Intensity of MRI Gadolinium Enhancement in Cerebral Adrenoleukodystrophy: A Biomarker for Inflammation and Predictor of Outcome following Transplantation in Higher Risk Patients

Abstract

BACKGROUND AND PURPOSE Outcomes following hematopoietic stem cell transplantation for higher-risk childhood-onset cerebral adrenoleukodystrophy are variable. We explored whether a brain MRI gadolinium intensity scoring system improves prediction of neurologic outcome. METHODS A four-point scale of gadolinium intensity relative to the choroid plexus was developed: 0 = no enhancement; 1 = hypo-intense; 2 = iso-intense; 3 = hyper-intense. The scale’s inter-observer concordance was assessed on 30 randomly chosen studies. Scores were generated for 64 evaluable patients and compared with cerebrospinal fluid chitotriosidase levels, a known inflammatory marker correlating with outcomes following transplant. For 25 evaluable higher-risk patients (Loes ≥ 10), the gadolinium intensity score was compared with longer-term post-transplant clinical change. RESULTS The gadolinium intensity scoring system showed good inter-observer reproducibility (kappa = 0.72). Of 64 evaluable boys, the score positively correlated with average concomitant cerebrospinal fluid chitotriosidase activity in ng/mL/hr: (0), 2,717, n=5; (1), 3,218, n=13; (2), 6,497, n=23; and (3), 12,030, n=23 (p < 0.01). For 25 evaluable higher-risk patients, more intense pre-transplant brain MRI gadolinium enhancement predicted greater average loss on the adrenoleukodystrophy neurologic function scale following transplant: (0/1), ΔNFS = 4.3, n = 7; (2/3), ΔNFS = 10.4, n = 18 (p = 0.05). CONCLUSION Gadolinium enhancement intensity on brain MRI can be scored simply and reproducibly for cerebral adrenoleukodystrophy. Enhancement score significantly correlates with chitotriosidase. In boys with higher-risk cerebral disease (Loes ≥ 10), enhancement score itself predicts neurologic outcome following treatment. Such data may help to guide treatment decisions for clinicians and families.

ABCD1 dysfunction alters white matter microvascular perfusion

“…Currently, the only approved treatment to arrest CALD is HSCT, presumably by bone marrow-derived monocytes with healthy ABCD1 that migrate into the brain and differentiate into less inflammatory macrophages and microglia ( Rafii and Lyden, 2003 ; Yamada et al , 2004 ; Mahmood et al , 2007 ; Kemp et al , 2016 ). The success of this effective but highly toxic treatment has been associated with disappearance of contrast enhancement and normalization of perfusion in T 2 -weighted hyperintense cerebral tissue ( Musolino et al , 2012 ; Miller et al , 2016 ). Following subjects treated with HSCT, we found a significant decrease (normalization) in capillary flow heterogeneity in the outer rim of the T 2 -weighted hyperintense region as well as in the adjacent NAWM.…”

Childhood Cerebral Adrenoleukodystrophy: MR Perfusion Measurements and Their Use in Predicting Clinical Outcome after Hematopoietic Stem Cell Transplantation

“…Meanwhile, within a sub-group of patients with higher Loes scores (≥10), a recent study found that the intensity of visible enhancement on postcontrast T1WI may lend predictive value to clinical outcome, and this was found to be relatively simple to measure, as well as reproducible between observers. 27 …”

“…Therefore, as mentioned previously, this study’s findings regarding response to HSCT cannot be generalized to the subset of cALD patients that present with much higher Loes MRI severity scores on initial evaluation for HSCT, which may be better addressed by gadolinium intensity measurements. 27 …”

Modeling and rescue of defective blood–brain barrier function of induced brain microvascular endothelial cells from childhood cerebral adrenoleukodystrophy patients

“…ccALD affects about 40% of males with an ABCD1 mutation [ 15 , 16 ]. MRI observation of gadolinium enhancement in the brain remains the only method to detect this progression [ 17 – 21 ]. Infections or head trauma have been described as initiators of the conversion from AMN to ccALD, but typically no extrinsic factor can be identified [ 22 – 24 ].…”