Understanding Mechanisms of Lower Extremity Strengthening in Women Heterozygous for X-ALD

Principal Investigator: Kathleen Zackowski

Sponsored by the ELA Foundation.

X-linked adrenoleukodystrophy (X-ALD), a sex-linked progressive neurodegenerative disease, is caused by a defect in the ABCD1 gene. The disease is expressed in multiple ways, but the most common adult form is adrenomyeloneuropathy (AMN), which results in slowly progressive changes in muscle tone and weakness, sensory loss, and dysfunction of the autonomic nervous system. There are no specific treatments that have been shown to be broadly effective, therefore, it is critical that new studies evaluate better outcome measures so as to test relevant pharmacologic and rehabilitative therapies.

In a previous study, we linked abnormalities in the brainstem to lower extremity weakness in men with AMN; however, there have been no studies evaluating these relationships in women 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. We hypothesize that by evaluating the relevant pathways in the brain and spinal cord of female carriers we will be able to better predict disability and determine who is likely to respond best to a strengthening program.

To do this, we propose using magnetization transfer (MT) and diffusion tensor imaging (DTI), two advanced magnetic resonance imaging (MRI) modalities that evaluate specific properties of the relevant pathways in the brain and spinal cord. We expect that these more advanced imaging techniques will be more sensitive and accurate to subtle abnormalities allowing for improved correlations with sensory and motor function. We anticipate that women with greater abnormalities in DTI will have more irreversible disability than women with greater abnormalities in MTI measures. To test this hypothesis, women with AMN will receive MRI scans at baseline and complete measures of global walking and lower extremity impairments of vibration sensation, spasticity, and strength twice before starting a 12-week progressive resistance training (PRT) program and twice upon completion of the PRT program. MRI data will be correlated to changes over time in measures of impairment to determine their relationships. A control group will also complete the 12-week PRT program. The linking of this information will not only be important for better defining disability in women with 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 the effects of future pharmacological interventions.