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Association between radiation dose to
neuronal progenitor cell niches and temporal
lobes and performance on neuropsychological
testing in children: a prospective study
Kristin J. Redmond, E. Mark Mahone, Stephanie Terezakis, Omar Ishaq, Eric Ford,
Todd McNutt, Lawrence Kleinberg, Kenneth J. Cohen, Moody Wharam, and
Alena Horska
Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University,
Baltimore, Maryland (K.J.R., S.T., O.I., T.M., L.K., M.W.); Department of Neuropsychology, Kennedy Krieger
Institute, Baltimore, Maryland (E.M.M.); Department of Radiation Oncology, University of Washington,
Seattle, Washington (E.F.); Division of Pediatric Oncology, The Sidney Kimmel Comprehensive Cancer Center,
Baltimore, Maryland (K.J.C.); Russell H. Morgan Department of Radiology and Radiological Science,
The Johns Hopkins University, Division of Neuroradiology, Baltimore, Maryland (A.H.)
Background. Neurocognitive toxicity from radiation
therapy (RT) for brain tumors may be related to
damage to neural progenitor cells that reside in the sub-
ventricular zone and hippocampus. This prospective
study examines the relationship between RT dose to
neural progenitor cell niches, temporal lobes, and cere-
brum and neurocognitive dysfunction following cranial
irradiation.
Methods. Standardized assessments of motor speed/
dexterity, verbal memory, visual perception, vocabulary,
and visuospatial working memory were conducted in 19
pediatric patients receiving cranial RT and 55 controls at
baseline and 6, 15, and 27 months following completion
of RT. Prescription doses ranged from 12 Gy to 59.4 Gy.
Linear mixed effects regression model analyses were
used to examine the relationships among neuropsycho-
logical performance, age, and radiation dose to the
subventricular zone, hippocampus, temporal lobes, and
cerebrum.
Results. Performance on all neuropsychological tests,
except vocabulary, was significantly reduced in patients
relative to controls, particularly among younger
children. Performance on motor speed/ dexterity de-
creased with increasing dose to hippocampus (P , .05)
and temporal lobes (P , .035). There was also a signifi-
cant relationship between (i) reduced performance on
verbal learning and increasing dose to the cerebrum
(P ¼ .022) and (ii) reduced performance on visual per-
ception and increasing dose to the left temporal lobe
(P ¼ .038). There was no association between radiation
dose to evaluated structures and performance on vocab-
ulary or visuospatial working memory.
Conclusions. These prospective data demonstrate a
significant association between increasing RT dose to
hippocampus and temporal lobes and decline in neuro-
cognitive skills following cranial irradiation. These find-
ings have important implications for trials, including
RTOG 0933 (hippocampal-sparing whole brain radia-
tion therapy for brain metastases).
Keywords: brain irradiation, brain tumor, neural
progenitor cell niches, neuropsychological performance.
Radiation therapy (RT) is integral to the manage-
ment of a wide variety of both pediatric and
adult brain tumors. However, RT to the brain is
associated with neurocognitive toxicity – The etiology
of radiation injury to the brain is likely multifactorial,
but data suggest that injury to neural progenitor cells
(NPCs) plays a role –
Within the mammalian brain, NPCs are known to
reside in 2 areas, or NPC niches: the subventricular
Presented in part at the American Society for Radiation Oncology 2011
Annual Meeting in Miami, FL and at the Society for Neuro-Oncology
2011 Annual Meeting in Anaheim, CA.
Corresponding Author: Kristin J. Redmond, MD, MPH, 401 North
Broadway, Suite 1440, Baltimore, MD 21231 .
Received August 8, 2012; accepted October 30, 2012.
Neuro-Oncology 15(3):360–369, 2013.
doi:10.1093/neuonc/nos303 NEURO - ONCOLOGY
Advance Access publication January 14, 2013
# The Author(s) 2013. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.
All rights reserved. For permissions, please e-mail:
at Universitaet Leipzig, Institut fuer Informatik/URZ, Bibliothek on August 25, 2014
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