Abstract
Atrophy has become a clinically relevant marker of progressive neurodegeneration in multiple sclerosis (MS). To better understand atrophy, mouse models that feature atrophy along with other aspects of MS are needed. The experimental autoimmune encephalomyelitis (EAE) mouse model of MS was used to determine the extent of atrophy in a model of inflammation-associated central nervous system pathology. High-resolution magnetic resonance imaging (MRI) and atlas-based volumetric analysis were performed to measure brain regional volumes in EAE mice. EAE brains were larger at peak clinical disease (days 14–16) compared to controls, with affected regions including the cerebellum, hippocampus, and corpus callosum. Following peak clinical disease, EAE mice exhibited significant loss of volume at chronic long-term disease duration (day 66+). Atrophy was identified in both white and grey matter regions including the cerebral cortex, cerebellum, hippocampus, corpus callosum, basal forebrain, midbrain, optic tract, and colliculus. Histological analysis of the atrophied cortex, cerebellum, and hippocampus showed demyelination, and axonal/neuronal loss. We hypothesize this atrophy could be a result of inflammatory associated neurodegenerative processes, which may also be involved in MS. Using MRI and atlas-based volumetrics, EAE has the potential to be a test bed for treatments aimed at reducing progressive neurological deterioration in MS.
Highlights
Multiple sclerosis (MS) has generally been thought of as a white matter (WM) disease characterized by neuroinflammation and demyelination of the brain and spinal cord
The regions studied were limited and so it is unknown how widespread atrophy is in EAE, if WM atrophy occurs alongside grey matter (GM), and if the regions affected are similar to multiple sclerosis (MS)
After correcting for body weight, we found that EAE mice imaged at peak clinical disease had significantly larger brain sizes compared to the Complete Freund’s Adjuvant (CFA) or Naïve controls (422 ± 9 mm3, 407 ± 18 mm[3], and 405 ± 15 mm[3], respectively; F(3,22) = 4.86, q = 0.042, analysis of covariance (ANCOVA))
Summary
Multiple sclerosis (MS) has generally been thought of as a white matter (WM) disease characterized by neuroinflammation and demyelination of the brain and spinal cord. Indicates that neurodegenerative processes including axonal degeneration, and the loss of cells including neurons and oligodendrocytes, play an important role alongside inflammation and affects both white and grey matter (GM) in the brain[1,2,3] The accumulation of these neurodegenerative processes results in a loss of brain volume known as atrophy[4,5,6]. Inflammation is still present during secondary progressive MS (SPMS), and is associated with active demyelination and neurodegeneration[16] suggesting it may still be associated with atrophy in this phase of the disease Despite this evidence, anti-inflammatory drugs have had little effect at reducing atrophy, and have not been affective at treating clinical disability in progressive forms of the disease when atrophy is most prominent. High-resolution MRI, and atlas-based regional volumetrics were used in this study to measure the volumes of anatomical regions in the brains of living EAE mice
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