Onset of multiple sclerosis before adulthood leads to failure of age-expected brain growth.
OBJECTIVE
To determine the impact of pediatric-onset multiple sclerosis (MS) on age-expected brain growth.


METHODS
Whole brain and regional volumes of 36 patients with relapsing-remitting MS onset prior to 18 years of age were segmented in 185 longitudinal MRI scans (2-11 scans per participant, 3-month to 2-year scan intervals). MRI scans of 25 age- and sex-matched healthy normal controls (NC) were also acquired at baseline and 2 years later on the same scanner as the MS group. A total of 874 scans from 339 participants from the NIH-funded MRI study of normal brain development acquired at 2-year intervals were used as an age-expected healthy growth reference. All data were analyzed with an automatic image processing pipeline to estimate the volume of brain and brain substructures. Mixed-effect models were built using age, sex, and group as fixed effects.


RESULTS
Significant group and age interactions were found with the adjusted models fitting brain volumes and normalized thalamus volumes (p < 10(-4)). These findings indicate a failure of age-normative brain growth for the MS group, and an even greater failure of thalamic growth. In patients with MS, T2 lesion volume correlated with a greater reduction in age-expected thalamic volume. To exclude any scanner-related influence on our data, we confirmed no significant interaction of group in the adjusted models between the NC and NIH MRI Study of Normal Brain Development groups.


CONCLUSIONS
Our results provide evidence that the onset of MS during childhood and adolescence limits age-expected primary brain growth and leads to subsequent brain atrophy, implicating an early onset of the neurodegenerative aspect of MS.
From the McConnell Brain Imaging Center (B.A.-B., V.F., S.N., D.L.A., D.A., D.F., D.L.C.), Montreal Neurological Institute, McGill University; The Hospital for Sick Children (C.T., J.G.S., B.B.), University of Toronto; York University (C.T.), Toronto, Canada; and Children's Hospital of Philadelphia (B.B.), University of Pennsylvania.
Bérengère
B
Aubert-Broche
From the McConnell Brain Imaging Center (B.A.-B., V.F., S.N., D.L.A., D.A., D.F., D.L.C.), Montreal Neurological Institute, McGill University; The Hospital for Sick Children (C.T., J.G.S., B.B.), University of Toronto; York University (C.T.), Toronto, Canada; and Children's Hospital of Philadelphia (B.B.), University of Pennsylvania.
Vladimir
V
Fonov
From the McConnell Brain Imaging Center (B.A.-B., V.F., S.N., D.L.A., D.A., D.F., D.L.C.), Montreal Neurological Institute, McGill University; The Hospital for Sick Children (C.T., J.G.S., B.B.), University of Toronto; York University (C.T.), Toronto, Canada; and Children's Hospital of Philadelphia (B.B.), University of Pennsylvania.
Sridar
S
Narayanan
From the McConnell Brain Imaging Center (B.A.-B., V.F., S.N., D.L.A., D.A., D.F., D.L.C.), Montreal Neurological Institute, McGill University; The Hospital for Sick Children (C.T., J.G.S., B.B.), University of Toronto; York University (C.T.), Toronto, Canada; and Children's Hospital of Philadelphia (B.B.), University of Pennsylvania.
Douglas L
DL
Arnold
From the McConnell Brain Imaging Center (B.A.-B., V.F., S.N., D.L.A., D.A., D.F., D.L.C.), Montreal Neurological Institute, McGill University; The Hospital for Sick Children (C.T., J.G.S., B.B.), University of Toronto; York University (C.T.), Toronto, Canada; and Children's Hospital of Philadelphia (B.B.), University of Pennsylvania.
David
D
Araujo
From the McConnell Brain Imaging Center (B.A.-B., V.F., S.N., D.L.A., D.A., D.F., D.L.C.), Montreal Neurological Institute, McGill University; The Hospital for Sick Children (C.T., J.G.S., B.B.), University of Toronto; York University (C.T.), Toronto, Canada; and Children's Hospital of Philadelphia (B.B.), University of Pennsylvania.
Dumitru
D
Fetco
From the McConnell Brain Imaging Center (B.A.-B., V.F., S.N., D.L.A., D.A., D.F., D.L.C.), Montreal Neurological Institute, McGill University; The Hospital for Sick Children (C.T., J.G.S., B.B.), University of Toronto; York University (C.T.), Toronto, Canada; and Children's Hospital of Philadelphia (B.B.), University of Pennsylvania.
Christine
C
Till
From the McConnell Brain Imaging Center (B.A.-B., V.F., S.N., D.L.A., D.A., D.F., D.L.C.), Montreal Neurological Institute, McGill University; The Hospital for Sick Children (C.T., J.G.S., B.B.), University of Toronto; York University (C.T.), Toronto, Canada; and Children's Hospital of Philadelphia (B.B.), University of Pennsylvania.
John G
JG
Sled
From the McConnell Brain Imaging Center (B.A.-B., V.F., S.N., D.L.A., D.A., D.F., D.L.C.), Montreal Neurological Institute, McGill University; The Hospital for Sick Children (C.T., J.G.S., B.B.), University of Toronto; York University (C.T.), Toronto, Canada; and Children's Hospital of Philadelphia (B.B.), University of Pennsylvania. banwellb@email.chop.edu.
Brenda
B
Banwell
From the McConnell Brain Imaging Center (B.A.-B., V.F., S.N., D.L.A., D.A., D.F., D.L.C.), Montreal Neurological Institute, McGill University; The Hospital for Sick Children (C.T., J.G.S., B.B.), University of Toronto; York University (C.T.), Toronto, Canada; and Children's Hospital of Philadelphia (B.B.), University of Pennsylvania.
D Louis
DL
Collins
D000293:Adolescent; D000367:Age Factors; D001284:Atrophy / Q000473:pathology; D001921:Brain / Q000254:growth & development / Q000473:pathology* / Q000503:physiopathology; D003430:Cross-Sectional Studies; D004185:Disability Evaluation; D018450:Disease Progression; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D009103:Multiple Sclerosis / Q000175:diagnosis / Q000473:pathology* / Q000503:physiopathology*; D055815:Young Adult