New research from the University of Texas at Austin has shed more light on hereditary factors that may make cancer patients more vulnerable to cognitive impairment following chemotherapy treatment.
The study, published last Tuesday in Scientific Reports, examined measures of cognitive function in breast cancer patients who had undergone chemotherapy, breast cancer patients who had never received chemotherapy, and a control group of healthy participants. Subjects also underwent fMRI so that researchers could create a connectivity matrix for each participant based on temporal correlations of activity within ninety different nodes based on anatomical regions of interest.
Cancer patients that received chemotherapy did not demonstrate wide levels of cognitive impairment, but they did score lower on a processing speed test than both cancer patients that had not undergone chemotherapy and healthy controls. These patients also self-reported more difficulty with executive functioning than the other groups.
Compared to the patients that did not undergo chemotherapy, the chemotherapy group demonstrated less functional clustering between neighboring nodes. Surprisingly, this group also had lower path length of connections between nodes. In studies of brain connectivity, path of connection length does not refer to the physical distance between two nodes but rather the amount of nodes must be traversed to connect one node to the others and can be thought of as a measure of efficiency.
The researchers performed genotype analysis on participant saliva samples, looking for variations in a handful of candidate genes (APOE, COMT, MDR1, BDNF, and GST) known to be associated with cognitive function. They compared participant results on the connectivity and cognitive function assays with the version, or allele, of each gene that they carry.
Among breast cancer survivors who had undergone chemotherapy, only the APOE-ε4 allele was associated with worse processing speed. No other differences in cognitive performance between groups were linked to the candidate genes. The researchers suggest that this could be due to the low levels of cognitive impairment in the chemotherapy patient group overall.
More of the candidate genes seemed to play a role in functional connectivity, at least at the regional level. The BDNF Met allele and the MDR1 T allele were associated with less connectivity between regions called the left calcarine sulcus and left cuneus in chemotherapy patients. Both regions are related to visual processing. Lower connectivity between the left calcarine sulcus and left cuneus was associated with many of the risk-related alleles in chemotherapy-naive patients as well. Previous research from this team found higher levels of connectivity between the left calcarine sulcus and left cuneus in breast cancer survivors compared to healthy controls. This leads the author to conclude that the difference in connectivity is driven by these at-risk alleles. Chemotherapy patients with MDR1 T allele also demonstrated less connectivity between the right and left paracentral lobule than either control group. The paracentral lobule is involved in motor and sensory activity in the lower body.
None of the alleles had any affect on global connectivity between groups, which the authors of the study suggest may be related to the limited number of candidate genes selected for analysis as well as differences between allele frequencies in the broader population and their participant groups.
The researchers emphasize that the alleles studied in this experiment have all been linked to brain aging, which has been hypothesized as being conceptually similar to cancer-related cognitive impairment. For example, the APOE-ε4 allele is associated with higher vulnerability to Alzheimer’s disease.
The authors acknowledge that the five year period between chemotherapy treatment and cognitive test administration may weaken their claim that any cognitive deficit was caused by chemotherapy. They also consider the wide gap between self-reported cognitive difficulties among chemotherapy patients and their low levels of cognitive deficit on tests, suggesting that their battery of cognitive testing may not have been sensitive to the type of decline the patients experienced.
Despite these limitations, the researchers present a clear link between genetics and chemotherapy treatment as it pertains to cancer-related cognitive impairment and make a compelling case that this field demands further study.