TY - JOUR
T1 - Quantification of Silent Cerebral Infarction on High-Resolution FLAIR and Cognition in Sickle Cell Anemia
AU - Stotesbury, Hanne
AU - Kawadler, Jamie M.
AU - Clayden, Jonathan D.
AU - Saunders, Dawn E.
AU - Hood, Anna M.
AU - Koelbel, Melanie
AU - Sahota, Sati
AU - Rees, David C.
AU - Wilkey, Olu
AU - Layton, Mark
AU - Pelidis, Maria
AU - Inusa, Baba P.D.
AU - Howard, Jo
AU - Chakravorty, Subarna
AU - Clark, Chris A.
AU - Kirkham, Fenella J.
N1 - Funding Information:
FK was grantholder for GN2509, V4615, PB-PG-1112-29099 and R01HL079937 and has received honoraria from Global Blood Therapeutics, Bluebird Bio, Novartis, BIAL, Shire and Johnson and Johnson. JH received research funding from Bluebird Bio, and payments in relation to work as an advisory board member from IMR, Novartis, Global Blood Therapeutics, Novo Nordisk, Forma therapeutics, Agios, Add Medica, and Terumo, and also received a travel grant from Novartis and payments relating to work as a panel speaker from Novartis and Global Blood Therapeutics. 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.
Funding Information:
HS and MK were funded by Action Medical Research (GN2509) and JK by Great Ormond Street Children's Charity (V4615). AH was supported by an NIH grant (1F32HL143915). The National Institute for Health Research (PB-PG-1112-29099) and NIH (R01HL079937) provided funding for patient recruitment. The work was supported by the National Institute for Health Research Biomedical Research Centre (IS-BRC-1215-20012) at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London.
Publisher Copyright:
Copyright © 2022 Stotesbury, Kawadler, Clayden, Saunders, Hood, Koelbel, Sahota, Rees, Wilkey, Layton, Pelidis, Inusa, Howard, Chakravorty, Clark and Kirkham.
PY - 2022/6/29
Y1 - 2022/6/29
N2 - Research in sickle cell anemia (SCA) has used, with limited race-matched control data, binary categorization of patients according to the presence or absence of silent cerebral infarction (SCI). SCI have primarily been identified using low-resolution MRI, with radiological definitions varying in lesion length and the requirement for abnormality on both fluid attenuated inversion recovery (FLAIR) and T1-weighted images. We aimed to assess the effect of published SCI definitions on global, regional, and lobar lesion metrics and their value in predicting cognition. One hundred and six patients with SCA and 48 controls aged 8–30 years underwent 3T MRI with a high-resolution FLAIR sequence and Wechsler cognitive assessment. Prevalence, number, and volume of lesions were calculated using a semi-automated pipeline for SCI defined as: (1) Liberal: any length (L-SCI); (2) Traditional: >3 mm in greatest dimension (T-SCI); (3) Restrictive; >3 mm in greatest dimension with a corresponding T1-weighted hypo-intensity (R-SCI). Globally, as hypothesized, there were large effects of SCI definition on lesion metrics in patients and controls, with prevalence varying from 24–42% in patients, and 4–23% in controls. However, contrary to hypotheses, there was no effect of any global metric on cognition. Regionally, there was a consistent distribution of SCI in frontal and parietal deep and juxta-cortical regions across definitions and metrics in patients, but no consistent distribution in controls. Effects of regional SCI metrics on cognitive performance were of small magnitude; some were paradoxical. These findings expose the challenges associated with the widespread use of SCI presence as a biomarker of white-matter injury and cognitive dysfunction in cross-sectional high-resolution MRI studies in patients with SCA. The findings indicate that with high-resolution MRI: (1) radiological definitions have a large effect on resulting lesion groups, numbers, and volumes; (2) there is a non-negligible prevalence of lesions in young healthy controls; and (3) at the group-level, there is no cross-sectional association between global lesion metrics and general cognitive impairment irrespective of lesion definition and metric. With high-resolution multi-modal MRI, the dichotomy of presence or absence of SCI does not appear to be a sensitive biomarker for the detection of functionally significant pathology; the search for appropriate endpoints for clinical treatment trials should continue.
AB - Research in sickle cell anemia (SCA) has used, with limited race-matched control data, binary categorization of patients according to the presence or absence of silent cerebral infarction (SCI). SCI have primarily been identified using low-resolution MRI, with radiological definitions varying in lesion length and the requirement for abnormality on both fluid attenuated inversion recovery (FLAIR) and T1-weighted images. We aimed to assess the effect of published SCI definitions on global, regional, and lobar lesion metrics and their value in predicting cognition. One hundred and six patients with SCA and 48 controls aged 8–30 years underwent 3T MRI with a high-resolution FLAIR sequence and Wechsler cognitive assessment. Prevalence, number, and volume of lesions were calculated using a semi-automated pipeline for SCI defined as: (1) Liberal: any length (L-SCI); (2) Traditional: >3 mm in greatest dimension (T-SCI); (3) Restrictive; >3 mm in greatest dimension with a corresponding T1-weighted hypo-intensity (R-SCI). Globally, as hypothesized, there were large effects of SCI definition on lesion metrics in patients and controls, with prevalence varying from 24–42% in patients, and 4–23% in controls. However, contrary to hypotheses, there was no effect of any global metric on cognition. Regionally, there was a consistent distribution of SCI in frontal and parietal deep and juxta-cortical regions across definitions and metrics in patients, but no consistent distribution in controls. Effects of regional SCI metrics on cognitive performance were of small magnitude; some were paradoxical. These findings expose the challenges associated with the widespread use of SCI presence as a biomarker of white-matter injury and cognitive dysfunction in cross-sectional high-resolution MRI studies in patients with SCA. The findings indicate that with high-resolution MRI: (1) radiological definitions have a large effect on resulting lesion groups, numbers, and volumes; (2) there is a non-negligible prevalence of lesions in young healthy controls; and (3) at the group-level, there is no cross-sectional association between global lesion metrics and general cognitive impairment irrespective of lesion definition and metric. With high-resolution multi-modal MRI, the dichotomy of presence or absence of SCI does not appear to be a sensitive biomarker for the detection of functionally significant pathology; the search for appropriate endpoints for clinical treatment trials should continue.
KW - anemia
KW - cognition
KW - intelligence quotient
KW - ischemia
KW - magnetic resonance imaging
KW - sickle cell
KW - silent cerebral infarction
KW - white matter hyperintensities
UR - http://www.scopus.com/inward/record.url?scp=85134189314&partnerID=8YFLogxK
U2 - 10.3389/fneur.2022.867329
DO - 10.3389/fneur.2022.867329
M3 - Article
AN - SCOPUS:85134189314
SN - 1664-2295
VL - 13
JO - Frontiers in Neurology
JF - Frontiers in Neurology
M1 - 867329
ER -