Abnormal White Matter Microstructure in the Limbic System Is Associated With Tuberous Sclerosis Complex-Associated Neuropsychiatric Disorders.

Yoko Kato,Kai Makita,Yoshiko Iwatani,Koji Tominaga,Mari Wataya-Kaneda,Masako Taniike,Kuriko Kagitani-Shimono,Akemi Sato,Kiyotaka Nemoto

doi:10.3389/fneur.2022.782479

Abstract

ObjectiveTuberous sclerosis complex (TSC) is a genetic disease that arises from TSC1 or TSC2 abnormalities and induces the overactivation of the mammalian/mechanistic target of rapamycin pathways. The neurological symptoms of TSC include epilepsy and tuberous sclerosis complex-associated neuropsychiatric disorders (TAND). Although TAND affects TSC patients' quality of life, the specific region in the brain associated with TAND remains unknown. We examined the association between white matter microstructural abnormalities and TAND, using diffusion tensor imaging (DTI).MethodsA total of 19 subjects with TSC and 24 age-matched control subjects were enrolled. Tract-based spatial statistics (TBSS) were performed to assess group differences in fractional anisotropy (FA) between the TSC and control groups. Atlas-based association analysis was performed to reveal TAND-related white matter in subjects with TSC. Multiple linear regression was performed to evaluate the association between TAND and the DTI parameters; FA and mean diffusivity in seven target regions and projection fibers.ResultsThe TBSS showed significantly reduced FA in the right hemisphere and particularly in the inferior frontal occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF), uncinate fasciculus (UF), and genu of corpus callosum (CC) in the TSC group relative to the control group. In the association analysis, intellectual disability was widely associated with all target regions. In contrast, behavioral problems and autistic features were associated with the limbic system white matter and anterior limb of the internal capsule (ALIC) and CC.ConclusionThe disruption of white matter integrity may induce underconnectivity between cortical and subcortical regions. These findings suggest that TANDs are not the result of an abnormality in a specific brain region, but rather caused by connectivity dysfunction as a network disorder. This study indicates that abnormal white matter connectivity including the limbic system is relevant to TAND. The analysis of brain and behavior relationship is a feasible approach to reveal TAND related white matter and neural networks. TAND should be carefully assessed and treated at an early stage.

Highlights

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by multiple organ hamartomas, including the brain, heart, skin, kidney, and liver [1]
Our results suggest that Tuberous sclerosis complex associated neuropsychiatric disorders (TAND) are not the result of an abnormality of specific brain region, but rather caused by connectivity dysfunction as a network disorder
Our results suggest that refractory epilepsy influences the alternation of the white matter microstructure integrity in the frontal and temporal areas, which are strongly associated with intellectual ability and sociability

Summary

Introduction

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by multiple organ hamartomas, including the brain, heart, skin, kidney, and liver [1]. The hamartintuberin complex inhibits the mammalian/mechanistic target of rapamycin (mTOR) pathways, which play a role in controlling cellular growth, cell proliferation, and suppressing tumor formation [2]. The neurological manifestations of TSC include cortical tubers noted in more than 80% [1, 4], subependymal nodules (SEN) noted in 70–84% [5], subependymal giant cell astrocytomas (SEGAs) noted in 5–15% [4], and epilepsy noted in 80– 90% of patients [6, 7]. Tuberous sclerosis complex associated neuropsychiatric disorders (TAND) is a new term coined at the 2012 International TSC Consensus Conference to unite the neurological manifestations of TSC, such as intellectual disability (ID), autistic spectrum disorders (ASD), behavioral difficulties (aggression, anxiety, and self-injury), and other psychiatric symptoms [8, 9]. The neurological pathophysiology in TSC, such as that relating to epilepsy and TAND, remains unknown [3]

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