TY - JOUR
T1 - Longitudinal CSF Iron Pathway Proteins in Posthemorrhagic Hydrocephalus
T2 - Associations with Ventricle Size and Neurodevelopmental Outcomes
AU - and for the Hydrocephalus Clinical Research Network
AU - Strahle, Jennifer M.
AU - Mahaney, Kelly B.
AU - Morales, Diego M.
AU - Buddhala, Chandana
AU - Shannon, Chevis N.
AU - Wellons, John C.
AU - Kulkarni, Abhaya V.
AU - Jensen, Hailey
AU - Reeder, Ron W.
AU - Holubkov, Richard
AU - Riva-Cambrin, Jay K.
AU - Whitehead, William E.
AU - Rozzelle, Curtis J.
AU - Tamber, Mandeep
AU - Pollack, Ian F.
AU - Naftel, Robert P.
AU - Kestle, John R.W.
AU - Limbrick, David D.
N1 - Funding Information:
This project was supported by the Doris Duke Fund to Retain Clinical Scientists (J.M.S.), National Institutes of Health (NIH) R01 NS110793 (J.M.S.), and K23 NS075151‐01A1 (D.L.), Neurosurgeon Research Career Development Program (J.M.S.), the Gerber Foundation Ref. 1692‐3638 (C.N.S.), NIH/NINDS 1RC1NS068943, private philanthropy, and the Hydrocephalus Association. No industry funding was used during the completion of this study. None of the sponsors participated in the design and conduct of this study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of this manuscript.
Funding Information:
Sources of funding for the HCRN: The HCRN is thankful for the following sources of funding: National Institute of Neurological Disorders and Stroke (NINDS grant nos. 1U01NS107486‐01A1 and 1RC1NS068943‐01), Patient Centered Outcome Research Institute (PCORI grant no. CER‐1403‐13857), The Gerber Foundation (reference no. 1692–3638), private philanthropy, and the Hydrocephalus Association. None of the sponsors participated in the design and conduct of this study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of this manuscript. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the sponsors.
Publisher Copyright:
© 2021 American Neurological Association.
PY - 2021/8
Y1 - 2021/8
N2 - Objective: Iron has been implicated in the pathogenesis of brain injury and hydrocephalus after preterm germinal matrix hemorrhage-intraventricular hemorrhage, however, it is unknown how external or endogenous intraventricular clearance of iron pathway proteins affect the outcome in this group. Methods: This prospective multicenter cohort included patients with posthemorrhagic hydrocephalus (PHH) who underwent (1) temporary and permanent cerebrospinal fluid (CSF) diversion and (2) Bayley Scales of Infant Development-III testing around 2 years of age. CSF proteins in the iron handling pathway were analyzed longitudinally and compared to ventricle size and neurodevelopmental outcomes. Results: Thirty-seven patients met inclusion criteria with a median estimated gestational age at birth of 25 weeks; 65% were boys. Ventricular CSF levels of hemoglobin, iron, total bilirubin, and ferritin decreased between temporary and permanent CSF diversion with no change in CSF levels of ceruloplasmin, transferrin, haptoglobin, and hepcidin. There was an increase in CSF hemopexin during this interval. Larger ventricle size at permanent CSF diversion was associated with elevated CSF ferritin (p = 0.015) and decreased CSF hemopexin (p = 0.007). CSF levels of proteins at temporary CSF diversion were not associated with outcome, however, higher CSF transferrin at permanent CSF diversion was associated with improved cognitive outcome (p = 0.015). Importantly, longitudinal change in CSF iron pathway proteins, ferritin (decrease), and transferrin (increase) were associated with improved cognitive (p = 0.04) and motor (p = 0.03) scores and improved cognitive (p = 0.04), language (p = 0.035), and motor (p = 0.008) scores, respectively. Interpretation: Longitudinal changes in CSF transferrin (increase) and ferritin (decrease) are associated with improved neurodevelopmental outcomes in neonatal PHH, with implications for understanding the pathogenesis of poor outcomes in PHH. ANN NEUROL 2021;90:217–226.
AB - Objective: Iron has been implicated in the pathogenesis of brain injury and hydrocephalus after preterm germinal matrix hemorrhage-intraventricular hemorrhage, however, it is unknown how external or endogenous intraventricular clearance of iron pathway proteins affect the outcome in this group. Methods: This prospective multicenter cohort included patients with posthemorrhagic hydrocephalus (PHH) who underwent (1) temporary and permanent cerebrospinal fluid (CSF) diversion and (2) Bayley Scales of Infant Development-III testing around 2 years of age. CSF proteins in the iron handling pathway were analyzed longitudinally and compared to ventricle size and neurodevelopmental outcomes. Results: Thirty-seven patients met inclusion criteria with a median estimated gestational age at birth of 25 weeks; 65% were boys. Ventricular CSF levels of hemoglobin, iron, total bilirubin, and ferritin decreased between temporary and permanent CSF diversion with no change in CSF levels of ceruloplasmin, transferrin, haptoglobin, and hepcidin. There was an increase in CSF hemopexin during this interval. Larger ventricle size at permanent CSF diversion was associated with elevated CSF ferritin (p = 0.015) and decreased CSF hemopexin (p = 0.007). CSF levels of proteins at temporary CSF diversion were not associated with outcome, however, higher CSF transferrin at permanent CSF diversion was associated with improved cognitive outcome (p = 0.015). Importantly, longitudinal change in CSF iron pathway proteins, ferritin (decrease), and transferrin (increase) were associated with improved cognitive (p = 0.04) and motor (p = 0.03) scores and improved cognitive (p = 0.04), language (p = 0.035), and motor (p = 0.008) scores, respectively. Interpretation: Longitudinal changes in CSF transferrin (increase) and ferritin (decrease) are associated with improved neurodevelopmental outcomes in neonatal PHH, with implications for understanding the pathogenesis of poor outcomes in PHH. ANN NEUROL 2021;90:217–226.
UR - http://www.scopus.com/inward/record.url?scp=85108894778&partnerID=8YFLogxK
U2 - 10.1002/ana.26133
DO - 10.1002/ana.26133
M3 - Article
C2 - 34080727
AN - SCOPUS:85108894778
SN - 0364-5134
VL - 90
SP - 217
EP - 226
JO - Annals of neurology
JF - Annals of neurology
IS - 2
ER -