Assessing the Impact of Cognitive Load on Resting State Tissue Oxygen Saturation in Adult Patients with Sickle Cell Disease

Patients with sickle cell disease (SCD) suffer from chronic anemia, cognitive decline, and lack of effective oxygen delivery to tissue. Cerebral tissue oxygen saturation (StO₂) is a critical endpoint for monitoring tissue perfusion in SCD, reflecting the percentage of dissolved oxygen in the tissue and the efficiency of circulation. Near-infrared spectroscopy (NIRS) is a noninvasive optical imaging technique that measures changes in oxy- and deoxyhemoglobin concentrations, allowing indirect monitoring of hemodynamics and StO₂. While differences in resting StO2 between patients with SCD and healthy controls are well documented, the changes in resting StO₂ following perturbations to cerebral hemodynamics have not been explored. Cognitive tasks lead to dynamic changes in the brain and increase oxygen demand. Analyzing these changes is important for understanding how cerebral hemodynamics are affected in patients with SCD. This study aimed to investigate the impact of the Digit Symbol Substitution Test (DSST), a cognitive task assessing cognitive flexibility, processing speed, attention and visual-motor coordination, on resting StO₂in adult patients with SCD compared to controls. As patients with SCD are reported to exhibit compensatory mechanisms such as increased cerebral blood flow (CBF), we hypothesized there would be no significant difference in StO₂ between patients with SCD and controls after the DSST.

The protocol was approved by the Institutional Review Board (IRB) and informed consent was obtained from all 28 participants. Adults with SCD (n=14, age=31±11, F=8) were recruited from the University of Pittsburgh Sickle Cell Center of Excellence with genotypes HbSS (n=6) and HbSC (n=8). Controls (n=14, age=37±14, F=9) with genotypes HbAA (n=9) and HbAS (n=5) were included and were recruited from the Pittsburgh community. Blood rheology measurements were collected for all participants. We collected cerebral hemodynamics from the prefrontal cortex using a frequency domain-NIRS system (ISS OxiplexTM (Champaign, IL) at a sampling frequency of 50 Hz to obtain StO₂ measurements. Baseline rest measurements were made for 90 seconds prior to the start of the task, followed by a 15-minute DSST task performance. Subjects were presented with symbols paired with numbers. Congruent pairs matched the reference table, while incongruent pairs did not. Behavioral responses, including response time and accuracy to each stimulus, were recorded. Post-stimulus baseline hemodynamics were measured after the task was completed as the participant rested for 90 seconds. T-test was used to compare and determine the significance between pre- and post-stimulus StO₂ measurements. We found that patients with SCD have a significantly lower baseline StO₂ than controls before starting the DSST task (SCD, Controls: 61.9±5.5%, 68.8±3.4%, p<0.001) and higher percent decrease in StO₂ after performing the DSST task (SCD, Controls: -2.3±4.5%, 1.2±3.9%, p=0.01), even though the cognitive performance with respect to accuracy was not significantly different (SCD, Controls: 80±25%, 89±15%, p>0.05). Clinical blood counts show patients with SCD have significantly lower hematocrit (SCD, Controls: 29.6±5.3%, 38.3±3.2%, p<0.001). There were no significant differences in the percent change in StO2 between HbSC and HbSS (p=0.3), and between HbAA and HbAS (p=0.2). Potential differences between genotypes will be explored further upon acquiring a larger sample size.

The findings in this study could be explained by the hallmark physiological changes reported in patients with SCD. Hemolysis leads to reduced hematocrit levels, and a decreased capacity to carry oxygen throughout the body. This deficit is potentially further increased during cognitive tasks. To compensate for these deficits, patients with SCD are reported to have elevated CBF and an increased oxygen extraction fraction (OEF). Despite the presence of these compensatory mechanisms, patients with SCD cannot meet increased oxygen demand due to impaired vascular reactivity and limited capacity for increased OEF. This could result in lower StO₂ levels and insufficient oxygen supply to brain tissue during cognitively demanding tasks. For future directions, incorporating cognitive tasks with correlations of CBF, StO₂ and changes in concentrations of oxyhemoglobin during the task could support the findings in this study.

Xu:GSK: Consultancy, Research Funding; Agios Pharmaceuticals: Consultancy.