Robert T. Naismith, MD - US grants

DESCRIPTION (provided by applicant): Developing a method to assess axonal integrity in vivo is paramount for the further understanding of multiple sclerosis (MS). Although the importance of Magnetic Resonance Imaging (MRI) in MS is indisputable, the current conventional MRI images in clinical practice correlate only modestly with measures of disability. Axonal loss has been proposed to contribute a large component to MS disability and disease progression. The rationale for this 'MRI paradox' is that the current imaging techniques are neither sensitive nor specific for the varying pathologies. The hypothesis of this project is that Magnetic Resonance Diffusion Tensor Imaging (DTI) can be used to evaluate both the structural integrity of axons, as well as the degree of demyelination in the human optic nerve in vivo. We propose to translate DTI from the animal model to the optic nerves of humans. We also hypothesize that this technique could be used to distinguish clinical outcomes and predict prognosis. Aim 1 will evaluate subjects with acute optic neuritis prospectively to determine if directional diffusivity correlates with clinical parameters. Imaging will be performed at 0, 0.5,1,3,6, and 12 months. The course for the diffusion parameters will be correlated with tests of visual function. These tests will include contrast sensitivity, visual acuity, visual evoked potentials, color vision, and retinal nerve fiber layer thickness. Aim 2 will correlate the histopathologic axonal loss in MS optic nerve autopsy specimens with the findings of ex-vivo diffusion imaging. Axonal loss, quantified by neurofilament and beta-amyloid precursor protein staining, demyelination, quantified by myelin basic protein staining, and inflammation, quantified by hematoxylin and eosin staining, will be correlated with diffusivity parameters in individual regions of the nerve. Aim 3 will compare directional diffusivity in a cross section of living MS patients with remote optic neuritis and poor visual recovery matched to patients with good visual recovery. Clinical parameters will include contrast sensitivity, visual acuity, color vision, visual-evoked potentials, and retinal nerve fiber layer thickness. Those patients who do not develop additional clinical episodes of optic neuritis in the next 12 months will be re-evaluated prospectively in regards to visual function and imaging to determine the stability of DTI measurements. Aim 4 will evaluate directional diffusivity of the optic nerve in living human subjects who have had unilateral retinal ischemia and poor visual recovery. Retinal ischemia represents a condition of retinal cell death with primary axonal degeneration and secondary demyelination. Tests of visual function will include those included in Aim 3. Aim 5 will determine the range of values for diffusivity parameters of normal optic nerves in healthy volunteers stratified by age and gender.

? DESCRIPTION (provided by applicant): Therapeutic agents of neural protection and repair in multiple sclerosis (MS) require proof-of-concept studies in model human systems to evaluate evolving histopathologic processes. Development of anti-inflammatory agents for relapsing MS has been tremendously accelerated by the use of gadolinium-enhanced MRI to screen anti-inflammatory therapies in short clinical trials. Lack of a comparable screening method to promptly monitor the effect of potential neural reparative agents has impeded the development of such treatments. Diffusion basis spectrum imaging (DBSI) represents a novel data-driven modeling of diffusion weighted MRI signals to address the shortcomings of other quantitative imaging techniques. DBSI has successfully differentiated and quantified axon and myelin injury from cellular inflammation and edema, correlating with visual acuity in optic neuritis of experimental autoimmune encephalomyelitis (EAE) mice with post-MRI histological validation. Herein, we seek to apply the DBSI method to human optic nerve imaging to create a complete acquisition/analyses package available to multiple centers for collaborative trials. Based upon our prior investigations, we hypothesize that, (1) In patients who present with acute optic neuritis, longitudinal ON DBSI metrics of axon density and injury at baseline and change over 3 months will predict 6 month OCT-derived average retinal nerve fiber layer (RNFL) thickness, ganglion cell/inner plexiform layer (GCIP) thickness, and VEP amplitude. Longitudinal ON DBSI myelin integrity at baseline and change over 3 months will predict 6 month VEP latency. We also hypothesize that, (2): In subjects with past optic neuritis, DBSI-derived axon density and axonal injury will demonstrate a close relationship with RNFL (GCIP) thickness and VEP amplitude. DBSI-derived myelin integrity will demonstrate a close relationship with VEP latency. Contrast sensitivity will be best predicted by a model that incorporates both DBSI axon and myelin metrics. To address these hypotheses, the aims of this proposal includes: (1) Twelve previously healthy subjects presenting within 30 days onset of acute optic neuritis will undergo DBSI, VEP, and OCT at baseline, 3-, and 6- months; and (2) Forty subjects with MS and a past history of optic neuritis will undergo ON DBSI, OCT, VEP, and contrast sensitivity. Thirty age- and gender-matched controls will be collected at Washington University (WU) and Mt. Sinai School of Medicine (MSSM). At completion, we will have established the relationships of inflammation, axon injury, demyelination, and remyelination to visual outcomes in acute and remote optic neuritis as the first step for multi-center studies.