MRI Gadolinium Volume in Cerebral Adrenoleukodystrophy: A Novel Biomarker to Quantify Cerebral Inflammation and Predict Transplant Response.

Abstract

Adrenoleukodystrophy (ALD) is caused by mutations within the X-linked <i>ABCD1</i> gene resulting in the inability to transport acylated very long chain fatty acids (VLCFA) into the peroxisome for degradation. VLCFA subsequently accumulate in tissues, including the central nervous system. Up to 40% of boys develop a severe, progressive demyelinating form of ALD, cerebral ALD (cALD), resulting in regions of demyelination observed on brain magnetic resonance imaging (MRI) that are associated with a "garland ring" of gadolinium contrast enhancement. Gadolinium enhancement indicates blood-brain-barrier (BBB) disruption and an active inflammatory disease process. Only hematopoietic cell transplant (HCT) is accepted as therapy sufficient to halt neurologic progression and resolve the observed gadolinium enhancement, although the mechanism of disease arrest is unknown. We have previously shown that rapid donor neutrophil recovery after HCT facilitates MRI gadolinium resolution. We now show early (28 days post HCT) gadolinium resolution correlates well with improved neurologic outcomes measured 1-year post HCT. We recently developed a method to quantify gadolinium on imaging and calculate a gadolinium (Gad) volume given in cubic centimeters (cc). We evaluated Gad volume and other previously described imaging and transplant related biomarkers in 66 boys who underwent HCT. In univariate analysis we found day 28 gadolinium resolution was associated with the following pre-transplant parameters: less Gad volume (7.3 cc versus 2.7 cc, p=0.01), less Gad intensity (p=0.04) and less extensive demyelination as determined by the Loes MRI scoring system (p=0.03). In addition, resolution of Gad enhancement by day 28 was associated with lower pre-HCT plasma and cerebral spinal fluid chitotriosidase activity (p=0.04 for both), and faster neutrophil recovery post HCT (less than 16 days versus greater than 16 days, p=0.03). Multivariate analysis revealed that only less Gad volume was predictive of rapid gadolinium resolution at 28 days post HCT (p = 0.02). This is the first data to quantify the extent of cerebral inflammation in cALD as defined by Gad positivity and its resolution after HCT. Future studies should consider use of Gad volume prior to HCT as a useful biomarker for time to resolution.