The overall goal of this proposal is to leverage the distinct advantages of different imaging modalities (PET and MRI) to facilitate the testing of therapeutic strategies aimed at limiting cytotoxic damage and oxidative stress within MS lesions for the promotion of myelin recovery and reduction of subsequent neurodegeneration. Mechanisms leading to tissue injury in MS are poorly understood, however sources of oxidative injury, such as the innate immune response and iron release, are felt to contribute to myelin damage, limited myelin repair and eventual axonal instability. Intervention with treatments targeting CNS pathways for immune modulation and reduction of oxidative damage requires validation of timing and extent of damage; gaining this knowledge provides the potential to intervene and prevent clinical disability. Our preliminary data demonstrates that PET PK11195, a measure of m/M activation, is high at the time of gadolinium (Gd) enhancement in acute MS lesions and quickly decreases in the following months, whereas lesion magnetic susceptibility, as measured by quantitative susceptibility mapping (QSM) and is sensitive to iron, significantly increases in the months after resolution of Gd-enhancement. Accordingly, this proposed research is to further describe these biological mechanisms in early MS lesions and confirm our hypothesis that acute lesions with high innate immune activity and high iron content would result in severe demyelination. We propose to test this hypothesis through our first aim.
Aim 1 : Lesion iron mapping and a higher specificity PET ligand (DPA713) will be applied to a longitudinal study of acute MS lesions and will define the relationship of iron release and m/M activation as well as determine their association with subsequent lesion myelin content, as measured by MRI myelin water content (MWC) imaging. We then hypothesize that residual lesion iron and myelin loss within chronic MS lesions will lead to subsequent neuronal degeneration. We propose to test this hypothesis in our second aim.
Aim 2 : To apply MWC/QSM to a well-defined cohort of MS patients for which we will measure the association of residual iron and myelin loss within chronic MS lesions on subsequent global neuronal loss and clinical disability. The overall goal of this proposal is to leverage the distinct advantages of different imaging modalities to facilitate the use of MRI to identify patients that would benefit from a therapeutic intervention targeting the reduction in CNS inflammation for the promotion of myelin recovery and reduction of disability.

Public Health Relevance

This research project will focus on establishing the pathological effect of both the innate immune response and iron on myelin within acute MS lesions. We will investigate long-term outcomes by associating the impact of residual iron and the extent of demyelination within chronic MS lesions on gray matter loss and clinical disability. Successful outcome of this research will to facilitate the use of MRI to identify patients that would benefit from a therapeutic intervention targeting the reduction in CNS inflammation for the promotion of myelin recovery and reduction of disability.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS104283-02
Application #
9790988
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Utz, Ursula
Project Start
2018-09-30
Project End
2023-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Neurology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065