Hope Center Member Publications

Clinical, histological, and molecular features of gliomas in adults with neurofibromatosis type 1
(2023) Neuro-oncology, 25 (8), pp. 1474-1486. 

Romo, C.G.^a , Piotrowski, A.F.^b , Campian, J.L.^c , Diarte, J.^b , Rodriguez, F.J.^d , Bale, T.A.^b , Dahiya, S.^c , Gutmann, D.H.^c , Lucas, C.-H.G.^e , Prichett, L.^a , Mellinghoff, I.^b , Blakeley, J.O.^a

^a Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^b Departments of Neurology and Pathology, Memorial Sloan Kettering Cancer CenterNY, United States
^c Departments of Neurology and Pathology, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Pathology, University of California Los Angeles, Los Angeles, CA, United States
^e Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Abstract
BACKGROUND: People with NF1 have an increased prevalence of central nervous system malignancy. However, little is known about the clinical course or pathologic features of NF1-associated gliomas in adults, limiting clinical care and research. METHODS: Adults (≥18 years) with NF1 and histologically confirmed non-optic pathway gliomas (non-OPGs) at Johns Hopkins Hospital, Memorial Sloan Kettering Cancer Center, and Washington University presenting between 1990 and 2020 were identified. Retrospective data were collated, and pathology was reviewed centrally. RESULTS: Forty-five patients, comprising 23 females (51%), met eligibility criteria, with a median of age 37 (18-68 years) and performance status of 80% (30%-100%). Tissue was available for 35 patients. Diagnoses included infiltrating (low-grade) astrocytoma (9), glioblastoma (7), high-grade astrocytoma with piloid features (4), pilocytic astrocytoma (4), high-grade astrocytoma (3), WHO diagnosis not reached (4) and one each of gliosarcoma, ganglioglioma, embryonal tumor, and diffuse midline glioma. Seventy-one percent of tumors were midline and underwent biopsy only. All 27 tumors evaluated were IDH1-wild-type, independent of histology. In the 10 cases with molecular testing, the most common genetic variants were NF1, EGFR, ATRX, CDKN2A/B, TP53, TERT, and MSH2/3 mutation. While the treatments provided varied, the median overall survival was 24 months [2-267 months] across all ages, and 38.5 [18-109] months in individuals with grade 1-2 gliomas. CONCLUSIONS: Non-OPGs in adults with NF1, including low-grade tumors, often have an aggressive clinical course, indicating a need to better understand the pathobiology of these NF1-associated gliomas. © The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
glioma;  Neurofibromatosis type 1;  Non-optic pathway glioma;  overall survival;  treatment outcome

Document Type: Article
Publication Stage: Final
Source: Scopus

Positron emission tomography and magnetic resonance imaging methods and datasets within the Dominantly Inherited Alzheimer Network (DIAN)
(2023) Nature Neuroscience, 26 (8), pp. 1449-1460. Cited 1 time.

McKay, N.S.^a , Gordon, B.A.^a , Hornbeck, R.C.^a , Dincer, A.^a , Flores, S.^a , Keefe, S.J.^a , Joseph-Mathurin, N.^a , Jack, C.R.^b , Koeppe, R.^c , Millar, P.R.^a , Ances, B.M.^a , Chen, C.D.^a , Daniels, A.^a , Hobbs, D.A.^a , Jackson, K.^a , Koudelis, D.^a , Massoumzadeh, P.^a , McCullough, A.^a , Nickels, M.L.^a , Rahmani, F.^a , Swisher, L.^a , Wang, Q.^a , Allegri, R.F.^d , Berman, S.B.^e , Brickman, A.M.^f , Brooks, W.S.^g , Cash, D.M.^h i , Chhatwal, J.P.^j , Day, G.S.^k , Farlow, M.R.^l , la Fougère, C.^m n , Fox, N.C.^h i , Fulham, M.^o , Ghetti, B.^l , Graff-Radford, N.^k , Ikeuchi, T.^p , Klunk, W.^e , Lee, J.-H.^q , Levin, J.^r , Martins, R.^s , Masters, C.L.^t , McConathy, J.^u , Mori, H.^v , Noble, J.M.^f , Reischl, G.^m , Rowe, C.^t , Salloway, S.^w , Sanchez-Valle, R.^x , Schofield, P.R.^g y , Shimada, H.^v , Shoji, M.^z , Su, Y.^aa , Suzuki, K.^ab , Vöglein, J.^r ac , Yakushev, I.^ad , Cruchaga, C.^a , Hassenstab, J.^a , Karch, C.^a , McDade, E.^a , Perrin, R.J.^a , Xiong, C.^a , Morris, J.C.^a , Bateman, R.J.^a , Benzinger, T.L.S.^a , Brickman, A.M.^f , la Fougère, C.^m , the Dominantly Inherited Alzheimer Network^ae

^a Washington University in St. Louis, St. Louis, MO, United States
^b Mayo Clinic, Rochester, MN, United States
^c University of Michigan, Ann Arbor, MI, United States
^d Institute of Neurological Research Fleni, Buenos Aires, Argentina
^e University of Pittsburgh, Pittsburgh, PA, United States
^f Columbia University Irving Medical Center, New York, NY, United States
^g Neuroscience Research Australia, Sydney, NSW, Australia
^h UK Dementia Research Institute at University College London, London, United Kingdom
ⁱ University College London, London, United Kingdom
^j Massachusetts General and Brigham & Women’s Hospitals, Harvard Medical School, Boston, MA, United States
^k Mayo Clinic, Jacksonville, FL, United States
^l Indiana University School of Medicine, Bloomington, IN, United States
^m Department of Radiology, University of Tübingen, Tübingen, Germany
ⁿ German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
^o Royal Prince Alfred Hospital, Sydney, NSW, Australia
^p Niigata University, Niigata, Japan
^q Asan Medical Center, Seoul, South Korea
^r German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
^s Edith Cowan University, Joondalup, WA, Australia
^t University of Melbourne, Melbourne, VIC, Australia
^u University of Alabama at Birmingham, Birmingham, AL, United States
^v Osaka City University, Osaka, Japan
^w Brown University. Butler Hospital, Providence, RI, United States
^x Alzheimer’s Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
^y School of Biomedical Sciences, University of New South Wales, Sydney, NSW, Australia
^z Hirosaki University, Hirosaki, Japan
^aa Banner Alzheimer’s Institute, Phoenix, AZ, United States
^ab University of Tokyo, Tokyo, Japan
^ac Department of Neurology, Ludwig-Maximilians-Universität München, München, Germany
^ad School of Medicine, Technical University of Munich, Munich, Germany

Abstract
The Dominantly Inherited Alzheimer Network (DIAN) is an international collaboration studying autosomal dominant Alzheimer disease (ADAD). ADAD arises from mutations occurring in three genes. Offspring from ADAD families have a 50% chance of inheriting their familial mutation, so non-carrier siblings can be recruited for comparisons in case–control studies. The age of onset in ADAD is highly predictable within families, allowing researchers to estimate an individual’s point in the disease trajectory. These characteristics allow candidate AD biomarker measurements to be reliably mapped during the preclinical phase. Although ADAD represents a small proportion of AD cases, understanding neuroimaging-based changes that occur during the preclinical period may provide insight into early disease stages of ‘sporadic’ AD also. Additionally, this study provides rich data for research in healthy aging through inclusion of the non-carrier controls. Here we introduce the neuroimaging dataset collected and describe how this resource can be used by a range of researchers. © 2023, The Author(s).

Funding details
National Institutes of HealthNIHK01-AG080123-01, K23-AG064029, P01-AG025204, R01-AG052550, R01-AG057840, R01-AG058676, R01-Ag068319, R03-AG072375, RF1-AG073424, RF1-AG079569, U01-AG059798, U19-AG024904, U19-AG053267
National Institute on AgingNIAU19-AG032438
Mayo Clinic
James S. McDonnell FoundationJSMF
Alzheimer’s AssociationAAAARF-21-722077, AARF-22-972678, AARF-D-20-681815, DIAN_ADNI-16-434364, SG-20-690363-DIAN
BrightFocus FoundationBFFA2022013F, A2022014F
University of WashingtonUW
Fondation Brain Canada
Japan Agency for Medical Research and DevelopmentAMEDJP22dk0207049
Washington University School of Medicine in St. LouisWUSM
Chan Zuckerberg InitiativeCZICS-0000000472
GHR FoundationGHR
Canadian Institutes of Health ResearchIRSCTAD-125697
Medical Research CouncilMRCMR/009076/1, MR/L023784/1
Alzheimer’s Society
Deutsche ForschungsgemeinschaftDFG
Alzheimer’s Research UKARUKARUK-PG2017-1946
Bundesministerium für Bildung und ForschungBMBF
Korea Health Industry Development InstituteKHIDI
Instituto de Salud Carlos IIIISCIII
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Fonds de recherche du QuébecFRQ

Document Type: Article
Publication Stage: Final
Source: Scopus

Synchronization, clustering, and weak chimeras in a densely coupled transcription-based oscillator model for split circadian rhythms
(2023) Chaos (Woodbury, N.Y.), 33 (8), .

Ocampo-Espindola, J.L.^a , Nikhil, K.L.^b , Li, J.-S.^c , Herzog, E.D.^b , Kiss, I.Z.^a

^a Department of Chemistry, Saint Louis University, 3501 Laclede Ave., St. Louis, MO 63103, United States
^b Department of Biology, Washington University in St. Louis, One Brookings Drive, St. Louis, Missouri 63130-4899, United States
^c Department of Electrical and Systems Engineering, Washington University in St Louis, 1 Brookings Drive, St. Louis, MO 63130, United States

Abstract
The synchronization dynamics for the circadian gene expression in the suprachiasmatic nucleus is investigated using a transcriptional circadian clock gene oscillator model. With global coupling in constant dark (DD) conditions, the model exhibits a one-cluster phase synchronized state, in dim light (dim LL), bistability between one- and two-cluster states and in bright LL, a two-cluster state. The two-cluster phase synchronized state, where some oscillator pairs synchronize in-phase, and some anti-phase, can explain the splitting of the circadian clock, i.e., generation of two bouts of daily activities with certain species, e.g., with hamsters. The one- and two-cluster states can be reached by transferring the animal from DD or bright LL to dim LL, i.e., the circadian synchrony has a memory effect. The stability of the one- and two-cluster states was interpreted analytically by extracting phase models from the ordinary differential equation models. In a modular network with two strongly coupled oscillator populations with weak intragroup coupling, with appropriate initial conditions, one group is synchronized to the one-cluster state and the other group to the two-cluster state, resulting in a weak-chimera state. Computational modeling suggests that the daily rhythms in sleep-wake depend on light intensity acting on bilateral networks of suprachiasmatic nucleus (SCN) oscillators. Addition of a network heterogeneity (coupling between the left and right SCN) allowed the system to exhibit chimera states. The simulations can guide experiments in the circadian rhythm research to explore the effect of light intensity on the complexities of circadian desynchronization. © 2023 Author(s). Published under an exclusive license by AIP Publishing.

Document Type: Article
Publication Stage: Final
Source: Scopus

Thalamo-cortical and cerebello-cortical functional connectivity in development
(2023) Cerebral Cortex (New York, N.Y. : 1991), 33 (15), pp. 9250-9262. 

Badke D’Andrea, C.^a b c , Marek, S.^c , Van, A.N.^d e , Miller, R.L.^b d , Earl, E.A.^f , Stewart, S.B.^g , Dosenbach, N.U.F.^{c d e h i} , Schlaggar, B.L.^j , Laumann, T.O.^b , Fair, D.A.^k l m , Gordon, E.M.^c , Greene, D.J.^a

^a Department of Cognitive Science, University of California San Diego, La Jolla, CA, 92093, United States
^b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
^f Data Science and Sharing Team, National Institute of Mental Health, NIH, DHHS, Bethesda, United States
^g Department of Psychiatry, University of Colorado School of Medicine, Aurora, CO 80045, United States
^h Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States
ⁱ Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO 63110, United States
^j Kennedy Krieger Institute, Baltimore, MD 21205, United States
^k Institute of Child Development, College of Education and Human Development, University of Minnesota, Minneapolis, United States
^l Department of Pediatrics, University of Minnesota Medical School, Minneapolis, United States
^m Masonic Institute for the Developing Brain, University of Minnesota, Minneapolis, United States

Abstract
The thalamus is a critical relay center for neural pathways involving sensory, motor, and cognitive functions, including cortico-striato-thalamo-cortical and cortico-ponto-cerebello-thalamo-cortical loops. Despite the importance of these circuits, their development has been understudied. One way to investigate these pathways in human development in vivo is with functional connectivity MRI, yet few studies have examined thalamo-cortical and cerebello-cortical functional connectivity in development. Here, we used resting-state functional connectivity to measure functional connectivity in the thalamus and cerebellum with previously defined cortical functional networks in 2 separate data sets of children (7-12 years old) and adults (19-40 years old). In both data sets, we found stronger functional connectivity between the ventral thalamus and the somatomotor face cortical functional network in children compared with adults, extending previous cortico-striatal functional connectivity findings. In addition, there was more cortical network integration (i.e. strongest functional connectivity with multiple networks) in the thalamus in children than in adults. We found no developmental differences in cerebello-cortical functional connectivity. Together, these results suggest different maturation patterns in cortico-striato-thalamo-cortical and cortico-ponto-cerebellar-thalamo-cortical pathways. © The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
brain networks;  cerebellum;  functional MRI;  neurodevelopment;  thalamus

Document Type: Article
Publication Stage: Final
Source: Scopus

Effect of exercise engagement and cardiovascular risk on neuronal injury
(2023) Alzheimer’s and Dementia, . 

Stojanovic, M.^a b , Schindler, S.E.^b c , Morris, J.C.^b c , Head, D.^a c d

^a Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^c Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
INTRODUCTION: Neuronal health as a potential underlying mechanism of the beneficial effects of exercise has been understudied in humans. Furthermore, there has been limited consideration of potential moderators (e.g., cardiovascular health) on the effects of exercise. METHODS: Clinically normal middle-aged and older adults completed a validated questionnaire about exercise engagement over a 10-year period (n = 75; age 63 ± 8 years). A composite estimate of neuronal injury was formulated that included cerebrospinal fluid-based measures of visinin-like protein-1, neurogranin, synaptosomal-associated protein 25, and neurofilament light chain. Cardiovascular risk was estimated using the Framingham Risk Score. RESULTS: Cross-sectional analyses showed that greater exercise engagement was associated with less neuronal injury in the group with lower cardiovascular risk (p = 0.008), but not the group with higher cardiovascular risk (p = 0.209). DISCUSSION: Cardiovascular risk is an important moderator to consider when examining the effects of exercise on cognitive and neural health, and may be relevant to personalized exercise recommendations. Highlights: We examined the association between exercise engagement and neuronal injury. Vascular risk moderated the association between exercise and neuronal injury. Cardiovascular risk may be relevant to personalized exercise recommendations. © 2023 the Alzheimer’s Association.

Author Keywords
cardiovascular risk;  NfL;  Ng;  SNAP-25;  VILIP-1

Funding details
National Institutes of HealthNIHK23AG053426, P01AG003991, P01AG026276, P30AG066444, R01AG070941, U19AG024904, U19AG032438

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