The goal of this study was to investigate the effects of NF1 in adults with respect to brain volume, brain composition with respect to grey or white matter, and the correlation of brain volume differences with function. Our current findings extend our previous study, which showed that adults with NF1 exhibit enlargement of brain structures that are mainly composed of white matter, a result similar to that seen in children with NF1(21).
NF1 is caused by mutations in the NF1 gene, resulting in reduced ability to produce neurofibromin. This neurofibromin deficiency leads to dysregulated myelin formation in the peripheral and central nervous systems(4). Previous brain volumetric studies, most of which were done in small groups of children with NF1, have usually found increased total brain volumes and total white matter volumes (6, 7, 9, 11–13, 16–18, 20). Our previous study, which was the first large-scale MRI investigation of unselected adults with NF1, demonstrated that the corpus callosum and mid-cerebellar peduncle (brain structures that are mainly composed of white matter), are larger than expected in NF1 patients(21). We correlated the brain structural data to total white matter volume in a small subset of these patients and found a strong correlation between planar MRI measurements of the corpus callosum and brainstem and total white matter volume in adults with NF1(21). These finding supported the hypothesis that the enlarged total brain volume seen in individuals with NF1 is due to an overgrowth of myelin, thus an increase in the size of white matter structures.
In the present study, we analysed volumetric MRI data in the whole brain and intracranial sub-regions of adults with NF1 and controls. 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(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. (2012)(16), with subsequent “catch-up” of the grey matter/white matter ratio in older NF1 patients, as proposed by Moore et al. (2000)(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.
Brain composition changes throughout the adult lifespan, and people with NF1 have a shorter average lifespan than unaffected people(37, 40). Thus, we were interested in the changes to white and grey matter volumes over age in adults with NF1. Our findings that age does not affect total brain volume or total white matter volume differs from observations in other patient groups, where total brain volume and white matter volume increase from early adulthood to around 45 years old then decreases afterwards(37). The difference in our findings could be due to the small size of our comparison group (n = 43) and the paucity of adults above 45 years old in our study. We note, however, that most previously-reported studies of brain composition changes with age encompass narrow age ranges, include small sample sizes, and involve patients with various brain diseases that might affect the findings (37). Interestingly, we were able to show that grey matter volume decreased faster in adults with NF1 than in our comparison group.
Some studies in children with NF1 have found correlations between cognitive and behavioural impairment and CC size, total grey matter volume, or total white matter volume(7, 9, 14, 18), although this was not found in other studies(6, 8, 13, 19, 20). Few studies of brain morphology and neuropsychometric function have been done in adults with NF1(21). Our morphology to neuropsychometric correlations should be interpreted cautiously because our sample size of adults with full neuropsychometric testing was quite small. As well, we were unable to study the effects of age and sex as confounding factors on our neuropsychometric correlations. In our small study, we found that increased total brain volume and white matter volume were significantly and consistently correlated with better clinical and psychometric function in adults with NF1. We did not find any correlation with total grey matter volume.
One of the main limitations of our study is the lack of 3D MRI scans for healthy adults. We used adults with NF2 or Schwannomatosis as a comparison group because a series of patient MRIs was available to us and neither of these conditions is thought to affect brain volume(26). We did not use published brain volumes for healthy adults as those studies included different age ranges, used different 3D MRI scanners, and included volumetric measurements of different regions of the brain.
Through our brain volumetric MRI analysis of the largest cohort of adults with NF1 studied to date, we showed that white matter volume is increased compared to adults with NF2 or Schwannomatosis. Thus, the increase in white matter volume previously found in children with NF1 persists into adulthood. This supports the hypothesis that NF1 causes a dysregulation of myelin production by Schwann cells in peripheral nerves and by oligodendrocytes in the central nervous system. Characterization of white matter composition and integrity using diffusion weighted imaging and studies of the relationship of the altered myelination to neuropsychometric function in adults with NF1 may help further elucidate the effects of the volumetric changes we observed on neural connectivity and function.