Frontal gray matter reduction after breast cancer chemotherapy and association with executive symptoms: A replication and extension study.
ABSTRACT Cognitive changes related to cancer and its treatment have been intensely studied, and neuroimaging has begun to demonstrate brain correlates. In the first prospective longitudinal neuroimaging study of breast cancer (BC) patients we recently reported decreased gray matter density one month after chemotherapy completion, particularly in frontal regions. These findings helped confirm a neural basis for previously reported cognitive symptoms, which most commonly involve executive and memory processes in which the frontal lobes are a critical component of underlying neural circuitry. Here we present data from an independent, larger, more demographically diverse cohort that is more generalizable to the BC population. BC patients treated with (N=27) and without (N=28) chemotherapy and matched healthy controls (N=24) were scanned at baseline (prior to systemic treatment) and one month following chemotherapy completion (or yoked intervals for non-chemotherapy and control groups) and APOE-genotyped. Voxel-based morphometry (VBM) showed decreased frontal gray matter density after chemotherapy, as observed in the prior cohort, which was accompanied by self-reported difficulties in executive functioning. Gray matter and executive symptom changes were not related to APOE ε4 status, though a somewhat greater percentage of BC patients who received chemotherapy were ε4 allele carriers than patients not treated with chemotherapy or healthy controls. These findings provide confirmatory evidence of frontal morphometric changes that may be a pathophysiological basis for cancer and treatment-related cognitive dysfunction. Further research into individual risk factors for such changes will be critical for development of treatment and prevention strategies.
- SourceAvailable from: Catherine Bielajew[show abstract] [hide abstract]
ABSTRACT: Introduction: Cognitive deficits are a side-effect of chemotherapy, however pre-treatment research is limited. This study examines neurofunctional differences during working memory between breast cancer (BC) patients and controls, prior to chemotherapy. Methods: Early stage BC females (23), scanned after surgery but before chemotherapy, were individually matched to non-cancer controls. Participants underwent functional magnetic resonance imaging (fMRI) while performing a Visuospatial N-back task and data was analyzed by multiple group comparisons. fMRI task performance, neuropsychological tests, hospital records, and salivary biomarkers were also collected. Results: There were no significant group differences on neuropsychological tests, estrogen, or cortisol. Patients made significantly fewer commission errors but had less overall correct responses and were slower than controls during the task. Significant group differences were observed for the fMRI data, yet results depended on the type of analysis. BC patients presented with increased activations during working memory compared to controls in areas such as the inferior frontal gyrus, insula, thalamus, and midbrain. Individual group regressions revealed a reverse relationship between brain activity and commission errors. Conclusion: This is the first fMRI investigation to reveal neurophysiological differences during visuospatial working memory between BC patients pre-chemotherapy and controls. These results also increase the knowledge about the effects of BC and related factors on the working memory network. Significance: This highlights the need to better understand the pre-chemotherapy BC patient and the effects of associated confounding variables.Frontiers in Human Neuroscience 01/2011; 5:122. · 2.91 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Prechemotherapy neuroimaging data are lacking in posttreatment cognitive impairment studies. Breast cancer patients and noncancer controls were scanned prior to chemotherapy during a response inhibition task. Task reaction times and error rates, as well as neuropsychological tests, hospital records, and salivary biomarkers, were investigated, yielding no significant group differences. Significant group differences observed for the functional magnetic resonance imaging (fMRI) data depended on the type of analysis performed, most consistently implicating widespread attenuated activations in patients. The patient group also revealed considerable variability in task-related brain activity. These pretreatment differences highlight the need to understand the effects of confounding variables before considering posttreatment effects. Role of the funding source: The Canadian Breast Cancer Foundation has funded this project. Their contribution was solely financial support.Journal of Clinical and Experimental Neuropsychology 03/2012; 34(5):543-60. · 1.86 Impact Factor
Article: Voxel-Based Morphometry—The Methods[show abstract] [hide abstract]
ABSTRACT: At its simplest, voxel-based morphometry (VBM) involves a voxel-wise comparison of the local concentration of gray matter between two groups of subjects. The procedure is relatively straightforward and involves spatially normalizing high-resolution images from all the subjects in the study into the same stereotactic space. This is followed by segmenting the gray matter from the spatially normalized images and smoothing the gray-matter segments. Voxel-wise parametric statistical tests which compare the smoothed gray-matter images from the two groups are performed. Corrections for multiple comparisons are made using the theory of Gaussian random fields. This paper describes the steps involved in VBM, with particular emphasis on segmenting gray matter from MR images with nonuniformity artifact. We provide evaluations of the assumptions that underpin the method, including the accuracy of the segmentation and the assumptions made about the statistical distribution of the data.NeuroImage 07/2000; · 6.25 Impact Factor
Frontal gray matter reduction after breast cancer chemotherapy and association
with executive symptoms: A replication and extension study
Brenna C. McDonald⇑, Susan K. Conroy, Dori J. Smith, John D. West, Andrew J. Saykin⇑
Center for Neuroimaging, Department of Radiology and Imaging Sciences and The Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis,
IN, United States
a r t i c l ei n f o
Available online 18 May 2012
Magnetic resonance imaging
a b s t r a c t
Cognitive changes related to cancer and its treatment have been intensely studied, and neuroimaging has
begun to demonstrate brain correlates. In the first prospective longitudinal neuroimaging study of breast
cancer (BC) patients we recently reported decreased gray matter density one month after chemotherapy
completion, particularly in frontal regions. These findings helped confirm a neural basis for previously
reported cognitive symptoms, which most commonly involve executive and memory processes in which
the frontal lobes are a critical component of underlying neural circuitry. Here we present data from an
independent, larger, more demographically diverse cohort that is more generalizable to the BC popula-
tion. BC patients treated with (N = 27) and without (N = 28) chemotherapy and matched healthy controls
(N = 24) were scanned at baseline (prior to systemic treatment) and one month following chemotherapy
completion (or yoked intervals for non-chemotherapy and control groups) and APOE-genotyped. Voxel-
based morphometry (VBM) showed decreased frontal gray matter density after chemotherapy, as
observed in the prior cohort, which was accompanied by self-reported difficulties in executive function-
ing. Gray matter and executive symptom changes were not related to APOE e4 status, though a somewhat
greater percentage of BC patients who received chemotherapy were e4 allele carriers than patients not
treated with chemotherapy or healthy controls. These findings provide confirmatory evidence of frontal
morphometric changes that may be a pathophysiological basis for cancer and treatment-related cognitive
dysfunction. Further research into individual risk factors for such changes will be critical for development
of treatment and prevention strategies.
? 2012 Elsevier Inc. All rights reserved.
Cognitive changes related to breast cancer and its treatment
have been an area of increasing study, with numerous reports
demonstrating cognitive impairment in patients relative to con-
trols. These changes have been differentially attributed to chemo-
therapy, radiation, and anti-estrogen treatment (Agrawal et al.,
2010; Ahles et al., 2010; Collins et al., 2009; Jim et al., 2009; Ques-
nel et al., 2009), and have been reported most prominently in exec-
utive functions (e.g., working memory) and processing speed,
cognitive processes largely subserved by frontally mediated brain
systems (impairment in other cognitive domains has also been
noted; for review and meta-analysis see (Anderson-Hanley et al.,
2003; Correa and Ahles, 2008; Stewart et al., 2006)). A higher than
expected incidence of impaired cognitive performance has also
been found in patients prior to systemic treatment (Ahles et al.,
2008; Wagner et al., 2006; Wefel et al., 2004), suggesting that host
factors and/or the cancer disease process itself may play a role. This
prior work demonstrates the continued need for further investiga-
tion of the effects of cancer treatment and the disease process on
cognition in vulnerable individuals (McDonald and Saykin, 2011;
Vardy et al., 2008).
The neural mechanisms underlying these cognitive changes
have likewise been the subject of increasing investigation. Several
cross-sectional, retrospective structural MRI studies have utilized
voxel-based morphometry (VBM) to assess gray matter changes
after breast cancer treatment quantitatively, in an automated,
unbiased manner (de Ruiter et al., in press; Hakamata et al.,
2007; Inagaki et al., 2007; McDonald et al., 2008; Saykin et al.,
2003; Yoshikawa et al., 2006). Those studies comparing gray mat-
ter between patients who did and did not receive chemotherapy
have demonstrated residual gray matter deficits in the chemother-
apy-treated group, even several years after treatment completion
(de Ruiter et al., in press; Inagaki et al., 2007; McDonald et al.,
2008; Saykin et al., 2003). We recently reported the first prospec-
tive VBM study examining such gray matter changes relative to
pre-treatment baseline (McDonald et al., 2010). We predicted that
0889-1591/$ - see front matter ? 2012 Elsevier Inc. All rights reserved.
⇑Corresponding authors. Address: Center for Neuroimaging, Department of
Radiology and Imaging Sciences, Indiana University School of Medicine, 950 W.
Walnut St., R2 E124, Indianapolis, IN 46202, United States. Tel.: +1 317 274 2067;
fax: +1 317 274 1067.
E-mail addresses: firstname.lastname@example.org (B.C. McDonald), email@example.com
Brain, Behavior, and Immunity 30 (2013) S117–S125
Contents lists available at SciVerse ScienceDirect
Brain, Behavior, and Immunity
journal homepage: www.elsevier.com/locate/ybrbi
these changes would be detectable in the short-term but would
recover at least partially over time, given prior cognitive studies
suggesting longitudinal improvement in brain function after che-
motherapy (Ahles et al., 2010; Collins et al., 2009; Jansen et al.,
2011; Jenkins et al., 2006; Schagen et al., 2002). Findings were con-
sistent with study hypotheses, demonstrating reduced gray matter
in chemotherapy-treated patients one month after chemotherapy
completion in bilateral frontal, medial temporal, and cerebellar re-
gions. One year later gray matter density had returned to baseline
levels in some regions, though not all. No between-group differ-
ences were found at baseline, and changes were not seen in pa-
tients who did not receive chemotherapy or healthy controls.
The purpose of the current investigation was to assess gray
matter alterations related to breast cancer and its treatment pro-
spectively in an independent cohort of patients treated with and
without standard-dose systemic chemotherapy and demographi-
cally matched healthy controls, in order to replicate our previous
findings. Given the prominence of executive function changes
among the cognitive domains affected in cancer patients after
treatment (Anderson-Hanley et al., 2003), and the recent finding
of a relationship between self-reported executive functioning and
altered brain activation after breast cancer chemotherapy (Kesler
et al., 2011), we also sought to examine the relationship of these
gray matter changes to self-reported executive functioning. Finally,
a large body of research has shown a significant relationship be-
tween the apolipoprotein E (APOE) e4 allele and Alzheimer’s dis-
ease and its precursors, and has demonstrated a role for APOE in
other neurocognitive disorders (for reviews see (Bookheimer and
Burggren, 2009; Smith, 2000)). Given prior work demonstrating
decreased cognitive functioning in cancer survivors treated with
chemotherapy who carried the e4 allele vs. those who did not
(Ahles et al., 2003), we further evaluated possible risk factors for
gray matter changes after chemotherapy by investigating their
relationship to presence or absence of the APOE e4 allele.
Written informed consent was obtained from all participants
according to the Declaration of Helsinki under a protocol approved
by the Indiana University Institutional Review Board. Participants
were female breast cancer patients treated with (CTx+, N = 27)
and without (CTx?, N = 28) systemic chemotherapy and healthy
controls (N = 24). Patients had non-invasive (stage 0) or non-met-
astatic invasive (stages I, II, or III) disease, and were treated with
common standard-dose chemotherapy
included a taxane (see Table 1 for demographic and treatment
data). Exclusion criteria for all groups were: (1) prior treatment
with cancer chemotherapy, CNS radiation, or intrathecal therapy;
(2) current or past alcohol or drug dependence; (3) neurobehavior-
al risk factors including neurologic, medical, or psychiatric condi-
tions known to affect brain structure or function, except history
of depression or anxiety in breast cancer patients. Potential partic-
ipants for all groups were excluded for current diagnosis of any
DSM-IV Axis I disorder or a history of any psychiatric disorder
requiring hospitalization. Anxiety and depression symptoms were
assessed at each study visit with the Center for Epidemiologic
Studies-Depression Scale (CES-D) (Radloff, 1977) and the State-
Trait Anxiety Inventory-State subscale (STAI-S) (Spielberger, 1983).
Study measures were completed at baseline (after surgery but
before radiation, chemotherapy, and/or anti-estrogen treatment)
and approximately one month following the completion of chemo-
therapy (M1), or yoked intervals for the CTx? and control groups,
for all participants except nine CTx+ patients who received neoad-
juvant chemotherapy prior to surgery and additional treatment.
For these nine participants the baseline study visit was prior to
both cancer surgery and systemic treatment, and the second study
visit was approximately one month after chemotherapy comple-
tion. For CTx+ patients the baseline visit was conducted on average
9.9 days (SD 11.0) prior to the start of chemotherapy (range 1–
43 days). One CTx? participant began tamoxifen about three
weeks prior to her baseline scan. Of note, data reported here are
drawn from a larger study in which participants undergo a com-
prehensive assessment including structural and functional neuro-
imaging, objective and subjective cognitive evaluation, and
genetic and other biomarkers at three time-points. Data collection
is ongoing, particularly for the final study visit (not reported here,
given our current partial sample), and the present findings there-
fore represent an interim analysis of a subset of the larger study.
2.1. Self-reported executive function
Self-report of executive functioning was obtained with the
Behavior Rating Inventory of Executive Function-Adult Version
(BRIEF-A) (Roth et al., 2005), which includes an overall composite
score (the Global Executive Composite, or GEC) and two major in-
dex scores: the Behavioral Regulation Index (BRI), composed of the
Inhibit, Shift, Emotional Control and Self-Monitor scales, and the
Metacognition Index (MI), which includes the Initiate, Working
Memory, Plan/Organize, Task Monitor, and Organization of Materi-
als scales. Between-group differences on BRIEF-A scale and index
T-scores were compared using the general linear model in SPSS
(SPSS Statistics 19, IBM Corporation, Somers, NY) to examine dif-
ferences in self-reported executive function at M1 controlling for
baseline levels. Of note, higher T-scores on this measure indicate
greater levels of executive complaints.
2.2. APOE genotyping
APOE alleles were determined using standard assays for the two
single nucleotide polymorphisms (SNPs) coding for the e4
(rs429358) and e2 (rs7412) vs. more common e3 allele of APOE.
Participants who were carriers of one or two copies of the e4 allele
were considered APOE e4 positive. Within the CTx+ group, differ-
ences between APOE e4 positive and negative patients for signifi-
cant gray matter clusters and BRIEF-A scales were compared
using the general linear model in SPSS (SPSS Statistics 19, IBM Cor-
poration, Somers, NY) to examine differences at M1 controlling for
2.3. MRI scan acquisition
All scans were acquired on the same Siemens Tim Trio 3T scan-
ner using a 12-channel head coil. A T1-weighted three-dimen-
sional magnetization prepared rapid gradient echo (MPRAGE)
volume was used for VBM, with the following parameters:
TR = 2300 ms,TE = 2.98 ms,FOV = 256 mm,
1.2 mm thick sagittal slices with no skip, 256 ? 256 matrix, in-
plane resolution of 1 mm2. This MPRAGE sequence has been
extensively tested and validated via the multicenter, international
Alzheimer’s Disease Neuroimaging Initiative (ADNI) study (see
http://adni.loni.ucla.edu/ for additional information). T2-weighted
and fluid-attenuated inversion recovery (FLAIR) sequences were
also acquired to rule out incidental pathology.
FA = 9 deg, 160
2.4. Image analysis
Locally developed MATLAB (R2009b, Mathworks, Inc., Natick,
MA) scripts were used to implement optimized VBM methods
B.C. McDonald et al./Brain, Behavior, and Immunity 30 (2013) S117–S125
(Ashburner and Friston, 2000; Ashburner and Friston, 2001; Good
et al., 2001) using SPM (Version 8, Wellcome Department of Imag-
ing Neuroscience, London, UK), similar to our prior longitudinal
study (McDonald et al., 2010). Briefly, after reconstruction
MPRAGE follow-up scans were registered to the baseline scan for
each subject. Scans were then registered to the Montreal Neurolog-
ical Institute (MNI) T1-weighted template and segmented into gray
matter, white matter, and cerebrospinal fluid compartments using
the MNI T1-weighted template and corresponding tissue probabil-
ity maps. Gray matter maps were then spatially normalized to MNI
space, resampled to 1 mm isotropic voxels, and smoothed using an
isotropic Gaussian spatial filter (FHWM = 10 mm) to reduce resid-
ual inter-individual variability. The smoothed, normalized gray
matter maps were subjected to statistical parametric mapping on
a voxel-by-voxel basis using the general linear model as imple-
mented in SPM8. The SPM8 prior probability gray matter template
was used to restrict the statistical comparisons to the gray matter
compartment. As multiple prior structural and functional MRI
studies in breast cancer patients have consistently shown altera-
tions in frontal brain regions (Cimprich et al., 2010; de Ruiter
et al., 2011; Inagaki et al., 2007; Kesler et al., 2009; Kesler et al.,
2011; McDonald et al., 2010; Scherling et al., 2011; Silverman
et al., 2007), all imaging analyses were restricted to the frontal
lobes using a mask composed of frontal lobe subregions from the
WFU PickAtlas toolbox in SPM8, which was included as an explicit
mask in the SPM8 design matrix.
Random effects analyses were conducted using analysis of
variance (ANOVA) to construct contrast maps of voxels in which
local gray matter density differed between groups and over time.
Comparisons were conducted within an omnibus group (three
independent levels: CTx+, CTx?, control) by time (two non-inde-
pendent levels: baseline, M1) ANOVA. The critical significance
threshold (Pcrit) was set to 0.001. Cluster extent (k) for all analyses
was set to limit results only to regions that survived an unbiased
search of the entire frontal region of interest at a cluster-level
threshold of PFWE-corrected< 0.05. Within the omnibus SPM8 ANOVA
design matrix between-group comparisons were conducted using
weighted contrast vectors. For example, pair-wise comparisons of
gray matter density at baseline (CTx+ vs. CTx?, CTx+ vs. control,
CTx? vs. control) were conducted by entering values of 1 and -1
in the appropriate columns in the matrix. In this manner examina-
tion of regions where controls showed greater gray matter density
than CTx+ at baseline would be conducted by entering 1 in the con-
trol baseline column and ?1 in the CTx+ baseline column. Group-
by-time interactions were conducted in a similar fashion. For
example, to evaluate regions in which the control and CTx+ groups
showed significant differences from baseline to M1, values of 1
would be entered in the CTx+ baseline and control M1 columns,
and values of ?1 would be entered in the CTx+ M1 and control
baseline columns (and vice versa for the inverse interaction).
We hypothesized that gray matter decreases would be seen
from baseline to M1 in the CTx+ group, consistent with our prior
findings in an independent cohort (McDonald et al., 2010). Mean
values for significant clusters in the analysis of regions showing
decreasing gray matter density from baseline to M1 in the CTx+
group were extracted using MarsBaR v0.42 (http://marsbar.source-
forge.net/). The general linear model in SPSS was used to investi-
gate the relationship of these mean gray matter change values in
(N = 27)
(N = 28)
(N = 24)
Age at baseline (yrs.)
Estimated full scale IQ (Barona Index (Barona et al., 1984))
Percent Caucasian, Non-hispanic
CES-D raw score: Baseline10.8 (9.5)
STAI-S raw score: baseline
Inter-scan interval (days)158.7 (68.9) 204.3 (151.7)160.8 (28.9)
Cancer stage: 0 (DCIS)0
Number on anti-estrogen therapya,b: baseline
Values are Mean (SD).
CES-D = Center for Epidemiologic Studies-Depression Scale.
STAI-S = State-Trait Anxiety Inventory-State subscale.
M1 = one month post chemotherapy completion (or yoked intervals).
aDetails regarding radiation, chemotherapy regimen, and anti-estrogen treatment were not available for one CTx+ patient.
bANA = anastrozole; TAM = tamoxifen; LET = letrozole; EXE = exemestane; RAL = raloxifene.
cNine CTx+ patients were also treated with trastuzumab; one was also treated with sunitinib; one was also treated with bevacizumab.
B.C. McDonald et al./Brain, Behavior, and Immunity 30 (2013) S117–S125
the CTx+ group to APOE status, examining between-group differ-
ences in M1 gray matter density accounting for baseline levels.
To evaluate relationships between self-reported executive function
symptoms and gray matter linear regression in SPSS was used to
calculate adjusted T-scores for M1 accounting for baseline score.
These were then entered as a covariate into the SPM8 design
matrix separately for each group (CTx+, CTx?, control) to assess
positive and negative correlations with gray matter density at M1.
As expected and consistent with conventional treatment pat-
terns, CTx+ patients had significantly higher stage disease than
CTx? patients (v2= 18.08, df = 3, P < 0.001). There were no other
between-group demographic differences, and no group-by-time
interactions were observed for depression or anxiety symptoms
(CES-D, STAI-S; P > 0.05, Table 1). The second scan session was
about six months after the baseline visit on average, and interscan
intervals did not differ between groups (P > 0.05, Table 1). MNI
coordinates, cluster extents, P values, T and Z scores, and region
descriptions are presented in Table 2. Imaging analyses described
below were repeated including age as a covariate to control for
possible gray matter density decline with aging, without a signifi-
cant change in the pattern of findings.
3.1. Between-group analyses
At baseline the only significant between-group difference was a
single cluster in the left cingulate gyrus in which controls showed
greater gray matter than CTx? patients (Table 2). Group-by-time
interaction analyses showed reduced gray matter density in CTx+
patients relative to controls at M1 relative to baseline in the left
middle frontal gyrus (Fig. 1). This pattern of change over time
was not apparent for the CTx- group. There were no regions where
the control group showed lower gray matter than either cancer
group at M1 relative to baseline, nor were there any regions where
a significant group-by-time interaction was found between the
two cancer groups from baseline to M1.
3.2. Within-group analyses
At M1 relative to baseline the CTx+ group showed decreased
gray matter density in the left middle and superior frontal gyri
(Fig. 2), including in the same middle frontal gyrus regions shown
to be significant in the interaction analyses above. Within the con-
trol and CTx? groups there were no gray matter regions which
showed significant decline from baseline to M1. There were also
no regions showing increased gray matter from baseline to M1
for any group.
3.3. Self-reported executive function changes and relationship to gray
There were no between-group differences in BRIEF-A T-scores
at baseline for any scale or index (Table 3). Longitudinal analysis
of BRIEF-A T-scores revealed a significant difference in the Initiate
scale (P = 0.011), with CTx+ patients showing increased scores over
time, indicating more self-perceived symptoms in the area of abil-
ity to initiate problem-solving or activity. A trend in the same
direction was also evident on the BRIEF-A Working Memory scale
(P = 0.054). No significant differences were evident on other scales.
Graphical representation of raw T-score changes (Fig. 3) demon-
strates that for many BRIEF-A scales, particularly those which
make up the Metacognition Index, CTx+ patients showed the great-
est score increase at M1 relative to baseline, indicative of greater
increase in self-perceived executive difficulties.
When BRIEF-A Initiate scale adjusted T-score was entered as a
covariate into the SPM8 design matrix, a significant negative corre-
lation with M1 gray matter density was seen in the left middle
frontal gyrus for the CTx+ group (Table 2, Fig. 4), indicating that
Regional gray matter changes (Pcrit< 0.001, cluster-level PFWE-corr< 0.05).
MNI coordinates (x y z)Cluster extent (k)Cluster-level PFWE-corrected
TZRegion description (for cluster peak)
Control > CTx? at baseline
?22 ?14 43
Interaction Control > CTx+ from baseline to M1
?49 41 30
Within-Group (CTx+) Analyses
Gray matter decline from baseline to M1
?12 36 50
?45 37 29
Correlation with BRIEF-A initiate scale adjusted T-score
?27 52 ?7
BA = Brodmann area.
1566 0.0015.78 5.49L cingulate gyrus (BA24)
13570.0024.18 4.06 L middle frontal gyrus (BA46)
L superior frontal gyrus (BA8)
L middle frontal gyrus (BA46)
14100.0357.19 5.24L middle frontal gyrus (BA10)
Fig. 1. Between-group interaction analyses of regional gray matter density declines in chemotherapy-treated breast cancer patients relative to healthy controls from baseline
to one month after chemotherapy (Pcrit< 0.001, cluster-level PFWE-corr< 0.05, see Table 2 for region descriptions).
B.C. McDonald et al./Brain, Behavior, and Immunity 30 (2013) S117–S125
reduced gray matter density was associated with higher levels of
executive complaints in this domain. There were no positive
correlations between Initiate scale adjusted T-score and gray mat-
ter density at M1 in the CTx+ group, and no significant relation-
ships in either direction were apparent at this threshold for the
CTx? or control groups.
3.4. Relationship of gray matter and BRIEF-A changes to APOE status
Regions of gray matter which showed significant decline from
baseline to M1 and BRIEF-A initiate scale T-scores (where a signif-
icant difference over time was seen in the CTx+ group, as noted
above) were compared between APOE e4 positive and negative
CTx+ patients, but no significant between-group differences were
observed (all P > 0.05). Of note, a higher percentage of patients in
the CTx+ group were e4 positive than in the other two groups
(CTx+ 42%, CTx? 21%, control 25%; APOE status was not available
for one CTx+ patient), though this difference was not statistically
These findings replicate our previous work showing decreased
frontal gray matter shortly after chemotherapy completion in
breast cancer patients. Relative to our prior study (McDonald
et al., 2010), the current cohort is larger, more racially and ethni-
cally diverse, includes patients receiving neoadjuvant chemother-
apy, and was conducted on a new generation 3T vs. older 1.5T
magnet. Demonstration of reduced frontal gray matter in this
cohort provides independent confirmation of the prior results,
strengthening the evidence that breast cancer chemotherapy is
associated with frontal gray matter changes. Also consistent with
our prior work, such changes were not evident in controls or pa-
tients who received anti-estrogen treatment but not chemother-
apy, suggesting that these frontal gray matter decreases are
specific to chemotherapy treatment, rather than solely reflecting
host factors, the cancer disease process, or effects of other cancer
treatments. Gray matter changes in the current study were also
consistent with frontal regions in which prior work has demon-
strated structural and functional abnormalities in breast cancer pa-
tients prior to adjuvant treatment (Scherling et al., 2011, 2012),
post-treatment (de Ruiter et al., 2011; Kesler et al., 2009; Kesler
et al., 2011; McDonald et al., 2010; Silverman et al., 2007), and lon-
gitudinally (McDonald et al., in press), further supporting the
importance of frontal abnormalities in the observed subjective
and objective cognitive changes.
These findings extend our prior prospective work by demon-
strating self-reported executive complaints that follow the same
pattern as gray matter changes. Across BRIEF-A subscales, and par-
ticularly in the area of metacognitive functioning, chemotherapy-
treated patients were more likely to show increased T-scores from
baseline to one month post-treatment, indicative of greater per-
ceived executive dysfunction. The CTx+ group also showed the only
significant increase in symptoms over time (on the Initiate scale),
and a trend in the same direction on the Working Memory scale.
Change in Initiate scale adjusted T-score showed a negative corre-
lation with gray matter density one month after chemotherapy
completion (reduced gray matter density at M1 was correlated
with greater executive complaints). No such correlation was seen
Fig. 2. Regional gray matter density declines in chemotherapy-treated breast cancer patients from baseline to one month after chemotherapy (Pcrit< 0.001, cluster-level PFWE-
corr< 0.05, see Table 2 for region descriptions).
Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) T-scores.
(N = 27)
(N = 28)
(N = 24)a
Baseline M1Baseline M1 BaselineM1
Behavioral regulation index
Organization of materials
Global executive composite
Values are mean (sd) of scale/index T-scores, higher score reflects greater complaints.
aOne control participant did not complete the BRIEF-A at M1.
*Significant between-group difference at M1 controlling for baseline (P = 0.011), CTx+ group showing greatest change.
^Trend for between-group difference at M1 controlling for baseline (P = 0.054), CTx+ group showing greatest change.
B.C. McDonald et al./Brain, Behavior, and Immunity 30 (2013) S117–S125
in patients who did not receive chemotherapy or controls. These
findings are consistent with prior cognitive studies showing great-
er symptoms in the short-term following chemotherapy treatment.
In addition, the frontal regions in which we found significant gray
matter changes over time and correlations with executive com-
plaints (Brodmann areas 8, 10, and 46) are the same regions where
a recent study demonstrated functional abnormalities in breast
cancer patients post-treatment and found relationships between
brain activation and self-perceived executive functioning as mea-
sured by the BRIEF-A (Kesler et al., 2011). Our findings therefore
provide independent support for Kesler et al.’s previous results.
In addition, previous work has demonstrated that BRIEF-A mea-
sures correlate with frontal lobe volume in schizophrenia (Garling-
house et al., 2010). Our findings therefore offer additional support
for the BRIEF-A as a measure sensitive to functionally meaningful
brain changes in neuropsychiatric populations.
In our prior cohort there were no between-group differences
apparent at baseline. In the current study, the only baseline
difference was a single cluster in the left cingulate gyrus in which
CTx? patients showed lower gray matter density than controls.
This finding seems unlikely to be related to cancer per se, as no
such group difference was seen in the CTx+ group. In addition,
our primary interest was in examination of changes over time. As
this region showed no significant change over time in within-
group or interaction analyses, it remains of uncertain clinical sig-
nificance. We also examined self-reported symptoms of depression
and anxiety (CES-D, STAI-S). As in our prior cohort, there were no
significant group-by-time interactions on these factors, and group
means were below levels typically considered to be clinically sig-
nificant, suggesting that these psychosocial factors do not account
for the observed differences in gray matter density or self-reported
While at present the systemic effects of chemotherapy and
other cancer treatments remain poorly understood, we and others
have proposed possible mechanisms for chemotherapy-induced
cognitive and brain changes, including chemotherapy-induced
DNA damage (directly or through increases in oxidative stress),
individual variation in genes related to neural repair and/or
Fig. 3. T-score changes for BRIEF-A scales and indexes from baseline to M1. Note relatively greater increases for CTx+ patients on scales which make up the Metacognition
Index (Initiate, WM, PO, TM, OM). (BRIEF-A = Behavior Rating Inventory of Executive Function-Adult Version, BL = baseline, M1 = one month after chemotherapy completion,
CTx+ = chemotherapy-treated, CTx? = nonchemotherapy-treated, HC = healthy control, EC = Emotional Control, SM = Self-Monitor, WM = Working Memory, PO = Plan/
Organize, TM = Task Monitor, OM = Organization of Materials, BRI = Behavioral Regulation Index, MI = Metacognition Index, GEC = Global Executive Composite).
Fig. 4. Negative correlation of BRIEF-A Initiate scale adjusted T-score with gray matter density one month after chemotherapy completion (Pcrit< 0.001, cluster-level
PFWE-corr< 0.05, see Table 2 for region descriptions, BRIEF-A = Behavior Rating Inventory of Executive Function-Adult Version).
B.C. McDonald et al./Brain, Behavior, and Immunity 30 (2013) S117–S125
plasticity, and chemotherapy-induced hormonal changes (Ahles
and Saykin, 2007). The question of whether chemotherapy-related
cognitive and brain changes are related to direct cytotoxic effects
of chemotherapeutic agents crossing the blood–brain barrier has
not been conclusively addressed. All but one of the CTx+ partici-
pants in the current study received cyclophosphamide, carbo-
platin, or cisplatin, and all CTx+ patients in the prior cohort
received cyclophosphamide. As these agents are believed to cross
the blood–brain barrier to some degree, this remains a possible
explanation for the observed decreases in gray matter density.
Prior work has also suggested that such cancer and treatment-
related changes are likely to affect only a subgroup of cancer
patients, who may be more vulnerable to these effects for as yet
undetermined reasons. Previous studies have suggested that pa-
tients who have more advanced stage disease, are older at the time
of breast cancer diagnosis, have lower baseline cognitive reserve, or
are APOE e4 positive may be at increased risk for cognitive changes
related to cancer and its treatment (Ahles et al., 2008; Ahles et al.,
2010; Ahles et al., 2003). To examine a potential biological mecha-
nism for the observed gray matter and executive symptom changes
we investigated their relationship to APOE status, but did not find a
significant effect of APOE e4 carrier status on either gray matter
change or increase in self-reported executive symptoms. This may
reflect relatively low power to detect genetic influences in the pres-
ent study. It was noteworthy that a relatively greater percentage of
chemotherapy-treated patients were e4 positive than in the other
two groups. This is consistent with prior work showing an associa-
tion between breast cancer ande4 status (Chang et al., 2005; Moys-
ich et al., 2000; Porrata-Doria et al., 2010), though other studies
have failed to find such an effect (Chang et al., 2006; Niemi et al.,
2000; Yaylim et al., 2003). By comparison, in a meta-analysis Farrer
et al. (1997) found that 25.7% of a group of 6262 Caucasian healthy
older adults were APOEe4 positive, in contrast to patients with Alz-
heimer’s disease, of whom 58.5% were APOE e4 positive. While
these figures were drawn from an older population, recruited for
comparison to individuals with Alzheimer’s disease, we note that
the percentages of APOE e4 positive participants in our CTx? and
control groups (21% and 25%, respectively) are similar to the control
group of Farrer et al., while our CTx+ group had a notably higher
percentage of APOE e4 positive individuals (42%).
Some limitationsof the currentwork should be considered. First,
while group sizes were larger than in our prior cohort, they remain
relatively small, particularly for exploration of genetic or other risk
also a highly educated cohort. As noted above, previous work has
shown that patients with lower baseline cognitive reserve (for
which level of education is sometimes used as a proxy) appear to
be at greater risk for cancer- and treatment-related cognitive
changes. It may therefore be that even greater treatment-related
cohort. Alternatively, it may be that individuals with greater educa-
tion are more likely to be aware of literature regarding cognitive ef-
fects of cancer treatment, and may therefore report subjective
changes morefrequently(see(Schagen et al., 2009)for examination
of priming effects in cancer patients). Also, as noted above, CTx+ pa-
is consistent with standard clinical care, as patients with more ad-
vanced disease are more likely to receive chemotherapy; however,
disease stage. While there was significant commonality in treat-
ment regimen for CTx+ patients (all received a taxane, most also
received cyclophosphamide) and anti-estrogen treatment for CTx?
patients (over half received tamoxifen), variation in treatment may
potentially contribute to data variability (e.g., more patients in the
CTx+ than CTx? group received local radiation). The inclusion of
patients who received neoadjuvant treatment (one third of the
CTx+ group) also potentially increases data variability; this group
has not yet been exposed to some surgery-related variables at the
M1 visit, but also may have somewhat more advanced disease than
patients receiving standard adjuvant treatment.
It is also possible that changes in hormonal status (e.g., chemo-
therapy-induced ovarian failure) might play a role in the functional
and structural brain changes noted in this population. In the CTx+
group 44% (12 of 27 patients) reported that periods were regular at
the baseline visit, but had stopped or begun to stop at M1, a change
they most commonly attributed to chemotherapy. However, as
might be expected, patients who were menstruating at study entry
were on average 10 years younger than those who were postmen-
opausal at study entry (mean age (SD) 44.6 (4.7) and 54.1 (6.9),
respectively, P < 0.001), such that change in menstrual status is
confounded with age. Comparison of values for the regions where
significant gray matter changes were found from baseline to M1
between patients with and without changes in menstrual status
showed no group-by-time interaction (P > 0.05), suggesting that
chemotherapy-induced ovarian failure did not account for the ob-
served structural changes. However, it will be important to con-
tinue to examine the effects of changes in hormonal (estrogen)
status on brain functioning in future studies while also considering
Regarding these limitations, it will be advantageous in future
work to pool samples when possible, to allow further investigation
of APOE and/or other genetic or other biological factors thought
likely to convey risk for these changes, as well as examination of
individual contributions of specific cancer treatments and demo-
graphic factors (e.g., education, cognitive reserve). It will also be
beneficial in the future to examine the relationship of these gray
matter changes to objective psychometrically defined cognitive
functioning. While prior work has consistently shown increases in
both objective and subjective cognitive impairment after cancer
chemotherapy, objective cognitive performance and subjective
complaints are often not directly correlated, highlighting the need
to examine both factors. It will also be helpful to examine other po-
tentialgeneticfactorswhichmaybe contributory(e.g., COMT(Small
et al., 2011)). In our prior cohort (McDonald et al., 2010), reductions
in gray matter density in the CTx+ group showed partial but not
complete recovery to baseline levels at a follow-up scan conducted
one year after the M1 visit. Other recent work (Koppelmans et al.,
2012) has shown persistentdecreases intotal brain and graymatter
volume in breast cancer survivors on average 21 years post-treat-
ment. These findings suggest that while some improvement may
be expected over time, persistent brain changes may be apparent,
examine longer-term outcome in terms of gray matter density,
when members of this cohort complete additional follow-up visits.
In summary, the current findings replicate and extend our prior
work and that of others demonstrating structural brain changes re-
lated to breast cancer chemotherapy and concurrent changes in
perceived cognitive functioning. This pattern of gray matter change
was not observed in breast cancer patients who did not receive
chemotherapy or healthy controls, and was found in frontal re-
gions important for attentional and executive functioning, domains
commonly found to be affected by cancer and its treatment. These
findings therefore provide additional supportive data for a struc-
tural neuroanatomic basis for the cognitive problems most com-
monly reported during and after chemotherapy.
This work was supported, in part, by the National Institutes of
Health, including National Cancer Institute Grant Nos. R01
B.C. McDonald et al./Brain, Behavior, and Immunity 30 (2013) S117–S125
CA101318, P30 CA082709, and R25 CA117865, National Center for
Research Resources Grant Nos. U54 RR025761, C06 RR020128, and
S10 RR027710, and National Institute on Aging F30 AG039959, R01
AG019771, P30 AG010133, and U24 AG021886, as well as the
Indiana Economic Development Corporation (Grant No. 87884).
Conflict of Interest
The authors of this manuscript have nothing to declare.
The authors thank Kim Wagler-Ziner, PhD, the Indiana Univer-
sity-Melvin and Bren Simon Cancer Center recruitment core, and
our oncologist colleagues for their invaluable assistance with pa-
tient recruitment. We also thank Bryan P. Schneider, MD, Darren
P. O’Neill, MD, Michele A. Beal, RT, Courtney R. Robbins, RT, Sung-
eun Kim, PhD, and Kelly Holohan, BS for their assistance with as-
pects of this work, as well as the NIA National Cell Repository for
Alzheimer’s Disease (NCRAD) for assistance with DNA preparation
for genotyping. Finally, we are very grateful to our participants for
their time and effort; this research would not have been possible
without their willingness to participate during a challenging time
in their lives.
Agrawal, K., Onami, S., Mortimer, J.E., Pal, S.K., 2010. Cognitive changes associated
with endocrine therapy for breast cancer. Maturitas 67, 209–214.
Ahles, T.A., Saykin, A.J., 2007. Candidate mechanisms for chemotherapy-induced
cognitive changes. Nat. Rev. Cancer 7, 192–201.
Ahles, T.A., Saykin, A.J., McDonald, B.C., Furstenberg, C.T., Cole, B.F., Hanscom, B.S.,
Mulrooney, T.J., Schwartz, G.N., Kaufman, P.A., 2008. Cognitive function in
breast cancer patients prior to adjuvant treatment. Breast Cancer Res. Treat.
Ahles, T.A., Saykin, A.J., McDonald, B.C., Li, Y., Furstenberg, C.T., Hanscom, B.S.,
Mulrooney, T.J., Schwartz, G.N., Kaufman, P.A., 2010. Longitudinal assessment of
cognitive changes associated with adjuvant treatment for breast cancer: impact
of age and cognitive reserve. J. Clin. Oncol. 28, 4434–4440.
Ahles, T.A., Saykin, A.J., Noll, W.W., Furstenberg, C.T., Guerin, S., Cole, B., Mott, L.A.,
2003. The relationship of APOE genotype to neuropsychological performance in
long-term cancer survivors treated with standard dose chemotherapy.
Psychooncology 12, 612–619.
Anderson-Hanley, C., Sherman, M.L., Riggs, R., Agocha, V.B., Compas, B.E., 2003.
Neuropsychological effects of treatments for adults with cancer: a meta-
analysis and review of the literature. J. Int. Neuropsychol. Soc. 9, 967–982.
Ashburner, J., Friston, K.F., 2000. Voxel-based morphometry – the methods.
Neuroimage 11, 805–821.
Ashburner, J., Friston, K.J., 2001. Why voxel-based morphometry should be used.
Neuroimage 14, 1238–1243.
Barona, A., Reynolds, C., Chastain, R., 1984. A demographically based index of pre-
morbid intelligence for the WAIS-R. J. Consult. Clin. Psychol. 52, 885–887.
Bookheimer, S., Burggren, A., 2009. APOE-4 genotype and neurophysiological
vulnerability to Alzheimer’s and cognitive aging. Annu 5, 343–362.
Chang, N.-W., Chen, D.-R., Wu, C.-T., Aouizerat, B.E., Chen, F.-N., Hung, S.-J., Wang,
S.-H.,Wei, M.-F., Chang,C.-S., 2005.
polymorphism on the risk for breast cancer and HER2/neu status in Taiwan.
Breast Cancer Res. Treat. 90, 257–261.
Chang, S.-J., Hou, M.-F., Tsai, S.-M., Kao, J.-T., Wu, S.-H., Hou, L.A., Tsai, L.-Y., 2006.
Association between the apolipoprotein E genotypes and breast cancer patients
in Taiwanese. Breast Cancer Res. Treat. 98, 109–113.
Cimprich, B., Reuter-Lorenz, P., Nelson, J., Clark, P.M., Therrien, B., Normolle, D.,
Berman,M.G., Hayes, D.F., Noll,
Prechemotherapy alterations in brain function in women with breast cancer.
J. Clin. Exp. Neuropsychol. 32, 324–331.
Collins, B., Mackenzie, J., Stewart, A., Bielajew, C., Verma, S., Collins, B., Mackenzie, J.,
Stewart, A., Bielajew, C., Verma, S., 2009. Cognitive effects of chemotherapy in
post-menopausal breast cancer patients 1 year after treatment. Psychooncology
Correa, D.D., Ahles, T.A., 2008. Neurocognitive changes in cancer survivors. Cancer J.
de Ruiter, M.B., Reneman, L., Boogerd, W., Veltman, D.J., Caan, M., Douaud, G., Lavini,
C., Linn, S.C., Boven, E., van Dam, F.S.A.M., Schagen, S.B., in press, epub ahead of
print. Late effects of high-dose adjuvant chemotherapy on white and gray
matter in breast cancer survivors: converging results from multimodal
magnetic resonance imaging. Hum Brain Mapp.
de Ruiter, M.B., Reneman, L., Boogerd, W., Veltman, D.J., van Dam, F.S.A.M.,
Nederveen, A.J., Boven, E., Schagen, S.B., 2011. Cerebral hyporesponsiveness
D.C.,Peltier,S., Welsh, R.C.,2010.
and cognitive impairment 10 years after chemotherapy for breast cancer. Hum.
Brain Mapp. 32, 1206–1219.
Farrer, L.A., Cupples, L.A., Haines, J.L., Hyman, B., Kukull, W.A., Mayeux, R., Myers,
R.H., Pericak-Vance, M.A., Risch, N., van Duijn, C.M., 1997. Effects of age, sex, and
ethnicity on the association between apolipoprotein E genotype and Alzheimer
consortium. JAMA 278, 1349–1356.
Garlinghouse, M.A., Roth, R.M., Isquith, P.K., Flashman, L.A., Saykin, A.J., 2010.
Subjective rating of working memory is associated with frontal lobe volume in
schizophrenia. Schizophr. Res. 120, 71–75.
Good, C.D., Johnsrude, I.S., Ashburner, J., Henson, R.N., Friston, K.J., Frackowiak, R.S.,
2001. A voxel-based morphometric study of ageing in 465 normal adult human
brains. Neuroimage 14, 21–36.
Hakamata, Y., Matsuoka, Y., Inagaki, M., Nagamine, M., Hara, E., Imoto, S., Murakami,
K., Kim, Y., Uchitomi, Y., 2007. Structure of orbitofrontal cortex and its
longitudinal course in cancer-related post-traumatic stress disorder. Neurosci.
Res. 59, 383–389.
Inagaki, M., Yoshikawa, E., Matsuoka, Y., Sugawara, Y., Nakano, T., Akechi, T., Wada,
N., Imoto, S., Murakami, K., Uchitomi, Y., 2007. Smaller regional volumes of
brain gray and white matter demonstrated in breast cancer survivors exposed
to adjuvant chemotherapy. Cancer 109, 146–156.
Jansen, C.E., Cooper, B.A., Dodd, M.J., Miaskowski, C.A., 2011. A prospective
longitudinal study of chemotherapy-induced cognitive changes in breast
cancer patients. Support. Care Cancer 19, 1647–1656.
Jenkins, V., Shilling, V., Deutsch, G., Bloomfield, D., Morris, R., Allan, S., Bishop,
H., Hodson, N., Mitra, S., Sadler, G., Shah, E., Stein, R., Whitehead, S.,
Winstanley, J., 2006. A 3-year prospective study of the effects of adjuvant
treatments on cognition in women with early stage breast cancer. Brit J
Cancer 94, 828–834.
Jim, H.S.L., Donovan, K.A., Small, B.J., Andrykowski, M.A., Munster, P.N., Jacobsen,
P.B., 2009. Cognitive functioning in breast cancer survivors: a controlled
comparison. Cancer 115, 1776-1183.
Kesler, S.R., Bennett, F.C., Mahaffey, M.L., Spiegel, D., 2009. Regional brain activation
during verbal declarative memory in metastatic breast cancer. Clin. Cancer Res.
Kesler, S.R., Kent, J.S., O’Hara, R., 2011. Prefrontal cortex and executive function
impairments in primary breast cancer. Arch. Neurol. 68, 1447–1453.
Koppelmans, V., de Ruiter, M.B., van der Lijn, F., Boogerd, W., Seynaeve, C.,
van der Lugt, A., Vrooman, H., Niessen, W.J., Breteler, M.M.B., Schagen,
S.B., 2012. Global and focal brain volume in long-term breast cancer
survivors exposed to adjuvant chemotherapy. Breast Cancer Res. Treat.
McDonald, B.C., Conroy, S.K., Ahles, T.A., West, J.D., Saykin, A.J., 2010. Gray matter
reduction associated with systemic chemotherapy for breast cancer: a
prospective MRI study. Breast Cancer Res. Treat. 123, 819–828.
McDonald, B.C., Conroy, S.K., Ahles, T.A., West, J.D., Saykin, A.J., in press. Alterations
in brain activation during working memory processing associated with breast
cancer and treatment: a prospective functional MRI study. J. Clin. Oncol.
McDonald, B.C., Saykin, A.J., 2011. Neurocognitive dimensions of breast cancer and
its treatment. Neuropsychopharmacology 36, 355–356.
McDonald, B.C., Saykin, A.J., Ahles, T.A., 2008. Brain imaging investigation of
chemotherapy-induced neurocognitive changes. In: Meyers, C.A., Perry, J.R.
(Eds.), Cognition and Cancer. Cambridge University Press, Cambridge, MA, pp.
Moysich, K.B., Freudenheim, J.L., Baker, J.A., Ambrosone, C.B., Bowman, E.D.,
Schisterman, E.F., Vena, J.E., Shields, P.G., 2000. Apolipoprotein E genetic
polymorphism, serum lipoproteins, and breast cancer risk. Mol. Carcinog. 27, 2–
Niemi, M., Kervinen, K., Kiviniemi, H., Lukkarinen, O., Kyllonen, A.P., Apaja-
Sarkkinen, M., Savolainen, M.J., Kairaluoma, M.I., Kesaniemi, Y.A., 2000.
Apolipoprotein E phenotype, cholesterol and breast and prostate cancer. J.
Epidemiol. Community Health 54, 938–939.
Porrata-Doria, T., Matta, J.L., Acevedo, S.F., 2010. Apolipoprotein E allelic frequency
altered in women with early-onset breast cancer. Breast cancer 4, 43–48.
Quesnel, C., Savard, J., Ivers, H., Quesnel, C., Savard, J., Ivers, H., 2009. Cognitive
impairments associated with breast cancer treatments: results from a
longitudinal study. Breast Cancer Res. Treat. 116, 113–123.
Radloff, L.S., 1977. The CES-D Scale: A self-report depression scale for research in
the general population. Appl. Psychol. Meas. 1, 385–401.
Roth, R.M., Isquith, P.K., Gioia, G.A., 2005. BRIEF-A Behavior Rating Inventory of
Assessment Resources, Inc., Lutz, FL.
Saykin, A.J., Ahles, T.A., McDonald, B.C., 2003. Mechanisms of chemotherapy-
induced cognitive disorders: neuropsychological, pathophysiological, and
neuroimaging perspectives. Semin Clin Neuropsychiatry 8, 201–216.
Schagen, S.B., Das, E., van Dam, F.S.A.M., 2009. The influence of priming and pre-
existing knowledge of chemotherapy-associated cognitive complaints on the
reporting of such complaints in breast cancer patients. Psychooncology 18,
Schagen, S.B., Muller, M.J., Boogerd, W., Rosenbrand, R.M., van Rhijn, D., Rodenhuis,
S., van Dam, F.S., 2002. Late effects of adjuvant chemotherapy on cognitive
function: a follow-up study in breast cancer patients. Ann. Oncol. 13, 1387–
Scherling, C., Collins, B., Mackenzie, J., Bielajew, C., Smith, A., 2011. Pre-
chemotherapy differences in visuospatial working memory in breast cancer
patients compared to controls: an FMRI study. Front. Hum. Neurosci. 5, 122.
B.C. McDonald et al./Brain, Behavior, and Immunity 30 (2013) S117–S125
Prechemotherapy differences in response inhibition in breast cancer patients
compared to controls: a functional magnetic resonance imaging study. J. Clin.
Exp. Neuropsychol. 34, 543–560.
Silverman, D.H., Dy, C.J., Castellon, S.A., Lai, J., Pio, B.S., Abraham, L., Waddell, K.,
Petersen, L., Phelps, M.E., Ganz, P.A., 2007. Altered frontocortical, cerebellar, and
basal ganglia activity in adjuvant-treated breast cancer survivors 5–10 years
after chemotherapy. Breast Cancer Res. Treat. 103, 303–311.
Small, B.J., Rawson, K.S., Walsh, E., Jim, H.S.L., Hughes, T.F., Iser, L., Andrykowski,
M.A., Jacobsen, P.B., 2011. Catechol-O-methyltransferase genotype modulates
cancer treatment-related cognitive deficits in breast cancer survivors. Cancer
Smith, J.D., 2000. Apolipoprotein E4: an allele associated with many diseases. Ann.
Med. 32, 118–127.
Spielberger, C.D., 1983. State-Trait Anxiety Inventory. Consulting Psychologists
Press, Inc., Palo Alto, CA.
Stewart, A., Bielajew, C., Collins, B., Parkinson, M., Tomiak, E., 2006. A meta-analysis
of the neuropsychological effects of adjuvant chemotherapy treatment in
women treated for breast cancer. Clin. Neuropsychol. 20, 76–89.
C., Collins,B., Mackenzie,J., Bielajew,C., Smith,A.,2012.
Vardy, J., Wefel, J.S., Ahles, T., Tannock, I.F., Schagen, S.B., 2008. Cancer and cancer-
therapy related cognitive dysfunction: an international perspective from the
Venice cognitive workshop. Ann. Oncol. 19, 623–629.
Wagner, L., Sweet, J., Butt, Z., Beaumont, J., Havlin, K., Sabatino, T., Cella, D., 2006.
Trajectory of cognitive impairment during breast cancer treatment: a
prospective analysis. J. Clin. Oncol. 24, S8500.
Wefel, J.S., Lenzi, R., Theriault, R., Buzdar, A.U., Cruickshank, S., Meyers, C.A., 2004.
‘Chemobrain’ in breast carcinoma? A prologue. Cancer 101, 466–475.
Yaylim, I., Bozkurt, N., Yilmaz, H., Isbir, T., Isik, N., Arikan, S., 2003. The
apolipoprotein E epsilon 4 allele is not a risk factor for Turkish breast cancer
patients. Cancer Genet. Cytogenet. 146, 86–87.
Yoshikawa, E., Matsuoka, Y., Yamasue, H., Inagaki, M., Nakano, T., Akechi, T.,
Kobayakawa, M., Fujimori, M., Nakaya, N., Akizuki, N., Imoto, S., Murakami, K.,
Kasai, K., Uchitomi, Y., 2006. Prefrontal cortex and amygdala volume in first
minor or major depressive episode after cancer diagnosis. Biol. Psychiatry 59,
B.C. McDonald et al./Brain, Behavior, and Immunity 30 (2013) S117–S125