X-linked adrenoleukodystrophy (X-ALD), a progressive neurodegenerative disease, is caused by a defect in the ABCD1 gene. The disease has multiple phenotypes, but the most common adult form is adrenomyeloneuropathy (AMN), which presents as a slowly progressing spastic paraparesis with sensory and autonomic dysfunction.
In a previous study, we linked corticospinal tract (CST) and Dorsal Column (DC) abnormalities to lower extremity sensory loss and weakness in men with AMN; however, there have been no studies evaluating these relationships in woman heterozygote carriers (i.e., women with AMN). It is unknown, in women with AMN, how the pattern of damage in the brain and spinal cord relates to disability and if these patterns predict responsiveness to treatment. While conventional magnetic resonance imaging (MRI) techniques have been used to evaluate progression of X-ALD disease burden, attempts at correlating clinical disability with axonal injury have had limited success due to clinical rating scales that do not adequately measure all aspects of the disease, coupled with an inability for routine imaging techniques to quantify relevant fiber tracts in the brain and spinal cord.
In this study, we proposed to comprehensively evaluate the CST and DC across the brain and cervical spinal cord with the purpose of understanding mechanisms of disability in women with AMN. We hypothesized that: 1) tract-specific magnetization transfer imaging (MTI) and diffusion tensor imaging (DTI) will predict specific sensory and motor impairments (i.e., sensory loss and weakness) and disability; and 2) tract-specific MTI and DTI will predict who is likely to respond best to progressive resistive training (PRT).
For this project, we used a rigorous biologic approach that combined clinical evaluation, neuroimaging, and measures of impairment and disability to provide a more precise prognosis in terms of physical disability and to predict who is likely to respond to a physical intervention. We predicted that many of the women will improve their strength and function following the PRT program. Specifically, we predicted that axonal loss will be associated with irreversible disability. By contrast, demyelination may have potentially reversible injuries that would benefit from PRT in improving disability.
The linking of this information will not only be important for better defining disability in women heterozygote carriers of AMN, but it will also help to guide physicians and rehabilitation therapists in predicting who is likely to respond to rehabilitative interventions, as well as for optimizing outcomes for future neuroprotective pharmacological interventions.
We have currently finished the study and are now working on analyzing the data. We’ve written one paper using baseline data only, implicating strength as the most relevant factor to functional performance in women with AMN. For more information with our recommendations from experience for people with AMN and for caregivers of people with AMN, go here.