List of publications for the week of June 7, 2021
Electronic clinical decision support for children with minor head trauma and intracranial injuries: a sociotechnical analysis
(2021) BMC Medical Informatics and Decision Making, 21 (1), art. no. 161, .
Greenberg, J.K.a , Otun, A.a , Nasraddin, A.b , Brownson, R.C.b , Kuppermann, N.d , Limbrick, D.D.a , Yen, P.-Y.c , Foraker, R.E.c
a Departments of Neurological Surgery, Washington University School of Medicine, 660 S. Euclid Ave., Box 8057, St. Louis, MO 63110, United States
b Brown School of Social Work, Washington University School of Medicine, St. Louis, MO, United States
c Institute for Informatics, Washington University School of Medicine, St. Louis, MO, United States
d Department of Emergency Medicine, University of California Davis, Davis, CA, United States
Abstract
Background: Current management of children with minor head trauma (MHT) and intracranial injuries is not evidence-based and may place some children at risk of harm. Evidence-based electronic clinical decision support (CDS) for management of these children may improve patient safety and decrease resource use. To guide these efforts, we evaluated the sociotechnical environment impacting the implementation of electronic CDS, including workflow and communication, institutional culture, and hardware and software infrastructure, among other factors. Methods: Between March and May, 2020 semi-structured qualitative focus group interviews were conducted to identify sociotechnical influences on CDS implementation. Physicians from neurosurgery, emergency medicine, critical care, and pediatric general surgery were included, along with information technology specialists. Participants were recruited from nine health centers in the United States. Focus group transcripts were coded and analyzed using thematic analysis. The final themes were then cross-referenced with previously defined sociotechnical dimensions. Results: We included 28 physicians and four information technology specialists in seven focus groups (median five participants per group). Five physicians were trainees and 10 had administrative leadership positions. Through inductive thematic analysis, we identified five primary themes: (1) clinical impact; (2) stakeholders and users; (3) tool content; (4) clinical practice integration; and (5) post-implementation evaluation measures. Participants generally supported using CDS to determine an appropriate level-of-care for these children. However, some had mixed feelings regarding how the tool could best be used by different specialties (e.g. use by neurosurgeons versus non-neurosurgeons). Feedback from the interviews helped refine the tool content and also highlighted potential technical and workflow barriers to address prior to implementation. Conclusions: We identified key factors impacting the implementation of electronic CDS for children with MHT and intracranial injuries. These results have informed our implementation strategy and may also serve as a template for future efforts to implement health information technology in a multidisciplinary, emergency setting. © 2021, The Author(s).
Author Keywords
Electronic clinical decision support; Head trauma; Health information technology; Implementation science; Sociotechnical analysis; Traumatic brain injury
Funding details
Agency for Healthcare Research and QualityAHRQ
Thrasher Research FundTRF
Document Type: Article
Publication Stage: Final
Source: Scopus
Localizing focal brain injury via EEG spectral variance
(2021) Biomedical Signal Processing and Control, 68, art. no. 102746, .
Khanmohammadi, S.a b , Laurido-Soto, O.b , Eisenman, L.N.b , Kummer, T.T.b , Ching, S.a c d
a Department of Electrical & Systems Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
d Division of Biology and Biomedical Science, Washington University in St. Louis, St. Louis, MO 63130, United States
Abstract
In this study, we consider the problem of localizing focal brain injuries from surface electroencephalogram (EEG) recordings. To this end, we introduce a new analysis technique termed frequency-based intrinsic network dynamic reactivity (FINDR), which quantifies the extent to which different brain regions (defined in EEG channel space) are responsive to each other in terms of their frequency-domain activity. The technique generalizes the idea of EEG reactivity, a measure of how well EEG signals react/respond to exogenous stimuli. In the present work we generalize this notion to endogenous ‘stimuli,’ defined as short-time window frequency domain motifs that are most predominant on a per channel basis. For each of these predominant motifs, we quantify the variance of the activity in all other channels as a measure of ‘intrinsic reactivity’, under the hypothesis that channels proximal to injured regions will be systematically disassociated from other brain areas. We use this method as a front-end to a neural network classifier to predict injury location in a cohort of etiologically heterogeneous comatose patients. We achieve a 0.6 correlation between the predicted injury location and the actual brain injury. These results suggest a possibility of precise localization of brain injury using EEG. © 2021 Elsevier Ltd
Author Keywords
Brain injury; Electroencephalography; Injury location; Spectral variance
Funding details
National Science FoundationNSF1R21-EY027590-01, ECCS 1509342, NSF CMMI 1537015, UL1 TR000448
National Institutes of HealthNIH
Burroughs Wellcome FundBWF
Document Type: Article
Publication Stage: Final
Source: Scopus
Sonothermogenetics for noninvasive and cell-type specific deep brain neuromodulation
(2021) Brain Stimulation, 14 (4), pp. 790-800.
Yang, Y.a , Pacia, C.P.a , Ye, D.b , Zhu, L.a , Baek, H.a , Yue, Y.a , Yuan, J.a , Miller, M.J.c , Cui, J.a , Culver, J.P.a d e , Bruchas, M.R.f , Chen, H.a g
a Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO 63130, United States
b Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, Saint Louis, MO 63130, United States
c Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, United States
d Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO 63110, United States
e Department of Physics, Washington University in St. Louis, Saint Louis, MO 63110, United States
f Department of Anesthesiology and Pain Medicine. Center for Neurobiology of Addiction, Pain, and Emotion. University of Washington, Seattle, WA 98195, United States
g Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO 63108, United States
Abstract
Background: Critical advances in the investigation of brain functions and treatment of brain disorders are hindered by our inability to selectively target neurons in a noninvasive manner in the deep brain. Objective: This study aimed to develop sonothermogenetics for noninvasive, deep-penetrating, and cell-type-specific neuromodulation by combining a thermosensitive ion channel TRPV1 with focused ultrasound (FUS)-induced brief, non-noxious thermal effect. Methods: The sensitivity of TRPV1 to FUS sonication was evaluated in vitro. It was followed by in vivo assessment of sonothermogenetics in the activation of genetically defined neurons in the mouse brain by two-photon calcium imaging. Behavioral response evoked by sonothermogenetic stimulation at a deep brain target was recorded in freely moving mice. Immunohistochemistry staining of ex vivo brain slices was performed to evaluate the safety of FUS sonication. Results: TRPV1 was found to be an ultrasound-sensitive ion channel. FUS sonication at the mouse brain in vivo selectively activated neurons that were genetically modified to express TRPV1. Temporally precise activation of TRPV1-expressing neurons was achieved with its success rate linearly correlated with the peak temperature within the FUS-targeted brain region as measured by in vivo magnetic resonance thermometry. FUS stimulation of TRPV1-expressing neurons at the striatum repeatedly evoked locomotor behavior in freely moving mice. FUS sonication was confirmed to be safe based on inspection of neuronal integrity, inflammation, and apoptosis markers. Conclusions: This noninvasive and cell-type-specific neuromodulation approach with the capability to stimulate deep brain has the promise to advance the study of the intact nervous system and uncover new ways to treat neurological disorders. © 2021 The Author(s)
Author Keywords
Calcium imaging; Focused ultrasound; Ion channel; Neuromodulation; Sonothermogenetics
Funding details
National Institutes of HealthNIHR01MH116981
National Institute of Biomedical Imaging and BioengineeringNIBIBR01EB027223, R01EB030102
University of WashingtonUW
Document Type: Article
Publication Stage: Final
Source: Scopus
Temporal and spectral unmixing of photoacoustic signals by deep learning
(2021) Optics Letters, 46 (11), pp. 2690-2693.
Zhou, Y., Zhong, F., Hu, S.
Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
Abstract
Improving the imaging speed of multi-parametric photoacoustic microscopy (PAM) is essential to leveraging its impact in biomedicine.However, to avoid temporal overlap, the A-line rate is limited by the acoustic speed in biological tissues to a few megahertz.Moreover, to achieve high-speed PAMof the oxygen saturation of hemoglobin, the stimulated Raman scattering effect in optical fibers has been widely used to generate 558 nm from a commercial 532 nm laser for dual-wavelength excitation. However, the fiber length for effective wavelength conversion is typically short, corresponding to a small time delay that leads to a significant overlap of the A-lines acquired at the two wavelengths. Increasing the fiber length extends the time interval but limits the pulse energy at 558 nm. In this Letter, we report a conditional generative adversarial network-based approach that enables temporal unmixing of photoacoustic A-line signals with an interval as short as ~38 ns, breaking the physical limit on the A-line rate. Moreover, this deep learning approach allows the use of multi-spectral laser pulses for PAM excitation, addressing the insufficient energy of monochromatic laser pulses. This technique lays the foundation for ultrahigh-speed multi-parametric PAM. © 2021 Optical Society of America.
Funding details
National Science FoundationNSF2023988
National Institutes of HealthNIHNS099261
Document Type: Article
Publication Stage: Final
Source: Scopus
Simultaneous imaging of amyloid deposition and cerebrovascular function using dual-contrast photoacoustic microscopy
(2021) Optics Letters, 46 (11), pp. 2561-2564.
Zhou, Y.a , Zhong, F.a , Yan, P.b , Lee, J.-M.a b , Hu, S.a
a Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Pathological aggregation of Aβ peptides results in the deposition of amyloid in the brain parenchyma (senile plaques in Alzheimer’s disease [AD]) and around cerebral microvessels (cerebral amyloid angiopathy [CAA]). Our current understanding of the amyloid-induced microvascular changes has been limited to the structure and hemodynamics—leaving the oxygen-metabolic aspect unattended. In this Letter, we report a dual-contrast photoacoustic microscopy (PAM) technique, which integrates the molecular contrast of dichroism PAM and the physiological contrast of multi-parametric PAM for simultaneous, intravital imaging of amyloid deposition and cerebrovascular function in a mouse model that develops AD and CAA. This technique opens up new opportunities to study the spatiotemporal interplay between amyloid deposition and vascular-metabolic dysfunction in AD and CAA. © 2021 Optical Society of America
Document Type: Article
Publication Stage: Final
Source: Scopus
Prospective Quantification of CSF Biomarkers in Antibody-Mediated Encephalitis
(2021) Neurology, 96 (20), pp. e2546-e2557.
Day, G.S., Yarbrough, M.Y., Körtvelyessy, P., Prüss, H., Bucelli, R.C., Fritzler, M.J., Mason, W., Tang-Wai, D.F., Steriade, C., Hébert, J., Henson, R.L., Herries, E.M., Ladenson, J.H., Lopez-Chiriboga, A.S., Graff-Radford, N.R., Morris, J.C., Fagan, A.
From the Department of Neurology (G.S.D., A.S.L.-C., N.R.G.-R.), Mayo Clinic, Jacksonville, FL; Departments of Pathology and Immunology (M.Y.Y., E.M.H., J.H.L.) and Neurology (R.C.B., R.L.H., E.M.H., J.H.L., J.C.M., A.F.) and The Charles F. and Joanne Knight Alzheimer Disease Research Center (R.L.H., J.C.M., A.F.), Washington University School of Medicine, St. Louis, MO; Department of Neurology (P.M.D.K.), University of Magdeburg; Department of Neurology and Experimental Neurology (P.M.D.K., H.P.) Charité, Universitätmedizin Berlin, Germany; Department of Medicine (M.J.F.), Cumming School of Medicine, University of Calgary; Department of Medicine (W.M., D.F.T.-W., J.H.), Division of Neurology, University of Toronto, Canada; and NYU Langone Comprehensive Epilepsy Center (C.S.), NYU Langone Health, New York, NY
Abstract
OBJECTIVE: To determine whether neuronal and neuroaxonal injury, neuroinflammation, and synaptic dysfunction associate with clinical course and outcomes in antibody-mediated encephalitis (AME), we measured biomarkers of these processes in CSF from patients presenting with AME and cognitively normal individuals. METHODS: Biomarkers of neuronal (total tau, VILIP-1) and neuroaxonal damage (neurofilament light chain [NfL]), inflammation (YKL-40), and synaptic function (neurogranin, SNAP-25) were measured in CSF obtained from 45 patients at the time of diagnosis of NMDA receptor (n = 34) or LGI1/CASPR2 (n = 11) AME and 39 age- and sex-similar cognitively normal individuals. The association between biomarkers and modified Rankin Scale (mRS) scores were evaluated in a subset (n = 20) of longitudinally followed patients. RESULTS: Biomarkers of neuroaxonal injury (NfL) and neuroinflammation (YKL-40) were elevated in AME cases at presentation, whereas markers of neuronal injury and synaptic function were stable (total tau) or decreased (VILIP-1, SNAP-25, neurogranin). The log-transformed ratio of YKL-40/SNAP-25 optimally discriminated patients from cognitively normal individuals (area under the receiver operating characteristic curve 0.99; 95% confidence interval 0.97, >0.99). Younger age (ρ = -0.56; p = 0.01), lower VILIP-1 (ρ = -0.60; p < 0.01) and SNAP-25 (ρ = -0.54; p = 0.01), and higher log10(YKL-40/SNAP-25) (ρ = 0.48; p = 0.04) associated with greater disease severity (higher mRS score) in prospectively followed patients. Higher YKL-40 (ρ = 0.60; p = 0.02) and neurogranin (ρ = 0.55; p = 0.03) at presentation were associated with higher mRS scores 12 months following hospital discharge. CONCLUSIONS: CSF biomarkers suggest that neuronal integrity is acutely maintained in AME, despite neuroaxonal compromise. Low levels of biomarkers of synaptic function may reflect antibody-mediated internalization of cell surface receptors and may represent an acute correlate of antibody-mediated synaptic dysfunction, with the potential to inform disease severity and outcomes. © 2021 American Academy of Neurology.
Document Type: Article
Publication Stage: Final
Source: Scopus
Aging-associated deficit in CCR7 is linked to worsened glymphatic function, cognition, neuroinflammation, and β-amyloid pathology
(2021) Science Advances, 7 (21), art. no. eabe4601, .
Mesquita, S.D.a , Herz, J.b c , Wall, M.a , Dykstra, T.b c , de Lima, K.A.b c , Norris, G.T.d , Dabhi, N.a , Kennedy, T.a , Baker, W.a , Kipnis, J.a b c
a Department of Neuroscience, Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, United States
b Center for Brain Immunology and Glia (BIG), Washington University in St. Louis, St. Louis, MO, United States
c Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
d Department of Immunology, University of Washington, Seattle, WA 98109, United States
Abstract
Aging leads to a progressive deterioration of meningeal lymphatics and peripheral immunity, which may accelerate cognitive decline. We hypothesized that an age-related reduction in C-C chemokine receptor type 7 (CCR7)–dependent egress of immune cells through the lymphatic vasculature mediates some aspects of brain aging and potentially exacerbates cognitive decline and Alzheimer’s disease–like brain β-amyloid (Aβ) pathology. We report a reduction in CCR7 expression by meningeal T cells in old mice that is linked to increased effector and regulatory T cells. Hematopoietic CCR7 deficiency mimicked the aging-associated changes in meningeal T cells and led to reduced glymphatic influx and cognitive impairment. Deletion of CCR7 in 5xFAD transgenic mice resulted in deleterious neurovascular and microglial activation, along with increased Aβ deposition in the brain. Treating old mice with anti-CD25 antibodies alleviated the exacerbated meningeal regulatory T cell response and improved cognitive function, highlighting the therapeutic potential of modulating meningeal immunity to fine-tune brain function in aging and in neurodegenerative diseases. © 2021 The Authors, some rights reserved;
Document Type: Article
Publication Stage: Final
Source: Scopus
Sex-related Differences in Tau Positron Emission Tomography (PET) and the Effects of Hormone Therapy (HT)
(2021) Alzheimer disease and associated disorders, 35 (2), pp. 164-168. Cited 2 times.
Wisch, J.K.a , Meeker, K.L.a , Gordon, B.A.a , Flores, S.a , Dincer, A.a , Grant, E.A.b c , Benzinger, T.L.c d , Morris, J.C.a c , Ances, B.M.a c d
a Departments of Neurology
b Biostatistics
c Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO
d Radiology, Washington University in St. Louis
Abstract
IMPORTANCE: Female sex is a major risk factor for late-onset Alzheimer disease (AD), and sex hormones have been implicated as a possible protective factor. Neuroimaging studies that evaluated the effects of sex hormones on brain integrity have primarily emphasized neurodegenerative measures rather than amyloid and tau burden. OBJECTIVE: We compared cortical amyloid and regional tau positron emission tomography (PET) deposition between cognitively normal males and females. We also compared preclinical AD pathology between females who have and have not used hormone therapy (HT). Finally, we compared the effects of amyloid and tau pathology on cognition, testing for both sex and HT effects. DESIGN, SETTING, AND PARTICIPANTS: We analyzed amyloid, tau, and cognition in a cognitively normal cross-sectional cohort of older individuals (n=148) followed at the Knight Alzheimer Disease Research Center. Amyloid and tau PET, medication history, and neuropsychological testing were obtained for each participant. RESULTS: Within cognitively normal individuals, there was no difference in amyloid burden by sex. Whether or not we controlled for amyloid burden, female participants had significantly higher tau PET levels than males in multiple regions, including the rostral middle frontal and superior and middle temporal regions. HT accounted for a small reduction in tau PET; however, males still had substantially lower tau PET compared with females. Amyloid PET and tau PET burden were negatively associated with cognitive performance, although increasing amyloid PET did not have a deleterious effect on cognitive performance for women with a history of HT. CONCLUSIONS AND RELEVANCE: Regional sex-related differences in tau PET burden may contribute to the disparities in AD prevalence between males and females. The observed decreases tau PET burden in HT users has important implications for clinical practice and trials and deserves future consideration in longitudinal studies. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
Document Type: Article
Publication Stage: Final
Source: Scopus
Undetected Neurodegenerative Disease Biases Estimates of Cognitive Change in Older Adults
(2021) Psychological Science, .
Harrington, K.D.a b c , Aschenbrenner, A.J.d e , Maruff, P.a f , Masters, C.L.a , Fagan, A.M.d e g , Benzinger, T.L.S.d h i , Gordon, B.A.d g h , Cruchaga, C.j k , Morris, J.C.d e l m n , Hassenstab, J.d e o
a The Florey Institute, The University of Melbourne, Australia
b Cooperative Research Centre for Mental Health, Parkville, VIC, Australia
c Center for Healthy Aging, The Pennsylvania State University, United States
d Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St. Louis, United States
e Department of Neurology, Washington University in St. Louis, United States
f CogState, Melbourne, VIC, Australia
g Hope Center for Neurological Disorders, Washington University in St. Louis, United States
h Department of Radiology, Washington University in St. Louis, United States
i Department of Neurological Surgery, Washington University in St. Louis, United States
j Department of Psychiatry, Washington University in St. Louis, United States
k Department of Developmental Biology, Washington University in St. Louis, United States
l Department of Pathology and Immunology, Washington University in St. Louis, United States
m Department of Physical Therapy, Washington University in St. Louis, United States
n Department of Occupational Therapy, Washington University in St. Louis, United States
o Department of Psychological & Brain Sciences, Washington University in St. Louis, United States
Abstract
Neurodegenerative disease is highly prevalent among older adults and, if undetected, may obscure estimates of cognitive change among aging samples. Our aim in this study was to determine the nature and magnitude of cognitive change in the absence of common neuropathologic markers of neurodegenerative disease. Cognitively normal older adults (ages 65–89 years, N = 199) were classified as normal or abnormal using neuroimaging and cerebrospinal-fluid biomarkers of β-amyloid, tau, and neurodegeneration. When cognitive change was modeled without accounting for biomarker status, significant decline was evident for semantic memory, processing speed, and working memory. However, after adjusting for biomarker status, we found that the rate of change was attenuated and that the biomarker-normal group demonstrated no decline for any cognitive domain. These results indicate that estimates of cognitive change in otherwise healthy older adults will be biased toward decline when the presence of early neurodegenerative disease is not accounted for. © The Author(s) 2021.
Author Keywords
cognitive aging; memory; neurodegeneration; processing speed; tau; β-amyloid
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
PedsQL Multiple Sclerosis Module Domain and Item Development: Qualitative Methods
(2021) Journal of Child Neurology, .
Gaudioso, C.a , Oo, S.a , Mar, S.a , Hendricks-Ferguson, V.L.b , Newland, P.c , Varni, J.W.d
a Department of Neurology, Division of Pediatric Neurology, Washington University School of Medicine, St Louis, MO, United States
b Trudy Busch Valentine School of Nursing, Saint Louis University, St Louis, MO, United States
c Goldfarb School of Nursing, Barnes Jewish College, St Louis, MO, United States
d Department of Pediatrics, College of Medicine, Department of Landscape Architecture and Urban Planning, College of Architecture, Texas AM University, College Station, TX, United States
Abstract
Background: The objective of this qualitative methods study was to develop the domains and items to support the content validity for the Pediatric Quality of Life Inventory (PedsQL) Multiple Sclerosis Module for youth with pediatric-onset multiple sclerosis. Methods: A literature review of multiple sclerosis–specific questionnaires and clinical research was conducted to generate domains. An expert panel composed of 12 neurologists who were pediatric-onset multiple sclerosis specialists provided feedback on the conceptual framework. Focus interviews with 9 youth with pediatric-onset multiple sclerosis and 6 parents were conducted to develop the relevant domains and item content from the patient and parent perspective. In the cognitive interviews phase, 9 youth with pediatric-onset multiple sclerosis and 6 parents provided feedback on item content, relevance, importance, and understandability of the pediatric-onset multiple sclerosis–specific domains and items. The final interview phase with 5 youth with pediatric-onset multiple sclerosis and 5 parents comprised a pilot testing of the new PedsQL MS Module. Results: Eighteen domains were derived from the qualitative methods with item content saturation achieved at 100 items based on 40 interviews with 23 youth with pediatric-onset multiple sclerosis aged 10-21 years and 17 parents. The domains derived include general fatigue, sleep/rest fatigue, cognitive functioning, tingling sensations, numbness sensations, physical weakness, pain, speech, balance, fine motor, vision, urination, constipation, bowel incontinence, worry, communication, treatment, and medicines. Conclusions: Qualitative methods involving 23 youth with pediatric-onset multiple sclerosis and 17 parents in the domain and item development process support the content validity for the new PedsQL MS Module. Future plans include a national field test of the PedsQL MS Module scales and items. © The Author(s) 2021.
Author Keywords
health-related quality of life; multiple sclerosis; patient-reported outcomes; pediatrics; PedsQL; qualitative methods; symptoms
Funding details
National Multiple Sclerosis Society
PP-1712-29484
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
The Longitudinal Early-onset Alzheimer’s Disease Study (LEADS): Framework and methodology
(2021) Alzheimer’s and Dementia, .
Apostolova, L.G.a b aa , Aisen, P.c , Eloyan, A.d , Fagan, A.e , Fargo, K.N.f , Foroud, T.b , Gatsonis, C.d , Grinberg, L.T.g h , Jack, C.R., Jr.i , Kramer, J.h , Koeppe, R.j , Kukull, W.A.k , Murray, M.E.l , Nudelman, K.b , Rumbaugh, M.b , Toga, A.m , Vemuri, P.i , Trullinger, A.n , Iaccarino, L.h , Day, G.S.o , Graff-Radford, N.R.o , Honig, L.S.p , Jones, D.T.i q , Masdeu, J.r , Mendez, M.s , Musiek, E.e , Onyike, C.U.t , Rogalski, E.u , Salloway, S.v , Wolk, D.A.w , Wingo, T.S.x , Carrillo, M.C.y , Dickerson, B.C.z , Rabinovici, G.D.h , the LEADS Consortiumaa
a Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine Indianapolis, Indianapolis, IN, United States
b Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
c Alzheimer’s Therapeutic Research Institute, University of Southern California, San Diego, CA, United States
d Department of Biostatistics, Center for Statistical Sciences, Brown University, Providence, RI, United States
e Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
f Charcot-Marie Tooth Research Foundation, Naperville, IL, United States
g Department of Pathology, University of California, San Francisco, CA, United States
h Department of Neurology, University of California, San Francisco, CA, United States
i Department of Radiology, Mayo Clinic, Rochester, MN, United States
j Department of Radiology, University of Michigan, Ann Arbor, MI, United States
k Department of Epidemiology, University of Washington, Seattle, WA, United States
l Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
m Laboratory of Neuro Imaging, USC Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, Los Angeles, CA, United States
n Indiana Clinical and Translational Sciences Institute, Indiana University School of Medicine Indianapolis, Indianapolis, IN, United States
o Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
p Taub Institute and Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States
q Department of Neurology, Mayo Clinic, Rochester, MN, United States
r Nantz National Alzheimer Center, Houston Methodist and Weill Cornell Medicine, Houston, TX, United States
s Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
t Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States
u Department of Psychiatry and Behavioral Sciences, Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
v Department of Neurology, Alpert Medical School, Brown University, Providence, RI, United States
w Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
x Department of Neurology and Human Genetics, Emory University School of Medicine, Atlanta, GA, United States
y Medical & Scientific Relations Division, Alzheimer’s Association, Chicago, IL, United States
z Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
aa Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, United States
Abstract
Patients with early-onset Alzheimer’s disease (EOAD) are commonly excluded from large-scale observational and therapeutic studies due to their young age, atypical presentation, or absence of pathogenic mutations. The goals of the Longitudinal EOAD Study (LEADS) are to (1) define the clinical, imaging, and fluid biomarker characteristics of EOAD; (2) develop sensitive cognitive and biomarker measures for future clinical and research use; and (3) establish a trial-ready network. LEADS will follow 400 amyloid beta (Aβ)-positive EOAD, 200 Aβ-negative EOnonAD that meet National Institute on Aging–Alzheimer’s Association (NIA-AA) criteria for mild cognitive impairment (MCI) or AD dementia, and 100 age-matched controls. Participants will undergo clinical and cognitive assessments, magnetic resonance imaging (MRI), [18F]Florbetaben and [18F]Flortaucipir positron emission tomography (PET), lumbar puncture, and blood draw for DNA, RNA, plasma, serum and peripheral blood mononuclear cells, and post-mortem assessment. To develop more effective AD treatments, scientists need to understand the genetic, biological, and clinical processes involved in EOAD. LEADS will develop a public resource that will enable future planning and implementation of EOAD clinical trials. © 2021 the Alzheimer’s Association
Author Keywords
Alzheimer’s disease; early-onset; EOAD; LEADS; YOAD; young onset
Funding details
National Institutes of HealthNIH
Foundation for the National Institutes of HealthFNIH
National Institute on AgingNIA
Mayo Clinic
Alzheimer’s AssociationAALEADS GENETICS‐19‐639372, P30 AG010124, P30 AG010133, P30 AG013854, P30 AG062421, P30 AG062422, P50 AG005146, P50 AG005681, P50 AG008702, P50 AG023501, P50 AG025688, U01 AG016976
Alzheimer’s Drug Discovery FoundationADDF
Novartis
Roche
Biogen
Janssen Pharmaceuticals
American College of RadiologyACR
Rainwater Charitable FoundationRCF
Eisai
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
NF1 mutation drives neuronal activity-dependent initiation of optic glioma
(2021) Nature, .
Pan, Y.a , Hysinger, J.D.a , Barron, T.a , Schindler, N.F.a , Cobb, O.b , Guo, X.b , Yalçın, B.a , Anastasaki, C.b , Mulinyawe, S.B.a , Ponnuswami, A.a , Scheaffer, S.b , Ma, Y.b , Chang, K.-C.c , Xia, X.c , Toonen, J.A.b , Lennon, J.J.a , Gibson, E.M.a d , Huguenard, J.R.a , Liau, L.M.e , Goldberg, J.L.c , Monje, M.a d f g h , Gutmann, D.H.b
a Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, United States
b Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
c Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Stanford, CA, United States
d Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, United States
e Department of Neurosurgery, University of California Los Angeles, Los Angeles, CA, United States
f Department of Pediatrics, Stanford University, Stanford, CA, United States
g Department of Neurosurgery, Stanford University, Stanford, CA, United States
h Department of Pathology, Stanford University, Stanford, CA, United States
Abstract
Neurons have recently emerged as essential cellular constituents of the tumour microenvironment, and their activity has been shown to increase the growth of a diverse number of solid tumours1. Although the role of neurons in tumour progression has previously been demonstrated2, the importance of neuronal activity to tumour initiation is less clear—particularly in the setting of cancer predisposition syndromes. Fifteen per cent of individuals with the neurofibromatosis 1 (NF1) cancer predisposition syndrome (in which tumours arise in close association with nerves) develop low-grade neoplasms of the optic pathway (known as optic pathway gliomas (OPGs)) during early childhood3,4, raising the possibility that postnatal light-induced activity of the optic nerve drives tumour initiation. Here we use an authenticated mouse model of OPG driven by mutations in the neurofibromatosis 1 tumour suppressor gene (Nf1)5 to demonstrate that stimulation of optic nerve activity increases optic glioma growth, and that decreasing visual experience via light deprivation prevents tumour formation and maintenance. We show that the initiation of Nf1-driven OPGs (Nf1-OPGs) depends on visual experience during a developmental period in which Nf1-mutant mice are susceptible to tumorigenesis. Germline Nf1 mutation in retinal neurons results in aberrantly increased shedding of neuroligin 3 (NLGN3) within the optic nerve in response to retinal neuronal activity. Moreover, genetic Nlgn3 loss or pharmacological inhibition of NLGN3 shedding blocks the formation and progression of Nf1-OPGs. Collectively, our studies establish an obligate role for neuronal activity in the development of some types of brain tumours, elucidate a therapeutic strategy to reduce OPG incidence or mitigate tumour progression, and underscore the role of Nf1mutation-mediated dysregulation of neuronal signalling pathways in mouse models of the NF1 cancer predisposition syndrome. © 2021, The Author(s), under exclusive licence to Springer Nature Limited.
Funding details
National Institutes of HealthNIHDP1NS111132
U.S. Department of DefenseDODW81XWH-15-1-0131, W81XWH-19-1-0260
National Eye InstituteNEIF32EY029137, P30EY026877
National Cancer InstituteNCIP50CA165962
National Institute of Neurological Disorders and StrokeNINDSR01NS092597, R35NS07211
Alex’s Lemonade Stand Foundation for Childhood CancerALSF
Research to Prevent BlindnessRPB
Ian’s Friends FoundationIFF
Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation
Stanford Maternal and Child Health Research InstituteMCHRI
Gilbert Family FoundationGFF
Cancer Research UKCRUK
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Hemispheric CSF volume ratio quantifies progression and severity of cerebral edema after acute hemispheric stroke
(2021) Journal of Cerebral Blood Flow and Metabolism, .
Dhar, R.a , Hamzehloo, A.a , Kumar, A.a , Chen, Y.a , He, J.b , Heitsch, L.a c , Slowik, A.d , Strbian, D.e , Lee, J.-M.a f g
a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
c Department of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, United States
d Department of Neurology, Jagiellonian University Medical College, Krakow, Poland
e Department of Neurology, Helsinki University Hospital, Helsinki, Finland
f Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
g Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
Abstract
As swelling occurs, CSF is preferentially displaced from the ischemic hemisphere. The ratio of CSF volume in the stroke-affected hemisphere to that in the contralateral hemisphere may quantify the progression of cerebral edema. We automatically segmented CSF from 1,875 routine CTs performed within 96 hours of stroke onset in 924 participants of a stroke cohort study. In 737 subjects with follow-up imaging beyond 24-hours, edema severity was classified as affecting less than one-third of the hemisphere (CED-1), large hemispheric infarction (LHI, over one-third the hemisphere), without midline shift (CED-2) or with midline shift (CED-3). Malignant edema was LHI resulting in deterioration, requiring osmotic therapy, surgery, or resulting in death. Hemispheric CSF ratio was lower on baseline CT in those with LHI (0.91 vs. 0.97, p < 0.0001) and decreased more rapidly in those with LHI who developed midline shift (0.01 per hour for CED-3 vs. 0.004/hour CED-2). The ratio at 24-hours was lower in those with midline shift (0.41, IQR 0.30–0.57 vs. 0.66, 0.56–0.81 for CED-2). A ratio below 0.50 provided 90% sensitivity, 82% specificity for predicting malignant edema among those with LHI (AUC 0.91, 0.85–0.96). This suggests that the hemispheric CSF ratio may provide an accessible early biomarker of edema severity. © The Author(s) 2021.
Author Keywords
brain edema; cerebrospinal fluid; CT; imaging; Stroke
Funding details
National Institutes of HealthNIHK23NS099440, K23NS099487, R01NS085419, U24NS107230
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation
(2021) Genetics in Medicine, . Cited 1 time.
Legius, E.a , Messiaen, L.b , Wolkenstein, P.c , Pancza, P.d , Avery, R.A.e , Berman, Y.f , Blakeley, J.g , Babovic-Vuksanovic, D.h , Cunha, K.S.i , Ferner, R.j , Fisher, M.J.k , Friedman, J.M.l , Gutmann, D.H.m , Kehrer-Sawatzki, H.n , Korf, B.R.b , Mautner, V.-F.o , Peltonen, S.p q , Rauen, K.A.r , Riccardi, V.s , Schorry, E.t , Stemmer-Rachamimov, A.u , Stevenson, D.A.v , Tadini, G.w , Ullrich, N.J.x , Viskochil, D.y , Wimmer, K.z , Yohay, K.aa , Gomes, A.b , Jordan, J.T.ad , Mautner, V.o , Merker, V.L.ad , Smith, M.J.ac , Stevenson, D.v , Anten, M.ae , Aylsworth, A.af , Baralle, D.ag , Barbarot, S.ah , Barker, F., IIai , Ben-Shachar, S.aj , Bergner, A.ak , Bessis, D.al , Blanco, I.am , Cassiman, C.an , Ciavarelli, P.ao , Clementi, M.ap , Frébourg, T.aq , Giovannini, M.ar , Halliday, D.as , Hammond, C.at , Hanemann, C.O.au , Hanson, H.av , Heiberg, A.aw , Joly, P.ax , Kalamarides, M.ay , Karajannis, M.az , Kroshinsky, D.ba , Larralde, M.bb , Lázaro, C.bc , Le, L.bd , Link, M.be , Listernick, R.bf , MacCollin, M.bg , Mallucci, C.bh , Moertel, C.bi , Mueller, A.bj , Ngeow, J.bk , Oostenbrink, R.bl , Packer, R.bm , Papi, L.bn , Parry, A.bo , Peltonen, J.bp , Pichard, D.bq , Poppe, B.br , Rezende, N.bs , Rodrigues, L.O.bt , Rosser, T.bt , Ruggieri, M.bu , Serra, E.bv , Steinke-Lange, V.bw , Stivaros, S.M.bx , Taylor, A.by , Toelen, J.bz , Tonsgard, J.ca , Trevisson, E.ap , Upadhyaya, M.cb , Varan, A.cc , Wilson, M.cd , Wu, H.ce , Zadeh, G.cf , Huson, S.M.ab , Evans, D.G.ac , Plotkin, S.R.ad , International Consensus Group on Neurofibromatosis Diagnostic Criteria (I-NF-DC)cg
a Department of Human Genetics, KU Leuven and University Hospital, Leuven, Belgium
b Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, United States
c Assistance Publique-Hôpital Paris (AP-HP), Hôpital Henri-Mondor, UPEC, Service de Dermatologie, Créteil, France
d Children’s Tumor Foundation, New York, NY, United States
e Division of Ophthalmology, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
f Clinical Genetics, Royal North Shore Hospital, St. Leonards, NSW, Australia and University of Sydney, Sydney, Australia
g Johns Hopkins Comprehensive Neurofibromatosis Center, Baltimore, MD, United States
h Department of Clinical Genomics, Mayo Clinic College of Medicine, Rochester, MN, United States
i Department of Pathology, Universidade Federal Fluminense, Niteroi, Brazil
j Neurology, Guy’s and St. Thomas’ Hospital and NHS Trust, London, United Kingdom
k Division of Oncology, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
l Medical Genetics, University of British Columbia, Vancouver, BC, Canada
m Neurology, Washington University, St. Louis, MO, United States
n Institute of Human Genetics, University of Ulm, Ulm, Germany
o Neurology, University Hospital of Hamburg-Eppendorf, Hamburg, Germany
p Dermatology, University of Turku and Turku University Hospital, Turku, Finland
q Department of Dermatology and Venereology, University of Gothenburg, Gothenburg, Sweden
r Pediatrics, University of California Davis, Sacramento, CA, United States
s The Neurofibromatosis Institute, La Crescenta, CA, United States
t Medical Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
u Neuropathology, Massachusetts General Hospital, Boston, MA, United States
v Medical Genetics, Stanford University, Stanford, CA, United States
w Pediatric Dermatology, University of Milan, Milan, Italy
x Department of Neurology, Boston Children’s Hospital, Boston, MA, United States
y Medical Genetics, University of Utah, Salt Lake City, UT, United States
z Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria
aa NYU Langone Health, New York, NY, United States
ab Clinical Genetics, (Formerly) Manchester Center for Genomic Medicine, Manchester University Hospitals, NHS Foundation Trust, Manchester, United Kingdom
ac Department of Genomic Medicine, St Mary’s Hospital, Manchester Academic Health Sciences Centre (MAHSC), Division of Evolution and Genomic Science, University of Manchester, Manchester, United Kingdom
ad Department of Neurology and Cancer Center, Massachusetts General Hospital, Boston, MA, United States
ae Department of Neurology, Maastricht University Medical Center, Maastricht, Netherlands
af Department of Genetics, University of North Carolina, Chapel Hill, NC, United States
ag Department of Human Development and Health, University of Southampton, Southampton, United Kingdom
ah Centre Hospitalier Universitaire de Nantes, Nantes, France
ai Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, United States
aj Clalit Research Institute, & Schneider Children’s Medical Center, Ramat-Gan, Israel
ak Department of Genetics and Development, Columbia University Medical Center, New York, NY, United States
al Department of Dermatology, Centre Hospitalier Universitaire de Montpellier, Montpellier, France
am Department of Clinical Genetics, Hospital Universitari Germans Trias I Pujol, Badalona, Spain
an Department of Ophthalmology, University Hospitals Leuven, Leuven, Belgium
ao Department of Neurosurgery, Hospital de Clinicas Gral San Martin, San Martin, Argentina
ap Department of Clinical Genetics, University of Padova, Padova, Italy
aq Department of Genetics, University Hospital Rouen, Rouen, France
ar Department of Head and Neck Surgery, David Geffen School of Medicine, University of California–Los Angeles, Los Angeles, CA, United States
as Department of Clinical Genetics, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
at Department of Ophthalmology, King’s College London, London, United Kingdom
au Institute of Translational and Stratified Medicine, Peninsula Medical School, University of Plymouth, Plymouth, United Kingdom
av Department of Genetics, St George’s University Hospitals, London, United Kingdom
aw Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
ax Department of Dermatology, University Hospital Rouen, Rouen, France
ay Department of Neurosurgery, Hôpital Pitié Salpêtrière, Paris, France
az Department of Pediatrics and Otolaryngology, Memorial Sloan Kettering Cancer Center, New York, NY, United States
ba Department of Dermatology, Massachusetts General Hospital, Boston, MA, United States
bb Department of Dermatology, Hospital Aleman, Buenos Aires, Argentina
bc Institut Català d’Oncologia (ICO-IDIBELL-CIBERONC), Hospitalet de Llobregat, Barcelona, Spain
bd Department of Dermatology, University of Texas, Southwestern, Dallas, TX, United States
be Department of Neurosurgery and Otolaryngology, Mayo Clinic, Rochester, MN, United States
bf Department of Pediatrics, Ann and Robert H Lurie Children’s Hospital of Chicago, Chicago, IL, United States
bg Bend, OR, United States
bh Department of Neurosurgery, Alder Hey Children’s Hospital NHS, Liverpool, United Kingdom
bi Department of Pediatrics, University of Minnesota, Minneapolis, MN, United States
bj Cancer Genetics, Massachusetts General Hospital, Boston, MA, United States
bk Lee Kong Chian School of medicine, Nanyang Technological University, Singapore and Cancer Genetics Service, National Cancer Center, Singapore, Singapore
bl Department of Pediatrics, Erasmus University Medical Center, Rotterdam, Netherlands
bm The Brain Tumor Institute, Gilbert Family Neurofibromatosis Institute, Children’s National Medical Center, Washington, DC, United States
bn Department of Experimental and Clinical Biomedical Science “Mario Serio”, University of Florence, Florence, Italy
bo Department of Neurology, John Radcliff Hospital, Oxford, United Kingdom
bp Institute of Biomedicine, University of Turku and Turku University Hospital, Turku, Finland
bq National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, United States
br Department of Medical Genetics, University Hospital Ghent, Ghent, Belgium
bs School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil
bt Department of Neurology, Children’s Hospital Los Angeles, Los Angeles, CA, United States
bu Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, Catania, Italy
bv The Institute for Health Science Research Germans Trias i Pujol (IGTP), Barcelona, Spain
bw Center of Medical Genetics, Munich, Germany
bx Division of Informatics, Imaging and Data Sciences, University of Manchester, Manchester, United Kingdom
by Clinical Genetics Department, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
bz Department of Pediatrics, University Hospital Leuven, Leuven, Belgium
ca Department of Pediatrics and Neurology, University of Chicago Medicine, Chicago, IL, United States
cb Institute of Cancer Genetics, Cardiff University, Cardiff, United Kingdom
cc Department of Pediatric Oncology, Hacettepe University, Ankara, Turkey
cd Department of Clinical Genetics, Children’s Hospital Westmead, Sydney, Australia
ce Shanghai Ninth People’s Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shangai, China
cf Princess Margaret Cancer Centre, Toronto Western Hospital, Toronto, ON, Canada
Abstract
Purpose: By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS). Methods: We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. Results: We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. Conclusion: The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS. [Figure not available: see fulltext.] © 2021, The Author(s).
Funding details
IS-BRC-1215-20007
Children’s Tumor FoundationCTF
Document Type: Article
Publication Stage: Article in Press
Source: Scopus