutes of HealthNIHR01AG054517, R01AT009741, T32GM108539-06
Washington University in St. LouisWUSTL

The nonhuman primate neuroimaging and neuroanatomy project
(2021) NeuroImage, 229, art. no. 117726, . 

Hayashi, T.^a b , Hou, Y.^c , Glasser, M.F.^d e , Autio, J.A.^a , Knoblauch, K.^c , Inoue-Murayama, M.^f , Coalson, T.^d , Yacoub, E.^g , Smith, S.^h , Kennedy, H.^c i , Van Essen, D.C.^d

^a Laboratory for Brain Connectomics Imaging, RIKEN Center for Biosystems Dynamics Research, 6-7-3 MI R&D Center 3F, Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan
^b Department of Neurobiology, Kyoto University Graduate School of Medicine, Kyoto, Japan
^c Inserm, Stem Cell and Brain Research Institute U1208, Univ Lyon, Université Claude Bernard Lyon 1, Bron, France
^d Department of Neuroscience, Washington University Medical School, St Louis, MO, United States
^e Department of Neuroscience and Radiology, Washington University Medical School, St Louis, MO, United States
^f Wildlife Research Center, Kyoto University, Kyoto, Japan
^g Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, United States
^h Oxford Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB), Wellcome Centre for Integrative Neuroimaging (WIN), Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, United Kingdom
ⁱ Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences (CAS) Key Laboratory of Primate Neurobiology, CAS, Shanghai, China

Abstract
Multi-modal neuroimaging projects such as the Human Connectome Project (HCP) and UK Biobank are advancing our understanding of human brain architecture, function, connectivity, and their variability across individuals using high-quality non-invasive data from many subjects. Such efforts depend upon the accuracy of non-invasive brain imaging measures. However, ‘ground truth’ validation of connectivity using invasive tracers is not feasible in humans. Studies using nonhuman primates (NHPs) enable comparisons between invasive and non-invasive measures, including exploration of how “functional connectivity” from fMRI and “tractographic connectivity” from diffusion MRI compare with long-distance connections measured using tract tracing. Our NonHuman Primate Neuroimaging & Neuroanatomy Project (NHP_NNP) is an international effort (6 laboratories in 5 countries) to: (i) acquire and analyze high-quality multi-modal brain imaging data of macaque and marmoset monkeys using protocols and methods adapted from the HCP; (ii) acquire quantitative invasive tract-tracing data for cortical and subcortical projections to cortical areas; and (iii) map the distributions of different brain cell types with immunocytochemical stains to better define brain areal boundaries. We are acquiring high-resolution structural, functional, and diffusion MRI data together with behavioral measures from over 100 individual macaques and marmosets in order to generate non-invasive measures of brain architecture such as myelin and cortical thickness maps, as well as functional and diffusion tractography-based connectomes. We are using classical and next-generation anatomical tracers to generate quantitative connectivity maps based on brain-wide counting of labeled cortical and subcortical neurons, providing ground truth measures of connectivity. Advanced statistical modeling techniques address the consistency of both kinds of data across individuals, allowing comparison of tracer-based and non-invasive MRI-based connectivity measures. We aim to develop improved cortical and subcortical areal atlases by combining histological and imaging methods. Finally, we are collecting genetic and sociality-associated behavioral data in all animals in an effort to understand how genetic variation shapes the connectome and behavior. © 2021 The Authors

Author Keywords
Connectivity;  Connectome;  Diffusion MRI;  Functional MRI;  Hierarchy;  Human;  Macaque;  Marmoset;  Retrograde tracer

Funding details
National Institutes of HealthNIHMH060974, P50NS098573, RF1 MH116978
Japan Agency for Medical Research and DevelopmentAMEDJP20dm0307006h0002
Wellcome TrustWT
Ministry of Education, Culture, Sports, Science and TechnologyMonbusho19H04904
Chinese Academy of SciencesCAS2018VBA0011, DUAL_STREAMS ANR‐19‐CE37‐0025
Université de LyonUDLSCUSI 1700933701

TRIM67 regulates exocytic mode and neuronal morphogenesis via SNAP47
(2021) Cell Reports, 34 (6), art. no. 108743, . 

Urbina, F.L.^a , Menon, S.^a , Goldfarb, D.^a b c d , Edwards, R.^a , Ben Major, M.^a b c , Brennwald, P.^a , Gupton, S.L.^a b e

^a Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
^b Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
^c Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Institute for Informatics, Washington University in St. Louis, St. Louis, MO 63110, United States
^e Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States

Abstract
Neuronal morphogenesis involves dramatic plasma membrane expansion, fueled by soluble N-ethylmaleimide-sensitive factor attachment protein eceptors (SNARE)-mediated exocytosis. Distinct fusion modes described at synapses include full-vesicle fusion (FVF) and kiss-and-run fusion (KNR). During FVF, lumenal cargo is secreted and vesicle membrane incorporates into the plasma membrane. During KNR, a transient fusion pore secretes cargo but closes without membrane addition. In contrast, fusion modes are not described in developing neurons. Here, we resolve individual exocytic events in developing murine cortical neurons and use classification tools to identify four distinguishable fusion modes: two FVF-like modes that insert membrane material and two KNR-like modes that do not. Discrete fluorescence profiles suggest distinct behavior of the fusion pore. Simulations and experiments agree that FVF-like exocytosis provides sufficient membrane material for morphogenesis. We find the E3 ubiquitin ligase TRIM67 promotes FVF-like exocytosis in part by limiting incorporation of the Qb/Qc SNARE SNAP47 into SNARE complexes and, thus, SNAP47 involvement in exocytosis. © 2021 The Author(s)

Urbina et al. identify four exocytic modes in developing neurons: KNRd, KNRi, FVFd, FVFi. Simulations and experiments suggest that FVFi and FVFd provide material for plasma membrane expansion. Deletion of Trim67 decreases FVFi and FVFd while reducing surface area. SNAP47 incorporation into SNARE complexes alters fusion pore behavior, increasing KNRd. © 2021 The Author(s)

Author Keywords
classification;  clustering;  exocytosis;  fusion;  mode;  morphogenesis;  neuron;  plasma membrane;  SNARE;  TIRF

Funding details
National Institutes of HealthNIHF31NS103586, R01NS112326, R35GM135160
University of North CarolinaUNCP30 NS045892, U54 HD079124

Measuring activities of daily living in stroke patients with motion machine learning algorithms: A pilot study
(2021) International Journal of Environmental Research and Public Health, 18 (4), art. no. 1634, pp. 1-16. 

Chen, P.-W.^a b , Baune, N.A.^a b , Zwir, I.^c d , Wang, J.^c , Swamidass, V.^a , Wong, A.W.K.^c e f

^a PlatformSTL, St. Louis, MO 63110, United States
^b Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO 63108, United States
^c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Department of Computer Science and Artificial Intelligence, University of Granada, Granada, 18010, Spain
^e Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
^f Center for Rehabilitation Outcomes Research, Shirley Ryan AbilityLab, Chicago, IL 60611, United States

Abstract
Measuring activities of daily living (ADLs) using wearable technologies may offer higher precision and granularity than the current clinical assessments for patients after stroke. This study aimed to develop and determine the accuracy of detecting different ADLs using machine-learning (ML) algorithms and wearable sensors. Eleven post-stroke patients participated in this pilot study at an ADL Simulation Lab across two study visits. We collected blocks of repeated activity (“atomic” activity) performance data to train our ML algorithms during one visit. We evaluated our ML algorithms using independent semi-naturalistic activity data collected at a separate session. We tested Decision Tree, Random Forest, Support Vector Machine (SVM), and eXtreme Gradient Boosting (XGBoost) for model development. XGBoost was the best classification model. We achieved 82% accuracy based on ten ADL tasks. With a model including seven tasks, accuracy improved to 90%. ADL tasks included chopping food, vacuuming, sweeping, spreading jam or butter, folding laundry, eating, brushing teeth, taking off/putting on a shirt, wiping a cupboard, and buttoning a shirt. Results provide preliminary evidence that ADL functioning can be predicted with adequate accuracy using wearable sensors and ML. The use of external validation (independent training and testing data sets) and semi-naturalistic testing data is a major strength of the study and a step closer to the long-term goal of ADL monitoring in real-world settings. Further investigation is needed to improve the ADL prediction accuracy, increase the number of tasks monitored, and test the model outside of a laboratory setting. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Author Keywords
Activities of daily living;  Machine learning;  Rehabilitation;  Remote sensing technology;  Stroke;  Telemedicine;  Wearable electronic devices

Funding details
National Institutes of HealthNIHK01HD095388
National Institute on Disability, Independent Living, and Rehabilitation ResearchNIDILRR90BISA0015

Proof of concept of a personalized genetic risk tool to promote smoking cessation: High acceptability and reduced cigarette smoking
(2021) Cancer Prevention Research, 14 (2), pp. 253-262. 

Ramsey, A.T.^a , Bourdon, J.L.^a , Bray, M.^a , Dorsey, A.^a , Zalik, M.^a , Pietka, A.^a , Salyer, P.^a , Chen, L.-S.^a , Baker, T.B.^b , Munafò, M.R.^c d , Bierut, L.J.^a

^a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Medicine, University of Wisconsin, School of Medicine and Public Health, Madison, WI, United States
^c School of Psychological Science, University of Bristol, Bristol, England, United Kingdom
^d MRC Integrative Epidemiology Unit, University of Bristol, Bristol, England, United Kingdom

Abstract
Relatively little is known about the possible effects of personalized genetic risk information on smoking, the leading preventable cause of morbidity and mortality. We examined the acceptability and potential behavior change associated with a personalized genetically informed risk tool (RiskProfile) among current smokers. Current smokers (n = 108) were enrolled in a pre-post study with three visits. At visit 1, participants completed a baseline assessment and genetic testing via 23andMe. Participants’ raw genetic data (CHRNA5 variants) and smoking heaviness were used to create a tailored RiskProfile tool that communicated personalized risks of smoking-related diseases and evidence-based recommendations to promote cessation. Participants received their personalized RiskProfile intervention at visit 2, approximately 6 weeks later. Visit 3 involved a telephone-based follow-up assessment 30 days after intervention. Of enrolled participants, 83% were retained across the three visits. Immediately following intervention, acceptability of RiskProfile was high (M=4.4; SD=0.6 on scale of 1 to 5); at 30-day follow-up, 89% of participants demonstrated accurate recall of key intervention messages. In the full analysis set of this single-arm trial, cigarettes smoked per day decreased from intervention to 30- day follow-up [11.3 vs. 9.8; difference = 1.5; 95% confidence interval (0.6-2.4); P = 0.001]. A personalized genetically informed risk tool was found to be highly acceptable and associated with a reduction in smoking, although the absence of a control group must be addressed in future research. This study demonstrates proof of concept for translating key basic science findings into a genetically informed risk tool that was used to promote progress toward smoking cessation. Prevention Relevance: This study demonstrates that personal genetic information can be incorporated into a risk feedback tool that was highly acceptable to current smokers and associated with reductions in smoking. These findings may pave the way for effectiveness and implementation research on genetically-informed behavior change interventions to enhance cancer prevention efforts. © 2020 American Association for Cancer Research.

Funding details
National Institute on Drug AbuseNIDAK12DA041449
National Cancer InstituteNCIP30CA091842, P50CA244431, R01DA036583, R01DA038076, T32DA015035
National Center for Advancing Translational SciencesNCATSUL1TR002345

Barbara Geller, MD (1939-2020)
(2021) Journal of the American Academy of Child and Adolescent Psychiatry, 60 (2), pp. 205-206. 

Luby, J.L.

Washington University School of Medicine, St. Louis, MO, United States

Abstract
Barbara Geller, MD, was born on April 21, 1939, and passed away on May 8, 2020, in St. Louis, Missouri at the age of 81 after a brief illness. She was widely known to members of the American Academy of Child and Adolescent Psychiatry and the broader field of child and adolescent psychiatry for her rigorous body of work on childhood mood disorders and more specifically for her pioneering work in the description and validation of prepubertal bipolar disorder. She was a prolific investigator, mentor, teacher, and clinician. When she chose to retire in 2009, she was at the height of her academic career. Copyright © 2020.

Anti-CD20 B Cell Treatment for Relapsing Multiple Sclerosis
(2021) Frontiers in Neurology, 11, art. no. 595547, . 

Roach, C.A., Cross, A.H.

Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Several clinical trials have demonstrated the efficacy of lytic therapies targeting B cells in the treatment of relapsing multiple sclerosis (MS). More modest efficacy has been noted in the primary progressive subtype of MS. Clinical success has increased interest in the role of B cells in the pathogenesis of MS and in ways to potentially improve upon current B cell therapies. In this mini review, we will critically review previous and ongoing clinical trials of anti-CD20 monoclonal antibodies in MS, including rituximab, ocrelizumab, ofatumumab, and ublituximab. Side effects and adverse event profiles will be discussed. Studies examining the proposed mechanisms of action of B cell depleting therapies will also be reviewed. © Copyright © 2021 Roach and Cross.

Author Keywords
anti-CD20 agent;  multiple sclerosis;  ocrelizumab;  ofatumumab;  rituximab;  ublituximab

Funding details
National Multiple Sclerosis Society
Foundation for Barnes-Jewish Hospital

Diffusion Basis Spectrum Imaging Detects Axonal Loss After Transient Dexamethasone Treatment in Optic Neuritis Mice
(2021) Frontiers in Neuroscience, 14, art. no. 592063, . 

Lin, T.-H.^a , Zhan, J.^a g , Song, C.^b , Wallendorf, M.^c , Sun, P.^a , Niu, X.^a , Yang, R.^a f , Cross, A.H.^d e , Song, S.-K.^a b e

^a Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
^c Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^e Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Radiology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China
^g Department of Radiology, The First Affiliated Hospital, Nanchang University, Jiangxi, China

Abstract
Optic neuritis is a frequent first symptom of multiple sclerosis (MS) for which corticosteroids are a widely employed treatment option. The Optic Neuritis Treatment Trial (ONTT) reported that corticosteroid treatment does not improve long-term visual acuity, although the evolution of underlying pathologies is unclear. In this study, we employed non-invasive diffusion basis spectrum imaging (DBSI)-derived fiber volume to quantify 11% axonal loss 2 months after corticosteroid treatment (vs. baseline) in experimental autoimmune encephalomyelitis mouse optic nerves affected by optic neuritis. Longitudinal DBSI was performed at baseline (before immunization), after a 2-week corticosteroid treatment period, and 1 and 2 months after treatment, followed by histological validation of neuropathology. Pathological metrics employed to assess the optic nerve revealed axonal protection and anti-inflammatory effects of dexamethasone treatment that were transient. Two months after treatment, axonal injury and loss were indistinguishable between PBS- and dexamethasone-treated optic nerves, similar to results of the human ONTT. Our findings in mice further support that corticosteroid treatment alone is not sufficient to prevent eventual axonal loss in ON, and strongly support the potential of DBSI as an in vivo imaging outcome measure to assess optic nerve pathology. © Copyright © 2021 Lin, Zhan, Song, Wallendorf, Sun, Niu, Yang, Cross and Song.

Author Keywords
anti-inflammation;  axonal loss;  dexamethasone;  Diffusion basis spectrum imaging (DBSI);  diffusion MRI;  multiple sclerosis (MS);  optic neuritis (ON)

Funding details
P01-NS059560, R01-NS047592, U01- EY025500
U.S. Department of DefenseDODW81XWH-12-1-0457
National Multiple Sclerosis SocietyFG-1507-05315, RG 4549A4/1, RG1701-26617
Foundation for Barnes-Jewish Hospital
National Natural Science Foundation of ChinaNSFC81971574
Natural Science Foundation of Guangdong Province2018A030313282
Guangzhou Municipal Science and Technology Project202002030268

Assessment of Potential Risk Factors for the Development of Persistent Postural-Perceptual Dizziness: A Case-Control Pilot Study
(2021) Frontiers in Neurology, 11, art. no. 601883, . 

Trinidade, A.^a , Harman, P.^a , Stone, J.^b , Staab, J.P.^c , Goebel, J.A.^d

^a Southend University Hospital NHS Foundation Trust, Southend-on-Sea, United Kingdom
^b Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
^c Mayo Clinic, Rochester, MN, United States
^d Washington University in St. Louis School of Medicine, St. Louis, MO, United States

Abstract
Objectives: (1) To assess whether neuroticism, state anxiety, and body vigilance are higher in patients with persistent postural-perceptual dizziness (PPPD) compared to a recovered vestibular patient group and a non-dizzy patient group; (2) To gather pilot data on illness perceptions of patients with PPPD. Materials and Methods: 15 cases with PPPD and two control groups: (1) recovered vestibular patients (n = 12) and (2) non-dizzy patients (no previous vestibular insult, n = 12). Main outcome measures: Scores from the Big Five Inventory (BFI) of personality traits, Generalized Anxiety Disorder – 7 (GAD-7) scale, Body Vigilance Scale (BVS), Dizziness Handicap Inventory (DHI), modified Vertigo Symptom Scale (VSS) and Brief Illness Perception Questionnaire (BIPQ). Results: Compared to non-dizzy patients, PPPD cases had higher neuroticism (p = 0.02), higher introversion (p = 0.008), lower conscientiousness (p = 0.03) and higher anxiety (p = 0.02). There were no differences between PPPD cases and recovered vestibular patients in BFI and GAD-7. PPPD cases had higher body vigilance to dizziness than both control groups and their illness perceptions indicated higher levels of threat than recovered vestibular patients. Conclusion: PPPD patients showed statistically significant differences to non-dizzy patients, but not recovered vestibular controls in areas such as neuroticism and anxiety. Body vigilance was increased in PPPD patients when compared with both recovered vestibular and non-dizzy patient groups. PPPD patients also exhibited elements of negative illness perception suggesting that this may be the key element driving the development of PPPD. Large scale studies focusing on this area in the early stages following vestibular insult are needed. © Copyright © 2021 Trinidade, Harman, Stone, Staab and Goebel.

Author Keywords
body vigilance;  illness perceptions;  neuroticism;  PPPD;  state anxiety

Insights From Genetic Studies of Cerebral Palsy
(2021) Frontiers in Neurology, 11, art. no. 625428, . 

Lewis, S.A.^a b , Shetty, S.^a b , Wilson, B.A.^a b , Huang, A.J.^c , Jin, S.C.^d , Smithers-Sheedy, H.^e , Fahey, M.C.^f , Kruer, M.C.^a b c

^a Pediatric Movement Disorders Program, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ, United States
^b Departments of Child Health, Neurology, and Cellular & Molecular Medicine and Program in Genetics, University of Arizona College of Medicine, Phoenix, AZ, United States
^c Programs in Neuroscience and Molecular Cellular Biology, School of Life Sciences, Arizona State University, Tempe, AZ, United States
^d Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
^e Cerebral Palsy Alliance, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
^f Department of Paediatrics, Monash University, Melbourne, VIC, Australia

Abstract
Cohort-based whole exome and whole genome sequencing and copy number variant (CNV) studies have identified genetic etiologies for a sizable proportion of patients with cerebral palsy (CP). These findings indicate that genetic mutations collectively comprise an important cause of CP. We review findings in CP genomics and propose criteria for CP-associated genes at the level of gene discovery, research study, and clinical application. We review the published literature and report 18 genes and 5 CNVs from genomics studies with strong evidence of for the pathophysiology of CP. CP-associated genes often disrupt early brain developmental programming or predispose individuals to known environmental risk factors. We discuss the overlap of CP-associated genes with other neurodevelopmental disorders and related movement disorders. We revisit diagnostic criteria for CP and discuss how identification of genetic etiologies does not preclude CP as an appropriate diagnosis. The identification of genetic etiologies improves our understanding of the neurobiology of CP, providing opportunities to study CP pathogenesis and develop mechanism-based interventions. © Copyright © 2021 Lewis, Shetty, Wilson, Huang, Jin, Smithers-Sheedy, Fahey and Kruer.

Author Keywords
cerebral palsy;  genetics;  genomics;  neurodevelopmental disorders;  neurogenetics

Funding details
K99HL143036, R00HL143036-02
1144566
National Institutes of HealthNIH1R01NS106298

Dementia Research in the Caribbean Hispanic Islands: Present Findings and Future Trends
(2021) Frontiers in Public Health, 8, art. no. 611998, . 

Acosta, D.^a , Llibre-Guerra, J.J.^b c , Jiménez-Velázquez, I.Z.^d , Llibre-Rodríguez, J.J.^a e

^a Department of Internal Medicine, Universidad Nacional Pedro Henriquez Urena, Santo Domingo, Dominican Republic
^b Department of Neurology, Washington University School of Medicine in St. Louis, St. LouisMO, United States
^c National Institute of Neurology and Neurosurgery, Habana, Cuba
^d Department of Internal Medicine, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico
^e Finlay-Albarrán Medicine Faculty, Universidad de Ciencias Medicas, Habana, Cuba

Abstract
During the last decade, the Caribbean Hispanic islands experienced accelerated demographic aging, representing the fastest aging region within Latin America. Age-related non-communicable diseases, including dementia, are now reported at high prevalence. The Caribbean islands share similar genetic ancestry, culture, migration patterns, and risk profiles, providing a unique setting to understand dementia in the Caribbean-Hispanics. This perspective article aimed to describe the impact of dementia in the Caribbean, at a local and regional level and reflect on research strategies to address dementia. We report on 10/66 project findings, described research projects and regional plans for the region. According to our results, the prevalence of dementia in the Caribbean is the highest in Latin America, with 11.7% in Dominican Republic, 11.6% in Puerto Rico, and 10.8% in Cuba. Preliminary data from new waves of the 10/66 study shows increasing numbers of dementia cases. Furthermore, dementia is expected to be one of the most serious medical and social issues confronted by Caribbean health systems. However, there is a scarcity of knowledge, awareness, and health services to deal with this public health crisis. In light of the new evidence, local and regional strategies are underway to better understand dementia trends for the region and develop policies aimed to decrease the impact of dementia. Implementation of our national plans is critical to deal with an aging population with high dementia rates. Current recommendations include emphasizing public health prevention campaigns to address modifiable risk factors and expand support to caregiver and family interventions. © Copyright © 2021 Acosta, Llibre-Guerra, Jiménez-Velázquez and Llibre-Rodríguez.

Author Keywords
Caribbean hispanics;  dementia;  incidence;  prevalence;  regional policies

Funding details
2018-2019-2A3-208
GR066133, GR080002
National Institutes of HealthNIHR01AG064778
National Institute on AgingNIA
Alzheimer’s AssociationAASG-20-690363
World Federation of NeurologyWFN
Ministerio de Educación Superior, Ciencia y Tecnología, República DominicanaMESCYT

A Clinician’s Guide for Navigating the World of ADHD Medications
(2021) CNS Spectrums, . 

Mattingly, G.W.^a , Young, J.^b

^a Midwest Research Group, Washington University School of Medicine, St. Louis, MO, United States
^b Rochester Center for Behavioral Medicine, Rochester Hills, MI, United States

Abstract
Once considered a condition of hyperactive boys, our knowledge and understanding of attention deficit hyperactivity disorder (ADHD) and has dramatically evolved. Landmark studies by Biederman, Kessler, Faraone and others have changed and deepened our understanding of ADHD to include a condition which not only affects boys but quite often affects girls1,The evolution of symptoms across the lifespan and the concomitant neurologic changes which underlie this symptomatic expression has similarly evolved.Studies by Dalsgaard and others have brought to light the significantly increased morbidity and mortality associated with preschoolers, children and adults struggling with ADHD and associated conditions. © 2021 BMJ Publishing Group. All rights reserved.

Functional characterization of the dural sinuses as a neuroimmune interface
(2021) Cell, . Cited 1 time.

Rustenhoven, J.^a b , Drieu, A.^a b , Mamuladze, T.^a b , de Lima, K.A.^a b , Dykstra, T.^a b , Wall, M.^c , Papadopoulos, Z.^a b d , Kanamori, M.^a b , Salvador, A.F.^a b c e , Baker, W.^c , Lemieux, M.^b l , Da Mesquita, S.^c f , Cugurra, A.^c g , Fitzpatrick, J.^h i , Sviben, S.^h , Kossina, R.^h , Bayguinov, P.^h , Townsend, R.R.^j , Zhang, Q.^j , Erdmann-Gilmore, P.^j , Smirnov, I.^a b , Lopes, M.-B.^k , Herz, J.^a b , Kipnis, J.^{a b c d e g}

^a Center for Brain Immunology and Glia (BIG), Washington University in St. Louis, St. Louis, MO 63110, United States
^b Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, United States
^c Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, United States
^d Neuroscience Graduate Program, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, United States
^e Neuroscience Graduate Program, University of Virginia, Charlottesville, VA 22908, United States
^f Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, United States
^g Gutenberg Research Fellowship Group of Neuroimmunology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn²), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
^h Washington University Center for Cellular Imaging, Washington University School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, United States
ⁱ Departments of Neuroscience and Cell Biology and Physiology, Washington University School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, United States
^j Department of Medicine, Washington University School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, United States
^k Department of Pathology, School of Medicine, University of Virginia, Charlottesville, VA 22908, United States
^l Medical Scientist Training Program (MSTP), School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, United States

Abstract
Rustenhoven et al. identify the dural sinuses as a neuroimmune interface, where patrolling T cells survey brain- and CSF-derived antigens to enable CNS immune surveillance. This niche is altered during aging and neuroinflammation and may represent a new therapeutic target for neurological diseases. © 2020 Elsevier Inc.

Despite the established dogma of central nervous system (CNS) immune privilege, neuroimmune interactions play an active role in diverse neurological disorders. However, the precise mechanisms underlying CNS immune surveillance remain elusive; particularly, the anatomical sites where peripheral adaptive immunity can sample CNS-derived antigens and the cellular and molecular mediators orchestrating this surveillance. Here, we demonstrate that CNS-derived antigens in the cerebrospinal fluid (CSF) accumulate around the dural sinuses, are captured by local antigen-presenting cells, and are presented to patrolling T cells. This surveillance is enabled by endothelial and mural cells forming the sinus stromal niche. T cell recognition of CSF-derived antigens at this site promoted tissue resident phenotypes and effector functions within the dural meninges. These findings highlight the critical role of dural sinuses as a neuroimmune interface, where brain antigens are surveyed under steady-state conditions, and shed light on age-related dysfunction and neuroinflammatory attack in animal models of multiple sclerosis. © 2020 Elsevier Inc.

Author Keywords
antigen presentation;  CNS autoimmunity;  CSF flow;  dura mater;  meningeal immunity;  meningeal lymphatics;  meninges;  neuroimmunology;  sinus;  stromal cells

Funding details
CDI-CORE-2015-505, CDI-CORE-2019-813
National Institutes of HealthNIH
National Institute on AgingNIAAG034113, AG057496, AT010416
National Cancer InstituteNCIP30 CA091842
National Institute of General Medical SciencesNIGMSP41 GM103422
National Center for Advancing Translational SciencesNCATSUL1 TR000448
Foundation for Barnes-Jewish Hospital
Cure Alzheimer’s FundCAF
University of WashingtonUW
Institute of Clinical and Translational SciencesICTS
University of VirginiaUV
Center for Cellular Imaging, Washington UniversityWUCCI

Pharmacotherapy to Manage Central Post-Stroke Pain
(2021) CNS Drugs, . 

Choi, H.R.^a , Aktas, A.^b , Bottros, M.M.^c

^a Department of Anesthesiology, Virginia Mason Medical Center, Seattle, WA, United States
^b Division of Neurorehabilitation, Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Anesthesiology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, United States

Abstract
Central post-stroke pain is a chronic neuropathic pain syndrome following a cerebrovascular accident. The development of central post-stroke pain is estimated to occur in 8 to 55% of stroke patients and is described as constant or intermittent neuropathic pain accompanied by dysesthesia of temperature and/or pressure sensations. These pain and sensory deficits are within the area of the body corresponding to the stroke lesion. The onset of pain is usually gradual, though it can develop either immediately after stroke or years after. Given the diversity in its clinical presentation, central post-stroke pain is a challenging diagnosis of exclusion. Furthermore, central post-stroke pain is often resistant to pharmacological treatment options and a clear therapeutic algorithm has not been established. Based on current evidence, amitriptyline, lamotrigine, and gabapentinoids should be used as first-line pharmacotherapy options when central post-stroke pain is suspected. Other drugs, such as fluvoxamine, steroids, and Intravenous infusions of lidocaine, ketamine, or even propofol, can be considered in intractable cases. In addition, interventional therapies such as motor cortex stimulation or transcranial magnetic stimulation have been shown to provide relief in difficult-to-treat patients. © 2021, The Author(s), under exclusive licence to Springer Nature Switzerland AG part of Springer Nature.

Treatment of small and medium retinoblastoma tumors with Iris diode laser
(2021) European Journal of Ophthalmology, . 

Reynolds, M.M.^a , Sein, J.^a , Hayashi, R.^b , Lueder, G.^a

^a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Hematology and Oncology, Saint Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Purpose: Differing techniques have been reported for focal laser therapy for patients with small and medium retinoblastoma. We report the technique used at our center; and report the functional and anatomical outcomes for small and medium retinoblastomas treated with focal laser therapy with or without systemic chemotherapy. Methods: A retrospective case study was conducted including pediatric patients with macular retinoblastoma treated with systemic chemotherapy and laser ablation from July 1990 to July 2015 at Washington University School of Medicine/Saint Louis Children’s Hospital. Results: Fourteen eyes (11 patients) with small and medium retinoblastoma tumors were treated with repetitive indirect laser hyperthermia and seven of those patients were treated with systemic chemotherapy as well. Using the International Retinoblastoma classification, one eye was stage A, 10 eyes were stage B, and three eyes were stage C. The mean follow-up time was 7.7 years. There were no recurrences of tumor in the patients. Final visual acuity outcomes were 20/20 to 20/50 in four eyes, 20/60 to 20/200 in four eyes, and 20/400 or less in six eyes. None of the patients developed metastatic disease. Conclusions: The evidence for systemic chemotherapy and diode laser therapy is limited to case series and retrospective reviews, but evidence suggests that it is an effective treatment for small and medium sized retinoblastoma tumors involving the macula with the potential for good visual outcomes. © The Author(s) 2021.

Author Keywords
childhood tumors;  retina – medical therapies;  Retinoblastoma;  tumors/neoplasms;  vitreous/retinal disease

Waning efficacy in a long-term AAV-mediated gene therapy study in the murine model of Krabbe disease
(2021) Molecular Therapy, . 

Heller, G.J.^a , Marshall, M.S.^a , Issa, Y.^a , Marshall, J.N.^a , Nguyen, D.^a , Rue, E.^b , Pathmasiri, K.C.^c , Domowicz, M.S.^d , van Breemen, R.B.^b , Tai, L.M.^a , Cologna, S.M.^c , Crocker, S.J.^e , Givogri, M.I.^a , Sands, M.S.^f , Bongarzone, E.R.^a

^a Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, United States
^b Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, United States
^c Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, United States
^d Department of Pediatrics, University of Chicago, Chicago, IL 60612, United States
^e Department of Neuroscience, University of Connecticut School of Medicine, Farmington, CT 06030, United States
^f Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, United States

Abstract
Heller and colleagues demonstrate the formation of demyelinating lesions in the adult brain of the Twitcher mouse, following neonatal AAV9 gene therapy for the treatment of GALC deficiency. Lesions lack therapeutic levels of AAV-GALC and show a resurgence of the gliotic lysosomal phenotype. Their study identifies long-term safety aspects of the use of AAV vectors for the gene therapy of genetic leukodystrophies in need of further improvement. © 2021 The Author(s)

Neonatal AAV9-gene therapy of the lysosomal enzyme galactosylceramidase (GALC) significantly ameliorates central and peripheral neuropathology, prolongs survival, and largely normalizes motor deficits in Twitcher mice. Despite these therapeutic milestones, new observations identified the presence of multiple small focal demyelinating areas in the brain after 6–8 months. These lesions are in stark contrast to the diffuse, global demyelination that affects the brain of naive Twitcher mice. Late-onset lesions exhibited lysosomal alterations with reduced expression of GALC and increased psychosine levels. Furthermore, we found that lesions were closely associated with the extravasation of plasma fibrinogen and activation of the fibrinogen-BMP-SMAD-GFAP gliotic response. Extravasation of fibrinogen correlated with tight junction disruptions of the vasculature within the lesioned areas. The lesions were surrounded by normal appearing white matter. Our study shows that the dysregulation of therapeutic GALC was likely driven by the exhaustion of therapeutic AAV episomal DNA within the lesions, paralleling the presence of proliferating oligodendrocyte progenitors and glia. We believe that this is the first demonstration of diminishing expression in vivo from an AAV gene therapy vector with detrimental effects in the brain of a lysosomal storage disease animal model. The development of this phenotype linking localized loss of GALC activity with relapsing neuropathology in the adult brain of neonatally AAV-gene therapy-treated Twitcher mice identifies and alerts to possible late-onset reductions of AAV efficacy, with implications to other genetic leukodystrophies. © 2021 The Author(s)

Author Keywords
AAV9;  demyelination;  fibrinogen;  gene therapy;  globoid cell leukodystrophy;  lysosomal dysfunction;  microglia;  multi-focal sclerosis;  psychosine;  tight junction

Funding details
National Institutes of HealthNIHF30NS090684, R01 NS065808
Washington University in St. LouisWUSTL
Israel National Road Safety AuthorityNRSA
Association Européenne contre les LeucodystrophiesELA

Clinical epigenomics: genome-wide DNA methylation analysis for the diagnosis of Mendelian disorders
(2021) Genetics in Medicine, . 

Sadikovic, B.^a b , Levi, M.A.^a b , Kerkhof, J.^a b , Aref-Eshghi, E.^a b , Schenkel, L.^a b , Stuart, A.^a b , McConkey, H.^a b , Henneman, P.^c , Venema, A.^c , Schwartz, C.E.^d , Stevenson, R.E.^d , Skinner, S.A.^d , DuPont, B.R.^d , Fletcher, R.S.^d , Balci, T.B.^e f , Siu, V.M.^e f , Granadillo, J.L.^g , Masters, J.^a b , Kadour, M.^a b , Friez, M.J.^d , van Haelst, M.M.^c , Mannens, M.M.A.M.^c , Louie, R.J.^d , Lee, J.A.^d , Tedder, M.L.^d , Alders, M.^c

^a Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON, Canada
^b Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada
^c Amsterdam University Medical Center, University of Amsterdam, Department of Clinical Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam, Netherlands
^d Greenwood Genetic Center, Greenwood, SC, United States
^e Department of Pediatrics, Division of Medical Genetics, Western University, London, ON, Canada
^f Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre, London, ON, Canada
^g Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Abstract
Purpose: We describe the clinical implementation of genome-wide DNA methylation analysis in rare disorders across the EpiSign diagnostic laboratory network and the assessment of results and clinical impact in the first subjects tested. Methods: We outline the logistics and data flow between an integrated network of clinical diagnostics laboratories in Europe, the United States, and Canada. We describe the clinical validation of EpiSign using 211 specimens and assess the test performance and diagnostic yield in the first 207 subjects tested involving two patient subgroups: the targeted cohort (subjects with previous ambiguous/inconclusive genetic findings including genetic variants of unknown clinical significance) and the screening cohort (subjects with clinical findings consistent with hereditary neurodevelopmental syndromes and no previous conclusive genetic findings). Results: Among the 207 subjects tested, 57 (27.6%) were positive for a diagnostic episignature including 48/136 (35.3%) in the targeted cohort and 8/71 (11.3%) in the screening cohort, with 4/207 (1.9%) remaining inconclusive after EpiSign analysis. Conclusion: This study describes the implementation of diagnostic clinical genomic DNA methylation testing in patients with rare disorders. It provides strong evidence of clinical utility of EpiSign analysis, including the ability to provide conclusive findings in the majority of subjects tested. © 2021, The Author(s).

Identifying preclinical Alzheimer’s disease using everyday driving behavior: Proof of concept
(2021) Journal of Alzheimer’s Disease, 79 (3), pp. 1009-1014. 

Babulal, G.M.^a b , Johnson, A.^d , Fagan, A.M.^a b c , Morris, J.C.^{a b c e f g} , Roe, C.M.^a b

^a Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University, School of Medicine, St. Louis, MO, United States
^b Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
^c Hope Center for Neurological Disorders, Washington University, School of Medicine, St. Louis, MO, United States
^d Center for Clinical Studies, Washington University, School of Medicine, St. Louis, MO, United States
^e Departments of Pathology and Immunology, Washington University, School of Medicine, St. Louis, MO, United States
^f Department of Physical Therapy, Washington University, School of Medicine, St. Louis, MO, United States
^g Department of Occupational Therapy, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
We examined whether driving behavior can predict preclinical Alzheimer’s disease (AD). Data from 131 cognitively normal older adults with cerebrospinal fluid (CSF) and/or positron emission tomography (PET) biomarkers were examined with naturalistic driving behavior. Receiver operating characteristic curves were used to predict the highest 10%, 25%, and 50% of values for CSF tau/Aβ42, ptau181/Aβ42, or amyloid PET. Six in vivo driving variables alone yielded area under the curves (AUC) from 0.64-0.82. Addition of age, Apolipoprotein ε4, and neuropsychological measures to the models improved the AUC (0.81 to 0.90). Driving can be used as novel neurobehavioral marker to identify presence of preclinical AD. © 2021 – IOS Press. All rights reserved.

Author Keywords
Aging drivers;  Alzheimer’s disease;  Biomarkers;  Driving decline;  Preclinical

Funding details
National Institute on AgingNIAP01AG 003991, P01AG026276, P50AG005681, R01 AG067428, R01AG043434, R01AG056466, R01AG068183
Alzheimer’s Disease Research Center, Emory UniversityADRC
Alzheimer’s Disease Research Center, University of WashingtonADRC, UW

Clinical utility of anticytosolic 5’-nucleotidase 1A antibody in idiopathic inflammatory myopathies
(2021) Annals of Clinical and Translational Neurology, . 

Ikenaga, C.^a , Findlay, A.R.^a , Goyal, N.A.^b , Robinson, S.^a , Cauchi, J.^b , Hussain, Y.^c , Wang, L.H.^d , Kershen, J.C.^e , Beson, B.A.^e , Wallendorf, M.^f , Bucelli, R.C.^a , Mozaffar, T.^b , Pestronk, A.^a , Weihl, C.C.^a

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Neurology, University of California, Irvine, CA, United States
^c Austin Neuromuscular Center, The University of Texas Dell Medical School, Austin, TX, United States
^d Department of Neurology, University of Washington, Seattle, WA, United States
^e Integris Southwest Medical Center, Oklahoma City, OK, United States
^f Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Objective: To define the clinicopathologic features and diagnostic utility associated with anticytosolic 5′-nucleotidase 1A (NT5C1A) antibody seropositivity in idiopathic inflammatory myopathies (IIMs). Methods: Anti-NT5C1A antibody status was clinically tested between 2014 and 2019 in the Washington University neuromuscular clinical laboratory. Using clinicopathologic information available for 593 patients, we classified them as inclusion body myositis (IBM), dermatomyositis, antisynthetase syndrome, immune-mediated necrotizing myopathy (IMNM), nonspecific myositis, or noninflammatory muscle diseases. Results: Of 593 patients, anti-NT5C1A antibody was found in 159/249 (64%) IBM, 11/53 (21%) dermatomyositis, 7/27 (26%) antisynthetase syndrome, 9/76 (12%) IMNM, 20/84 (24%) nonspecific myositis, and 6/104 (6%) noninflammatory muscle diseases patients. Among patients with IBM, anti-NT5C1A antibody seropositive patients had more cytochrome oxidase-negative fibers compared with anti-NT5C1A antibody seronegative patients. Among 14 IBM patients initially negative for anti-NT5C1A antibody, three patients (21%) converted to positive. Anti-NT5C1A antibody seropositivity did not correlate with malignancy, interstitial lung disease, response to treatments in dermatomyositis, antisynthetase syndrome, and IMNM, or survival in IIMs. Interpretation: Anti-NT5C1A antibody is associated with IBM. However, the seropositivity can also be seen in non-IBM IIMs and it does not correlate with any prognostic factors or survival. © 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association

Funding details
Myositis AssociationTMA
School of Public Health, University of California BerkeleyUCB
Muscular Dystrophy AssociationMDA

Radial Nerve Palsy: Nerve Transfer Versus Tendon Transfer to Restore Function
(2021) Hand, . 

Patterson, J.M.M.^a , Russo, S.A.^b , El-Haj, M.^c , Novak, C.B.^d , Mackinnon, S.E.^b

^a The University of North Carolina at Chapel Hill, United States
^b Washington University School of Medicine in St. LouisMO, United States
^c Hadassah Hebrew University Medical Center, Jerusalem, Israel
^d University of TorontoON, Canada

Abstract
Background: Radial nerve injuries cause profound disability, and a variety of reconstruction options exist. This study aimed to compare outcomes of tendon transfers versus nerve transfers for the management of isolated radial nerve injuries. Methods: A retrospective chart review of 30 patients with isolated radial nerve injuries treated with tendon transfers and 16 patients managed with nerve transfers was performed. Fifteen of the 16 patients treated with nerve transfer had concomitant pronator teres to extensor carpi radialis brevis tendon transfer for wrist extension. Preoperative and postoperative strength data, Disabilities of the Arm, Shoulder, and Hand (DASH) scores, and quality-of-life (QOL) scores were compared before and after surgery and compared between groups. Results: For the nerve transfer group, patients were significantly younger, time from injury to surgery was significantly shorter, and follow-up time was significantly longer. Both groups demonstrated significant improvements in grip and pinch strength after surgery. Postoperative grip strength was significantly higher in the nerve transfer group. Postoperative pinch strength did not differ between groups. Similarly, both groups showed an improvement in DASH and QOL scores after surgery with no significant differences between the 2 groups. Conclusions: The nerve transfer group demonstrated greater grip strength, but both groups had improved pain, function, and satisfaction postoperatively. Patients who present early and can tolerate longer time to functional recovery would be optimal candidates for nerve transfers. Both tendon transfers and nerve transfers are good options for patients with radial nerve palsy. © The Author(s) 2021.

Author Keywords
diagnosis;  nerve;  nerve injury;  nerve reconstruction;  outcomes;  research and health outcomes;  specialty;  surgery;  tendon

Excellent Outcome of Acute Necrotizing Encephalopathy in an Adult With Bacterial Infections, Case Report
(2021) Neurohospitalist, . 

Wang, Y.^a , Younce, J.R.^a , Perlmutter, J.S.^a b , Mar, S.S.^c

^a Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
^b Department of Radiology, Washington University School of Medicine, Saint Louis, MO, United States
^c Department of Pediatric Neurology, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
Acute necrotizing encephalopathy (ANE) is a rare para-infectious encephalopathy that classically occurs in children. However, ANE should be considered in the differential diagnosis of adults with symmetric brain lesions after a prodromal illness given recent reports of coronavirus disease of 2019 (COVID-19) to presumably cause ANE in adults. We report a case of a 29-year-old male presenting with fever, malaise, and rapid deterioration into coma. Brain magnetic resonance imaging revealed multifocal symmetric areas of diffusion restriction and surrounding vasogenic edema involving bilateral thalami, pons and cerebellar hemispheres with a core of susceptibility artifact, and minimal thalamic contrast enhancement, most consistent with ANE. Extensive infectious workup revealed isolated Escherichia coli and Neisseria gonorrhoeae in his urine. Despite the severe encephalopathy on initial presentation, the patient improved with intravenous antibiotics and supportive management with minimal residual deficits at 9 months follow-up. We aim to provide an overview of the radiological features, differential diagnosis, treatment and prognosis of ANE. Becoming familiarized with this rare but devastating disease will improve detection, treatment, and ultimately prognosis, especially in the era of a new pandemic. © The Author(s) 2021.

Author Keywords
all immunology;  all infections;  case report;  MRI;  post infectious

Focused ultrasound-enhanced delivery of intranasally administered anti-programmed cell death-ligand 1 antibody to an intracranial murine glioma model
(2021) Pharmaceutics, 13 (2), art. no. 190, pp. 1-12. 

Ye, D.^a , Yuan, J.^b , Yue, Y.^b , Rubin, J.B.^c d , Chen, H.^b e

^a Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO 63130, United States
^b Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
^c Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108, United States

Abstract
Immune checkpoint inhibitors have great potential for the treatment of gliomas; however, their therapeutic efficacy has been partially limited by their inability to efficiently cross the blood– brain barrier (BBB). The objective of this study was to evaluate the capability of focused-ultrasound-mediated intranasal brain drug delivery (FUSIN) in achieving the locally enhanced delivery of anti-programmed cell death-ligand 1 antibody (aPD-L1) to the brain. Both non-tumor mice and mice transcranially implanted with GL261 glioma cells at the brainstem were used in this study. aPD-L1 was labeled with a near-infrared fluorescence dye (IRDye 800CW) and administered to mice through the nasal route to the brain, followed by focused ultrasound sonication in the presence of systemically injected microbubbles. FUSIN enhanced the accumulation of aPD-L1 at the FUS-targeted brainstem by an average of 4.03-and 3.74-fold compared with intranasal (IN) administration alone in the non-tumor mice and glioma mice, respectively. Immunohistochemistry staining found that aPD-L1 was mainly located within the perivascular spaces after IN delivery, while FUSIN further enhanced the penetration depth and delivery efficiency of aPD-L1 to the brain parenchyma. The delivered aPD-L1 was found to be colocalized with the tumor cells after FUSIN delivery to the brainstem glioma. These findings suggest that FUSIN is a promising technique to enhance the delivery of immune checkpoint inhibitors to gliomas. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Author Keywords
Blood-brain barrier;  Brain drug delivery;  Brainstem glioma;  Focused ultrasound;  Immune checkpoint in-hibitor;  Intranasal delivery

Funding details
National Institutes of HealthNIHR01EB027223, R01EB030102, R01MH116981

Classification and prediction of post-trauma outcomes related to PTSD using circadian rhythm changes measured via wrist-worn research watch in a large longitudinal cohort
(2021) IEEE Journal of Biomedical and Health Informatics, . 

Cakmak, A.S.^a , Perez Alday, E.A.^b , Da Poian, G.^c , Bahrami Rad, A.^d , Metzler, T.J.^e , Neylan, T.C.^f , House, S.L.^g , Beaudoin, F.L.^h , An, X.ⁱ , Stevens, J.^j , Zeng, D.^k , Linnstaedt, S.D.^l , Jovanovic, T.^m , Germine, L.T.ⁿ , Bollen, K.A.^o , Rauch, S.L.^p , Lewandowski, C.^q , Hendry, P.L.^r , Sheikh, S.^s , Storrow, A.B.^t , Musey, P.I.^u , Haran, J.P.^v , Jones, C.W.^w , Punches, B.E.^x , Swor, R.A.^y , Gentile, N.T.^z , Mcgrath, M.E.^aa , Seamon, M.J.^ab , Mohiuddin, K.^ac , Chang, A.M.^ad , Pearson, C.^ae , Domeier, R.M.^af , Bruce, S.E.^ag , O’Neil, B.J.^ah , Rathlev, N.K.^ai , Sanchez, L.D.^aj , Pietrzak, R.H.^ak , Joormann, J.^al , Barch, D.M.^am , Pizzagalli, D.^an , Harte, S.E.^ao , Elliott, J.M.^ap , Koenen, K.C.^aq , Ressler, K.J.^ar , Kessler, R.^as , Li, Q.^at , Mclean, S.A.^au , Clifford, G.D.^av

^a ECE, Georgia Institute of Technology College of Engineering, 115724 Atlanta, Georgia, United States, 30332-0250 (e-mail: acakmak3@gatech.edu)
^b Department of Biomedical Informatics, Emory University, 1371 Atlanta, Georgia, United States, (e-mail: erick@dbmi.emory.edu)
^c Department of Health Sciences and Technology, ETH Zurich, 27219 Zurich, Switzerland, 8092 (e-mail: giulia.dap@gmail.com)
^d Department of Biomedical Informatics, Emory University, 1371 Atlanta, Georgia, United States, (e-mail: abahramir@gmail.com)
^e Departments of Psychiatry and Neurology, University of California San Francisco, 8785 San Francisco, California, United States, (e-mail: thomas.metzler@va.gov)
^f Departments of Psychiatry and Neurology, University of California San Francisco, 8785 San Francisco, California, United States, (e-mail: thomas.neylan@ucsf.edu)
^g Department of Emergency Medicine, Washington University in St Louis School of Medicine, 12275 St Louis, Missouri, United States, (e-mail: staceyhouse@wustl.edu)
^h Department of Emergency Medicine & Health Services, Policy, and Practice, Brown University Warren Alpert Medical School, 12321 Providence, Rhode Island, United States, (e-mail: francesca_beaudoin@brown.edu)
ⁱ Institute for Trauma Recovery, Department of Anesthesiology, University of North Carolina at Chapel Hill, 2331 Chapel Hill, North Carolina, United States, (e-mail: xinming_an@med.unc.edu)
^j Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 12239 Atlanta, Georgia, United States, (e-mail: jennifer.stevens@emory.edu)
^k Department of Biostatistics, University of North Carolina at Chapel Hill, 2331 Chapel Hill, North Carolina, United States, (e-mail: DZENG@EMAIL.UNC.EDU)
^l Institute for Trauma Recovery, Department of Anesthesiology, University of North Carolina at Chapel Hill, 2331 Chapel Hill, North Carolina, United States, (e-mail: sarah_linnstaedt@med.unc.edu)
^m Wayne State University School of Medicine, 12267 Detroit, Michigan, United States, (e-mail: tjovanovic@med.wayne.edu)
ⁿ Department of Psychiatry, Harvard Medical School, 1811 Boston, Massachusetts, United States, (e-mail: lgermine@mclean.harvard.edu)
^o Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, 2331 Chapel Hill, North Carolina, United States, (e-mail: bollen@email.unc.edu)
^p Department of Psychiatry, McLean Hospital, 24472 Belmont, Massachusetts, United States, (e-mail: srauch@partners.org)
^q Department of Emergency Medicine, Henry Ford Health System, 2971 Detroit, Michigan, United States, (e-mail: clewand1@hfhs.org)
^r Department of Emergency Medicine, University of Florida College of Medicine, 12233 Gainesville, Florida, United States, (e-mail: phyllis.hendry@jax.ufl.edu)
^s Department of Emergency Medicine, University of Florida College of Medicine, 12233 Gainesville, Florida, United States, (e-mail: Sophia.Sheikh@jax.ufl.edu)
^t Department of Emergency Medicine, Vanderbilt University Medical Center, 12328 Nashville, Tennessee, United States, (e-mail: alan.storrow@vumc.org)
^u Department of Emergency Medicine, Indiana University School of Medicine, 12250 Indianapolis, Indiana, United States, (e-mail: pmusey@iu.edu)
^v Department of Emergency Medicine, University of Massachusetts Medical School, 12262 Worcester, Massachusetts, United States, (e-mail: john.haran@umassmed.edu)
^w Department of Emergency Medicine, Cooper Medical School of Rowan University, 363994 Camden, New Jersey, United States, (e-mail: jones-christopher@cooperhealth.edu)
^x Department of Emergency Medicine, University of Cincinnati College of Medicine, 12303 Cincinnati, Ohio, United States, (e-mail: murrisbe@ucmail.uc.edu)
^y Department of Medicine, Oakland University William Beaumont School of Medicine, 159878 Rochester, Michigan, United States, (e-mail: robert.swor@beaumont.edu)
^z Department of Emergency Medicine, Lewis Katz School of Medicine at Temple University, 12314 Philadelphia, Pennsylvania, United States, (e-mail: ngentile@temple.edu)
^aa Department of Emergency Medicine, Boston Medical Center, 1836 Boston, Massachusetts, United States, (e-mail: meghan.mcgrath@bmc.org)
^ab Division of Traumatology, Surgical Critical Care and Emergency Surgery, University of Pennsylvania, 6572 Philadelphia, Pennsylvania, United States, (e-mail: mark.seamon@pennmedicine.upenn.edu)
^ac Dept. of Emergency Medicine/Internal Medicine, Albert Einstein Medical Center, 6566 Philadelphia, Pennsylvania, United States, (e-mail: mohiuddk@einstein.edu)
^ad Department of Emergency Medicine, Thomas Jefferson University Hospitals, 6529 Wayne, Pennsylvania, United States, (e-mail: annamarie.chang@jefferson.edu)
^ae Department of Emergency Medicine, Ascension St John Hospital, 21928 Detroit, Michigan, United States, (e-mail: cpearson@med.wayne.edu)
^af Department of Emergency Medicine, Saint Joseph Mercy Saline Hospital, 25220 Saline, Michigan, United States, (e-mail: rdomeier@epmg.com)
^ag Department of Psychological Sciences, University of Missouri-St Louis, 14611 St Louis, Missouri, United States, (e-mail: brucese@umsl.edu)
^ah Department of Emergency Medicine, Wayne State University School of Medicine, 12267 Detroit, Michigan, United States, (e-mail: boneil@med.wayne.edu)
^ai Department of Emergency Medicine, University of Massachusetts Medical School – Baystate Campus, 550083 Springfield, Massachusetts, United States, (e-mail: niels.rathlev@baystatehealth.org)
^aj Department of Emergency Medicine, Beth Israel Deaconess Medical Center, 1859 Boston, Massachusetts, United States, (e-mail: lsanche1@bidmc.harvard.edu)
^ak Department of Psychiatry, Yale University School of Medicine, 12228 New Haven, Connecticut, United States, (e-mail: robert.pietrzak@yale.edu)
^al Department of Psychology, Yale University, Yale University, 5755 New Haven, Connecticut, United States, (e-mail: jutta.joormann@yale.edu)
^am Department of Psychological & Brain Sciences, College of Arts & Sciences, Washington University in Saint Louis, 7548 Saint Louis, Missouri, United States, (e-mail: dbarch@wustl.edu)
^an Department of Psychiatry, Harvard Medical School, 1811 Boston, Massachusetts, United States, (e-mail: dap@mclean.harvard.edu)
^ao Chronic Pain and Fatigue Research Center, Departments of Anesthesiology and Internal Medicine-Rheumatology, University of Michigan Medical School, 12266 Ann Arbor, Michigan, United States, (e-mail: seharte@med.umich.edu)
^ap The Kolling Institute of Medical Research, Northern Clinical School, The University of Sydney, 4334 Sydney, New South Wales, Australia, (e-mail: jim.elliott@sydney.edu.au)
^aq Department of Epidemiology, Harvard University T H Chan School of Public Health, 1857 Boston, Massachusetts, United States, (e-mail: kkoenen@hsph.harvard.edu)
^ar Department of Psychiatry, Harvard Medical School, 1811 Boston, Massachusetts, United States, (e-mail: kressler@mclean.harvard.edu)
^as Harvard Medical School Department of Health Care Policy, 158795 Boston, Massachusetts, United States, 02115-5821 (e-mail: kessler@hcp.med.harvard.edu)
^at Department of Biomedical Informatics, Emory University School of Medicine, 12239 Atlanta, Georgia, United States, (e-mail: qiaoli@dbmi.emory.edu)
^au Department of Emergency Medicine, Institute for Trauma Recovery, Department of Anesthesiology, University of North Carolina at Chapel Hill, 2331 Chapel Hill, North Carolina, United States, (e-mail: samuel_mclean@med.unc.edu)
^av Department of Biomedical Informatics, Emory University School of Medicine, 12239 Atlanta, Georgia, United States, (e-mail: gari@alum.mit.edu)

Abstract
Post-Traumatic Stress Disorder (PTSD) is a psychiatric condition resulting from threatening or horrifying events. We hypothesized that circadian rhythm changes, measured by a wrist-worn research watch are predictive of post-trauma outcomes. Approach: 1618 post-trauma patients were enrolled after admission to emergency departments (ED). Three standardized questionnaires were administered at week eight to measure post-trauma outcomes related to PTSD, sleep disturbance, and pain interference with daily life. Pulse activity and movement data were captured from a research watch for eight weeks. Standard and novel movement and cardiovascular metrics that reflect circadian rhythms were derived using this data. These features were used to train different classifiers to predict the three outcomes derived from week-eight surveys. Clinical surveys administered at ED were also used as features in the baseline models. Results: The highest cross-validated performance of research watch-based features was achieved for classifying participants with pain interference by a logistic regression model, with an area under the receiver operating characteristic curve (AUC) of 0.70. The ED survey-based model achieved an AUC of 0.77, and the fusion of research watch and ED survey metrics improved the AUC to 0.79. Significance: This work represents the first attempt to predict and classify post-trauma symptoms from passive wearable data using machine learning approaches that leverage the circadian desynchrony in a potential PTSD population. IEEE

Author Keywords
Actigraphy;  Circadian rhythm;  Circadian rhythms;  Heart rate variability;  Interference;  Ion radiation effects;  Magnetosphere;  mHealth;  Pain;  Photoplethysmography;  Post-traumatic stress disorder;  Standards;  Wearables

Histologic and functional outcomes of conduit wrapping for peripheral nerve repair: Early results in a rat model
(2021) Journal of Reconstructive Microsurgery, . 

Brogan, D.M.^a , Dy, C.J.^a , Lee, T.Y.^a , Rioux-Forker, D.^b , Wever, J.^a , Leversedge, F.J.^c

^a Department of Orthopedic Surgery, Washington University in St. Louis, St. Louis, MO, United States
^b Division of Plastic Surgery, University of Missouri, Columbia, MO, United States
^c Department of Orthopedic Surgery, University of Colorado, Aurora, CO, United States

Abstract
Background â The concept of utilizing a nerve conduit for augmentation of a primary nerve repair has been advocated as a method to prevent neural scarring and decrease adhesions. Despite clinical use, little is known about the effects of a nerve conduit wrapped around a primary repair. To better understand this, we investigated the histologic and functional effects of use of a nerve conduit wrapped around a rat sciatic nerve repair without tension. Methods Twenty Lewis’ rats were divided into two groups of 10 rats each. In each group, unilateral sciatic nerve transection and repair were performed, with the opposite limb utilized as a matched control. In the first group, direct repair alone was performed; in the second group, this repair was augmented with a porcine submucosa conduit wrapped around the repair site. Sciatic functional index (SFI) was measured at 6 weeks with walking track analysis in both groups. Nonsurvival surgeries were then performed in all animals to harvest both the experimental and control nerves to measure histomorphometric parameters of recovery. Histomorphometric parameters assessed included total number of neurons, nerve fiber density, nerve fiber width, G-ratio, and percentage of debris. Unpaired t-Test was used to compare outcomes between the two groups. Results All nerves healed uneventfully but compared with direct repair; conduit usage was associated with greater histologic debris, decreased axonal density, worse G-ratio, and worse SFI. No significant differences were found in total axon count or gastrocnemius weight. Conclusion In the absence of segmental defects, conduit wrapping primary nerve repairs seem to be associated with worse functional and mixed histologic outcomes at 6 weeks, possibly due to debris from conduit resorption. While clinical implications are unclear, more basic science and clinical studies should be performed prior to widespread adoption of this practice. © 2021 Georg Thieme Verlag. All rights reserved.

Author Keywords
conduit;  conduit wrap;  nerve repair;  nerve wrap;  peripheral nerve;  regeneration

The AT(N) framework for Alzheimer’s disease in adults with Down syndrome
(2020) Alzheimer’s and Dementia: Diagnosis, Assessment and Disease Monitoring, 12 (1), art. no. e12062, . 

Rafii, M.S.^a , Ances, B.M.^b , Schupf, N.^c d e f , Krinsky-McHale, S.J.^g , Mapstone, M.^h , Silverman, W.ⁱ , Lott, I.ⁱ , Klunk, W.^j , Head, E.^k , Christian, B.^l , Lai, F.^m , Rosas, H.D.ⁿ , Zaman, S.^o p , Petersen, M.E.^q , Strydom, A.^r , Fortea, J.^s , Handen, B.^j , O’Bryant, S.^t

^a Alzheimer’s Therapeutic Research Institute (ATRI), Keck School of Medicine, University of Southern California, San Diego, CA, United States
^b Center for Advanced Medicine Neuroscience, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^c Taub Institute for Research on Alzheimer’s Disease and the Aging Brain/G.H. Sergievsky Center, Columbia University Irving Medical Center, New York, NY, United States
^d Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, United States
^e Department of Neurology, Neurological Institute of New York, Columbia University Irving Medical Center, New York, NY, United States
^f Department of Psychiatry, Columbia University Medical Center, New York, NY, United States
^g Department of Psychology, NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY, United States
^h Department of Neurology, University of California, Irvine, CA, United States
ⁱ Department of Pediatrics, School of Medicine, University of California, Irvine, CA, United States
^j Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
^k Department of Pathology, Gillespie Neuroscience Research Facility, University of California, Irvine, CA, United States
^l Department of Medical Physics and Psychiatry, University of Wisconsin Madison, Madison, WI, United States
^m Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
ⁿ Departments of Neurology and Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
^o Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
^p Cambridgeshire and Peterborough NHS Foundation Trust, Fulbourn Hospital, Cambridge, United Kingdom
^q Department of Family Medicine and Institute for Translational Research, University of North Texas Health Science Center, Fort Worth, TX, United States
^r Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
^s Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
^t Institute for Translational Research and Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, United States

Abstract
The National Institute on Aging in conjunction with the Alzheimer’s Association (NIA-AA) recently proposed a biological framework for defining the Alzheimer’s disease (AD) continuum. This new framework is based upon the key AD biomarkers (amyloid, tau, neurodegeneration, AT[N]) instead of clinical symptoms and represents the latest understanding that the pathological processes underlying AD begin decades before the manifestation of symptoms. By using these same biomarkers, individuals with Down syndrome (DS), who are genetically predisposed to developing AD, can also be placed more precisely along the AD continuum. The A/T(N) framework is therefore thought to provide an objective manner by which to select and enrich samples for clinical trials. This new framework is highly flexible and allows the addition of newly confirmed AD biomarkers into the existing AT(N) groups. As biomarkers for other pathological processes are validated, they can also be added to the AT(N) classification scheme, which will allow for better characterization and staging of AD in DS. These biological classifications can then be merged with clinical staging for an examination of factors that impact the biological and clinical progression of the disease. Here, we leverage previously published guidelines for the AT(N) framework to generate such a plan for AD among adults with DS. © 2020 The Authors. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, Inc. on behalf of the Alzheimer’s Association.

Author Keywords
Alzheimer’s disease;  biomarkers;  Down syndrome