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.

Challenges in research on the neural basis of „chemobrain”

“…Examinations of cortical structure using magnetic resonance imaging (MRI) have demonstrated reductions of both gray and white matter volume when comparing chemotherapy-treated patients with either healthy controls [25] or untreated patients [26]. Prospective studies have revealed that both frontal and temporal cortex showed the most pronounced volume reductions [27,28]. A recent cross-sectional investigation provided evidence for hippocampal damage that was related to decreased verbal memory performance [29].…”

Impact of Physical Inactivity on the Multifactorial Process of Developing Cancer-Related Cognitive Impairments

“…Furthermore, cytostatic therapy induces reduction of the gray matter in certain brain areas, such as the cerebellum and the prefrontal cortex. Loss of gray matter density seems to be associated with impairment in executive functions, verbal memory und working memory [9,19,29].…”

“…For example, Koleck et al have shown in a prospective, longitudinal study that cancer patients with ApoEe4 have worse results in verbal learning and memory than controls [39]. ApoEe4 is also often present in patients suffering from Alzheimer's disease [3,29].…”

“…decreased levels of neuroprotective estrogen) which favor the development of CRCI [3,29]. Among several aspects, risk for developing CRCI seems to be associated with genotype of catechol o-methyltransferase (COMT) thereby where the gene coding for this enzyme is located on chromosome 22q11.…”

“…Furthermore, cytostatic therapy induces reduction of the gray matter in certain brain areas, such as the cerebellum and the prefrontal cortex. Loss of gray matter density seems to be associated with impairment in executive functions, verbal memory und working memory [9,19,29].Several anti-tumor therapies also appear to lead to alterations in cerebral blood flow. For example, some medical treatments induce cerebral hyperperfusion accompanied by impairment in neuropsychological test performance.…”