Whether patients with tuberous sclerosis complex (TSC) have brain normal-appearing white matter (NAWM) damage and whether such damage contributes to their intellectual disability were examined in 15 TSC patients and 15 gender- and age-matched healthy controls using diffusion tensor imaging (DTI). Histogram and region of interest (ROI) analyses of the mean diffusivity (MD) and fractional anisotropy (FA) were performed in the NAWM. Correlations between diffusion indices and the full-scale intelligence quotient (FSIQ) and normalized lesion volume were also investigated. Compared with controls, both histogram and ROI analyses showed significant (P < .05) increased MD and decreased FA in the NAWM of TSC patients. In TSC patients, some of the histogram- and ROI-derived diffusion indices of the NAWM were correlated with FSIQ (P < .01), but none of them were correlated with the normalized lesion volume. These findings indicate that TSC patients have occult damage in the NAWM, which might be an important neural basis for intellectual disability in these patients.
Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by the involvement of multiple organs including the brain. More than 40% of patients with TSC have intellectual disability (Joinson et al., 2003, Seidenwurm and Barkovich, 1992 and Shepherd and Stephenson, 1992). The neural basis of intellectual disability in TSC has been attributed to the cortical tubers and epilepsy (Goh et al., 2005, Jambaqué et al., 1991, Jambaqué et al., 2000, O'Callaghan et al., 2004, Raznahan et al., 2007, Shepherd and Stephenson, 1992, Takanashi et al., 1995 and Zaroff et al., 2006). Conventional MRI has been widely used to detect the four major cerebral lesions: cortical tubers, white matter abnormalities, subependymal nodules and subependymal giant-cell astrocytomas (Braffman et al., 1992). However, subtle pathological changes in the structure of the brain have not been studied extensively. A previous study has shown that neuropathological changes associated with TSC may be more extensive than previously suspected, involving the normal-appearing white matter (NAWM) (Ridler et al., 2001).
Diffusion weighted and diffusion tensor imaging (DTI) techniques have the potential to detect the occult damage in the brain tissue (especially brain white matter) which appears normal on conventional MRI (Ceccarelli et al., 2007 and Yu et al., 2007). With the use of these techniques, several studies have attempted to investigate whether the NAWM is damaged in patients with TSC using region of interest (ROI) analysis (Firat et al., 2006, Garaci et al., 2004, Karadag et al., 2005 and Peng et al., 2004). However, conflicting results are obtained. Moreover, most of the previous studies have focused on the correlations of the cortical lesions and epilepsy with intellectual disability in TSC patients (Goh et al., 2005, Jambaqué et al., 1991, Jambaqué et al., 2000, O'Callaghan et al., 2004, Raznahan et al., 2007, Shepherd and Stephenson, 1992, Takanashi et al., 1995 and Zaroff et al., 2006), but none of them have investigated the contribution of the NAWM damage to intelletual disability in these patients. The purposes of this study are to determine whether patients with TSC have brain NAWM damage using both DTI histogram and ROI analyses, and to investigate whether such damage contributes to the intellectual disability of these patients.
