Neuropsychol Rev doi: 10.1007/s11065-020-09441-9.
This systematic review explored the neurobiological mechanisms underlying the clinical time course of cancer-related cognitive impairment (CRCI) in breast cancer patients through the review of longitudinal neuroimaging studies. Before chemotherapy, results reported no evidence for neuropsychological, structural (gray matter) and brain perfusion changes. However, functional brain alterations were evident and revealed a frontoparietal hyperactivation during working memory tasks. Fatigue and number of days since surgery were the two suggested confounding factors. Acutely after chemotherapy, this review found no evidence for neuropsychological changes while suggesting a pattern of frontal structural, perfusion and functional brain abnormalities. These findings seemed to be dependent on age, menopausal status at baseline, and fMRI task performed. Years after chemotherapy, results revealed evidence of partial neuropsychological, structural, and functional brain recovery. Regarding brain abnormality, this review suggested that it may begin quite early in the disease course, be more prominent shortly after chemotherapy and partially recover over time. Several hypotheses underlying these changes were discussed. The present review also provided important information for developing a time-specific treatment and prevention strategies and for the consideration of functional neuroimaging as a relevant tool for CRCI diagnosis, clinical monitoring, and intervention studies. The findings also suggested the need to implement studies with longitudinal designs, including a pre-treatment assessment, since cross-sectional studies were not able to detect this pattern of recovery over time, supporting only the theory of brain abnormalities, in breast cancer survivors.
This review found no evidence for neuropsychological, gray matter structural and perfusion changes before chemotherapy treatment. Functional changes were evident and demonstrated a frontoparietal hyperactivation during working memory tasks, suggestive of higher fMRI sensitivity to detect lower task performance and cognitive impairment at this early stage of the disease process. Fatigue and number of days since surgery were the two confounding factors proposed to mediate these findings, suggesting a direct effect of cancer on the brain via mechanisms such as neuroinflammation (Kesler et al., 2017a). Acutely, after chemotherapy, the present review suggested that a pattern of frontal structural, perfusion and functional changes could be found in a subset of breast cancer patients.
Working memory was the most predominant cognitive domain across studies, showing correlations with structural changes in frontal GMV (Lepage et al., 2014) and WMintegrity (Billiet et al., 2018; Deprez et al., 2012). Findings of frontal hyper and hypo-activity seem to be dependent on age, menopausal status at baseline and domain targeted by a specific fMRI task, although requiring further investigation. Years after chemotherapy, the present review showed evidence of a partial neuropsychological, structural, and functional recovery. This evidence was already present in GMD and VBM studies one year after chemotherapy ended. Depending on the post-chemotherapy interval, some regions (such as inferior frontal regions and hippocampus) remained affected chronically by adjuvant treatments, suggesting that some abnormalities might still persist over time and never entirely normalize.
This review found converging evidence fromstructural and functional studies that show a particular vulnerability of frontal lobes to CRCI, known to be critical for working memory (Wefel & Schagen, 2012). Possible CRCI neuromarkers were also discussed. Since working memory is the most reportedly affected cognitive domain in these studies, the present review can also point to a specific vulnerability of working memory due to chemotherapy treatment and a later improvement. However, most of the included studies focused on the consequences of chemotherapy for patients’ working memory and, therefore, future research with magnetic resonance imaging should focus on other cognitive domains such as learning ability, executive function, attention, decision-making, language, and processing speed.
In conclusion, the present review suggests that brain abnormalities (especially compensatory frontal hyperactivation) may begin quite early in the disease course, being more prominent shortly after chemotherapy with a partial recovery over time (Kesler et al., 2017a). The developmental trajectory of CRCI confirms the need to implement longitudinal designs including a pre-surgery assessment, since cross-sectional studies were not able to detect this pattern of recovery over time, supporting only the theory of brain abnormality in breast cancer survivors.