Original ArticleDiffusion Features of White Matter in Tuberous Sclerosis With Tractography
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.
Section snippets
Subjects
Ten patients (age range, 1.5-25 years) with an established diagnosis of tuberous sclerosis complex were imaged with 3 T magnetic resonance imaging (Siemens TrioTim) as part of their routine care. Six control subjects (age range, 1.1-25 years) had the same type of imaging. All the patients fulfilled the clinical criteria for definite tuberous sclerosis complex, as defined by the Tuberous Sclerosis Consensus Conference [13]. All patients with tuberous sclerosis complex were monitored in the
Results
All 16 cases (i.e., both patients and control subjects) yielded excellent quality diffusion tensor imaging and structural scans that were successfully registered. Seeding of tracts between the primary visual cortex and lateral geniculate nucleus bilaterally produced anatomically plausible conditioned-probability maps and masks (Fig 3). Although clinically the tuberous sclerosis complex patients were characterized as either typically developing (n = 3), developmentally delayed (n = 2), or
Discussion
Diffusion tensor imaging and tractography methods were applied to the analysis of white matter in tuberous sclerosis complex. Differences in diffusion characteristics were found predominantly in the geniculocalcarine tract and splenium of the corpus callosum, as well as in the anterior limb of the internal capsule and the superior temporal gyrus. Lower fractional anisotropy in the tuberous sclerosis complex group suggests the presence of disorganized and poorly myelinated axons [23], [24], [25]
Conclusion
The differences in diffusion properties of white matter between the tuberous sclerosis complex group and the control group suggest disorganized and structurally compromised axons with poor myelination. The visual and social cognition systems appear to be differentially involved, and these differences may correlate with the behavioral phenotype.
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2022, NeuroImage: ClinicalCitation Excerpt :Numerous studies converge on the finding of altered diffusion characteristics measured specifically within tuber regions (Tsai et al., 2021; Jansen et al., 2003; Tiwari et al., 2012); however, there has been some inconsistency with respect to white matter regions appearing “normal” on conventional MR. While some studies have reported increased diffusivity (in terms of mean diffusivity or apparent diffusion coefficient) and decreased anisotropy, indicative of compromised structural integrity, in normal-appearing white matter in TSC compared to controls (Garaci et al., 2004; Makki et al., 2007), other studies have found no or only weak differences between groups in these extra-lesional regions (Karadag et al., 2005; Firat et al., 2006; Arulrajah et al., 2009). Further studies investigating a range of major white matter tracts throughout the brain have variably observed altered microstructure in several tracts such as corpus callosum (Peters et al., 2012; Krishnan et al., 2010), inferior (Ridler et al., 2001) and superior longitudinal (Taoka et al., 2020; Zikou et al., 2016) and uncinate (Prohl et al., 2019) fasciculi. The mixed findings within the TSC diffusion literature may reflect in part the shortcomings of conventional diffusion imaging techniques, which are typically unable to characterise microstructural properties in regions of multiple fibre orientations or differentiate between micro- and macrostructural properties of specific fibre bundles.
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2019, Handbook of Behavioral NeuroscienceCitation Excerpt :On a macroscopic level, there are three types of CNS lesions associated with TSC: cortical tubers, subependymal nodules (SENs), and subependymal giant cell astrocytomas (SEGAs) (Mizuguchi & Takashima, 2001). Furthermore, in the disease, there is strong evidence for microstructural changes in the brain, including hypomyelination and the loss of axonal integrity, based on both histologic (Ruppe et al., 2014) and radiographic studies (Krishnan et al., 2010; Peters et al., 2012). Overall, these abnormalities convey a picture of altered neuronal connectivity in TSC that may serve as the basis for targeted therapies (Khwaja & Sahin, 2011).
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