Myelin, accounting for 14% of white matter, is predominantly composed of a dielectric lipid-protein bilayer that is paramount to efficient neural current transport. Defects in myelin integrity are associated with numerous common neurologic abnormalities. Although demyelinating diseases first come to mind, myelin abnormalities have also been implicated in Alzheimer's disease, schizophrenia, traumatic brain injury, addiction, and dementias. Thus, improved myelin imaging may have profound impact on characterization of many CNS diseases. Virtually all current, noninvasive, methods for evaluating the integrity of the myelin sheath rely on indirect measures, principally magnetization transfer and myelin water fraction. Both measures have been shown to correlate to varying degrees with optical density in stained histological sections but both have shortcomings. Importantly, the biophysical mechanisms of these surrogates are not completely understood, thereby complicating data interpretation. They further require a number of conditions to be satisfied that may not apply across a range of myelin abnormalities, and achievement of absolute quantification is questionable at best. Here, we hypothesize that direct detection and quantification of myelin is practical. Building on preliminary work characterizing the proton and 31P signal from the liquid-crystalline matrix of the myelin lipid bilayer, and showing its detectability by ultra-short echo-time (UTE) imaging on a 9.4T laboratory micro- imaging system, we delineate a path toward image-based myelin quantification on a clinical imaging system. Central to this proposal is the development and evaluation of 3D zero-echo-time (ZTE) quantitative MRI acquisition and analysis methods involving tissue water suppression and compressed sensing reconstruction, with subsequent translation to a 3T clinical imager. Initial results on reconstituted myelin and intact neural tissue performed by UTE and ZTE methods demonstrate the proposed method's feasibility. The work's longer- term goal is translation to the clinic as an alternative and possibly superior technique for regional myelin quantification in patients with myelin abnormalities and for providing means to evaluate treatment effectiveness.

Public Health Relevance

Myelin plays a pivotal role as an insulator that ensures efficient neuronal current transport. Defects in the myelin sheath, such as in multiple sclerosis or in a spinal cord injury, cause a variety of functional deficits. There is currently no imaging method that allows direct detection and quantification of myelin in humans. The proposed work lays the foundation for a new method to noninvasively assess regional myelin density with the long-term goal of monitoring patients with myelin disorders during treatment.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (NOIT)
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Ludwig, Kip A
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University of Pennsylvania
Schools of Medicine
United States
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