Loss of White Matter Microstructural Integrity Is Associated with Adverse Neurological Outcome in Tuberous Sclerosis Complex

Abstract

Rationale and Objectives Tuberous Sclerosis Complex (TSC) is a genetic neurocutaneous syndrome in which cognitive and social-behavioral outcomes for patients vary widely in an unpredictable manner. The cause of adverse neurological outcome remains unclear. We investigated the hypothesis that disordered white matter and abnormal neural connectivity are associated with adverse neurological outcome. Materials and Methods Structural and diffusion magnetic resonance imaging was carried out in 40 subjects with TSC (age range 0.5 – 25 years, mean age 7.2 and median age 5 years), 12 of whom had autism spectrum disorders (ASD), and in 29 age-matched controls. Tractography of the corpus callosum was used to define a 3-dimensional volume of interest. Regional averages of four diffusion scalar parameters of the callosal projections were calculated for each subject. These were the average fractional anisotropy (AFA) and average mean, radial and axial diffusivity (AMD, ARD, AAD). Results Subjects with TSC had significantly lower AFA and higher AMD, ARD and AAD values compared to controls. Subjects with TSC and ASD had significantly lower AFA values compared to those without ASD, and compared to controls. TSC subjects without ASD had similar AFA values compared to controls. Conclusion Diffusion tensor scalar parameters provided measures of properties of the three-dimensional callosal projections. In TSC, changes in these parameters may reflect microstructural changes in myelination, axonal integrity, or extracellular environment. Alterations in white matter microstructural properties were associated with TSC and larger changes were associated with TSC and ASD, thus establishing a relationship between altered white matter microstructural integrity and brain function.

Reduction in retinal nerve fiber layer thickness in tuberous sclerosis complex

“…Although there is no clear relationship between the extent and the degree of WM alterations and the clinical phenotype, there is some evidence that the more the WM is disrupted, the more severe the neurological phenotype might be [24,25,30]. Therefore, it is noteworthy to emphasize that we observed a statistically significant thinning of RNFL, even if our sample was constituted by patients who presented a relatively mild neurological phenotype.…”

“…The low fractional anisotropy frequently observed in neuroimaging studies of TSC strongly supports disorganized and poorly myelinated axons, while a primary poor integrity of the axons themselves is suggested by lower axial diffusivity [22,23]. Although an axonal involvement has been hypothesized after analyzing neuroimaging data [24,25], in humans, axonal structure has never been studied in detail before. Animal models showed that there is a primary axonal developmental defect caused by the genetic mutation in the TSC genes, which leads to a secondary myelination failure [26]; the TSC/mTOR pathway appears to limit multiple axon formation and acts to confine polarized growth within a single axon in the mammalian brain, and its deregulation likely contributes to the neurological symptoms commonly observed in TSC patients [8].…”

Pharmacologic management of tuberous sclerosis complex-associated subependymal giant cell astrocytomas

“…This finding is significant in that other investigators have found that abnormalities in FA in normal-appearing white matter correlate with the presence and severity of cognitive impairment in TSC patients. This suggests that mTOR inhibitors may reverse microscopic structural abnormalities, resulting in improved cognition and/or seizure control, in addition to effects on cortical tubers and SEGAs [51,52]. Furthermore, no patients developed new lesions or worsening hydrocephalus or required additional surgery intervention for SEGA during the evaluation phase of the trial or during the extension study [47,49].…”

Early developmental pathways to autism spectrum disorder in tuberous sclerosis complex

“…These studies have revealed significant associations with ASD and the TSC2 mutation, cortical tuber burden and location in the temporal lobe and cerebellum, and the age at onset, severity and type of seizures, particularly a history of infantile spasms (Bolton et al, 2002, Numis et al, 2011. Moreover, several findings implicate aberrant connectivity as a key biomarker of behavioural outcome in TSC; the number of radial migration lines (white matter abnormalities) have been found to be associated with age at seizure onset, cognitive development and autistic features, and white matter alterations and loss of structural integrity are associated with the presence of ASD (Peters et al, 2012, Lewis et al, 2013 et al, 2013b). No single clinical feature, however, is predictive of ASD outcome.…”