Since the seminal paper by Schaumburg et al. (1975)
, the prominent perivascular inflammation at the leading edge of demyelination is known to occur in cerebral adrenoleukodystrophy. This study demonstrates that distinct regional magnetic resonance perfusion changes correspond to these previously recognized pathological zones. The premise underlying these zonal changes is one of concentric and centrifugal disease progression. The zonal sequence as evidenced by advanced magnetic resonance techniques is one of decreased perfusion at the necrotic demyelinated core, normalized perfusion at the inflammatory leading edge, and significantly decreased yielding to normal perfusion beyond the contrast enhancing region.
Overall, significant perfusion abnormalities only occurred in patients with brain lesions demonstrable with conventional imaging. In both children (n = 6) and adults (n = 2) with brain lesions, we found 80% lower normalized cerebral blood volume in the lesion core, while the contrast enhancing zone demonstrated normalized cerebral blood volume (). Surprisingly, the area beyond the contrast enhancement showed moderately decreased perfusion in all patients with cerebral adrenoleukodystrophy who had evidence of disease progression in follow-up MRIs. This hypoperfused region matches the full extent of the T2-hyperintense zone that lies between the contrast enhancing and the normal-appearing white matter, suggesting abnormal distribution of extracellular fluid.
In patients with progressive cerebral disease, the region of contrast enhancement invariably moved into areas of previously decreased perfusion on follow-up examination. This may represent shunting of perfusion from adjacent areas to sites of active inflammation, but it may also be evidence of early tissue injury or dysfunction of the neurovascular unit. In contrast, patients with normal brain MRI (adrenomyeloneuropathy, female heterozygote and asymptomatic adrenoleukodystrophy) did not show significant perfusion changes. Although there was a tendency towards decreased perfusion within the affected corticospinal tracts in patients with adrenomyeloneuropathy, this did not reach statistical significance.
Schaumburg et al. (1975)
partitioned the disease process of cerebral adrenoleukodystrophy into three concentric zones where the core Zone 1 corresponded to the quiescent initial focus where disease activity had run its course, adjacent area Zone 2 populated with lipid-laden macrophages and the outer Zone 3, the leading edge of demyelination, where there was an ongoing myelinolytic–macroglial process marked by prominent perivascular inflammation (Schaumburg et al., 1975
). This pattern of perfusion abnormalities maps upon the known zonal pathology at autopsy of cerebral adrenoleukodystrophy. It suggests a disease process during which mildly decreased perfusion anticipates an inflammatory surge in perfusion followed by decreased perfusion once the acute process is spent. It further invites speculation on the contribution of blood volume and vascular density to the pathogenesis of demyelination as it has for decades in the field of multiple sclerosis (Putnam, 1933
; Arnold et al., 1984
; Lightman et al., 1987
). In both cerebral adrenoleukodystrophy and multiple sclerosis, the decreased perfusion at the innermost core may be the result of severe tissue destruction and gliosis (Schaumburg et al., 1975
; Melhem et al., 2000
). Decreases in brain perfusion have also been observed in patients with relapsing-remitting multiple sclerosis preceding the appearance of T2
-hyperintense lesions, at times without signs of clinical decline (Law et al., 2004
; Wuerfel et al., 2004
). It is possible that inflammatory cytokines produced in the active demyelinating zone trigger vasoconstriction and/or cytotoxicity of perivascular elements without leaving lasting structural damage.
The observation of decreased perfusion preceding lesion extension in cerebral adrenoleukodystrophy adds to a list of known magnetic resonance abnormalities predictive of disease progression. The most well-recognized marker is the presence of contrast enhancement on conventional imaging (Melhem et al., 2000
). Proton magnetic resonance spectroscopy data obtained from patients with X-linked adrenoleukodystrophy show elevation in the choline-to-total creatine ratio in regions of normal-appearing white matter prior to progression (Eichler et al., 2002
). Magnetization transfer imaging and diffusion tensor imaging differentiate regions of T2
hyperintensity but have not been shown to be predictive of lesion progression (Melhem et al., 1996
; Ito et al., 2001
Although our study suggests that perfusion imaging is a promising and likely clinically relevant technique to investigate patients with adrenoleukodystrophy, there are some reservations at this stage. Manual selection of the regions of assessment was necessary and precluded the implementation of possibly more reliable, semi-automated, computer-based methods for quantification of cerebral blood volume within zonal pathology. While perfusion in one patient stabilized after haematopoietic stem cell transplantation, no patients during our study period converted from non-cerebral to the cerebral form of adrenoleukodystrophy, preventing us from drawing conclusions about this key transition and its potential relationship to perfusion changes. Future prospective studies are needed to address the role of perfusion in the conversion from asymptomatic to symptomatic cerebral adrenoleukodystrophy.
In summary, this is the first report of in vivo brain magnetic resonance perfusion abnormalities that correspond with the known zonal pathology of patients with cerebral adrenoleukodystrophy. Our study suggests that dynamic susceptibility contrast perfusion could be a powerful biomarker of lesion progression and could help elucidate the pathophysiology of inflammatory demyelination in adrenoleukodystrophy.