TY - JOUR
T1 - Functional Connectivity Decreases with Metabolic Stress in Sickle Cell Disease
AU - Fields, Melanie E.
AU - Mirro, Amy E.
AU - Guilliams, Kristin P.
AU - Binkley, Michael M.
AU - Gil Diaz, Luisa
AU - Tan, Jessica
AU - Fellah, Slim
AU - Eldeniz, Cihat
AU - Chen, Yasheng
AU - Ford, Andria L.
AU - Shimony, Joshua S.
AU - King, Allison A.
AU - An, Hongyu
AU - Smyser, Christopher D.
AU - Lee, Jin Moo
N1 - Funding Information:
This research was supported by National Institutes of Health, National Heart, Lung, and Blood Institute (K23HL136904 [M.E.F.], R01HL129241 [A.L.F.]), the National Institute of Neurological Disorders and Stroke (K23NS099472 [K.P.G.], K02NS089852 [C.D.S.], U24NS107230 [J.‐M.L.], R01NS085419 [J.‐M.L.]), the National Institute of Mental Health (R01MH113570 [C.D.S.], R01MH113883 [C.D.S.]), the National Center for Advancing Translational Sciences (UL1TR002345 [M.E.F.]), the Eunice Kennedy Shriver National Institute of Child Health & Human Development (U54HD087011), Intellectual and Developmental Disabilities Research Center at Washington University (J.S.S. and C.D.S.), the American Society of Hematology (M.E.F.), the Doris Duke Charitable Foundation (M.E.F.), and The Foundation for Barnes‐Jewish Hospital (M.E.F.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Information:
The authors would like to acknowledge and thank Rachel Shields for her assistance with study set‐up and coordination, and Dr. Abraham Snyder for his work developing the 4dfp suite used in the analyses of this work (supported by the Intellectual and Developmental Disabilities Research Center at Washington University (Eunice Kennedy Shriver National Institute of Child Health & Human Development U54HD087011) and Neuroimaging Informatics and Analysis Center at Washington University (P30NS048056).
Publisher Copyright:
© 2020 American Neurological Association
PY - 2020/11/1
Y1 - 2020/11/1
N2 - Objective: Children with sickle cell disease (SCD) experience cognitive deficits even when unaffected by stroke. Using functional connectivity magnetic resonance imaging (MRI) as a potential biomarker of cognitive function, we tested our hypothesis that children with SCD would have decreased functional connectivity, and that children experiencing the greatest metabolic stress, indicated by elevated oxygen extraction fraction, would have the lowest connectivity. Methods: We prospectively obtained brain MRIs and cognitive testing in healthy controls and children with SCD. Results: We analyzed data from 60 participants (20 controls and 40 with sickle cell disease). There was no difference in global cognition or cognitive subdomains between cohorts. However, we found decreased functional connectivity within the sensory-motor, lateral sensory-motor, auditory, salience, and subcortical networks in participants with SCD compared with controls. Further, as white matter oxygen extraction fraction increased, connectivity within the visual (p = 0.008, parameter estimate = −0.760 [95% CI = −1.297, −0.224]), default mode (p = 0.012, parameter estimate = −0.417 [95% CI = −0.731, −0.104]), and cingulo-opercular (p = 0.009, parameter estimate = −0.883 [95% CI = −1.517, −0.250]) networks decreased. Interpretation: We conclude that there is diminished functional connectivity within these anatomically contiguous networks in children with SCD compared with controls, even when differences are not seen with cognitive testing. Increased white matter oxygen extraction fraction was associated with decreased connectivity in select networks. These data suggest that elevated oxygen extraction fraction and disrupted functional connectivity are potentially presymptomatic neuroimaging biomarkers for cognitive decline in SCD. ANN NEUROL 2020;88:995–1008.
AB - Objective: Children with sickle cell disease (SCD) experience cognitive deficits even when unaffected by stroke. Using functional connectivity magnetic resonance imaging (MRI) as a potential biomarker of cognitive function, we tested our hypothesis that children with SCD would have decreased functional connectivity, and that children experiencing the greatest metabolic stress, indicated by elevated oxygen extraction fraction, would have the lowest connectivity. Methods: We prospectively obtained brain MRIs and cognitive testing in healthy controls and children with SCD. Results: We analyzed data from 60 participants (20 controls and 40 with sickle cell disease). There was no difference in global cognition or cognitive subdomains between cohorts. However, we found decreased functional connectivity within the sensory-motor, lateral sensory-motor, auditory, salience, and subcortical networks in participants with SCD compared with controls. Further, as white matter oxygen extraction fraction increased, connectivity within the visual (p = 0.008, parameter estimate = −0.760 [95% CI = −1.297, −0.224]), default mode (p = 0.012, parameter estimate = −0.417 [95% CI = −0.731, −0.104]), and cingulo-opercular (p = 0.009, parameter estimate = −0.883 [95% CI = −1.517, −0.250]) networks decreased. Interpretation: We conclude that there is diminished functional connectivity within these anatomically contiguous networks in children with SCD compared with controls, even when differences are not seen with cognitive testing. Increased white matter oxygen extraction fraction was associated with decreased connectivity in select networks. These data suggest that elevated oxygen extraction fraction and disrupted functional connectivity are potentially presymptomatic neuroimaging biomarkers for cognitive decline in SCD. ANN NEUROL 2020;88:995–1008.
UR - http://www.scopus.com/inward/record.url?scp=85090943822&partnerID=8YFLogxK
U2 - 10.1002/ana.25891
DO - 10.1002/ana.25891
M3 - Article
C2 - 32869335
AN - SCOPUS:85090943822
SN - 0364-5134
VL - 88
SP - 995
EP - 1008
JO - Annals of neurology
JF - Annals of neurology
IS - 5
ER -