Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Mar 31:14:1112865.
doi: 10.3389/fneur.2023.1112865. eCollection 2023.

Silent infarction in sickle cell disease is associated with brain volume loss in excess of infarct volume

R Sky Jones  1 , Manus J Donahue  2   3   4 , L Taylor Davis  2 , Sumit Pruthi  2 , Spencer L Waddle  2 , Chelsea Custer  1   2 , Niral J Patel  1   2 , Michael R DeBaun  5 , Adetola A Kassim  6 , Mark Rodeghier  7 , Lori C Jordan  1   2   3
Affiliations

Silent infarction in sickle cell disease is associated with brain volume loss in excess of infarct volume

R Sky Jones et al. Front Neurol. .

Abstract

Introduction: Sickle cell disease (SCD) increases cerebral infarct risk, but reported effects on brain volume have varied. More detailed information using larger cohorts and contemporary methods could motivate the use of longitudinal brain volume assessment in SCD as an automated marker of disease stability or future progression. The purpose of this study was to rigorously evaluate whether children and young adults with SCD have reduced gray matter volume (GMV) and white matter volume (WMV) compared to healthy controls using high-resolution MRI. We tested the hypotheses that (i) elevated CBF, a marker of cerebral hemodynamic compensation in SCD, is associated with global and regional brain atrophy, and (ii) silent cerebral infarct burden is associated with brain atrophy in excess of infarct volume.

Methods: Healthy controls (n = 49) and SCD participants without overt stroke (n = 88) aged 7-32 years completed 3 T brain MRI; pseudocontinuous arterial spin labeling measured CBF. Multivariable linear regressions assessed associations of independent variables with GMV, WMV, and volumes of cortical/subcortical regions.

Results: Reduced hemoglobin was associated with reductions in both GMV (p = 0.032) and WMV (p = 0.005); reduced arterial oxygen content (CaO2) was also associated with reductions in GMV (p = 0.035) and WMV (p = 0.006). Elevated gray matter CBF was associated with reduced WMV (p = 0.018). Infarct burden was associated with reductions in WMV 30-fold greater than the infarct volume itself (p = 0.005). Increased GM CBF correlated with volumetric reductions of the insula and left and right caudate nuclei (p = 0.017, 0.017, 0.036, respectively). Infarct burden was associated with reduced left and right nucleus accumbens, right thalamus, and anterior corpus callosum volumes (p = 0.002, 0.002, 0.009, 0.002, respectively).

Discussion: We demonstrate that anemia and decreased CaO2 are associated with reductions in GMV and WMV in SCD. Increased CBF and infarct burden were also associated with reduced volume in subcortical structures. Global WMV deficits associated with infarct burden far exceed infarct volume itself. Hemodynamic compensation via increased cerebral blood flow in SCD seems inadequate to prevent brain volume loss. Our work highlights that silent cerebral infarcts are just a portion of the brain injury that occurs in SCD; brain volume is another potential biomarker of brain injury in SCD.

Keywords: MRI; brain volume; cerebral blood flow; infarction; sickle cell; silent cerebral infarct.

PubMed Disclaimer

Conflict of interest statement

MJD is a paid consultant for Global Blood Therapeutics, receives advisory board receives research-related support from Philips North America, and is the CEO of Biosight LLC, which provides healthcare technology consulting services. These agreements have been approved by Vanderbilt University Medical Center in accordance with its conflict-of-interest policy. MR is an independent statistical consultant. He owns Rodeghier Consulting, Chicago, IL, United States. He was paid for his work on this manuscript via NIH grant funding. MRD and his institution are the sponsor of two externally funded research investigator-initiated projects. Global Blood Therapeutics will provide funding for the cost of these clinical studies but will not be a cosponsor of either study. MRD is not receiving any compensation for the conduct of these two-investigator initiated observational studies. MRD is a member of the Global Blood Therapeutics advisory board for a proposed randomized controlled trial for which he receives compensation. MRD is the steering committee for a Novartis-sponsored phase 2 trial to prevent priapism in men. MRD was a medical advisor for the development of the CTX001 Early Economic Model. MRD provided medical input on the economic model as part of an expert reference group for Vertex/CRISPR CTX001 Early Economic Model in 2020. MRD provided a onetime consultation to the Forma Pharmaceutical company about sickle cell disease in 2021. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Study exclusion flowchart.
Figure 2
Figure 2
Representative comparison of structural images of participant brains along with FreeSurfer-derived gray and white matter segmentations (blue overlay and white overlay, respectively). Tissue volume differences between healthy controls (HC) and individuals with sickle cell disease (SCD) with and without silent cerebral infarcts (SCI) are often not immediately apparent on structural imaging modalities, barring large overt ischemic strokes that were excluded from this sample.
Figure 3
Figure 3
Plots of gray matter volume and white matter volume with hemoglobin, gray matter CBF, or log-transformed infarct (lesion) burden, displaying the multivariable regression model-predicted association between each covariate and volume, controlling for age, sex, and intracranial volume, with 95% confidence intervals (gray line and shaded area). Models include healthy controls and participants with SCD (A,B) or participants with SCD and silent cerebral infarcts only (C). Overlaid on the model predictions are the raw data.
Figure 4
Figure 4
3D parcellation of a representative participant with SCD. (A) Shows FreeSurfer cortical parcellation. (B) Shows gray matter segmentation (translucent gray) over white matter segmentation (green). (C) Shows subcortical and cortical structures for which significant associations with tested independent variables were found. Other structures are displayed in gray as spatial references.
See this image and copyright information in PMC

References

    1. Piel FB, Steinberg MH, Rees DC. Sickle cell disease. N Engl J Med. (2017) 376:1561–73. doi: 10.1056/NEJMra1510865 - DOI - PubMed
    1. Kassim AA, Pruthi S, Day M, Rodeghier M, Gindville MC, Brodsky MA, et al. . Silent cerebral infarcts and cerebral aneurysms are prevalent in adults with sickle cell anemia. Blood. (2016) 127:2038–40. doi: 10.1182/blood-2016-01-694562, PMID: - DOI - PubMed
    1. Sacco RL, Kasner SE, Broderick JP, Caplan LR, Connors JJ, Culebras A, et al. . An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. (2013) 44:2064–89. doi: 10.1161/STR.0b013e318296aeca, PMID: - DOI - PMC - PubMed
    1. DeBaun MR, Gordon M, McKinstry RC, Noetzel MJ, White DA, Sarnaik SA, et al. . Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia. N Engl J Med. (2014) 371:699–710. doi: 10.1056/NEJMoa1401731, PMID: - DOI - PMC - PubMed
    1. Prussien KV, Jordan LC, DeBaun MR, Compas BE. Cognitive function in sickle cell disease across domains, cerebral infarct status, and the lifespan: a meta-analysis. J Pediatr Psychol. (2019) 44:948–58. doi: 10.1093/jpepsy/jsz031, PMID: - DOI - PMC - PubMed

LinkOut - more resources