Cerebral Perfusion and Gray Matter Changes Associated With Chemotherapy-Induced Peripheral Neuropathy

Abstract

Purpose: To investigate the longitudinal relationship between chemotherapy-induced peripheral neuropathy (CIPN) symptoms (sx) and brain perfusion changes in patients with breast cancer. Interaction of CIPN-sx perfusion effects with known chemotherapy-associated gray matter density decrease was also assessed to elucidate the relationship between CIPN and previously reported cancer treatment-related brain structural changes.

Methods: Patients with breast cancer treated with (n = 24) or without (n = 23) chemotherapy underwent clinical examination and brain magnetic resonance imaging at the following three time points: before treatment (baseline), 1 month after treatment completion, and 1 year after the 1-month assessment. CIPN-sx were evaluated with the self-reported Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity four-item sensory-specific scale. Perfusion and gray matter density were assessed using voxel-based pulsed arterial spin labeling and morphometric analyses and tested for association with CIPN-sx in the patients who received chemotherapy.

Results: Patients who received chemotherapy reported significantly increased CIPN-sx from baseline to 1 month, with partial recovery by 1 year (P < .001). CIPN-sx increase from baseline to 1 month was significantly greater for patients who received chemotherapy compared with those who did not (P = .001). At 1 month, neuroimaging showed that for the group that received chemotherapy, CIPN-sx were positively associated with cerebral perfusion in the right superior frontal gyrus and cingulate gyrus, regions associated with pain processing (P < .001). Longitudinal magnetic resonance imaging analysis in the group receiving chemotherapy indicated that CIPN-sx and associated perfusion changes from baseline to 1 month were also positively correlated with gray matter density change (P < .005).

Conclusion: Peripheral neuropathy symptoms after systemic chemotherapy for breast cancer are associated with changes in cerebral perfusion and gray matter. The specific mechanisms warrant further investigation given the potential diagnostic and therapeutic implications.

Fig 1.

CONSORT diagram. Number of individuals considered at each stage of the study, as well as number and reasons for excluded individuals. 1M, 1 month after chemotherapy treatment completion (or yoked interval for patients who did not receive chemotherapy and controls); 1Y, 1 year after 1M time point; BL, baseline (before chemotherapy treatment for the majority of patients); CIPN, chemotherapy-induced peripheral neuropathy; Ctx+, patients with breast cancer treated with chemotherapy; CTx–, patients with breast cancer treated without chemotherapy; HC, healthy controls; SD, standard deviation.

Fig 2.

Chemotherapy-induced peripheral neuropathy symptoms (CIPN-sx) positively associated with perfusion. Surface rendering of the positive association of 1-month post-treatment perfusion with level of CIPN-sx reported at 1 month after treatment (P_crit < .001, k = 25); colored regions indicate increasing statistical significance, as shown on the color scale.

Fig 3.

Chemotherapy-induced peripheral neuropathy symptoms (CIPN-sx) associated with perfusion increase. Colored regions of brain sections show areas with statistically significant association of baseline (before chemotherapy treatment) to 1-month post-treatment perfusion increase and 1-month post-treatment CIPN-sx covarying for baseline (P_crit < .001, k = 25); colored regions indicate increasing statistical significance, as shown on the color scale.

Fig 4.

Gray matter density (GMD), perfusion, and chemotherapy-induced peripheral neuropathy symptom (CIPN-sx) change correlations. (A) Scatter plot of baseline (prechemotherapy treatment) to 1-month post-treatment (1M) change in GMD frontal clusters (as seen in McDonald et al; x-axis) and the CIPN-sx–associated perfusion change cluster in the left cingulate gyrus (LCG). These variables showed a Pearson correlation (r = 0.598, P = .002), as labeled on the fit line. (B) Scatter plot of baseline to 1M change in GMD frontal clusters (x-axis) and CIPN-sx change. These variables showed a Pearson correlation (r = 0.704, P < .001), as labeled on the fit line.

Fig 5.

Cerebral perfusion decrease associated with gray matter density decrease in chemotherapy-induced peripheral neuropathy symptom–related regions of interest. A mask of regions where chemotherapy-induced peripheral neuropathy symptoms correlated with perfusion at 1 month after chemotherapy completion superimposed on the analysis presented in Nudelman et al of gray matter density frontal cluster change (baseline to 1 month after treatment) with perfusion change identifies clusters of overlap (P_crit < .01, k = 25) in the cingulate gyrus and superior frontal gyrus; colored regions indicate increasing statistical significance, as shown on the color scale.