Quantitative Assessment of White Matter Tracts of the Spinal Cord in Adrenomyeloneuropathy using Global Magnetization Transfer Imaging

Hugo W. Moser, M.D.

Kennedy Krieger Institute

Funded in September, 2003: $100000 for 2 years
LAY SUMMARY . ABSTRACT . HYPOTHESIS . SELECTED PUBLICATIONS .

ABSTRACT

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Quantitative Assessment of White Matter Tracts of the Spinal Cord in Adrenomyeloneuropathy Using Global Magnetization Transfer Imaging

Adrenomyeloneuropathy (AMN) is the non inflammatory adult variant of X-linked Adrenoleukodystrophy, a genetic disorder characterized by accumulation of very long chain fatty acids in the central nervous system, the adrenal cortex, and testes due to mutations in ABCD1. In affected men, AMN presents most commonly in the late twenties as a spastic paraparesis that is progressive over decades and often leads to severe disability in the fourth or fifth decades. AMN involves mainly the spinal cord, and neuropathological studies have shown a distal axonopathy that involves most severely the ascending dorsal columns in the cervical regions and the descending corticospinal tracts in the lower thoracic and lumbosacral region.

The evaluation of therapies in AMN has been hampered by its slow rate of progression and the lack of sensitivity of currently available instruments to assess the degree of involvement. Currently the assessment of spinal cord involvement in AMN is mainly limited to clinical and neurophysiologic tests. With these methods, five or more years are required to assess the effects of therapy. Routine MRI studies of the spine show cord atrophy but are not sensitive enough to detect white matter abnormalities in AMN. We have recently developed a new imaging approach, referred to as Global Magnetization Transfer Imaging (GMTI), which allows the quantitative assessment of spinal cord white matter.

We propose to conduct GMTI studies in 15 healthy adults and 15 patients with AMN in order to determine whether GMTI is sensitive enough to detect spinal cord pathology and whether the GMTI abnormalities correlate with the degree of clinical severity as assessed by neurologic examination and quantitative tests of sensory and motor function. Furthermore, we envision to conduct a 12 month long follow-up study in 15 adult men with AMN to evaluate whether the GMTI abnormalities change within this time period and can therefore serve as markers for timely evaluation of therapy.

HYPOTHESIS

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Hypothesis:
Global Magnetization Transfer Imaging can accurately detect white matter abnormalities in the cervical dorsal column and the lower thoracic and lumbar columns of the spinal cord in AMN patients.  GMTI changes will correlate with neurological disability.

Goals:
1. Establish a preliminary database of GMTI scans of the spinal cord in AMN men and age matched healthy controls.

2. Compare the GMTI measures with sensory motor quantitative measures.

3. Conduct follow-up GMTI scans to pick up changes in the cord involvement and evaluate the sensitivity of GMTI changes relative to clinical markers in assessing progression.

SELECTED PUBLICATIONS

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Zackowski K.M., Dubey P., Raymond G.V., Mori S., Bastian A.J., and Moser H.W.  Sensorimotor function and axonal integrity in adrenomyeloneuropathy.  Arch Neurol. 2006 Jan;63(1):74-80.

Dubey P., Fatemi A., Huang H., Nagae-Poetscher L., Wakana S., Barker P.B., van Zijl P., Moser H.W., Mori S., and Raymond G.V. Diffusion tensor-based imaging reveals occult abnormalities in adrenomyeloneuropathy.  Ann Neurol. 2005 Nov;58(5):758-66.

Smith SA, Golay X, Fatemi A, Jones CK, Raymond GV, Moser HW, van Zijl PC. Magnetization transfer weighted imaging in the upper cervical spinal cord using cerebrospinal fluid as intersubject normalization reference (MTCSF imaging). Magn Reson Med. 2005 Jul;54(1):201-6.

Fatemi A., Smith S.A., Dubey P., Zackowski K.M., Bastian A.J., van Zijl P.C., Moser H.W., Raymond G.V., and Golay X. Magnetization transfer MRI demonstrates spinal cord abnormalities in adrenomyeloneuropathy. Neurology. 2005 May 24;64(10):1739-45