Diffusion Features of White Matter in Tuberous Sclerosis With Tractography

Normal-appearing white matter has been shown via diffusion tensor imaging to be affected in tuberous sclerosis complex. Under the hypothesis that some systems might be differentially affected, including the visual pathways and systems of social cognition, diffusion properties of various regions of white matter were compared. For 10 patients and 6 age-matched control subjects, 3 T magnetic resonance imaging was assessed using diffusion tensor imaging obtained in 35 directions. Three-dimensional volumes corresponding to the geniculocalcarine tracts were extracted via tractography, and two-dimensional regions of interest were used to sample other regions. Regression analysis indicated lower fractional anisotropy in the splenium of corpus callosum and geniculocalcarine tracts in tuberous sclerosis complex group, as well as lower axial diffusivity in the internal capsule, superior temporal gyrus, and geniculocalcarine tracts. Mean and radial diffusivity of the splenium of corpus callosum were higher in the tuberous sclerosis complex group. The differences in diffusion properties of white matter between tuberous sclerosis complex patients and control subjects suggest disorganized and structurally compromised axons with poor myelination. The visual and social cognition systems appear to be differentially involved, which might in part explain the behavioral and cognitive characteristics of the tuberous sclerosis complex population.

Introduction

Tuberous sclerosis complex, a neurocutaneous autosomal dominant disorder involving mutations of the TSC1 or TSC2 genes, is characterized by hamartomas in multiple organ systems [1]. Its prevalence is 1 in 6000 live births [2]. Close to 45% of patients have mild-to-profound intellectual disabilities [3], and 25-60% have autism [4]. Most patients with tuberous sclerosis complex have cortical tubers, which are dysplastic lesions composed of giant cells, maloriented dysmorphic neurons, and atypical astrocytes [1]. The association between tuber load and location and neurologic outcomes remains unclear [5], [6], [7]. Consequently, efforts are underway to understand what determines clinical phenotype and to identify prognostic indicators, so that targeted interventions can be developed.

Mouse models of tuberous sclerosis complex indicate decreased myelination throughout the cortex, as well as aberrant topographic projections of axon pathways in the reticulogeniculate tract [8], [9]. Disruption of white matter may contribute to the high incidence of behavioral and cognitive impairments in tuberous sclerosis complex.

Diffusion tensor imaging is a type of magnetic resonance imaging that examines the direction and magnitude of average water diffusion, allowing inferences about the underlying tissue structure. Water in a biological system does not diffuse equally in all directions, and anisotropy is a measure of directional preference of diffusion. Cortical tubers with higher apparent diffusion coefficient and lower fractional anisotropy seem to have a greater epileptogenic potential [10], [11], and in tuberous sclerosis complex patients normal-appearing white matter differs from that of control subjects [12].

Study aims were to test the application of tractography and to survey the condition of white matter in tuberous sclerosis complex, focusing on the visual system and areas of social cognition.