Diffusion Tensor Imaging Abnormalities in the Uncinate Fasciculus and Inferior Longitudinal Fasciculus in Phelan-McDermid Syndrome - 09/04/20
Doi : 10.1016/j.pediatrneurol.2020.01.006
Julia Bassell, BA a, ‡, Siddharth Srivastava, MD b, ‡, Anna K. Prohl, BA c, Benoit Scherrer, PhD c, Kush Kapur, PhD b, Rajna Filip-Dhima, MS d, Elizabeth Berry-Kravis, MD, PhD e, f, g, Latha Soorya, PhD h, Audrey Thurm, PhD i, Craig M. Powell, MD, PhD j, k, Jonathan A. Bernstein, MD, PhD l, Joseph D. Buxbaum, PhD m, n, o, p, Alexander Kolevzon, MD m, n, Simon K. Warfield, PhD c, Mustafa Sahin, MD, PhD b, d, ⁎ 
on behalf of
on behalf of
Developmental Synaptopathies Consortium†
Mustafa Sahin, MD, PhD a, b, Alexander Kolevzon, MD c, d, Joseph Buxbaum, PhD c, d, e, f, Elizabeth Berry Kravis, MD, PhD g, h, i, Latha Soorya, PhD j, Audrey Thurm, PhD k, Craig Powell, MD, PhD l, m, Jonathan A. Bernstein, MD, PhD n, Simon Warfield, PhD o, Benoit Scherrer, PhD o, Rajna Filip-Dhima, MS b, Kira Dies, ScM, CGC b, Paige Siper, PhD c, Ellen Hanson, PhD p, Jennifer M. Phillips, PhD q, Stormi P. White, Psy D r
a Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
b F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
c Seaver Autism Center for Research and Treatment, Mount Sinai School of Medicine, New York, New York
d Department of Psychiatry, Mount Sinai School of Medicine, New York, New York
e Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York
f Department of Neuroscience, Mount Sinai School of Medicine, New York, New York
g Department of Pediatrics, Rush University Medical Center, Chicago, Illinois
h Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois
i Department of Biochemistry, Rush University Medical Center, Chicago, Illinois
j Department of Psychiatry, Rush University Medical Center, Chicago, Illinois
k Pediatrics and Developmental Neuroscience Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland
l Department of Neurobiology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama
m Civitan International Research Center, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama
n Department of Pediatrics, Stanford University School of Medicine, Stanford, California
o Computational Radiology Laboratory, Department of Radiology, Boston Children's Hospital & Harvard Medical School, Boston, Massachusetts
p Department of Developmental Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
q Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California
r Center for Autism and Developmental Disabilities, University of Texas Southwestern Medical Center, Dallas, Texas
a Warren Alpert Medical School of Brown University, Providence, Rhode Island
b Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
c Computational Radiology Laboratory, Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
d F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
e Department of Pediatrics, Rush University Medical Center, Chicago, Illinois
f Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois
g Department of Biochemistry, Rush University Medical Center, Chicago, Illinois
h Department of Psychiatry, Rush University Medical Center, Chicago, Illinois
i Pediatrics and Developmental Neuroscience Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland
j Department of Neurobiology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama
k Civitan International Research Center, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama
l Department of Pediatrics, Stanford University School of Medicine, Stanford, California
m Seaver Autism Center for Research and Treatment, Mount Sinai School of Medicine, New York, New York
n Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York
o Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York
p Department of Neuroscience, Mount Sinai School of Medicine, New York, New York
∗Communications should be addressed to: Sahin; Department of Neurology; Boston Children's Hospital; 300 Longwood Avenue, Boston, MA 02115.Department of NeurologyBoston Children's Hospital300 Longwood AvenueBostonMA02115
Abstract |
Background |
This cohort study utilized diffusion tensor imaging tractography to compare the uncinate fasciculus and inferior longitudinal fasciculus in children with Phelan-McDermid syndrome with age-matched controls and investigated trends between autism spectrum diagnosis and the integrity of the uncinate fasciculus and inferior longitudinal fasciculus white matter tracts.
Methods |
This research was conducted under a longitudinal study that aims to map the genotype, phenotype, and natural history of Phelan-McDermid syndrome and identify biomarkers using neuroimaging (ClinicalTrial NCT02461420). Patients were aged three to 21 years and underwent longitudinal neuropsychologic assessment over 24 months. MRI processing and analyses were completed using previously validated image analysis software distributed as the Computational Radiology Kit (crl.med.harvard.edu/). Whole-brain connectivity was generated for each subject using a stochastic streamline tractography algorithm, and automatically defined regions of interest were used to map the uncinate fasciculus and inferior longitudinal fasciculus.
Results |
There were 10 participants (50% male; mean age 11.17 years) with Phelan-McDermid syndrome (n = 8 with autism). Age-matched controls, enrolled in a separate longitudinal study (NIH R01 NS079788), underwent the same neuroimaging protocol. There was a statistically significant decrease in the uncinate fasciculus fractional anisotropy measure and a statistically significant increase in uncinate fasciculus mean diffusivity measure, in the patient group versus controls in both right and left tracts (P ≤ 0.024).
Conclusion |
Because the uncinate fasciculus plays a critical role in social and emotional interaction, this tract may underlie some deficits seen in the Phelan-McDermid syndrome population. These findings need to be replicated in a larger cohort.
Le texte complet de cet article est disponible en PDF.Keywords : 22q13.3 deletion, SHANK3, DTI, Autism
Plan
| Trial registration: The study uses data from a clinical trial (ClinicalTrials.gov NCT02461420; NCT02461420). Date of registration was June 3, 2015. |
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| Declarations |
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| Ethics approval and consent to participate: The study was approved by the Institutional Review Board (IRB) at Boston Children's Hospital, which serves as the central IRB for all the sites included in this study. Informed consent was obtained from the caregivers and legal guardians of all participants. The study was conducted in accordance with Good Clinical Practice guidelines. |
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| Consent for publication: Not applicable. |
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| Availability of data and materials: Data were entered in a web-based system created and maintained by the data management and coordinating center at the University of South Florida, which met the Health Insurance Portability and Accountability Act privacy regulations. Additional MRI data were maintained at the Computational Radiology Laboratory at Boston Children's Hospital. Both clinical and MRI data presented here have been made available to the National Database for Autism Research, which is an NIH-funded data repository that aims to house and share with qualified researchers' data related to autism Spectrum disorder. |
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| Competing interests: S.S. has received consulting fees from Guidepoint. M.S. reports grant support from Novartis, Roche, Pfizer, Ipsen, LAM Therapeutics and Quadrant Biosciences, unrelated to this project. He has served on Scientific Advisory Boards for Sage, Roche, Celgene, and Takeda. A.K.P. receives research support from AMO Pharma and consults to Ovid Therapeutics, Coronis, 5AM Ventures, sema4, LabCorp, and Takeda. E.B.-K. has received funding from Seaside Therapeutics, Novartis, Roche, Alcobra, Neuren, Cydan, Fulcrum, GW, Neurotrope, Marinus, Zynerba, BioMarin, Ovid, Yamo, Acadia, Ionis, Ultragenyx, and Lumos Pharmaceuticals to consult on trial design or development strategies and/or conduct clinical studies in FXS or other neurodegenerative disorders; from Vtesse/Sucampo/Mallinckrodt Pharmaceuticals to conduct clinical trials in NP-C; and from Asuragen Inc to develop testing standards for FMR1 testing. All funding to Dr. E.B.-K. is directed to Rush University Medical Center (RUMC) in support of rare disease programs. C.M.P. has accepted travel funds and honoraria to speak once at each of the following companies: Psychogenics, Inc; Astra-Zeneca; Roche; Pfizer; and Dainippon Sumitomo Pharma Co C.M.P. also has investigator-initiated grant funding for clinical research with Novartis. None of these activities represents a competing interest to the current study. |
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| Funding: This study is supported by the Developmental Synaptopathies Consortium (U54NS092090), which is a part of the National Center for Advancing Translational Sciences Rare Diseases Clinical Research Network. The Rare Diseases Clinical Research Network is an initiative of the Office of Rare Diseases Research of the National Center for Advancing Translational Sciences, and Developmental Synaptopathies Consortium is funded through collaboration between the National Center for Advancing Translational Sciences, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. This research was also supported (in part) by the Intramural Research Program of the NIMH ZICMH002961. |
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| Authors' contributions: J.B. drafted the manuscript and analyzed the data. S.S. analyzed the data and performed critical revision of the manuscript for important intellectual content. A.K.P. and B.S. collected and analyzed the data and performed critical revision of the manuscript for important intellectual content. K.K. provided statistical analysis and performed critical revision of the manuscript for important intellectual content. R.F.-D. performed critical revision of the manuscript for important intellectual content. E.B.-K. performed critical revision of the manuscript for important intellectual content. L.S. performed critical revision of the manuscript for important intellectual content. A.T. performed critical revision of the manuscript for important intellectual content. C.M.P. performed critical revision of the manuscript for important intellectual content. J.D.B. performed critical revision of the manuscript for important intellectual content. A.K. performed critical revision of the manuscript for important intellectual content. S.K.W. and M.S. oversaw study concept and design; performed critical revision of the manuscript for important intellectual content. |
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