Abstract
Background/Purpose: Hodgkin Lymphoma (HL) survivors exposed to chest radiation and bleomycin are at increased risk for heart and lung morbidities, which have been shown to be associated with neurocognitive impairment. The mechanism linking lung morbidity and neurocognitive impairment is not well understood; however, it is known that cerebral blood flow, which can impact brain function, is regulated by O2, CO2 and pH changes in the bloodstream. This study aims to determine if HL survivors have altered cerebral blood flow compared to community controls and if cerebral blood flow is associated with lung function.
Methods: In this trial-in-progress, we measured lung function (FEV1, FEV1/FVC, DLCO), cardiopulmonary function (pkVO2, PkVCO2) and cerebral blood flow (CBF) of HL survivors (<21 years old at diagnosis, >18 years of age at assessment, >2 years post therapy, treated with chest radiation and/or bleomycin) and age matched controls. Cardiopulmonary testing was conducted on a treadmill using the Bruce Protocol to maximal exertion endpoint. Grade and speed were increased every 3 minutes until the participant reached anaerobic threshold, while simultaneously measuring cerebral blood flow from the anterior and posterior circulation using a mobile, whole-head, near-infrared device (NIRsport2, NIRx). The infrared signals were then low-pass filtered smoothed using a median filter to remove motion spikes and each channel signal was also processed by a bandpass filter, 0.8–1.5 Hz to isolate the cardiac component. Optical density data were subsequently converted into changes in hemoglobin concentration (Δ[HbO], Δ[HbR], and Δ[HbT]) using the modified Beer–Lambert law, assuming a partial pathlength factor of 0.1. Δ[HbT] is caused by CBF change and provides a measure of change in CBF for each participant. To analyze CBF response to exercise, Δ[HbT] whole head data in each stage were fitted using a linear model, and the absolute value of slope was measured and compared between groups. To examine similarities in CBF between anterior and posterior circulation, Pearson correlation coefficients between anterior and posterior Δ[HbT] were calculated in the stage when the participant had the strongest CBF response to the exercise (maximum absolute(slope) of Δ[HbT]). The Pearson correlation coefficient (r) of this stage was compared between groups. Unpaired t-tests were used to compare the means of pkVO2 and pkVCO2.
Results: Preliminary data from 39 HL survivors (n=20 females; mean[SD] age 40.2[8.8]) who were 25.3 [min-max: 19-42] years from diagnosis and 11 controls (n=8 females; 38.6[11.4]) showed female survivors had a significantly lower pkVO2 (21.9[6.4]) and pKVCO2(1851.4[505.6]) compared to female controls pkVO2 (27.9[5.9], p=0.044) and pKVCO2 (2509.2[736.3], p=0.011). Similar differences in males in pkVO2 or pkVCO2 cannot be ascertained at this time due to the small number of male controls to date. The correlation between anterior and posterior CBF was significantly different between controls (r=0.66) and survivors (r=0.30) during exercise max (p=0.004). 10 survivors (31%), but no controls, had a decrease in posterior CBF compared to an increase in anterior circulation at exercise max. FEV1 was significantly associated with the correlation between anterior and posterior CBF among controls (β=0.014, p=0.039) but not survivors. Among survivors, FEV1/FVC was significantly associated with the negative correlation between anterior and posterior CBF (β=0.085, p=0.018). No association was found among pkVO2, pkVCO2, DLCO, chest radiation dose, or bleomycin dose and negative correlation in anterior and posterior CBF.
Conclusions: Our study demonstrates that a reduced FEV1/FVC was significantly associated with a negative correlation between the anterior and posterior cerebral blood flow in response to exercise in HL survivors. These results may provide a physiological explanation for our previous findings showing that reduced expiratory volume was associated with impaired visuomotor and visual processing speed outcomes among HL survivors and suggests that interventions that target the posterior circulation in survivors with reduced FEV1/FVC may improve neurocognitive outcomes.
