Individual Watershed Areas in Sickle Cell Anemia: An Arterial Spin Labeling Study

Abstract

Previous studies have pointed to a role for regional cerebral hemodynamic stress in neurological complications in patients with sickle cell anemia (SCA), with watershed regions identified as particularly at risk of ischemic tissue injury. Using single- and multi-inflow time (TI) arterial spin labeling sequences (ASL) in 94 patients with SCA and 42 controls, the present study sought to investigate cerebral blood flow (CBF) and bolus arrival times (BAT) across gray matter, white matter with early arrival times, and in individual watershed areas (iWSAs). In iWSAs, associations between hemodynamic parameters, lesion burden, white matter integrity, and general cognitive performance were also explored. In patients, increases in CBF and reductions in BAT were observed in association with reduced arterial oxygen content across gray matter and white matter with early arrival times using both sequences (all p < 0.001, d = −1.55–−2.21). Across iWSAs, there was a discrepancy between sequences, with estimates based on the single-TI sequence indicating higher CBF in association with reduced arterial oxygen content in SCA patients, and estimates based on the multi-TI sequence indicating no significant between-group differences or associations with arterial oxygen content. Lesion burden was similar between white matter with early arrival times and iWSAs in both patients and controls, and using both sequences, only trend-level associations between iWSA CBF and iWSA lesion burden were observed in patients. Further, using the multi-TI sequence in patients, increased iWSA CBF was associated with reduced iWSA microstructural tissue integrity and slower processing speed. Taken together, the results highlight the need for researchers to consider BAT when estimating CBF using single-TI sequences. Moreover, the findings demonstrate the feasibility of multi-TI ASL for objective delineation of iWSAs and for detection of regional hemodynamic stress that is associated with reduced microstructural tissue integrity and slower processing speed. This technique may hold promise for future studies and treatment trials.

Quantification of Silent Cerebral Infarction on High-Resolution FLAIR and Cognition in Sickle Cell Anemia

“…These possibilities could also account for the paradoxical univariate association observed between higher volume and larger number of R-SCI and higher, rather than lower, IQ in children with SCA <16 years. Another possibility is that in the child's brain, adaptive physiology which may enable brain growth and development, e.g., higher cerebral blood flow (CBF), might eventually favor the development of SCI in the borderzone regions ( 64 , 65 ) related to vascular instability secondary to exhaustion of cerebral reserve mechanisms, shunting or steal. Such effects may plausibly improve or worsen over time depending on age, along with the severity of the disease course.…”

“…Using quantitative multi-modal methods to explore the haemodynamic, susceptibility, and microstructural characteristics of lesions, and of normal-appearing white-matter in anatomical regions “at-risk” of haemodynamic compromise ( 63 , 65 , 67 – 69 ), may enable better lesion classification, and may also shed further light on the underlying pathology. Understanding relationships between the microstructural tissue characteristics of lesions and normal-appearing white matter is particularly relevant in SCA, where studies have shown widespread and functionally significant reductions in the integrity of normal-appearing white matter ( 16 , 70 – 72 ), also in patients without lesions.…”

“…In parallel with quantification of SCI, documenting the effect of reduced arterial oxygen content secondary to anemia and hypoxia on cerebral blood flow ( 65 ) and oxygen extraction fraction ( 73 ), may shed light on the etiology of cognitive difficulties in SCA, alongside connectivity studies ( 74 ). In addition, regional brain volumes may be reduced in SCA ( 75 , 76 ); we did not find an effect of total intracranial volume in our regressions but further regional analyses are planned.…”

Quantitative susceptibility mapping (QSM) and R2* of silent cerebral infarcts in sickle cell anemia

“…Furthermore, spatial variation could be considered by examining the position of the SCI relative to the arterial territories. SCI are most commonly reported in the border zone region between arterial territories ( 11 ); however this finding comes mostly from low-resolution studies, and our recent high-resolution study suggests that smaller SCI may be just as common in juxta-cortical regions ( 64 ).…”

Data_Sheet_1.docx

“…Using quantitative multi-modal methods to explore the haemodynamic, susceptibility, and microstructural characteristics of lesions, and of normal-appearing white-matter in anatomical regions "at-risk" of haemodynamic compromise (63,65,(67)(68)(69), may enable better lesion classification, and may also shed further light on the underlying pathology. Understanding relationships between the microstructural tissue characteristics of lesions and normal-appearing white matter is particularly relevant in SCA, where studies have shown widespread and functionally significant reductions in the integrity of normal-appearing white matter (16, [70][71][72], also in patients without lesions.…”