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zone (SVZ) of the lateral ventricles and the dentate gyrus
of the hippocampus – NPCs are critical to recovery
of the CNS from damage, including RT-associated
injury However, NPCs and their progenitor stem
cell populations are highly radiosensitive –
Emerging data suggest that the human brain has neuro-
genic areas similar to the rodent brai that may be
associated with neurocognitive toxicity following RT
and chemotherapy.
Limited retrospective human studies suggest an asso-
ciation between radiation dose to the hippocampus and
temporal lobes and neurocognitive deficits following
cranial irradiation – The relationship between radia-
tion dose to the SVZ and neurocognitive sequelae
remains controversial. Although prophylactic intrathe-
cal methotrexate administration in children with acute
lymphoblastic leukemia has been associated with neuro-
logic toxicity – suggesting a potential relationship
with injury to cells immediately adjacent to the ventri-
cle retrospective data have not demonstrated a corre-
lation between RT dose to the SVZ and neurocognitive
decline following radiation therapy
We present one of the first prospective studies to
examine the relationship between RT dose to NPC
niches, temporal lobes, and cerebrum and neurocogni-
tive dysfunction in children following cranial irradiation
for brain tumors. The a priori hypothesis of this study
was that increased radiation dose to the temporal lobes
and NPC-containing niches would be associated with
decreased performance on follow-up neurocognitive
testing, specifically on tests of memory, executive func-
tion, and motor dexterity.
Materials and Methods
Study Population and Eligibility
Children (n ¼ 19) ages 1–18 years at the time of radia-
tion to the brain for tumors of any histology or prophy-
lactic cranial irradiation were eligible for enrollment in
this prospective study approved by the institutional
review board at The Johns Hopkins Hospital.
Procedures were followed in accordance with the
ethical standards of the Helsinki Declaration of the
World Medical Association. Written consent was ob-
tained prior to enrollment in the study. The comparison
group (n ¼ 55) were healthy, typically developing chil-
dren with no history of psychiatric disorder, neurologic
illness, or learning disability.
Radiation Dose to Brain Structures
The SVZ, hippocampus, temporal lobes, and cerebrum
were manually contoured using the treatment-planning
CT scan and co-registered T1-weighted postgadolinium
contrast and fluid attenuated inversion recovery (FLAIR)
MRIs. The SVZ was defined as a 5-mm region adjacent
to the lateral wall of the lateral ventricle. The contours of
the hippocampus, temporal lobes, and cerebrum were
delineated using an online radiographic atlas as a
reference (http:// . To mini-
mize interindividual differences in measurement, all con-
tours were drawn by a single physician. The initial
contours were then reviewed by a second physician to
confirm their accuracy. Figure shows representative
contours of the hippocampus on an axial T1-weighted
MRI postgadolinium contrast that has been fused to
the treatment-planning CT scan. The mean radiation
dose to each of these structures was calculated from
the dose volume histogram of the restored radiation
treatment plan using the Pinnacle planning system
(Philips).
Neuropsychological Measures
The neuropsychological assessment was designed to
provide a delineation of selected neurobehavioral func-
tions, using nationally standardized tests with good
test-retest reliability that have been validated in the age
range of interest. For this prospective study, we empha-
sized assessment of memory and motor speed, consid-
ered to be most sensitive to radiation effects to NPCs
in the hippocampus and SVZ, respectively. Testing was
performed by a trained master’s-level psychology associ-
ate or postdoctoral neuropsychology fellow under the
supervision of a board-certified neuropsychologist in
an outpatient clinic. Control participants were screened
for psychiatric disorders using the Diagnostic Interview
for Children and Adolescents, Fourth Edition
Neuropsychological testing was performed at baseline
and at approximately 6, 15, and 27 months following
completion of RT in patients and at matched time
points for controls. Not all patients were evaluated on
all tests at all time points, and missing patients varied
among time points. Additionally, some of the youngest
patients were not tested until the later time points. The
neuropsychological protocol was as follows:
Verbal memory was assessed using the Memory for
Words Test a measure of short-term auditory verbal
memory/learning. Tests of declarative learning and rec-
ognition vocabulary are considered to be dependent on
the integrity of subcortical systems, including the thala-
mus and hippocampus.
Vocabulary was measured via the Peabody Picture
Vocabulary Test, third edition which requires the par-
ticipant to identify a picture that best describes a word
by pointing to it or verbalizing its number. Tests of vo-
cabulary are considered to be dependent on temporal
lobe functioning, particularly that of the left temporal
lobe.
Working memory was assessed using (i) the Bead
Memory Test a measure of visual-spatial working
memory in which participants look at a picture of
beads in a given pattern and then reproduce the
pattern from memory; and (ii) the Auditory Working
Memory assessment (Woodcock Johnson version III
[WJ-III]), a measure of auditory verbal memory in
which patients are asked to repeat lists of unrelated
words. Working memory tests are considered to be
Redmond et al.: Radiation to neural progenitor niches and neurocognitive outcomes
NEURO-ONCOLOGY † M A R C H 2 0 1 3 361
at Universitaet Leipzig, Institut fuer Informatik/URZ, Bibliothek on August 25, 2014
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