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Detection of endophenotypes associated with neuropsychiatric deficiencies in a mouse model of tuberous sclerosis complex using diffusion tensor imaging.

ABSTRACT: Tuberous sclerosis complex (TSC) is a rare hereditary disease, which results from the mutation of either TSC1 or TSC2, and its clinical features include benign tumors and dysfunctions in numerous organs, including the brain. Many individuals with TSC manifest neuropsychiatric symptoms, such as learning impairments, cognitive deficits and anxiety. Current pharmacological treatment for TSC is the use of mTOR inhibitors. However, they are not effective in treating neuropsychiatric symptoms. We previously used curcumin, a diet-derived mTOR inhibitor, which possesses both anti-inflammatory and antiproliferative properties, to improve learning and memory deficits in Tsc2^+/- mice. Diffusion tensor imaging (DTI) provides microstructural information in brain tissue and has been used to study the neuropathological changes in TSC. In this study, we confirmed that the impaired recognition memory and increased anxiety-like behavior in Tsc2^+/- mice can be reversed by curcumin treatment. Second, we found altered fractional anisotropy and mean diffusivity in the anterior cingulate cortex and the hippocampus of the Tsc2^+/- mice, which may indicate altered circuitry. Finally, the mTOR complex 1 hyperactivity was found in the cortex and hippocampus, coinciding with abnormal cortical myelination and increased glial fibrillary acidic protein expression in the hippocampal CA1 of Tsc2^+/- mice, both of which can be rescued with curcumin treatment. Overall, DTI is sensitive to the subtle alterations that cannot be detected by conventional imaging, suggesting that noninvasive DTI may be suitable for longitudinally monitoring the in vivo neuropathology associated with the neuropsychiatric symptoms in TSC, thereby facilitating future clinical trials of pharmacological treatments.

SUBMITTER: Hsieh CC

PROVIDER: S-EPMC8018051 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:First- and second-degree relatives of people with amyotrophic lateral sclerosis report higher rates of neuropsychiatric disorders, indicating that risk genes may be pleiotropic, causing multiple phenotypes within kindreds. Such phenotypes may constitute a disease endophenotype that associates with disease liability. We have directly investigated cognitive functioning and neuropsychiatric traits among relatives of people with amyotrophic lateral sclerosis to identify potential endophenotypes of the disease. In a family-based, cross-sectional study design, first- and second-degree relatives of people with amyotrophic lateral sclerosis (n = 149) were compared to controls (n = 60) using an in-depth neuropsychological and neuropsychiatric assessment. Subgroup analyses examined the effect of family history and C9orf72 repeat expansion status (n = 16 positive carriers). Relatives of people with amyotrophic lateral sclerosis had lower scores on executive functioning, language and memory tasks compared to controls, with large effect sizes observed on object naming (d = 0.91, P = 0.00001) and phonemic verbal fluency (d = 0.81, P = 0.0003). Relatives also had higher autism quotient attention to detail traits (d = -0.52, P = 0.005), lower conscientiousness (d = 0.57, P = 0.003) and lower openness to experience personality traits (d = 0.54, P = 0.01) than controls. These effects were typically larger in relatives of people with familial, rather than sporadic, amyotrophic lateral sclerosis and were present in both gene carrier and non-carrier relatives of probands with a C9orf72 repeat expansion. Poorer phonemic fluency and object naming, along with autism and personality traits, are more frequent in relatives of people with amyotrophic lateral sclerosis. Among kindreds carrying the C9orf72 repeat expansion, these traits were identified in relatives regardless of their carrier status, suggesting the presence of a disease-associated endophenotype that is not exclusively mediated by the C9orf72 expansion.

Project description:BackgroundTuberous sclerosis complex (TSC) results in neurodevelopmental phenotypes, benign tumors, and cysts throughout the body. Recent studies show numerous rare findings in TSC. Guidelines suggest routine abdominal and chest imaging to monitor these thoracoabdominal findings, but imaging is not uniformly done across centers. Thus, the prevalence of many findings is unknown. To answer this, we categorized the clinical reads of 1398 thoracoabdominal scans from 649 patients of all ages in the Cincinnati Children's Hospital TSC Repository Database.ResultsTypical TSC findings were present in many patients: kidney cysts (72%), kidney fat-containing angiomyolipomas (51%), kidney lipid-poor angiomyolipomas (27%), liver angiomyolipomas (19%), and lung nodules thought to represent multifocal micronodular pneumocyte hyperplasia (MMPH) (18%). While many features were more common in TSC2 patients, TSC1 patients had a higher prevalence of MMPH than TSC2 patients (24% versus 13%, p = 0.05). Many rare findings (e.g., lymphatic malformations and liver masses) are more common in TSC than in the general population. Additionally, most thoracoabdominal imaging findings increased with age except kidney cysts which decreased, with the 0-10 years age group having the highest percentage (69% 0-10 years, 49% 10-21 years, 48% 21 + years, p < 0.001). Finally, in our population, no patients had renal cell carcinoma found on abdominal imaging.ConclusionsThese results show that regular thoracoabdominal scans in TSC may show several findings that should not be ignored or, conversely, over-reacted to when found in patients with TSC. Female sex, TSC2 mutation, and age are risk factors for many thoracoabdominal findings. The data suggest novel interactions of genetic mutation with pulmonary nodules and age with renal cysts. Finally, in agreement with other works, these findings indicate that several rare thoracoabdominal imaging findings occur at higher rates in the TSC population than in the general population. This work supports obtaining detailed thoracoabdominal imaging in patients with TSC.

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Detection of endophenotypes associated with neuropsychiatric deficiencies in a mouse model of tuberous sclerosis complex using diffusion tensor imaging.

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