Multiple sclerosis (MS) is a neurological disease that predominately affects young adults. Inflammatory mechanisms were believed to be the main contributor to the development of MS. However, more recent neuropathological and magnetic resonance imaging (MRI) studies suggest that neurodegenerative processes play an equivalent central role, that these degenerative processes commence during the early stages of the disease, and that neuronal and axonal loss may be the key substrate for the development of disability. One macroscopic hallmark of neurodegeneration is brain atrophy, which can be readily investigated non-invasively using MRI. We have recently demonstrated brain atrophy in pediatric-onset MS patients, further supporting a very early and possibly primary role for neurodegeneration in MS.
The three current hypotheses for the specific pathobiology underlying brain atrophy in MS are:
- 1) atrophy in focal lesions and normal-appearing brain tissue occurs secondary to neuroaxonal injury and Wallerian degeneration and loss of normal myelin or reduction in myelin density associated with inflammation-mediated tissue insult;
- 2) atrophy is due to a diffuse, primary degenerative process associated with neuronal cell death and subsequent loss of axons and myelinated pathways; and
- 3) atrophy is due to a combination of mechanisms 1 and 2. In children with MS, insult to precursors of primary myelination may further impede normal brain maturation contributing to failure of age-expected brain growth in addition to atrophic loss of established neural networks.
The onset of MS during childhood and adolescence provides a potentially enhanced capacity to distinguish the earliest aspects of MS pathobiology, as the young age of such patients inherently limits the time period available for subclinical disease. A further unique aspect of pediatric onset MS is the potential deleterious impact of MS pathobiology to the processes of primary myelination and normal brain maturation, and thus potential consequence of MS contributing to failure of age-expected brain growth. We have recently reported reduced brain volumes in pediatric-onset MS compared to pediatric normal controls in cross-sectional studies. We also noted that the reduction in brain volume was not only global, but also specifically notable in the thalamus. We now propose to delineate whether the reduced brain volumes reflect age-expected failure of normative growth or loss of previously developed brain tissue (atrophy), or both, and will further explore the selective vulnerability of specific brain regions.
MRI confirmation of progressive brain volume loss, detectable in children and adolescents with MS, will not only refute the concept of pediatric brain resiliency and enhanced repair, but will also emphasize the fundamental nature of neurodegenerative biology of MS. Such confirmation has significant import on future therapeutic strategies, as it implies that anti-inflammatory therapies alone may fail to mitigate the negative impact of MS, and that neuroprotective strategies will be required from onset. This study is supported by an operating grant (Biomedical Research) provided by the Multiple Sclerosis Society of Canada & The Multiple Sclerosis Scientific Research Foundation.
Reference
[1] R. Harmouche, N.K. Subbanna, D.L. Collins, D.L. Arnold, T. Arbel, “Probabilistic multiple sclerosis lesion classification based on modeling regional intensity variability and local neighbourhood information”, IEEE Transactions on Biomedical Engineering, 2015 May; 62(5): 1281–92.
[2] N Guizard, P Coupé, VS Fonov, JV Manjón, DL Arnold, DL Collins, “Rotation-invariant multi-contrast non-local means for MS lesion segmentation (RMNMS)”, NeuroImage: Clinical. 2015 May 8: 376–89.
[3] K. Weier, B. Banwell, A. Cerasa, D.L. Collins, A. Dogonowski, H. Lassmann, A. Quattrone, M.A. Sahraian, H.R. Siebner and T. Sprenger, “The role of the cerebellum in multiple sclerosis”, Cerebellum. 2015 Jun; 14(3); 364–74
[4] Aubert-Broche B, Fonov VS, Garcia-Lorenzo D, Mouiha A, Guizard N, Coupé P, Eskildsen SF, Collins DL. A new method for structural volume analysis of longitudinal brain MRI data and its application in studying the growth trajectories of anatomical brain structures in childhood. Neuroimage 2013;82C:393–402.
[5] Aubert-Broche B, Fonov V, Ghassemi R, Arnold DL, Banwell B, Sled JG, Collins DL. Regional brain atrophy in children with multiple sclerosis. Neuroimage 2011;58:409–415.
[6] Kerbrat A, Aubert-Broche B, Fonov V, Narayanan S, Sled JG, Arnold DL, Banwell B, Collins DL. Reduced head and brain size for age and disproportionately smaller thalami in child-onset MS. Neurology 2012;78:194–201.
