Alterations in White Matter Microstructure in Neurofibromatosis-1

Abstract

Neurofibromatosis (NF1) represents the most common single gene cause of learning disabilities. NF1 patients have impairments in frontal lobe based cognitive functions such as attention, working memory, and inhibition. Due to its well–characterized genetic etiology, investigations of NF1 may shed light on neural mechanisms underlying such difficulties in the general population or other patient groups. Prior neuroimaging findings indicate global brain volume increases, consistent with neural over-proliferation. However, little is known about alterations in white matter microstructure in NF1. We performed diffusion tensor imaging (DTI) analyses using tract-based spatial statistics (TBSS) in 14 young adult NF1 patients and 12 healthy controls. We also examined brain volumetric measures in the same subjects. Consistent with prior studies, we found significantly increased overall gray and white matter volume in NF1 patients. Relative to healthy controls, NF1 patients showed widespread reductions in white matter integrity across the entire brain as reflected by decreased fractional anisotropy (FA) and significantly increased absolute diffusion (ADC). When radial and axial diffusion were examined we found pronounced differences in radial diffusion in NF1 patients, indicative of either decreased myelination or increased space between axons. Secondary analyses revealed that FA and radial diffusion effects were of greatest magnitude in the frontal lobe. Such alterations of white matter tracts connecting frontal regions could contribute to the observed cognitive deficits. Furthermore, although the cellular basis of these white matter microstructural alterations remains to be determined, our findings of disproportionately increased radial diffusion against a background of increased white matter volume suggest the novel hypothesis that one potential alteration contributing to increased cortical white matter in NF1 may be looser packing of axons, with or without myelination changes. Further, this indicates that axial and radial diffusivity can uniquely contribute as markers of NF1-associated brain pathology in conjunction with the typically investigated measures.

White matter is increased in the brains of adults with neurofibromatosis 1

“…We found a generalized increase in white matter volume, but we did not observe an increase in total grey matter volume or in in the volume of grey matter in the frontal, parietal, occipital, or temporal lobes. This finding differs from those in previous studies in children and young adults with NF1 that found increased total grey matter volumes [ 6 , 7 , 16 ]. The difference in our findings may reflect a lag in brain development in younger adults with NF1, such as those studied by Karlsgodt et al [ 16 ], with subsequent “catch-up” of the grey matter/white matter ratio in older NF1 patients, as proposed by Moore et al [ 7 ].…”

“…This finding differs from those in previous studies in children and young adults with NF1 that found increased total grey matter volumes [ 6 , 7 , 16 ]. The difference in our findings may reflect a lag in brain development in younger adults with NF1, such as those studied by Karlsgodt et al [ 16 ], with subsequent “catch-up” of the grey matter/white matter ratio in older NF1 patients, as proposed by Moore et al [ 7 ]. Our finding of generalized white matter enlargement in the brains of adults with NF1 is consistent with dysregulated myelin proliferation in individuals with NF1.…”

White matter is increased in the brains of adults with neurofibromatosis 1

“…We found a generalized increase in white matter volume, but we did not observe an increase in total grey matter volume or in in the volume of grey matter in the frontal, parietal, occipital, or temporal lobes. This finding differs from those in previous studies in children and young adults with NF1 that found increased total grey matter volumes [ 6 , 7 , 16 ]. The difference in our findings may reflect a lag in brain development in younger adults with NF1, such as those studied by Karlsgodt et al [ 16 ], with subsequent “catch-up” of the grey matter/white matter ratio in older NF1 patients, as proposed by Moore et al [ 7 ].…”

“…This finding differs from those in previous studies in children and young adults with NF1 that found increased total grey matter volumes [ 6 , 7 , 16 ]. The difference in our findings may reflect a lag in brain development in younger adults with NF1, such as those studied by Karlsgodt et al [ 16 ], with subsequent “catch-up” of the grey matter/white matter ratio in older NF1 patients, as proposed by Moore et al [ 7 ]. Our finding of generalized white matter enlargement in the brains of adults with NF1 is consistent with dysregulated myelin proliferation in individuals with NF1.…”

White Matter is Increased in the Brains of Adults with Neurofibromatosis 1

“…We found a generalized increase in white matter volume, but we did not observe an increase in total grey matter volume or in in the volume of grey matter in the frontal, parietal, occipital, or temporal lobes. This finding differs from those in previous studies that found increased total grey matter volumes in children and young adults with NF1 7, 8, 17 . The difference in our findings may reflect a lag in brain development in younger adults with NF1, such as those studied by Karlsgodt et al (2012) 17 , with subsequent “catch-up” of the grey matter/white matter ratio in older NF1 patients, as proposed by Moore et al (2000) 8 .…”

“…This finding differs from those in previous studies that found increased total grey matter volumes in children and young adults with NF1 7, 8, 17 . The difference in our findings may reflect a lag in brain development in younger adults with NF1, such as those studied by Karlsgodt et al (2012) 17 , with subsequent “catch-up” of the grey matter/white matter ratio in older NF1 patients, as proposed by Moore et al (2000) 8 . Our finding of generalized white matter enlargement in the brains of adults with NF1 is consistent with dysregulated myelin proliferation in individuals with NF1.…”

Alterations in Brain Morphology by MRI in Adults with Neurofibromatosis 1

“…Our ndings are consistent with those of previous studies in children and smaller groups of adults with NF1 (23,25). Also, previous brain MRI studies in people with NF1 have found evidence of increased total white matter volume, increased brain volume, and megalencephaly (6,7,9,10,(19)(20)(21)(22). Similarly, we found strong correlation between 2D CC size and total and CC white matter volume.…”

White matter is increased in the brains of adults with neurofibromatosis 1

“…We found a generalized increase in white matter volume, but we did not observe an increase in total grey matter volume or in in the volume of grey matter in the frontal, parietal, occipital, or temporal lobes. This finding differs from those in previous studies in children and young adults with NF1 that found increased total grey matter volumes [ 6 , 7 , 16 ]. The difference in our findings may reflect a lag in brain development in younger adults with NF1, such as those studied by Karlsgodt et al [ 16 ], with subsequent “catch-up” of the grey matter/white matter ratio in older NF1 patients, as proposed by Moore et al [ 7 ].…”

“…This finding differs from those in previous studies in children and young adults with NF1 that found increased total grey matter volumes [ 6 , 7 , 16 ]. The difference in our findings may reflect a lag in brain development in younger adults with NF1, such as those studied by Karlsgodt et al [ 16 ], with subsequent “catch-up” of the grey matter/white matter ratio in older NF1 patients, as proposed by Moore et al [ 7 ]. Our finding of generalized white matter enlargement in the brains of adults with NF1 is consistent with dysregulated myelin proliferation in individuals with NF1.…”

White Matter is Increased in the Brains of Adults with Neurofibromatosis 1

“…We found a generalized increase in white matter volume, but we did not observe an increase in total grey matter volume or in in the volume of grey matter in the frontal, parietal, occipital, or temporal lobes. This finding differs from those in previous studies that found increased total grey matter volumes in children and young adults with NF1 7, 8, 17 . The difference in our findings may reflect a lag in brain development in younger adults with NF1, such as those studied by Karlsgodt et al (2012) 17 , with subsequent “catch-up” of the grey matter/white matter ratio in older NF1 patients, as proposed by Moore et al (2000) 8 .…”

“…This finding differs from those in previous studies that found increased total grey matter volumes in children and young adults with NF1 7, 8, 17 . The difference in our findings may reflect a lag in brain development in younger adults with NF1, such as those studied by Karlsgodt et al (2012) 17 , with subsequent “catch-up” of the grey matter/white matter ratio in older NF1 patients, as proposed by Moore et al (2000) 8 . Our finding of generalized white matter enlargement in the brains of adults with NF1 is consistent with dysregulated myelin proliferation in individuals with NF1.…”

Alterations in Brain Morphology by MRI in Adults with Neurofibromatosis 1

“…Our ndings are consistent with those of previous studies in children and smaller groups of adults with NF1 (23,25). Also, previous brain MRI studies in people with NF1 have found evidence of increased total white matter volume, increased brain volume, and megalencephaly (6,7,9,10,(19)(20)(21)(22). Similarly, we found strong correlation between 2D CC size and total and CC white matter volume.…”

White matter is increased in the brains of adults with neurofibromatosis 1

“…We found a generalized increase in white matter volume, but we did not observe an increase in total grey matter volume or in in the volume of grey matter in the frontal, parietal, occipital, or temporal lobes. This finding differs from those in previous studies in children and young adults with NF1 that found increased total grey matter volumes [ 6 , 7 , 16 ]. The difference in our findings may reflect a lag in brain development in younger adults with NF1, such as those studied by Karlsgodt et al [ 16 ], with subsequent “catch-up” of the grey matter/white matter ratio in older NF1 patients, as proposed by Moore et al [ 7 ].…”

“…This finding differs from those in previous studies in children and young adults with NF1 that found increased total grey matter volumes [ 6 , 7 , 16 ]. The difference in our findings may reflect a lag in brain development in younger adults with NF1, such as those studied by Karlsgodt et al [ 16 ], with subsequent “catch-up” of the grey matter/white matter ratio in older NF1 patients, as proposed by Moore et al [ 7 ]. Our finding of generalized white matter enlargement in the brains of adults with NF1 is consistent with dysregulated myelin proliferation in individuals with NF1.…”

White Matter is Increased in the Brains of Adults with Neurofibromatosis 1

“…We found a generalized increase in white matter volume, but we did not observe an increase in total grey matter volume or in in the volume of grey matter in the frontal, parietal, occipital, or temporal lobes. This finding differs from those in previous studies that found increased total grey matter volumes in children and young adults with NF1 7, 8, 17 . The difference in our findings may reflect a lag in brain development in younger adults with NF1, such as those studied by Karlsgodt et al (2012) 17 , with subsequent “catch-up” of the grey matter/white matter ratio in older NF1 patients, as proposed by Moore et al (2000) 8 .…”

“…This finding differs from those in previous studies that found increased total grey matter volumes in children and young adults with NF1 7, 8, 17 . The difference in our findings may reflect a lag in brain development in younger adults with NF1, such as those studied by Karlsgodt et al (2012) 17 , with subsequent “catch-up” of the grey matter/white matter ratio in older NF1 patients, as proposed by Moore et al (2000) 8 . Our finding of generalized white matter enlargement in the brains of adults with NF1 is consistent with dysregulated myelin proliferation in individuals with NF1.…”

Alterations in Brain Morphology by MRI in Adults with Neurofibromatosis 1

“…Our ndings are consistent with those of previous studies in children and smaller groups of adults with NF1 (23,25). Also, previous brain MRI studies in people with NF1 have found evidence of increased total white matter volume, increased brain volume, and megalencephaly (6,7,9,10,(19)(20)(21)(22). Similarly, we found strong correlation between 2D CC size and total and CC white matter volume.…”