Three‐Dimensional Lesion Phenotyping and Physiologic Characterization Inform Remyelination Ability in Multiple Sclerosis

Abstract

BACKGROUND AND PURPOSE Multiple sclerosis (MS) clinical management is based upon lesion characterization from 2‐dimensional (2D) magnetic resonance imaging (MRI) views. Such views fail to convey the lesion‐phenotype (ie, shape and surface texture) complexity, underlying metabolic alterations, and remyelination potential. We utilized a 3‐dimensional (3D) lesion phenotyping approach coupled with imaging to study physiologic profiles within and around MS lesions and their impacts on lesion phenotypes. METHODS Lesions were identified in 3T T2‐FLAIR images and segmented using geodesic active contouring. A calibrated fMRI sequence permitted measurement of cerebral blood flow (CBF), blood‐oxygen‐level‐dependent signal (BOLD), and cerebral metabolic rate of oxygen (CMRO2). These metrics were measured within lesions and surrounding tissue in concentric layers exact to the 3D‐lesion shape. BOLD slope was calculated as BOLD changes from a lesion to its surrounding perimeters. White matter integrity was measured using diffusion kurtosis imaging. Associations between these metrics and 3D‐lesion phenotypes were studied. RESULTS One hundred nine lesions from 23 MS patients were analyzed. We identified a noninvasive biomarker, BOLD slope, to metabolically characterize lesions. Positive BOLD slope lesions were metabolically active with higher CMRO2 and CBF compared to negative BOLD slope or inactive lesions. Metabolically active lesions with more intact white matter integrity had more symmetrical shapes and more complex surface textures compared to inactive lesions with less intact white matter integrity. CONCLUSION The association of lesion phenotypes with their metabolic signatures suggests the prospect for translation of such data to clinical management by providing information related to metabolic activity, lesion age, and risk for disease reactivation and self‐repair. Our findings also provide a platform for disease surveillance and outcome quantification involving myelin repair therapeutics.

Utility of shape evolution and displacement in the classification of chronic multiple sclerosis lesions

“…Beyond size and surface area metrics, we identified a significantly higher degree of displacement or distance deviation in lesion position from the origin in MS lesions when directly compared to SVD lesion transitions using a method employing 3D visual model data. The more dynamic transitions observed here may relate to physiological differences between the two lesion types with MS lesions being associated with greater imbalances in energy demand and supply with impaired mitochondrial energy production impacting ion homeostasis 19 , metabolic derangements with increased venous blood oxygenation compared to surrounding tissue 18 , inflammatory expansion 16 , and active remodeling or degenerative responses following injury 20 .…”

“…Our finding of a volume contraction was independent of the time interval between MRI studies, suggesting the promise for the early recognition of lesion changes between longitudinal MRI studies that may better indicate insights into cause. The observation of more modest surface area differences between MRI time points may be related to the more dynamic shapes associated with MS lesions, lesion age, or a combination of these factors 17,18 .…”

“…Analyses were implemented without knowledge of clinical history, current or past treatments, or disease duration. MRI studies from the two time points were initially registered based on anatomical positioning and intensity using an in-house developed software package previously utilized in prior studies, Med-IP 18,32 .…”

Reduced arterial compliance along the cerebrovascular tree predicts cognitive slowing in multiple sclerosis: Evidence for a neurovascular uncoupling hypothesis

“…These results are consistent with emerging evidence that the neural-glial-vascular system becomes dysfunctional in MS. 9, 21, 22 Disruption in this system, known to occur in MS, would lead to NVC and CBF dysregulation in response to neurometabolic activity, reductions in neural efficiency, and cognitive slowing. 9 In this view, the pathogenesis of MS-related cognitive impairment results from altered arterial compliance leading to impaired blood flow to active brain-regions upon neural stimulation.…”

Relationship between Physical Disability and Black Holes in Multiple Sclerosis: Upper Extremity Functions - an Important Parameter

“…While lesions can be seen in different locations, periventricular, corpus callosum, juxtacortical, brainstem, spinal cord, temporal lobe, optic nerve, cerebellum, and cerebellar peduncle involvement is typical for MS (4). Although the morphological characteristics of the lesions have been described in greater detail in recent years (5), typical features are an ovoid shape, perpendicularity to the ventricle, and size >3 mm (4).…”