Functional Connectivity Decreases with Metabolic Stress in Sickle Cell Disease

Abstract

Objective: Children with sickle cell disease (SCD) experience cognitive deficits even when unaffected by stroke. Using functional connectivity magnetic resonance imaging (MRI) as a potential biomarker of cognitive function, we tested our hypothesis that children with SCD would have decreased functional connectivity, and that children experiencing the greatest metabolic stress, indicated by elevated oxygen extraction fraction, would have the lowest connectivity. Methods: We prospectively obtained brain MRIs and cognitive testing in healthy controls and children with SCD. Results: We analyzed data from 60 participants (20 controls and 40 with sickle cell disease). There was no difference in global cognition or cognitive subdomains between cohorts. However, we found decreased functional connectivity within the sensory-motor, lateral sensory-motor, auditory, salience, and subcortical networks in participants with SCD compared with controls. Further, as white matter oxygen extraction fraction increased, connectivity within the visual (p = 0.008, parameter estimate = −0.760 [95% CI = −1.297, −0.224]), default mode (p = 0.012, parameter estimate = −0.417 [95% CI = −0.731, −0.104]), and cingulo-opercular (p = 0.009, parameter estimate = −0.883 [95% CI = −1.517, −0.250]) networks decreased. Interpretation: We conclude that there is diminished functional connectivity within these anatomically contiguous networks in children with SCD compared with controls, even when differences are not seen with cognitive testing. Increased white matter oxygen extraction fraction was associated with decreased connectivity in select networks. These data suggest that elevated oxygen extraction fraction and disrupted functional connectivity are potentially presymptomatic neuroimaging biomarkers for cognitive decline in SCD.

Cerebral Oxygen Metabolic Stress, Microstructural Injury, and Infarction in Adults With Sickle Cell Disease

“…We postulate that OEF may risk stratify microstructural impairment prior to irreversible structural damage. In support of our findings showing a relationship between oxygen metabolic stress and microstructural integrity, Fields et al 42 identified an association between oxygen metabolic stress and diminished functional connectivity in white matter unaffected by infarcts in children with SCD. In non-SCD sporadic small vessel disease, impairment in cerebrovascular reactivity, a metric of cerebral autoregulation, has been associated with disruption in microstructural integrity.…”

“…identified an association between oxygen metabolic stress and diminished functional connectivity in white matter unaffected by infarcts in children with SCD. 42 In non-SCD sporadic small vessel disease, impairment in cerebrovascular reactivity, a metric of cerebral autoregulation, has been associated with disruption in microstructural integrity. 43 Together, these studies contribute to the notion that inadequate oxygen delivery and elevation in oxygen metabolic stress may underlie the pathophysiology of microstructural disruption in SCD.…”

Cerebral and skeletal muscle tissue oxygenation during exercise challenge in children and young adults with sickle cell anaemia

“…The physiology of cerebral haemodynamics may explain alterations in cerebral StO 2 during exercise in SCA patients 12 . In SCA, individuals compensate for reduced arterial oxygen content by increasing cerebral blood flow and oxygen extraction 12,13 . Exhaustion of compensatory mechanisms may impact cerebral tissue oxygenation 10 .…”

Cerebral oxygen metabolic stress is increased in children with sickle cell anemia compared to anemic controls

“…The ASE data were then decomposed into contributions from each tissue type (i.e., gray matter, white matter, CSF) 36 . The tissue‐specific ASE signal was independently processed to compute voxel‐wise OEF per participant 13 . A hematocrit value is required for OEF processing, and linear regression accounting for age and sex was used to estimate hematocrit for control participants with missing lab values.…”

“…OEF peaks within the border zone of the brain, where CBF nadirs 9,12 . Furthermore, the regions with a greatest increase in OEF align with regions of diminished functional connectivity 13 and greatest risk for infarction in patients with SCA 9,12 . Primary disease modification with an increase in arterial oxygen content via transfusion of hemoglobin A laden red blood cells relieves ongoing metabolic stress with a resultant decrease in cerebral blood flow and OEF in patients with SCA 11,14 …”