During the initial funding period, our group developed a novel Diffusion Basis Spectrum Imaging (DBSI) method to simultaneously detect and quantitate inflammation, demyelination and axon injury in vivo using diffusion imaging (Wang et al. 2011). DBSI has substantially improved the accuracy and specificity of our prior diffusion tensor imaging (DTI) approach, by overcoming the main inadequacies of DTI. We hypothesize that DBSI can quantitate the proportions of axon injury, demyelination, and inflammation in CNS of MS patients. We previously showed using a mouse model that DBSI detects and quantitates axonal and myelin injuries that had escaped detection by standard imaging, and by DTI. Our preliminary data now include validation of DBSI using autopsied and biopsied human specimens, with favorable correlations with human histology. We also now have longitudinal data spanning 1.5 yrs, and comparisons of DBSI with magnetization transfer imaging (MTI). In Project 3, we will apply DBSI to humans with MS, comparing it to standard MRI, DTI and MTI. Project 3 will classify MS lesion subtypes by measures of axon injury, demyelination, and inflammation (cellularity and increased free water due to edema or tissue loss), and follow the patients over 4 years to identify predictors and correlates of clinical deterioration. We expect to achieve this using DBSI by differentiating prominent axonal injury vs. axon preservation, and demyelination vs. myelin preservation/ remyelination. We will examine established persistent black holes (PBHs) (new sub-aim), and perform longitudinal assessments of gadolinium-enhancing (Gd+) MS lesions to determine if DBSI will predict PBH formation, representing severe axon loss. With its ability to profile lesions and normal-appearing CNS, DBSI could help non-invasively elucidate the substrate of MS lesion formation and detect inflammation behind an intact blood-CNS-barrier (not detected by Gd+). DBSI has potential to aid development and testing of new therapies for progressive MS where loss of axons and tissue integrity are believed to play a large role.

Public Health Relevance

Multiple Sclerosis affects about 2 million people worldwide, yet we do not even understand what causes it. The pathogenesis of progressive MS, for which no effective disease modifying treatments have yet been developed, is particularly unclear. One reason the field has been slow to fully understand MS is that CNS tissue sampling is rare (due to potential to cause harm), and the disease changes with time. We developed a new imaging method for use in MS to detect and measure loss of myelin and nerve fibers, as well as inflammation. Using a clinical MRI scanner, this is a non-invasive and safe way to see the underlying pathology in brains of people with MS. Upon validation, this method will lead to better understanding of the underlying MS disease process, and should also improve our ability to test new treatments.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Saint Louis
United States
Zip Code
Spees, William M; Lin, Tsen-Hsuan; Sun, Peng et al. (2018) MRI-based assessment of function and dysfunction in myelinated axons. Proc Natl Acad Sci U S A 115:E10225-E10234
Zhan, Jie; Lin, Tsen-Hsuan; Libbey, Jane E et al. (2018) Diffusion Basis Spectrum and Diffusion Tensor Imaging Detect Hippocampal Inflammation and Dendritic Injury in a Virus-Induced Mouse Model of Epilepsy. Front Neurosci 12:77
Agner, Shannon C; Klein, Robyn S (2018) Viruses have multiple paths to central nervous system pathology. Curr Opin Neurol 31:313-317
Adusumilli, Gautam; Trinkaus, Kathryn; Sun, Peng et al. (2018) Intensity ratio to improve black hole assessment in multiple sclerosis. Mult Scler Relat Disord 19:140-147
Klein, Robyn S; Garber, Charise; Howard, Nicole (2017) Infectious immunity in the central nervous system and brain function. Nat Immunol 18:132-141
Lin, Tsen-Hsuan; Chiang, Chia-Wen; Perez-Torres, Carlos J et al. (2017) Diffusion MRI quantifies early axonal loss in the presence of nerve swelling. J Neuroinflammation 14:78
Cross, Anne H; Song, Sheng-Kwei (2017) ""A new imaging modality to non-invasively assess multiple sclerosis pathology"". J Neuroimmunol 304:81-85
Klein, Robyn S; Hunter, Christopher A (2017) Protective and Pathological Immunity during Central Nervous System Infections. Immunity 46:891-909
Hou, Jianghui; Baker, Lane A; Zhou, Lushan et al. (2016) Viral interactions with the blood-brain barrier: old dog, new tricks. Tissue Barriers 4:e1142492
Salimi, Hamid; Cain, Matthew D; Klein, Robyn S (2016) Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis. Neurotherapeutics 13:514-34

Showing the most recent 10 out of 62 publications