The contributions of myelin and axonal caliber to transverse relaxation time in shiverer and neurofilament-deficient mouse models

Abstract

White matter disorders can involve injury to myelin or axons but the respective contribution of each to clinical course is difficult to evaluate non-invasively. Here, to develop a paradigm for further investigations of axonal pathology by MRI, we compared two genetic mouse models exhibiting relatively selective axonal or myelin deficits using quantitative MRI relaxography of the transverse relaxation times (T2) in vivo and ultrastructural morphometry. In HM-DKO mice, which lack genes encoding the heavy (NF-H) and medium (NF-M) subunits of neurofilaments, neurofilament content of large myelinated axons of the central nervous system (CNS) is markedly reduced in the absence of changes in myelin thickness and volume. In shiverer mutant mice, which lack functional myelin basic protein, CNS myelin sheath formation is markedly reduced but neurofilament content is normal. We observed increases in T2 in nearly all white matter in Shiverer mice compared to their wild type, while more subtle increases in T2 were observed in HM-DKO in the corpus callosum. White matter T2 was generally greater in Shiverer mice than HM-DKO mice. Ultrastructural morphometry of the corpus callosum, which exhibited the greatest T2 differences, confirmed that total cross sectional area occupied by axons was similar in the two mouse models and that the major ultrastructural differences, determined by morphometry, were an absence of myelin and larger unmyelinated axons in shiverer mice and absence of neurofilaments in HM-DKO mice. Our findings indicate that T2 is strongly influenced by myelination state and axonal volume, while neurofilament structure within the intra-axonal compartment has a lesser effect upon single compartment T2 estimates.

Postmortem MRI: a novel window into the neurobiology of late life cognitive decline

“…In one plausible scenario, the R 2 alterations may reflect axonal loss secondary to neurodegenerative pathology, such as AD (Agosta et al, 2011, Alves et al, 2015, Bozzali et al, 2002). This dovetails with our observations in that the single compartment estimate of R 2 would be expected to decrease, either due to additional infiltration of the tissue by cerebrospinal fluid, reduction in myelin content (Dyakin et al, 2010), or both. The current study’s most compelling evidence in support of this Wallerian viewpoint is the sharply defined parahippocampal region of R 2 depression, whose shape, location, and preferential association with decline of episodic memory are suggestive of tract-specific damage to fibers serving the hippocampal formation (Salat et al, 2010).…”

Genome-Wide Transcriptional Profiling and Structural Magnetic Resonance Imaging in the Maternal Immune Activation Model of Neurodevelopmental Disorders

“…These data are in good agreement with relaxometry studies in dys-myelinated mice (Shiverer mutants), which show extended T 2 relaxation times relative to their WT littermates (Dyakin et al 2010) and our prior work in the cuprizone mouse model (Wood et al 2016a(Wood et al , 2016b. T 2 relaxation time is also reported to correlate with MWF values in human datasets, although these relationships appear to be inconsistent (positive and negative) over different developmental periods (Deoni et al 2012).…”

Novel pathologic findings in patients with Pelizaeus-Merzbacher disease

“…Quantitative MRI neuroimaging studies have proven instrumental in describing the axonal and myelin pathology in white matter diseases at a gross level [15]. However, MRI does not explain the basis for the fiber loss.…”