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\begin{document}

\title{Effects of Hydroxyurea on Brain Function in Children with Sickle Cell
Anemia}



\author[1]{Winfred Wang}%
\author[2]{Ping Zou}%
\author[2]{Scott Hwang}%
\author[3]{Guolian Kang}%
\author[4]{Juan Ding}%
\author[1]{Andrew Heitzer}%
\author[5]{Jane Schreiber}%
\author[1]{Kathleen Helton}%
\author[1]{Jane Hankins}%
\affil[1]{St Jude Children's Research Hospital}%
\affil[2]{St. Jude Children's Research Hospital}%
\affil[3]{St.Jude Children's Research Hospital}%
\affil[4]{St. Jude Children’s Research Hospital Memphis}%
\affil[5]{Children's Hospital of Philadelphia}%


\vspace{-1em}



  
  \date{May 28, 2024}


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\begin{abstract}
Introduction: Sickle cell anemia (SCA) results in numerous adverse
effects on the brain, including ischemic lesions and neurocognitive
dysfunction. Hydroxyurea has been utilized extensively for management of
SCA, but its effects on brain function have not been established.
Methods: We examined prospectively the effects of one year of treatment
with hydroxyurea on brain function in a cohort of children with SCA
(HbSS/HbS\selectlanguage{greek}β\selectlanguage{english}0-thalassemia) by baseline and exit evaluations, including
comprehensive neurocognitive testing, transcranial Doppler ultrasound
(TCD), and brain MRI {[}silent cerebral infarcts (SCI), gray matter
cerebral blood flow (GM-CBF), and blood oxygen level dependent (BOLD)
signal from visual stimulation{]}. Results: Nineteen patients with SCA,
mean age 12.4 years (range 7.2-17.8), were evaluated. At baseline,
subjects had these mean values: full scale IQ (FSIQ) 81.9, TCD velocity
133 cm/sec, GM-CBF 64.4 ml/100g/min, BOLD signal 2.34\% increase, and
frequency of SCI 47\%. After one year of hydroxyurea, there were
significant increases in FSIQ (+2.8, p=0.036) and reading comprehension
(+4.8, p=0.016), a significant decrease in TCD velocity (-11.4 cm/sec,
p=0.007), and no significant changes in GM-CBF, BOLD, or SCI frequency.
Furthermore, FSIQ was associated with higher hemoglobin F (HbF) and
lower GM-CBF, but not with hemoglobin level. Discussion: Significant
improvement of neurocognition and decreased TCD velocity following one
year of treatment support the use of hydroxyurea for improving
neurocognitive outcomes in SCA. Understanding the mechanisms of benefit,
as indicated by relationships of neurocognitive function with HbF,
hemoglobin, and CBF, requires further evaluation.%
\end{abstract}%



\sloppy


\textbf{Winfred C. Wang, MD} Emeritus, Member Department of Hematology t
901.595.3497 f 901.595.5696

\emph{winfred.wang@stjude.org}

February 22, 2021

Dr. Peter Newburger, Editor in Chief, Pediatric Blood and Cancer:

We would appreciate your review of ``Effects of Hydroxyurea on Brain
Function in Children with Sickle Cell Anemia'' by Drs. Wang, Zou, Hwang,
Kang, Ding, Heitzer, Schreiber, Helton and Hankins for publication as a
Research Article in PBC.

Our study is the first to study the effect of treatment with hydroxyurea
on brain function in children with sickle cell anemia using a
comprehensive evaluation, which included both neuropsychologic
assessment and functional MRI. Evaluations were performed immediately
before and at the end of one year of treatment with hydroxyurea.
Treatment led to significantly increased full scale IQ score and reading
comprehension and decreased transcranial Doppler velocities. Full scale
IQ was associated with higher Hemoglobin F and lower cerebral blood
velocity. These data provide further support for the use of hydroxyurea
in children with sickle cell anemia because of its enhancement of brain
function.

This manuscript has not been submitted elsewhere nor previously
published. The authors do not have any conflicts of interest. All
authors have contributed to the manuscript in significant ways and have
reviewed and agreed upon the manuscript content.

Potential reviewers: Dr. Alison King (Washington University), Dr. Daniel
Armstrong (University of Miami), Dr. Charles Quinn (University of
Cincinnati). There are no excluded reviewers.

Thank you for your consideration. Sincerely,

Winfred C. Wang, MD\selectlanguage{english}
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