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Late effects of high-dose adjuvant chemotherapy on white and gray matter in breast cancer survivors: converging results from multimodal magnetic resonance imaging.

ABSTRACT: The neural substrate underlying cognitive impairments after chemotherapy is largely unknown. Here, we investigated very late (>9 years) effects of adjuvant high-dose chemotherapy on brain white and gray matter in primary breast cancer survivors (n = 17) with multimodal magnetic resonance imaging (MRI). A group of breast cancer survivors who did not receive chemotherapy was scanned for comparison (n = 15). Neuropsychological tests demonstrated cognitive impairments in the chemotherapy group. Diffusion tensor imaging (DTI) with tract-based spatial statistics showed that chemotherapy was associated with focal changes in DTI values indicative for reduced white matter integrity. Single voxel proton MR spectroscopy (1H-MRS) in the left centrum semiovale (white matter) showed a reduction of N-acetylasparate/creatine indicative of axonal injury. Voxel-based morphometry demonstrated a reduction of gray matter volume that overlapped with fMRI hypoactivation (as reported in a previous publication) in posterior parietal areas and colocalized with DTI abnormalities. Also, DTI correlated with 1H-MRS only in the chemotherapy group. These results converge to suggest that high-dose adjuvant chemotherapy for breast cancer is associated with long-term injury to white matter, presumably reflecting a combination of axonal degeneration and demyelination, and damage to gray matter with associated functional deficits. Hormonal treatment with tamoxifen may also have contributed to the observed effects, although results from other studies indicate that it is unlikely that tamoxifen is solely or largely responsible. Using this multimodality approach we provide for the first time insight into the neural substrate underlying cognitive impairments following systemic administration of cytotoxic agents many years after treatment.

SUBMITTER: de Ruiter MB

PROVIDER: S-EPMC6870296 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Late effects of high-dose adjuvant chemotherapy on white and gray matter in breast cancer survivors: converging results from multimodal magnetic resonance imaging.

de Ruiter Michiel B MB Reneman Liesbeth L Boogerd Willem W Veltman Dick J DJ Caan Matthan M Douaud Gwenaëlle G Lavini Cristina C Linn Sabine C SC Boven Epie E van Dam Frits S A M FS Schagen Sanne B SB

Human brain mapping 20110923 12

The neural substrate underlying cognitive impairments after chemotherapy is largely unknown. Here, we investigated very late (>9 years) effects of adjuvant high-dose chemotherapy on brain white and gray matter in primary breast cancer survivors (n = 17) with multimodal magnetic resonance imaging (MRI). A group of breast cancer survivors who did not receive chemotherapy was scanned for comparison (n = 15). Neuropsychological tests demonstrated cognitive impairments in the chemotherapy group. Diff ...[more]

PMID: 22095746

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Project description:IntroductionCure rates for pediatric acute lymphoblastic leukemia (ALL) have reached an all-time high (>90%); however, neurocognitive difficulties continue to affect quality of life in at least a subset of survivors. There are relatively few quantitative neuroimaging studies in child and adolescent ALL survivors treated with chemotherapy only. Use of different outcome measures or limited sample sizes restrict our ability to make inferences about patterns of brain development following chemotherapy treatment. In this study, we used magnetic resonance imaging (MRI) to evaluate brain outcomes in ALL survivors, comparing against a group of typically developing, cancer free peers.Materials and methodsParticipants included 71 ALL survivors, on average 8 years after diagnosis and 8-18 years of age, and 83 typically developing controls. Anatomical MRI was performed to evaluate brain structure; diffusion and magnetization transfer MRI were used to examine brain tissue microstructure.ResultsSuccessful MRI scans were acquired in 67 survivors (94%) and 82 controls (99%). Structurally, ALL survivors exhibited widespread reductions in brain volume, with 6% less white matter and 5% less gray matter than controls (p = 0.003 and 0.0006 respectively). Much of the brain appeared affected - 71 of 90 evaluated structures showed smaller volume - with the most notable exception being the occipital lobe, where no significant differences were observed. Average full-scale IQ in the survivor and control groups were 95 (CI 92-99) and 110 (CI 107-113), respectively. Using data from the NIH Pediatric MRI Data Repository, we evaluated the extent to which elevated IQ in the control group might affect the structural differences observed. We estimated that two thirds of the observed brain differences were attributable to ALL and its treatment. In addition to the structural changes, survivors showed, on average, globally lower white matter fractional anisotropy (-3%) and higher radial diffusivity (+5%) (p < 10-6), but no differences in magnetization transfer ratio.ConclusionsNeuroanatomical alterations in late childhood and adolescent ALL survivors treated with chemotherapy-only protocols are widespread, with white matter being somewhat more affected than gray matter. These MRI results indicate brain development is altered in ALL survivors and highlight the need to examine how these alterations emerge.

Project description:It is well established that brain structures and cognitive functions change across the life span. A long-standing hypothesis called "age differentiation" additionally posits that the relations between cognitive functions also change with age. To date, however, evidence for age-related differentiation is mixed, and no study has examined differentiation of the relationship between brain and cognition. Here we use multigroup structural equation models (SEMs) and SEM trees to study differences within and between brain and cognition across the adult life span (18-88 years) in a large (N > 646, closely matched across sexes), population-derived sample of healthy human adults from the Cambridge Centre for Ageing and Neuroscience (www.cam-can.org). After factor analyses of gray matter volume (from T1- and T2-weighted MRI) and white matter organization (fractional anisotropy from diffusion-weighted MRI), we found evidence for the differentiation of gray and white matter, such that the covariance between brain factors decreased with age. However, we found no evidence for age differentiation among fluid intelligence, language, and memory, suggesting a relatively stable covariance pattern among cognitive factors. Finally, we observed a specific pattern of age differentiation between brain and cognitive factors, such that a white matter factor, which loaded most strongly on the hippocampal cingulum, became less correlated with memory performance in later life. These patterns are compatible with the reorganization of cognitive functions in the face of neural decline, and/or with the emergence of specific subpopulations in old age.SIGNIFICANCE STATEMENT The theory of age differentiation posits age-related changes in the relationships among cognitive domains, either weakening (differentiation) or strengthening (dedifferentiation), but evidence for this hypothesis is mixed. Using age-varying covariance models in a large cross-sectional adult life span sample, we found age-related reductions in the covariance among both brain measures (neural differentiation), but no covariance change among cognitive factors of fluid intelligence, language, and memory. We also observed evidence of uncoupling (differentiation) between a white matter factor and cognitive factors in older age, most strongly for memory. Together, our findings support age-related differentiation as a complex, multifaceted pattern that differs for brain and cognition, and discuss several mechanisms that might explain the changing relationship between brain and cognition.

Dataset Information

Late effects of high-dose adjuvant chemotherapy on white and gray matter in breast cancer survivors: converging results from multimodal magnetic resonance imaging.

Publications

Late effects of high-dose adjuvant chemotherapy on white and gray matter in breast cancer survivors: converging results from multimodal magnetic resonance imaging.

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