WashU weekly Neuroscience publications

C3 in the 10-20 system may not be the best target for the motor hand area
(2023) Brain Research, 1807, art. no. 148311, . 

Kim, H.^a , Wright, D.L.^a , Rhee, J.^b , Kim, T.^c

^a Motor Neuroscience Laboratory, Division of Kinesiology, Texas A&M University, College Station, TX, United States
^b Department of Environmental and Occupational Health, Texas A&M University, College Station, TX, United States
^c Neuroscience and Rehabilitation Laboratory, Program in Occupational Therapy, Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Abstract
The C3 region in the international 10-20 system for electroencephalography (EEG) recording is assumed to represent the right motor hand area. Therefore, in the absence of transcranial magnetic stimulation (TMS) or a neuronavigational system, neuromodulation methods, such as transcranial direct current stimulation, target C3 or C4, based on the international 10-20 system, to influence the cortical excitability of the right and left hand, respectively. The purpose of this study is to compare the peak-to-peak motor evoked potential (MEP) amplitudes of the right first dorsal interosseus (FDI) muscle after single-pulse TMS at C3 and C1 in the 10-20 system and at the region between C3 and C1 (i.e., C3h in the 10-5 system). Using an intensity of 110% of the resting motor threshold, 15 individual MEPs from each of C3, C3h, C1, and hotspots were randomly recorded from FDI for sixteen right-handed undergraduate students. Average MEPs were greatest at C3h and C1, with both being larger than those recorded at C3. These data are congruent with recent findings using topographic analysis of individual MRIs that revealed poor correspondence between C3/C4 and the respective hand knob. Implications for the use of scalp locations determined using the 10-20 system for localizing the hand area are highlighted. © 2023 Elsevier B.V.

Author Keywords
Cortical motor representation;  International 10-20 system;  Motor evoked potential;  Motor hand area;  Transcranial magnetic stimulation

Document Type: Article
Publication Stage: Final
Source: Scopus

Impaired neurogenesis with reactive astrocytosis in the hippocampus in a porcine model of acquired hydrocephalus
(2023) Experimental Neurology, 363, art. no. 114354, . 

Garcia-Bonilla, M.^a , Nair, A.^a , Moore, J.^a , Castaneyra-Ruiz, L.^b , Zwick, S.H.^a , Dilger, R.N.^c , Fleming, S.A.^c d , Golden, R.K.^c , Talcott, M.R.^a e , Isaacs, A.M.^f , Limbrick, D.D., Jr^a , McAllister, J.P., II^a

^a Department of Neurosurgery, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States
^b CHOC Children’s Research Institute, 1201 W. La Veta Avenue, Orange, CA 92868, United States
^c Neuroscience Program, Department of Animal Sciences, University of Illinois, Urbana-Champaign, IL 61801, United States
^d Traverse Science, Champaign, IL 61801, United States
^e AbbVie, Inc., North Chicago, IL 60064, United States
^f Department of Neurological Surgery, Vanderbilt, University Medical Center, Nashville, TN 37232, United States

Abstract
Background: Hydrocephalus is a neurological disease with an incidence of 0.3–0.7 per 1000 live births in the United States. Ventriculomegaly, periventricular white matter alterations, inflammation, and gliosis are among the neuropathologies associated with this disease. We hypothesized that hippocampus structure and subgranular zone neurogenesis are altered in untreated hydrocephalus and correlate with recognition memory deficits. Methods: Hydrocephalus was induced by intracisternal kaolin injections in domestic juvenile pigs (43.6 ± 9.8 days). Age-matched sham controls received similar saline injections. MRI was performed to measure ventricular volume, and/or hippocampal and perirhinal sizes at 14 ± 4 days and 36 ± 8 days post-induction. Recognition memory was assessed one week before and after kaolin induction. Histology and immunohistochemistry in the hippocampus were performed at sacrifice. Results: The hippocampal width and the perirhinal cortex thickness were decreased (p < 0.05) in hydrocephalic pigs 14 ± 4 days post-induction. At sacrifice (36 ± 8 days post-induction), significant expansion of the cerebral ventricles was detected (p = 0.005) in hydrocephalic pigs compared with sham controls. The area of the dorsal hippocampus exhibited a reduction (p = 0.035) of 23.4% in the hydrocephalic pigs at sacrifice. Likewise, in hydrocephalic pigs, the percentages of neuronal precursor cells (doublecortin+ cells) and neurons decreased (p < 0.01) by 32.35%, and 19.74%, respectively, in the subgranular zone of the dorsal hippocampus. The percentage of reactive astrocytes (vimentin+) was increased (p = 0.041) by 48.7%. In contrast, microglial cells were found to decrease (p = 0.014) by 55.74% in the dorsal hippocampus in hydrocephalic pigs. There was no difference in the recognition index, a summative measure of learning and memory, one week before and after the induction of hydrocephalus. Conclusion: In untreated juvenile pigs, acquired hydrocephalus caused morphological alterations, reduced neurogenesis, and increased reactive astrocytosis in the hippocampus and perirhinal cortex. © 2023

Author Keywords
Acquired hydrocephalus;  Hippocampus;  Neurogenesis;  Neuroinflammation;  Perirhinal cortex;  Pig model;  Recognition memory

Funding details
National Institutes of HealthNIH5R21NS111249–02

Document Type: Article
Publication Stage: Final
Source: Scopus

Translingual neurostimulation combined with physical therapy to improve walking and balance in multiple sclerosis (NeuroMSTraLS): Study protocol for a randomized controlled trial
(2023) Contemporary Clinical Trials, 127, art. no. 107142, . 

Ploughman, M.^a , Melam, G.R.^a , Buragadda, S.^a , Lohse, K.R.^b , Clift, F.^c , Stefanelli, M.^c , Levin, M.^d , Donkers, S.J.^e

^a Recovery and Performance Laboratory, Faculty of Medicine, Memorial University of Newfoundland, 100 Forest Rd, St. John’s, NL A1A 1E5, Canada
^b Program in Physical Therapy, Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^c Department of Neurology, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada
^d Department of Neurology and Anatomy and Cell Biology, College of Medicine, University of Saskatchewan, Saskatoon, Canada
^e School of Rehabilitation Science, College of Medicine, University of Saskatchewan, Saskatoon, Canada

Abstract
Introduction: Physical rehabilitation restores lost function and promotes brain plasticity in people with Multiple Sclerosis (MS). Research groups worldwide are testing the therapeutic effects of combining non-invasive neuromodulation with physical therapy (PT) to further improve functional outcomes in neurological disorders but with mixed results. Whether such devices enhance function is not clear. We present the rationale and study design for a randomized controlled trial evaluating if there is additional benefit to the synergistic pairing of translingual neurostimulation (TLNS) with PT to improve walking and balance in MS. Methods and analysis: A parallel group [PT + TLNS or PT + Sham], quadruple-blinded, randomized controlled trial. Participants (N = 52) with gait and balance deficits due to relapsing-remitting or progressive MS, who are between 18 and 70 years of age, will be recruited through patient registries in Newfoundland & Labrador and Saskatchewan, Canada. All participants will receive 14 weeks of PT while wearing either a TLNS or sham device. Dynamic Gait Index is the primary outcome. Secondary outcomes include fast walking speed, subjective ratings of fatigue, MS impact, and quality of life. Outcomes are assessed at baseline (Pre), after 14 weeks of therapy (Post), and 26 weeks (Follow Up). We employ multiple methods to ensure treatment fidelity including activity and device use monitoring. Primary and secondary outcomes will be analyzed using linear mixed-effect models. We will control for baseline score and site to test the effects of Time (Post vs. Follow-Up), Group and the Group x Time interaction as fixed effects. A random intercept of participant will account for the repeated measures in the Time variable. Participants must complete the Post testing to be included in the analysis. Ethics and dissemination: The Human Research Ethics Boards in Newfoundland & Labrador (HREB#2021.085) & Saskatchewan (HREB Bio 2578) approved the protocol. Dissemination avenues include peer-reviewed journals, conferences and patient-oriented communications. © 2023 The Authors

Author Keywords
Balance;  Gait;  Multiple sclerosis;  Neuromodulation;  Physical therapy;  Rehabilitation;  Translingual;  Walking

Document Type: Article
Publication Stage: Final
Source: Scopus

Macaques recognize features in synthetic images derived from ventral stream neurons
(2023) Proceedings of the National Academy of Sciences of the United States of America, 120 (10), pp. e2213034120. 

Mueller, K.N.^a , Carter, M.C.^b , Kansupada, J.A.^b , Ponce, C.R.^a

^a Department of Neurobiology, Harvard Medical School, Boston, MA 02215, United States
^b Department of Neuroscience, Washington University School of MedicineMO 63110

Abstract
Primates can recognize features in virtually all types of images, an ability that still requires a comprehensive computational explanation. One hypothesis is that visual cortex neurons learn patterns from scenes, objects, and textures, and use these patterns to interpolate incoming visual information. We have used machine learning algorithms to instantiate visual patterns stored by neurons-we call these highly activating images prototypes. Prototypes from inferotemporal (IT) neurons often resemble parts of real-world objects, such as monkey faces and body parts, a similarity established via pretrained neural networks [C. R. Ponce et al., Cell177, 999-1009.e10 (2019)] and naïve human participants [A. Bardon, W. Xiao, C. R. Ponce, M. S. Livingstone, G. Kreiman, Proc. Natl. Acad. Sci. U.S.A.119, e2118705119 (2022)]. However, it is not known whether monkeys themselves perceive similarities between neuronal prototypes and real-world objects. Here, we investigated whether monkeys reported similarities between prototypes and real-world objects using a two-alternative forced choice task. We trained the animals to saccade to synthetic images of monkeys, and subsequently tested how they classified prototypes synthesized from IT and primary visual cortex (V1). We found monkeys classified IT prototypes as conspecifics more often than they did random generator images and V1 prototypes, and their choices were partially predicted by convolutional neural networks. Further, we confirmed that monkeys could abstract general shape information from images of real-world objects. Finally, we verified these results with human participants. Our results provide further evidence that prototypes from cortical neurons represent interpretable abstractions from the visual world.

Author Keywords
inferotemporal cortex;  machine learning;  primary visual cortex;  rhesus monkey;  visual recognition

Document Type: Article
Publication Stage: Final
Source: Scopus

Investigating the Role of Rhodopsin F45L Mutation in Mouse Rod Photoreceptor Signaling and Survival
(2023) eNeuro, 10 (3), art. no. ENEURO.0330-22.2023, . 

Poria, D.^a , Kolesnikov, A.V.^a , Lee, T.J.^e , Salom, D.^a , Palczewski, K.^a b c d , Kefalov, V.J.^a c

^a Department of Ophthalmology, Gavin Herbert Eye Institute, University of California, Irvine, CA 92697, United States
^b Department of Chemistry, University of California, Irvine, CA 92697, United States
^c Department of Physiology and Biophysics, University of California, Irvine, CA 92697, United States
^d Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, United States
^e Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, MO 63110, United States

Abstract
Rhodopsin is the critical receptor molecule which enables vertebrate rod photoreceptor cells to detect a single photon of light and initiate a cascade of molecular events leading to visual perception. Recently, it has been suggested that the F45L mutation in the transmembrane helix of rhodopsin disrupts its dimerization in vitro. To determine whether this mutation of rhodopsin affects its signaling properties in vivo, we generated knock-in mice expressing the rhodopsin F45L mutant. We then examined the function of rods in the mutant mice versus wild-type controls, using in vivo electroretinography and transretinal and single cell suction recordings, combined with morphologic analysis and spectrophotometry. Although we did not evaluate the effect of the F45L mutation on the state of dimerization of the rhodopsin in vivo, our results revealed that F45L-mutant mice exhibit normal retinal morphology, normal rod responses as measured both in vivo and ex vivo, and normal rod dark adaptation. We conclude that the F45L mutation does not affect the signaling properties of rho-dopsin in its natural setting. © 2023 Poria et al.

Author Keywords
electroretinogram;  phototransduction;  retinal degeneration;  rhodopsin;  rods

Funding details
National Institutes of HealthNIHR01EY030873, R01EY030912
Research to Prevent BlindnessRPB
University of California, IrvineUCI

Document Type: Article
Publication Stage: Final
Source: Scopus

Silent findings: Examination of asymptomatic demyelination in a pediatric US cohort
(2023) Multiple Sclerosis and Related Disorders, 71, art. no. 104573, . 

Bhise, V.^a , Waltz, M.^b , Casper, T.C.^b , Aaen, G.^c , Benson, L.^d , Chitnis, T.^e , Gorman, M.^f , Goyal, M.S.^g , Wheeler, Y.^h , Lotze, T.ⁱ , Mar, S.^j , Rensel, M.^k , Abrams, A.^l , Rodriguez, M.^m , Rose, J.ⁿ , Schreiner, T.^o , Shukla, N.^p , Waubant, E.^q , Weinstock-Guttman, B.^r , Ness, J.^s , Krupp, L.^t , Mendelt-Tillema, J.^m , U.S. Network of Pediatric Multiple Sclerosis Centers^u

^a Robert Wood Johnson Medical – Rutgers, Pediatrics & Neurology, 89 French Street, Suite 2300, New Brunswick, NJ 08901, United States
^b University of Utah, Pediatrics, United States
^c Loma Linda University, Neurology, United States
^d Massachusetts General Hospital, Partners Pediatric Multiple Sclerosis Center, Neurology, United States
^e Brigham and Women’s Hospital, Neurology, United States
^f Massachusetts General Hospital, Partners Pediatric Multiple Sclerosis Center, United States
^g Washington University in Saint Louis, Neurology, United States
^h The University of Alabama at Birmingham School of Medicine Tuscaloosa, Neurology, United States
ⁱ Texas Childrens Hospital, Child Neurology, United States
^j Washington University St. Louis, Neurology, United States
^k Cleveland Clinic, Neurology, United States
^l Cleveland Clinic Neurological Institute, Pediatric Neurology, United States
^m Mayo Clinic, Neurology, United States
ⁿ University of Utah, Neurology, United States
^o University of Colorado School of Medicine, Neurology, United States
^p Texas Children’s Hospital, Child Neurology, United States
^q University of California San Francisco, Regional Pediatric Multiple Sclerosis Center, United States
^r University at Buffalo – The State University of New York, Pharmaceutical Sciences, United States
^s University of Alabama at Birmingham, Pediatrics, United States
^t New York University Medical Center, Neurology, United States

Abstract
Background and objectives: Limited data is available on children with evidence of silent central nervous system demyelination on MRI. We sought to characterize the population in a US cohort and identify predictors of clinical and radiologic outcomes. Methods: We identified 56 patients such patients who presented with incidental MRI findings suspect for demyelination, enrolled through our US Network of Pediatric Multiple Sclerosis Centers, and conducted a retrospective review of 38 patients with MR images, and examined risk factors for development of first clinical event or new MRI activity. MRI were rated based on published MS and radiologically isolated syndrome (RIS) imaging diagnostic criteria. Results: One-third had a clinical attack and ¾ developed new MRI activity over a mean follow-up time of 3.7 years. Individuals in our cohort shared similar demographics to those with clinically definite pediatric-onset MS. We show that sex, presence of infratentorial lesions, T1 hypointense lesions, juxtacortical lesion count, and callosal lesions were predictors of disease progression. Interestingly, the presence of T1 hypointense and infratentorial lesions typically associated with worse outcomes were instead predictive of delayed disease progression on imaging in subgroup analysis. Additionally, currently utilized diagnostic criteria (both McDonald 2017 and RIS criteria) did not provide statistically significant benefit in risk stratification. Conclusion: Our findings underscore the need for further study to determine if criteria currently used for pediatric patients with purely radiographic evidence of demyelination are sufficient. © 2023 Elsevier B.V.

Author Keywords
Demyelination;  Disease progression;  MRI;  Pediatric multiple sclerosis;  Radiologically isolated syndrome;  Risk factors

Funding details
SI-1808-32326
National Institutes of HealthNIH
U.S. Department of DefenseDOD
National Multiple Sclerosis SocietyNMSS
Roche
Biogen
Patient-Centered Outcomes Research InstitutePCORI
F. Hoffmann-La Roche
Guthy-Jackson Charitable Foundation
Capital Medical UniversityCCMU

Document Type: Article
Publication Stage: Final
Source: Scopus

Associations between daily step count trajectories and clinical outcomes among adults with comorbid obesity and depression
(2023) Mental Health and Physical Activity, 24, art. no. 100512, . 

Kringle, E.A.^a , Tucker, D.^b , Wu, Y.^c , Lv, N.^a , Kannampallil, T.^c , Barve, A.^a , Dosala, S.^a , Wittels, N.^a , Dai, R.^d , Ma, J.^a

^a Department of Medicine, University of Illinois, at Chicago, United States
^b Department of Mathematics, Statistics, and Computer Science, University of Illinois at Chicago, United States
^c Department of Anesthesiology, School of Medicine, Washington University in St. Louis, United States
^d Department of Computer Science and Engineering, McKelvey School of Engineering, Washington University in St. Louis, United States

Abstract
Purpose: To examine the relationship between features of daily measured step count trajectories and clinical outcomes among people with comorbid obesity and depression in the ENGAGE-2 Trial. Methods: This post hoc analysis used data from the ENGAGE-2 trial where adults (n = 106) with comorbid obesity (BMI ≥30.0 or 27.0 if Asian) and depressive symptoms (Patient Health Questionnaire-9 score ≥10) were randomized (2:1) to receive the experimental intervention or usual care. Daily step count trajectories over the first 60 days (Fitbit Alta HR) were characterized using functional principal component analyses. 7-day and 30-day trajectories were also explored. Functional principal component scores that described features of step count trajectories were entered into linear mixed models to predict weight (kg), depression (Symptom Checklist-20), and anxiety (Generalized Anxiety Disorder Questionnaire-7) at 2-months (2M) and 6-months (6M). Results: Features of 60-day step count trajectories were interpreted as overall sustained high, continuous decline, and disrupted decline. Overall sustained high step count was associated with low anxiety (2M, β = −0.78, p <.05; 6M, β = −0.80, p <.05) and low depressive symptoms (6M, β = −0.15, p <.05). Continuous decline in step count was associated with high weight (2M, β = 0.58, p <.05). Disrupted decline was not associated with clinical outcomes at 2M or 6M. Features of 30-day step count trajectories were also associated with weight (2M, 6M), depression (6M), and anxiety (2M, 6M); Features of 7-day step count trajectories were not associated with weight, depression, or anxiety at 2M or 6M. Conclusions: Features of step count trajectories identified using functional principal component analysis were associated with depression, anxiety, and weight outcomes among adults with comorbid obesity and depression. Functional principal component analysis may be a useful analytic method that leverages daily measured physical activity levels to allow for precise tailoring of future behavioral interventions. © 2023 Elsevier Ltd

Author Keywords
Activity;  Activity tracker;  Anxiety;  Body weight;  Physical activity

Funding details
National Institutes of HealthNIHK23 HL159240, R61 MH119237, T32 HL134634, UH3HL132368
National Institute of Mental HealthNIMH
National Heart, Lung, and Blood InstituteNHLBI

Document Type: Article
Publication Stage: Final
Source: Scopus

Radiomics-Derived Brain Age Predicts Functional Outcome after Acute Ischemic Stroke
(2023) Neurology, 100 (8), pp. E822-E833. 

Bretzner, M.^a , Bonkhoff, A.K.^a , Schirmer, M.D.^a , Hong, S.^a , Dalca, A.^a b f , Donahue, K.^a , Giese, A.-K.^a , Etherton, M.R.^a , Rist, P.M.^a , Nardin, M.^a , Regenhardt, R.W.^a , Leclerc, X.^s t , Lopes, R.^d , Gautherot, M.^e , Wang, C.^f , Benavente, O.R.^g , Cole, J.W.^h , Donatti, A.ⁱ , Griessenauer, C.^j k , Heitsch, L.^l , Holmegaard, L.^m o p , Jood, K.^m , Jimenez-Conde, J.ⁿ , Kittner, S.J.ⁿ , Lemmens, R.^m , Levi, C.R.^y , McArdle, P.F.^u v x , McDonough, C.W.^w , Meschia, J.F.^u , Phuah, C.-L.^m , Rolfs, A.^z , Ropele, S.^aa , Rosand, J.^c , Roquer, J.^ac , Rundek, T.^ab , Sacco, R.L.^o , Schmidt, R.^aa , Sharma, P.^z , Slowik, A.^ad , Sousa, A.ⁱ , Stanne, T.M.^q , Strbian, D.^r , Tatlisumak, T.^ae , Thijs, V.^af , Vagal, A.^ag , Wasselius, J.^ah , Woo, D.^ai , Wu, O.^b , Zand, R.^k , Worrall, B.B.^aj , Maguire, J.^ak , Lindgren, A.G.^al , Jern, C.^{am an ao ap} , Golland, P.^f , Kuchcinski, G.^a , Rost, N.S.^a

^a From the J. Philip Kistler Stroke Research Center, United States
^b A.A. Martinos Center for Biomedical Imaging, United States
^c Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Harvard Medical School, Boston, United States
^d Lille Neuroscience and Cognition, France
^e Inserm, CHU Lille, U1172 and Institut Pasteur de Lille, CNRS, Inserm, CHU Lille, US 41-UMS 2014 PLBS, Lille University, France
^f Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, United Kingdom
^g Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
^h Department of Medicine, Division of Neurology, University of British Columbia, Vancouver, Canada
ⁱ Department of Neurology, University of Maryland School of Medicine and Veterans Affairs Maryland Health Care System, Baltimore, MD, United States
^j School of Medical Sciences, University of Campinas and the Brazilian Institute of Neuroscience and Neurotechnology, Campinas, São Paulo, Brazil
^k Departments of Neurosurgery and Neurology, Geisinger, Danville, PA, United States
^l Department of Neurosurgery, Christian Doppler Klinik, Paracelsus Medical University, Salzburg, Austria
^m Division of Emergency Medicine, Washington University School of Medicine, St. Louis, United States
ⁿ Department of Neurology Washington University School of Medicine and Barnes-Jewish Hospital, St. Louis, MO, United States
^o Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Sweden
^p Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden
^q Department of Neurology, Neurovascular Research Group (NEUVAS), IMIM-Hospital Del Mar (Institut Hospital Del Mar d’Investigacions m’Ediques), Universitat Autonoma de Barcelona, Spain
^r Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven-University of Leuven, Belgium
^s Department of Neurology, Laboratory of Neurobiology, VIB Vesalius Research Center, University Hospitals Leuven, Belgium
^t School of Medicine and Public Health, University of NewcastleNSW, Australia
^u Department of Neurology, John Hunter Hospital, Newcastle, NSW, Australia
^v Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, United States
^w Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, University of Florida, Gainesville, United States
^x Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
^y Klinik und Poliklinik für Neurologie, Universitätsmedizin Rostock, Germany
^z Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Austria
^aa Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States
^ab Broad Institute, Cambridge, MA, United States
^ac Department of Neurology and Evelyn F. McKnight Brain Institute, Miller School of Medicine, University of MiamiFL, United States
^ad Institute of Cardiovascular Research, Royal Holloway University of London (ICR2UL), UK St Peter’s and Ashford Hospitals, Egham, United Kingdom
^ae Department of Neurology, Jagiellonian University Medical College, Krakow, Poland
^af Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Helsinki University Central Hospital, Finland
^ag Stroke Division, Florey Institute of Neuroscience and Mental Health, Heidelberg, Germany
^ah Department of Neurology, Austin Health, Heidelberg, Australia
^ai Departments of Radiology and Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, OH, United States
^aj Department of Clinical Sciences Lund, Radiology and Neurology, Lund University, Sweden
^ak Department of Radiology, Neuroradiology, Skåne University Hospital, Malmö, Sweden
^al Departments of Neurology and Public Health Sciences, University of Virginia, Charlottesville, VA, United States
^am University of Technology Sydney, Australia
^an Section of Neurology, Skåne University Hospital, Lund, Sweden
^ao Department of Laboratory Medicine, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Sweden
^ap Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden

Abstract
Background and ObjectivesWhile chronological age is one of the most influential determinants of poststroke outcomes, little is known of the impact of neuroimaging-derived biological “brain age.”We hypothesized that radiomics analyses of T2-FLAIR images texture would provide brain age estimates and that advanced brain age of patients with stroke will be associated with cardiovascular risk factors and worse functional outcomes.MethodsWe extracted radiomics from T2-FLAIR images acquired during acute stroke clinical evaluation. Brain age was determined from brain parenchyma radiomics using an ElasticNet linear regression model. Subsequently, relative brain age (RBA), which expresses brain age in comparison with chronological age-matched peers, was estimated. Finally, we built a linear regression model of RBA using clinical cardiovascular characteristics as inputs and a logistic regression model of favorable functional outcomes taking RBA as input.ResultsWe reviewed 4,163 patients from a large multisite ischemic stroke cohort (mean age = 62.8 years, 42.0% female patients). T2-FLAIR radiomics predicted chronological ages (mean absolute error = 6.9 years, r = 0.81). After adjustment for covariates, RBA was higher and therefore described older-Appearing brains in patients with hypertension, diabetes mellitus, a history of smoking, and a history of a prior stroke. In multivariate analyses, age, RBA, NIHSS, and a history of prior stroke were all significantly associated with functional outcome (respective adjusted odds ratios: 0.58, 0.76, 0.48, 0.55; all p-values < 0.001). Moreover, the negative effect of RBA on outcome was especially pronounced in minor strokes.DiscussionT2-FLAIR radiomics can be used to predict brain age and derive RBA. Older-Appearing brains, characterized by a higher RBA, reflect cardiovascular risk factor accumulation and are linked to worse outcomes after stroke. © American Academy of Neurology.

Funding details
20190203, ALFGBG-720081
National Institutes of HealthNIHK01 HL128791
National Institute of Neurological Disorders and StrokeNINDSR01NS086905
National Institute of Biomedical Imaging and BioengineeringNIBIBNAC P41EB015902
Medtronic
American Academy of NeurologyAAN
Helsingin ja Uudenmaan SairaanhoitopiiriHUS
Hjärt-Lungfonden
Sahlgrenska UniversitetssjukhusetSU
Göteborgs Universitet
Sigrid Juséliuksen Säätiö
Société Française de RadiologieSFR
Skånes universitetssjukhusSUS
Forschungsfabrik Mikroelektronik DeutschlandFMD

Document Type: Article
Publication Stage: Final
Source: Scopus

Aging impacts memory for perceptual, but not narrative, event details
(2023) Learning & Memory (Cold Spring Harbor, N.Y.), 30 (2), pp. 48-54. 

Delarazan, A.I.^a b , Ranganath, C.^a b , Reagh, Z.M.^a b

^a Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO 63130, United States
^b Center for Neuroscience, University of California, Davis, CA 95618, United States

Abstract
Memory is well known to decline over the course of healthy aging. However, memory is not a monolith and draws from different kinds of representations. Historically, much of our understanding of age-related memory decline stems from recognition of isolated studied items. In contrast, real-life events are often remembered as narratives, and this kind of information is generally missed in typical recognition memory studies. Here, we designed a task to tax mnemonic discrimination of event details, directly contrasting perceptual and narrative memory. Older and younger adults watched an episode of a television show and later completed an old/new recognition test featuring targets, novel foils, and similar lures in narrative and perceptual domains. While we observed no age-related differences on basic recognition of repeated targets and novel foils, older adults showed a deficit in correctly rejecting perceptual, but not narrative, lures. These findings provide insight into the vulnerability of different memory domains in aging and may be useful in characterizing individuals at risk for pathological cognitive decline. © 2023 Delarazan et al.; Published by Cold Spring Harbor Laboratory Press.

Document Type: Article
Publication Stage: Final
Source: Scopus

Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy
(2023) Nature, . Cited 1 time.

Chen, X.^a , Firulyova, M.^b , Manis, M.^a , Herz, J.^c d , Smirnov, I.^c d , Aladyeva, E.^c , Wang, C.^a , Bao, X.^a , Finn, M.B.^a , Hu, H.^a , Shchukina, I.^c , Kim, M.W.^c d , Yuede, C.M.^a , Kipnis, J.^a c d , Artyomov, M.N.^c , Ulrich, J.D.^a , Holtzman, D.M.^a d

^a Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St Louis, MO, United States
^b Almazov National Medical Research Centre, St Petersburg, Russian Federation
^c Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, United States
^d Center for Brain Immunology and Glia (BIG), Washington University School of Medicine, St Louis, MO, United States

Abstract
Extracellular deposition of amyloid-β as neuritic plaques and intracellular accumulation of hyperphosphorylated, aggregated tau as neurofibrillary tangles are two of the characteristic hallmarks of Alzheimer’s disease1,2. The regional progression of brain atrophy in Alzheimer’s disease highly correlates with tau accumulation but not amyloid deposition3–5, and the mechanisms of tau-mediated neurodegeneration remain elusive. Innate immune responses represent a common pathway for the initiation and progression of some neurodegenerative diseases. So far, little is known about the extent or role of the adaptive immune response and its interaction with the innate immune response in the presence of amyloid-β or tau pathology6. Here we systematically compared the immunological milieux in the brain of mice with amyloid deposition or tau aggregation and neurodegeneration. We found that mice with tauopathy but not those with amyloid deposition developed a unique innate and adaptive immune response and that depletion of microglia or T cells blocked tau-mediated neurodegeneration. Numbers of T cells, especially those of cytotoxic T cells, were markedly increased in areas with tau pathology in mice with tauopathy and in the Alzheimer’s disease brain. T cell numbers correlated with the extent of neuronal loss, and the cells dynamically transformed their cellular characteristics from activated to exhausted states along with unique TCR clonal expansion. Inhibition of interferon-γ and PDCD1 signalling both significantly ameliorated brain atrophy. Our results thus reveal a tauopathy- and neurodegeneration-related immune hub involving activated microglia and T cell responses, which could serve as therapeutic targets for preventing neurodegeneration in Alzheimer’s disease and primary tauopathies. © 2023, The Author(s), under exclusive licence to Springer Nature Limited.

Funding details
National Institutes of HealthNIHNS090934
Foundation for Barnes-Jewish HospitalFBJH3770, 4642
JPB FoundationJPBF
Cure Alzheimer’s FundCAF
Rainwater Charitable FoundationRCF
St. Louis Children’s HospitalSLCHCDI-CORE-2015-505, CDI-CORE-2019-813
Ministry of Education and Science of the Russian FederationMinobrnauka075-15-2022-301

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

Health literacy correlates with abbreviated full-scale IQ in adolescent and young adults with sickle cell disease
(2023) Pediatric Blood and Cancer, . 

Bhatt, N.^a , Calhoun, C.^b , Longoria, J.^c , Nwosu, C.^a , Howell, K.E.^d , Varughese, T.^e , Kang, G.^f , Jacola, L.M.^c , Hankins, J.S.^a , King, A.^e

^a Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN, United States
^b Department of Internal Medicine, Section of Hematology, Yale University School of Medicine, New Haven, CT, United States
^c Department of Psychology, St. Jude Children’s Research Hospital, Memphis, TN, United States
^d Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, TN, United States
^e Program in Occupational Therapy and Departments of Pediatrics and Medicine, Washington University, St. Louis, MO, United States
^f Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, United States

Abstract
Introduction: Sickle cell disease (SCD) is a chronic condition with progressive neurocognitive deficits. Health literacy (HL) is essential during adolescence and young adulthood, as the transition to adult care requires healthcare decisions. HL is known to be low in SCD; however, relation between general cognitive ability and HL has not been investigated. Methods: This cross-sectional study included adolescent and yound adults (AYAs) with SCD from two institutions. Logistic regression measured the association between HL, measured by the Newest Vital Sign tool, and general cognitive ability, measured with abbreviated full-scale intelligence quotient (FSIQ) on the Wechsler Abbreviated Scale of Intelligence. Results: Our cohort contained 93 participants at two sites: 47 (51%) at Memphis, TN and 46 (49%) at St. Louis, MO, ranging from ages 15–45 years (mean = 21 years) and with a majority (70%) possessing a high school education or greater. Only 40/93 participants (43%) had adequate HL. Lower abbreviated FSIQ (p <.0001) and younger age at assessment (p =.0003) were associated with inadequate HL. For every standard score point increase in abbreviated FSIQ, the odds of having adequate HL compared to limited or possibly limited HL increase by 1.142 (95% confidence interval [CI]: 1.019–1.322) and 1.116 (95% CI: 1.045–1.209), respectively, after adjusting for age, institution, income, and educational attainment. Conclusions: Understanding and addressing HL is imperative in improving self-management and health outcomes. Among AYA with SCD, low HL was prevalent and influenced by abbreviated FSIQ. Routine screening for neurocognitive deficits and HL should be performed to guide development of interventions to adapt to the HL of AYA with SCD. © 2023 Wiley Periodicals LLC.

Author Keywords
health literacy;  neurocognitive functioning;  sickle cell anemia;  stroke

Funding details
American Society of HematologyASH
St. Jude Children’s Research Hospital5U01HL133994
University of WashingtonUW

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

Multiomic analyses implicate a neurodevelopmental program in the pathogenesis of cerebral arachnoid cysts
(2023) Nature Medicine, . 

Kundishora, A.J.^a , Allington, G.^b c , McGee, S.^d , Mekbib, K.Y.^a c , Gainullin, V.^d , Timberlake, A.T.^e , Nelson-Williams, C.^f , Kiziltug, E.^a , Smith, H.^a c , Ocken, J.^a , Shohfi, J.^a , Allocco, A.^a , Duy, P.Q.^a , Elsamadicy, A.A.^a , Dong, W.^g , Zhao, S.^h , Wang, Y.-C.^h , Qureshi, H.M.^a , DiLuna, M.L.^a , Mane, S.^h i , Tikhonova, I.R.^j , Fu, P.-Y.^h , Castaldi, C.ⁱ , López-Giráldez, F.ⁱ , Knight, J.R.ⁱ , Furey, C.G.^a , Carter, B.S.^c , Haider, S.^k , Moreno-De-Luca, A.^l , Alper, S.L.^m n , Gunel, M.^a , Millan, F.^d , Lifton, R.P.^g , Torene, R.I.^d , Jin, S.C.^h o , Kahle, K.T.^a c p q

^a Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, United States
^b Department of Pathology, Yale University School of Medicine, New Haven, CT, United States
^c Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, United States
^d GeneDx, Gaithersburg, MD, United States
^e Hansjörg Wyss Department of Plastic Surgery, New York University Langone Medical Center, New York, NY, United States
^f Department of Genetics, Yale University School of Medicine, New Haven, CT, United States
^g Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, United States
^h Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
ⁱ Yale Center for Genomic Analysis, Yale University, West Haven, CT, United States
^j School of Pharmacy, Queen’s University Belfast, Belfast, United Kingdom
^k School of Pharmacy, University College London, London, United Kingdom
^l Department of Radiology, Autism and Developmental Medicine Institute, Genomic Medicine Institute, Geisinger, Danville, PA, United States
^m Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
ⁿ Department of Medicine, Harvard Medical School, Boston, MA, United States
^o Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^p Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, United States
^q Broad Institute of MIT and Harvard, Cambridge, MA, United States

Abstract
Cerebral arachnoid cysts (ACs) are one of the most common and poorly understood types of developmental brain lesion. To begin to elucidate AC pathogenesis, we performed an integrated analysis of 617 patient–parent (trio) exomes, 152,898 human brain and mouse meningeal single-cell RNA sequencing transcriptomes and natural language processing data of patient medical records. We found that damaging de novo variants (DNVs) were highly enriched in patients with ACs compared with healthy individuals (P = 1.57 × 10−33). Seven genes harbored an exome-wide significant DNV burden. AC-associated genes were enriched for chromatin modifiers and converged in midgestational transcription networks essential for neural and meningeal development. Unsupervised clustering of patient phenotypes identified four AC subtypes and clinical severity correlated with the presence of a damaging DNV. These data provide insights into the coordinated regulation of brain and meningeal development and implicate epigenomic dysregulation due to DNVs in AC pathogenesis. Our results provide a preliminary indication that, in the appropriate clinical context, ACs may be considered radiographic harbingers of neurodevelopmental pathology warranting genetic testing and neurobehavioral follow-up. These data highlight the utility of a systems-level, multiomics approach to elucidate sporadic structural brain disease. © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding details
National Institutes of HealthNIH5U54HG006504, K12 228168, R01 NS109358, R01 NS111029-01A1
Howard Hughes Medical InstituteHHMI
National Institute of General Medical SciencesNIGMST32GM007205
National Center for Advancing Translational SciencesNCATSR00HL143036, TL1 TR001864
Children’s Discovery InstituteCDICDI-FR-2021-926
Rudi Schulte Research InstituteRSRI

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