DTI and RS-fMRI as predictors of cognition in NF1

Neurofibromatosis, Type 1 (NF1), also known as Von Recklinghausen`s disease, is the most common monogenetic disorder affecting the human nervous system. NF1 is often associated with low IQ, learning disabilities, abnormal executive functioning, including deficits in working memory, inhibition, set shifting, monitoring and planning, language problems, and visual-spatial difficulties. Deficits in executive function are considered to have a pivotal role in the development of cognitive dysfunction in NF1 patients. The causes for cognitive dysfunction in NF1 are incompletely understood. So far, studies reported associations of T2-hyperintensities and abnormal white and grey matter volumes, all three commonly observed in NF1 children, with decreasing cognitive performance. However, results are inconsistent and these parameters appear insufficient in explaining cognitive deficits. The objective of this project proposal is to study the associations between structural and microstructural cerebral MRI changes and resting state FMRI connectivity, and their relationship to cognitive performance in NF1 patients. The project focuses on executive dysfunction as this is the most prominent cognitive deficit seen in children suffering from NF1. The study hypothesis is that microstructural changes of the thalamo-frontal pathway in NF1 relate to impairment of neuropsychological performance in executive function testing via a decline in functional connectivity within the executive resting state network. The analyses will be corrected for the modest cognitive effects of thalamic T2-hyperintensities as well as white and grey matter volumes. The methodology used in this project includes structural MRI, DTI, resting state fMRI and extensive executive function testing. The goal of the project is to increase the understanding of the pathophysiological processes underlying cognitive dysfunction in children with NF1.

Neurofibromatosis Type 1 (NF1) is a genetic disorder affecting the central and peripheral nervous system. It is accompanied by deficits of executive functions (e.g. planning, organizing or managing time and space), social skills and behavior. The neuropathological basis underlying these multiple deficits is not fully understood. Hence, we studied the deficits using functional and structural Magnetic Resonance Imaging and found relationships between brain alteration and the behavioral outcome.By the use of functional imaging, we aimed to investigate functional brain networks and the interaction of certain brain areas with each other to determine the functional organization and its divergence to healthy controls. We found that adolescents with NF1 show differences to healthy subjects in network allocation in areas which have been associated with cognitive or social dysfunction in other diseases, such as autism or schizophrenia (e.g. amygdala, orbitofrontal cortex, anterior cingulate cortex). Parallel, these changes in the functional networks partly also correlated with decreased executive functions, social skills and behavioral deficits.As functional networks are related to structural and micro-structural integrity, the additional examination of brain structure provides a more comprehensive and thorough description of disease-related alterations and their associated deficits in NF1. We found increased volumes of sub-cortical areas (e.g. thalamus, amygdala, hippocampus) as well as widespread pathological changes in the microstructure of the white matter. Both features were identified as valid predictors of social functions and executive skills in NF1 by us. These findings strongly supported our hypothesis of a neuropathological basis in cognitive and social dysfunction in NF1.Until now, imaging studies examining the relation between functional alterations, structural white matter pathology or volumes of specific brain areas with behavioral outcome in NF1 are scarce. Prior research highlighted the involvement of cerebral "unidentified bright objects" (seen on T2-weighted images) and macrocephaly, two common features in the course of NF1, in clinical and cognitive deficits. However, the present findings substantially extend the current knowledge of the brain-behavior relation in NF1 and enable a better understanding of the disease's neuropathological substrate. As most of the imaging and analyses techniques used in this project are relatively new, and as NF1 imaging studies are infrequent, the results constitute a major contribution to the description of brain alterations and their impact an behavior in NF1. This knowledge could be useful for intervention or pharmaceutical studies aiming to improve cognition and quality of life of NF1 patients.