Longitudinal Assessment of Chemotherapy-Induced Structural Changes in Cerebral White Matter and Its Correlation With Impaired Cognitive Functioning

  1. Stefan Sunaert⇓
  1. Sabine Deprez, Frederic Amant, Ann Smeets, Ronald Peeters, Wim Van Hecke, Judith S. Verhoeven, Marie-Rose Christiaens, Joris Vandenberghe, Mathieu Vandenbulcke, and Stefan Sunaert, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Leuven, Belgium; and Alexander Leemans, University Medical Center Utrecht, Utrecht, the Netherlands.
  1. Corresponding author: Stefan Sunaert, MD, Department of Radiology, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Herestraat 49, B-3000 Leuven, Belgium; e-mail: address: stefan.sunaert{at}uzleuven.be.
 
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Abstract

Purpose To uncover the neural substrate of cognitive impairment related to adjuvant chemotherapy, we studied cerebral white matter (WM) integrity before and after chemotherapy by using magnetic resonance diffusion tensor imaging (DTI) in combination with detailed cognitive assessment.

Patients and Methods Thirty-four young premenopausal women with early-stage breast cancer who were exposed to chemotherapy underwent neuropsychologic testing and DTI before the start of chemotherapy (t1) and 3 to 4 months after treatment (t2). Sixteen patients not exposed to chemotherapy and 19 age-matched healthy controls underwent the same assessment at matched intervals. In all groups, we used paired t tests to study changes in neuropsychologic test scores and whole-brain voxel-based paired t tests to study changes in WM fractional anisotropy (FA; a DTI measure that reflects WM tissue organization), with depression scores and intelligence quotient as included covariates. We correlated changes of neuropsychologic test scores with the mean change of FA for regions that survived the paired t tests in patients treated with chemotherapy.

Results In contrast to controls, the chemotherapy-treated group performed significantly worse on attention tests, psychomotor speed, and memory at t2 compared with t1 (P < .05). In the chemotherapy-treated group, we found significant decreases of FA in frontal, parietal, and occipital WM tracts after treatment (familywise error P < .05), whereas for both control groups, FA values were the same between t1 and t2. Furthermore, performance changes in attention and verbal memory correlated with mean regional FA changes in chemotherapy-treated patients (P < .05).

Conclusion We report evidence of longitudinal changes in cognitive functioning and cerebral WM integrity after chemotherapy as well as an association between both.

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INTRODUCTION

Women with breast cancer often complain about cognitive impairment after adjuvant chemotherapeutic treatment. Several cross-sectional and longitudinal neuropsychologic studies confirm chemotherapy-induced cognitive changes in memory, attention, psychomotor speed, and executive functioning in a subgroup of patients.1–3 These effects remain after controlling for potentially related factors such as anxiety, fatigue, mood, and intelligence quotient (IQ). Advanced neuroimaging techniques bring unique insight into the neural substrate of these complaints. Although the limited number and the cross-sectional nature of the studies carried out precludes us from drawing firm conclusions, the reported findings suggest both functional and structural changes in the brain.4–8

The pathophysiology of chemotherapy-induced cognitive impairment and its relation with structural or functional changes in the brain is still unclear. Despite the partial protection of the brain by the blood-brain barrier, one of the proposed mechanisms by which chemotherapy could impair cognitive functioning is through direct neurotoxicity,9,10 damaging brain parenchyma and altering white matter (WM) microstructure. Indirect neurotoxic effects may also be induced, possibly through oxidative stress, vascular damage, or immune response dysregulation.10 Support for these hypotheses comes from reports of patients who received high-dose chemotherapy leading to cerebral WM damage.11,12 In addition, a recent study13 reported neurotoxicity in patients with multiple sclerosis (MS) who received chemotherapy as preconditioning for bone marrow transplantation when compared with a matched group receiving placebo only. How chemotherapy crosses the blood-brain barrier remains a matter of debate. There is evidence that a frequently used chemotherapeutic agent, fluorouracil (FU), crosses the blood-brain barrier by simple diffusion.14,15 Systemic treatment with clinically relevant concentrations of FU in mice has been shown to cause damage to myelinated WM tracts of the CNS.16

Magnetic resonance diffusion tensor imaging (DTI)—a technique enabling the visualization and characterization of the WM architecture via the self-diffusion of water molecules—allows us to study potential chemotherapy-induced changes in WM.17–19 In intact WM tissue, the diffusion is highly directional because axonal membranes and myelin hinder the random motion of water molecules more across than along the local orientation of WM fiber pathways. Damage to WM structures may change quantitative DTI parameters, including fractional anisotropy (FA), which characterizes the degree of directional preference of diffusion.20

In our previous cross-sectional study,21 we reported significant differences between chemotherapy-treated patients and controls in FA values of important WM tracts involved in cognition. Furthermore, FA correlated significantly with performance on neuropsychologic tests. In addition, 10 years after treatment, de Ruiter et al22 found detrimental effects on WM as indicated by DTI and proton magnetic resonance spectroscopy. They hypothesized that both demyelination and axonal injury might underlie these observations. Both studies, however, are limited by the absence of a pretreatment baseline against which to compare post-treatment changes.

The purpose of this longitudinal DTI study is to analyze whole-brain WM before and after chemotherapy in a group of young women with breast cancer and evaluate potential changes in FA in combination with detailed cognitive assessment. We chose to study the DTI parameter FA for its better correlation with cognition,22a its promising results in our earlier cross-sectional study,21 and the recently reported ambiguities in the interpretation of other DTI parameters such as radial and parallel diffusivities.23 We hypothesize that a reduction of FA values will occur after chemotherapy treatment and that these changes will be associated with decreased performance in cognitive functioning.

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PATIENTS AND METHODS

Patients

The study was approved by the local ethical commission and was conducted in accordance with the Declaration of Helsinki. Patients were recruited after breast cancer surgery. Thirty-five young women with early-stage breast cancer who were scheduled to receive adjuvant chemotherapy (age 45.4 ± 4.2 years), 18 patients with early-stage breast cancer who were not scheduled to receive chemotherapy (age 42.9 ± 4 years), and 22 matched healthy controls (age 45.2 ± 3.9 years) participated in the study. All patients were premenopausal at the start of the study, and all had received a standard education. All patients were assessed with the Mini International Neuropsychiatric Interview24 to exclude psychiatric disorders such as depression and anxiety disorders. Other exclusion criteria included history of cancer, history of any neurologic condition, brain injury, mental retardation, and use of psychotropic medication.

Pretreatment assessment occurred after surgery but before the start of adjuvant therapy (time point t1). Follow-up assessment for chemotherapy-treated patients was conducted 3 to 5 months after the end of treatment (time point t2). The two control groups underwent assessment at matched intervals.

Neuropsychologic Assessment

All participants were evaluated by using the same neuropsychologic test battery as described in our cross-sectional study,21 which included the domains of attention, concentration, memory, executive functioning, and cognitive/psychomotor processing speed. If an alternate form was available, it was used for the assessment at t2. Self-reported cognitive functioning was assessed by using the Cognitive Failure Questionnaire (CFQ),25 providing subscales on distraction, distraction in social situations, names and word finding, orientation, and a total summary score. All participants completed the Spielberger State-Trait Anxiety Inventory (STAI)26 and the Beck Depression Inventory (BDI).27 Verbal IQ was measured by using a Dutch version of the National Adult Reading Test (Nederlandse Leestest voor Volwassenen [NLV]).28 Neuropsychologic evaluation and magnetic resonance imaging scans took place on the same day.

All statistics were performed with SPSS 18.0 (SPSS, Chicago, IL). One-way analysis of variance (ANOVA) analyses with group as a fixed factor were used to assess differences between groups at baseline. Because groups differed significantly in terms of BDI depression score at baseline (Table 1), and since a significant correlation between IQ and test performance was found, we included both variables as covariates. Paired t tests were used to assess changes in neuropsychologic test performance between t1 and t2 within the separate groups. To assess interaction of time and group, we used one-way repeated measures ANOVA with time as a within-subject factor, group as a between-subject factor, and IQ and BDI as covariates. Pearson's correlations were used to examine the relationship between changes in self-reported measures and changes in neuropsychologic test scores. Statistical significance was assessed at P < .05 with Bonferroni corrections for comparing multiple groups.

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Table 1.

Background and Clinical Characteristics of Patients and Controls

Acquisition Details for Magnetic Resonance Imaging Scans

Participants were imaged on a 3T scanner (Philips Intera, Best, the Netherlands) with an 8-channel phased-array head coil. Whole-brain DTI spin-echo echo planar imaging (SE-EPI), T1-weighted 3D-turbo field echo (TFE), T2-weighted turbo spin echo (TSE), and fluid attenuated inversion recovery (FLAIR) data were acquired by using the same parameters as described in our previous study.21

DTI Processing and Analysis

DTI preprocessing was performed by using ExploreDTI (http://www.ExploreDTI.com, Utrecht, the Netherlands), which consists of visual quality assurance, motion and distortion correction with reorientation of the b-matrix,29 and an iterative nonlinear tensor estimation process to generate maps of FA. The individual DTI data sets were nonrigidly registered to a population-based DTI atlas generated from all participants' DTI images.30,31 The spatially normalized maps were smoothed with an anisotropic smoothing kernel (full width at half maximum, 6 mm).32

SPM8 (statistical parametric mapping software; http://www.fil.ion.ucl.ac.uk/spm/software/spm8/, London, United Kingdom)34 whole-brain, voxel-based, paired t tests and ANOVA analyses were used to assess differences in FA values between the time points within each group and between the three groups at baseline, respectively. Verbal IQ and depression score were added as covariates of no interest. Because there is evidence that longitudinal DTI analysis may be sensitive to drift as well as the effects of upgrading and maintaining the scanner,35,36 we added extra covariates in our statistical analysis to take this into account (ie, scanner upgrade and goodness of tensor estimation fit).

A WM mask was used to limit the analysis to WM voxels. The resulting statistical parametric maps were thresholded at the voxel-level P < .001 uncorrected for multiple comparisons. Only clusters significant at the P < .05 level (familywise error) corrected for multiple comparisons were retained.

Correlation Analysis of Changes in Neuropsychologic Test Scores With Changes in FA Values in Chemotherapy-Treated Patients

To study the effect of cognitive impairment on WM integrity, we carried out a Pearson correlation analysis between the longitudinal change in test performance (calculated as test score at t2 minus test score at t1) and mean change of FA values for each cluster that survived the paired t test in chemotherapy-treated patients. To reduce the number of neuropsychologic tests included in this correlation analysis, we selected only the tests that showed significant changes in longitudinal performance between the groups as a result of the repeated measures ANOVA analysis.

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RESULTS

A total of 75 participants were initially recruited for the study. One patient who did not receive chemotherapy and one healthy control did not complete the follow-up assessment. Visual inspection of T1-weighted, T2-weighted, and FLAIR MR images resulted in the exclusion of one healthy volunteer who was diagnosed with MS. Three additional participants (one patient who did not receive chemotherapy, one chemotherapy-treated patient, and one healthy control) were excluded from the analysis because of excessive motion artifacts on their DTI images. Therefore, the final sample size for the longitudinal analysis was 19 healthy controls, 34 patients who received chemotherapy, and 16 patients who did not receive chemotherapy.

Participant Demographic and Clinical Data

Participant demographic and medical information is summarized in Table 1. All participants were active premenopausal women between 32 and 51 years old. Eighteen patients who received chemotherapy and 14 patients who did not receive chemotherapy had started additional hormonal treatment with tamoxifen, 7 months and 1 month after baseline, respectively. The chemotherapy-treated patients did not differ from the controls with regard to age, education, verbal IQ, and anxiety. However, significant differences in depression score BDI (P = .005) were found between the groups.

Neuropsychologic Assessment

At baseline, after controlling for depression scores and IQ, ANOVA did not reveal significant differences between patients with cancer and healthy controls for the different cognitive domains and self-reported cognitive functioning. Paired t tests showed that the chemotherapy-treated group performed significantly worse after chemotherapy on attention and concentration tests, psychomotor speed, and memory when compared with baseline (P < .05). Both control groups, however, showed significantly better performance in those domains at t2 versus t1 (P < .05), consistent with a learning effect. In contrast to both control groups, the chemotherapy-treated patients reported a significant increase in cognitive complaints at t2 in distraction, names and word finding, and CFQ total score. In addition, repeated measures ANOVA revealed significant interactions between groups and performance change over time for attention, psychomotor speed, and memory tests, after controlling for depression scores and IQ (F > 3.3; P < .05; Table 2). Longitudinal performance changes for these neuropsychologic tests (ie, Auditory Verbal Learning Test [AVLT], Wechsler Adult Intelligence Scale [WAIS] Digit Span, Test of Everyday Attention, WAIS Letter-Number Sequencing, and nine-hole pegboard [9PEG]) were selected for the correlation analysis with changes in FA values. Figure 1A illustrates longitudinal changes across groups for the AVLT and WAIS Digit Span tests.

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Table 2.

Summary of Neuropsychologic Assessment

Fig 1.
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Fig 1.

(A) Left: bars indicating the mean longitudinal change score for the Auditory Verbal Learning Test (AVLT) for each group. A negative score indicates a performance decrease at 3 to 5 months after treatment (t2) when compared with baseline (t1). By contrast, a positive score indicates a performance increase. Right: bars indicating the mean longitudinal change score for the Backward Digit Span score for each group. A negative score indicates a performance decrease at t2 when compared with baseline. By contrast, a positive score indicates a performance increase (B) Left: scatter plot of mean longitudinal change score for the AVLT and mean difference in fractional anisotropy (FA) values in a region covering part of the frontal superior longitudinal fasciculus in patients treated with chemotherapy (C+). Right: scatter plot of mean longitudinal change score for the Backward Digit Span Test and mean difference in fractional anisotropy values in a region covering part of the parietal superior longitudinal fasciculus in C+ patients. C−, patients not treated with chemotherapy; HC, healthy controls.1

Significant correlations were found between increased self-reported cognitive complaints in distraction from t1 to t2 and decreased performance from t1 to t2 on attention (Bourdon-Wiersma P = .009, Trailmaking Test Part A P = .048, WAIS Letter-Number Sequencing P = .05, Corsi Block Span P = .02) and verbal memory tests (AVLT recall P = .026). In addition, a significant correlation was found between increased self-reported cognitive complaints on name and word finding and decreased performance on the controlled word association test (P = .02).

Assessment of DTI Parameter Differences

No significant differences in FA values were detected between the three groups at baseline. Voxel-based paired t tests, however, revealed significantly decreased FA in the chemotherapy-treated patient group after treatment (t2) versus baseline (t1) in a region covering the corona radiata and corpus callosum (CC; familywise error [FWE] P = .002) and in frontal (superior longitudinal fasciculus [SLF]; FWE P = .021), parietal (SLF; FWE P < .001), and occipital (forceps major; FWE P = .017) WM tracts (Table 3; Fig 2). No WM regions were identified in which FA values were higher at t2 compared with t1. In both control groups (ie, in patients not exposed to chemotherapy and in healthy controls), no significant changes in FA were found between t1 and t2.

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Table 3.

FA Voxel-Wise Paired t Test for Patients Treated With Chemotherapy

Fig 2.
View larger version:
Fig 2.

Regions showing significantly decreased fractional anisotropy in chemotherapy-treated patients at 3 to 4 months after treatment (t2) when compared with baseline (t1). (A) t map (providing the t statistic in each voxel) overlaid on axial slices of the mean fractional anisotropy map from the whole group. (B) t map overlaid on reconstructed white matter tracts for a representative patient in the corpus callosum, superior longitudinal fasciculus, and forceps major. The white arrows indicate the reported regions significant at P < .05 familywise error–corrected for multiple comparisons: 1, cluster covering parietal part of corona radiata, corpus callosum; 2, cluster covering parietal part of superior longitudinal fasciculus; 3, cluster covering frontal part of superior longitudinal fasciculus; 4, cluster covering part of forceps major.

Correlation Analysis of Neuropsychologic Test Scores With FA Values in Chemotherapy-Treated Patients

Correlation analysis of differences in FA with differences in performance at t2 versus t1 in the above identified regions and tests revealed significant correlations in the domains of attention and verbal memory (P < .05 corrected for multiple testing) for chemotherapy-treated patients (Table 4; Fig 1B).

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Table 4.

Significant Correlations Between Differences in FA and Differences in Cognitive Tests (t2-t1) in Patients Treated With Chemotherapy

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DISCUSSION

To the best of our knowledge, this is the first longitudinal study to investigate potential chemotherapy-induced changes in WM integrity, as determined by quantitative DTI measures in combination with detailed cognitive assessments. We demonstrated changes in cerebral WM integrity by comparing DTI data obtained before and after chemotherapy in patients with breast cancer. We have shown significantly decreased FA (a measure of WM coherence and organization) after chemotherapy in important WM tracts involved in cognition (eg, SLF, CC), whereas this effect was not present in both control groups assessed at matched intervals. In addition, paired t tests showed that the chemotherapy-treated group performed worse on attention and verbal memory tests at t2 when compared with baseline, whereas both control groups showed increased performance. Furthermore, we found evidence that this decreased performance on attention and verbal memory tests significantly correlated with the observed decreases in WM FA values in chemotherapy-treated patients. These results suggest that microstructural WM changes in patients exposed to chemotherapy may underlie their cognitive dysfunction.

The decreased WM integrity in chemotherapy-treated patients could not be explained by differences in depression scores. Major depressive disorder has been associated with decreased FA in the limbic system and WM association tracts.37 However, we included the BDI depression score as a covariate of no interest and still observed significant differences in FA.

WM mediates communication among different brain regions and its integrity is important for optimal brain function. Damage to any part of the WM connections can lead to changes in cognitive performance.38 For instance, cognitive decline caused by increased age, neurodegenerative disease, or by alcohol neurotoxicity has been related to impaired WM integrity as reflected by decreased FA.39–43

All WM tracts reported in our study are known to be involved in cognitive functioning in both normal and diseased patients. For example, the FA value of the SLF, a long association tract integrating frontal and parietal association cortices, is known to be correlated with processing speed44 and memory45 in healthy volunteers, as well as with attention,46 working memory,46 and verbal memory47 in patients with MS. Other studies48 that investigated work-related neurotoxic exposure in manganese-exposed welders reported microstructural alterations linked with subtle cognitive impairment in the CC and frontal WM. The forceps major (the occipital radiation of the CC) has been linked to attention, memory, executive functioning, and multitasking.49–51

The observed changes in WM microstructure might be related to demyelination of WM axons or axonal injury. Postmortem examination of a 49-year-old female with chemotherapy-treated breast cancer demonstrated demyelination in several WM regions.52 Animal studies have also reported demyelination after administration of FU in mice.16

Although we believe the process of WM decline to be a globally distributed process rather than a decline of specific tracts, interesting similarities can be seen in the longitudinal gray matter voxel-based morphometry study of McDonald et al.7 The involvement of gray matter in the (middle and superior) frontal gyri is close to our WM cluster 3 (SLF). Other cross-sectional studies4,6,8 also reported structural and functional chemotherapy-induced changes in regions similar to ours.

Several studies53,54 reported that patients with breast cancer are already impaired at baseline. On the contrary, in our study, we did not find any significant differences between the patient group and the healthy controls after controlling for depression score and IQ. However, when we removed the covariate controlling for depression, we did find significant differences for attention tests (P < .03). This could indicate that impaired cognitive functioning at baseline may be explained mainly by emotional factors such as negative feelings linked to the diagnosis rather than an impairment of objective cognitive functioning. This link however, was not found in other studies. Interestingly, we also did not see any significant differences between the three groups in FA values at baseline.

The findings of decreased attention and verbal memory in patients after chemotherapy are in line with previous longitudinal studies.55–57 In contrast to other studies,58 however, we did find a correlation between self-reported cognitive function and objective neuropsychologic testing. Correlating longitudinal changes of self-reported scores with changes of objective test scores might be more sensitive than correlating the scores from one time point only.

Some limitations of this study should be mentioned. First, a substantial part of our patient group, 18 of 34 patients treated with chemotherapy and 14 of 16 patients who did not receive chemotherapy, started additional hormonal treatment with tamoxifen 7 months and 1 month after baseline, respectively. There is evidence that tamoxifen may impair cognition,58,59 although other studies reported no significant differences in cognitive performance between patients with and without antiestrogen treatment.55,60 This study seems to support the latter, because we did not find significant WM changes from baseline for the patients without chemotherapy, although 14 of 16 patients had been receiving tamoxifen for 7 months at t2. Therefore, our observations suggest that the cognitive impairment and decreased WM FA values in the chemotherapy-treated patients may be due to chemotherapy-induced neurotoxicity only. Hormonal changes linked to temporary chemotherapy-induced menopause in part of our patient population could potentially have influenced cognition. However, the cognitive effects associated with menopause are uncertain.61 Hermelink et al60 found no negative effects of therapy-induced menopause on cognition in patients with breast cancer. Interestingly, Schagen et al57 reported higher cognitive impairment in patients exposed to high-dose versus low-dose chemotherapy, although both groups had an equal distribution of pre- and postmenopausal women before and after treatment. Although high-dose chemotherapy is not the subject of our study, this finding suggests that if chemotherapy-induced menopause has an influence on cognition, there is still a strong remaining effect of the chemotherapy itself. Second, our patients were scanned shortly after completion of the chemotherapy (142 days on average). More research is needed to determine whether the detected chemotherapy-induced WM changes are reversible or whether there is long-term or even delayed WM damage. Some studies4,62 report long-term cognitive impairment for a subset of patients, whereas others6,63 describe recovery. The heterogeneity in the longitudinal course of cognitive impairment may be related to the degree of WM changes and should be investigated further.

In summary, our results provide the first longitudinal evidence that DTI-based assessment of the microstructural properties of WM may be sufficiently sensitive to investigate the neuronal substrate of chemotherapy-induced cognitive complaints. We have shown longitudinal changes in cerebral WM in chemotherapy-treated patients by comparing FA values of DTI images taken before and after treatment and linked those changes with decreased cognitive functioning. Longitudinal changes in FA may therefore serve as a neuropathologic biomarker for treatment-induced neurotoxicity.

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AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: Wim Van Hecke, icoMetrix (U) Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None

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AUTHOR CONTRIBUTIONS

Conception and design: Sabine Deprez, Frederic Amant, Joris Vandenberghe, Mathieu Vandenbulcke, Stefan Sunaert

Provision of study materials or patients: Frederic Amant, Ann Smeets, Marie-Rose Christiaens

Collection and assembly of data: Sabine Deprez, Frederic Amant, Ann Smeets, Marie-Rose Christiaens

Data analysis and interpretation: Sabine Deprez, Ronald Peeters, Alexander Leemans, Wim Van Hecke, Judith S. Verhoeven, Joris Vandenberghe, Mathieu Vandenbulcke, Stefan Sunaert

Manuscript writing: All authors

Final approval of manuscript: All authors

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Footnotes

  • See accompanying editorial on page 229

  • Supported by Grant No. G.048010N from Fonds Wetenschappelijk Onderzoek–Vlaanderen; by Stichting tegen Kanker; by Grant No. IUAP EMF-B6772-p6/29 from Inter-University-Attraction-Pole; and by Grant No. EF/05/014 from Excellentie-Financiering.

  • Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

  • Received May 18, 2011.
  • Accepted September 27, 2011.
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  1. Published online before print December 19, 2011, doi: 10.1200/JCO.2011.36.8571 JCO vol. 30 no. 3 274-281
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