Evaluation of White Matter Fiber Tracts in the Brain and Their Relationship to Recovery of Locomotion During an Acute Exacerbation of Multiple Sclerosis

Kathleen Zackowski, Ph.D., O.T.R.

Kennedy Krieger Institute, Baltimore, MD
Website

Grant Program:

David Mahoney Neuroimaging Program

Funded in:

June 2005, for 4 years

Funding Amount:

$100,000

Lay Summary

Can Imaging Predict the Extent of Motor Recovery from Multiple Sclerosis Attacks?

Studying patients with multiple sclerosis (MS), researchers will determine whether two types of imaging techniques can quantify the extent of neural damage from acute exacerbations of the disease, and thereby help to predict the extent of recovery.

MS involves repeated episodes of damage to the myelin sheath, which surrounds nerve axons and facilitates movement of electrical signals from one cell to another in the brain and spinal cord. Episodes also may damage the nerve cells. While conventional MRI reveals new damage, the damage seen does not correlate with patients’ clinical symptoms. Patients can have severe symptoms yet show little damage, or the opposite can occur. This incongruence makes it difficult to predict how well patients will recover movement. The researchers hypothesize that they will be able to predict recovery more accurately by using “magnetization transfer” with diffusion tensor imaging (DTI), which images patterns of damage to nerve axons.

Significance: Developing a more accurate assessment of damage from MS exacerbations could help guide better rehabilitation strategies. Additionally, the findings could advance the development of new types of therapies, based on a better understanding of neural damage.

Abstract

Evaluation of White Matter Fiber Tracts in the Brain and Their Relationship to Recovery of Locomotion During an Acute Exacerbation of Multiple Sclerosis

Multiple sclerosis (MS) affects approximately 300,000 adults in the United States and up to 2 million worldwide. It is a chronic recurrent inflammatory disorder that typically results in injury to the myelin sheaths, the oligodendrocytes, the axons, and the nerve cells themselves in both the brain and spinal cord. The CNS lesions that occur in multiple sclerosis can cause many clinical deficits, depending on their location and extent, often affecting locomotion to a great extent.

Conventional magnetic resonance imaging techniques provide a means for diagnosing and identifying new lesions in individuals with MS. However, the correlation between conventional MRI and clinical symptoms of MS is poor, possibly because conventional imaging modalities do not produce a quantitative evaluation of tissue and are relatively insensitive to specific underlying pathology such as demyelination and axonal damage. Therefore, it may be valuable to use alternative imaging techniques, such as magnetization transfer (MT) and diffusion tensor imaging (DTI) to quantify the extent of demyelination and axonal damage (and recovery), and track white matter pathways in the brain and spinal cord. These studies will incorporate measures of MT and DTI for the evaluation of white matter integrity; in addition, we will evaluate sensorimotor impairments of sensation, strength, spasticity, and ataxia, and relate these to locomotor function.

The proposed studies will test the general hypothesis that, following an acute exacerbation in MS, the pattern of white matter damage is predictive of locomotor recovery. The proposed studies will investigate: 1) whether specific white matter tract abnormalities that occur following an acute exacerbation of MS correlate with specific sensorimotor impairments and features of their walking patterns, and 2) whether damage to specific white matter tracts (i.e., the corticospinal, dorsal column medial lemniscal and tracts to and from the cerebellum) can predict the recovery of locomotion after a relapse of MS.

Results of the proposed studies will, for the first time, provide important new insights into how sensorimotor impairments relate to mechanisms of locomotion, as well as the role of white matter fiber tract changes during exacerbation and subsequent recovery of locomotion in people with MS. We think that studying the neurobiology of these changes (i.e., myelin and axon integrity) will lead to both theoretical insights into rehabilitation of individuals with MS and to novel treatment strategies based on biological rather than empirical principles.

Hypothesis

Hypothesis:
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized pathologically by demyelination and axonal injury. Conventional magnetic resonance imaging (MRI) techniques are extremely sensitive to changes associated with inflammation (free hydrogen protons), but do not adequately capture the pattern of demyelination and axonal loss that occur in the brain and spinal cord, thus there has been discordance between clinical disability and MRI lesion load. Demyelination and degeneration of axons are important pathogenic mechanisms of damage in MS. However, attempts at correlating clinical disability with demyelination and axonal injury have had limited success due to clinical rating scales that do not adequately measure all aspects of the disease, coupled with the inability for routine imaging techniques to depict specific clinically involved fiber tracts in the brain and spinal cord.

In this project we plan to capitalize upon the strengths of our motion laboratory, which can measure spasticity, ataxia, sensation, and muscle strength that contribute to impaired locomotion, in conjunction with advanced Magnetization Transfer (MT) and Diffusion Tensor imaging (DTI) metrics developed at the Kirby Imaging Center of the Kennedy Krieger Institute. The proposed studies will test the hypotheses that: 1) during an acute exacerbation, specific, MRI-demonstrable, white matter tract abnormalities will predict specific sensory, strength, spastic, or ataxic impairments that result in specific locomotor patterns, and 2) The pattern and extent of demyelination and axonal injury as measured by MT and DTI in the corticospinal tract, dorsal column-medial lemniscal tracts and cerebellar peduncles can predict the recovery of sensorimotor impairments and locomotion after a relapse of MS.

Goals:
1. To determine the contribution of specific white matter tract abnormalities to specific sensory, strength, spastic or ataxic impairments, and how they contribute to locomotor patterns during an acute exacerbation of MS.

2. To determine what extent pathological recovery (i.e., MT measures of demyelination and DTI measures of axonal integrity) is associated with recovery of locomotion (i.e., kinematic walking measures and quantitative sensorimotor impairments), following an acute exacerbation of MS. These studies will provide important new insights into how sensorimotor impairments relate to mechanisms of locomotion as well as the role of white matter fiber tract changes during exacerbation and subsequent recovery of locomotion in people with MS.

Methods:
Subjects will be tested at four time points: an initial session (for MS subjects, during an acute exacerbation), 6 weeks later, 3 months, and 6 months after the first session. During each session, subjects will undergo a clinical examination to systematically document each subject's status. In addition, we will use kinematic measures to determine how locomotion is affected by an acute exacerbation and how it changes over the time following an exacerbation of MS. Lastly, subjects will undergo an MRI in which MT and DTI techniques will be used to analyze new lesions in specific white matter tracts.

Selected Publications

Reich D.S., Smith S.A., Jones C.K., Zackowski K.M., van Zijl P.C., Calabresi P.A., and Mori S. Quantitative characterization of the corticospinal tract at 3T. AJNR Am J Neuroradiol. 2006 Nov-Dec;27(10):2168-78 .