Repair of the Blood Brain Barrier with Neutrophil Recovery Following HSCT for Cerebral Adrenoleukodystrophy
Year: 2019
Type: article
Study design: Observational Study
Abstract: Introduction Cerebral leukodystrophy is an X-linked peroxisomal disease characterized by mutations in the ABCD1 gene, resulting in the lack of very long chain fatty acid (VLCFA) transport into peroxisomes. Resultant VLCFA build up in the blood and tissues leads to adrenal gland insufficiency in 95% of boys and an inflammatory cerebral demyelinating process in 40% of patients, which is progressive and most often fatal (cALD). A key clinical feature of cALD is disruption of the blood brain barrier (BBB) illustrated by gadolinium (gad) contrast enhancement on brain MRI at diagnosis and as an indicator of "active" cerebral disease. Only hematopoietic stem cell transplant (HSCT) has been shown to halt cerebral disease progression. After HSCT, gad enhancement resolves in 90% of cases by 100 days post HSCT in our experience. Objective A seminal question in the field is how recovery of donor-derived hematopoiesis relates to BBB repair and gad resolution. Methods We evaluated the pre-HSCT characteristics and 1-year post-HSCT outcomes in 66 boys undergoing marrow or umbilical cord blood HSCT for cALD. Results The median total nucleated cell (TNC) dose was 0.8 × 10 8 cells/kg and CD34+ cell dose was 1.27 × 10 6 cells/kg. Pre-HSCT characteristics included: cALD on MRI quantified using the Loes scoring system, neurologic disability using the neurologic function scale (NFS), plasma and cerebral spinal fluid (CSF) chitotriosidase level, and intensity of gadolinium on pre-HSCT MRI (gad score). We found 77% boys had gad resolution by day +28 (early) post-HSCT and 90% had gad resolution by day +100 (later) post-HSCT. Patients with gad resolution by day +60 post-HSCT had lower Loes scores at 1-year (p = 0.008), lower absolute NFS (p = 0.004), and less progression of neurologic symptoms (post-HSCT NFS – pre-HSCT NFS, p = 0.02). Importantly, we found neutrophil recovery occurred at a mean of 16 days in the patients with day +60 gad resolution compared to 20 days in those without gad resolution (p = 0.008). Other factors associated with early gad resolution were: lower Loes score (p = 0.003), lower NFS (p = 0.003), lower plasma chitotriosidase (p = 0.02), lower CSF chitotriosidase (p = 0.02), and lower gad score (p = 0.02). On multivariate analysis, only the day of neutrophil recovery post-HSCT remained significant with p = 0.04). There was no significant difference in cell dose between the groups. In patients with graft failure, day +60 gad resolution occurred in only 8% (n = 18, p = 0.01). Conclusion This is the first study to link neutrophil recovery following HSCT and early repair of the BBB (gadolinium resolution). This is an important observation, as gad resolution is thought to be an indicator of cerebral disease arrest and activity of neuroinflammation. This observation may also serve as a useful biomarker as new therapies for cALD are being developed, including gene therapy and CD34 expansion.
Language: English
Subfield: Clinical Biochemistry
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,650
OpenAlex ID: W2913445230