Abstract
AimsMultiple sclerosis (MS) leaves a signature on the phosphorylation and thus proton binding capacity of axonal neurofilament (Nf) proteins. The proton binding capacity in a tissue is the major determinant for exchange between bound and free protons and thus the magnetisation transfer ratio (MTR). This study investigated whether the MTR of non-lesional white matter (NLWM) was related to the brain tissue concentration of neurofilament phosphoforms. MethodsUnfixed post-mortem brain slices of 12 MS patients were analysed using MTR, T1 at 1.5T. Blocks containing NLWM were processed for embedding in paraffin and inspected microscopically. Adjacent tissue was microdissected, homogenised and specific protein levels were quantified by ELISA for the Nf heavy chain (NfH) phosphoforms, glial fibrillary acidic protein (GFAP), S100B and ferritin. ResultsAveraged hyperphosphorylated NfH (SMI34) but not phosphorylated NfH (SMI35) levels were different between individual patients NLWM. The concentration of hyperphosphorylated NfH-SMI34 correlated with T1 (R=0.70, p=0.0114) and — inversely — with MTR (R=−0.73, p=0.0065). NfH-SMI35 was not correlated to any of the MR indices. ConclusionsPost-translational modifications of axonal proteins such as phosphorylation of neurofilaments occur in NLWM and may precede demyelination. The resulting change of proton mobility influences MTR and T1. This permits the in vivo detection of these subtle tissue changes on a proteomic level in patients with MS.
Highlights
In this study we investigated the association between magnetisation transfer ratio (MTR) and proteomic alterations of axons in Multiple sclerosis (MS) non-lesional white matter (NLWM)
The number of samples analysed per patient varied from 4 to 18 (Table 1)
The magnetic resonance imaging (MRI) data is consistent with previous studies
Summary
Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS) with associated neurodegeneration. ⁎ Corresponding author at: VU University Medical Centrum, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands and UCL Institute of Neurology, Department of Neuroimmunology, Queen Square, London, WC1N 3BG, UK. (Lassmann et al, 2007; Trapp and Nave, 2008). The most obvious pathological finding in MS brain tissue is focal demyelination, which may affect any part of the CNS (Chard and Miller, 2009). New MS lesions may result in neurological symptoms and/or signs, a clinical situation called “relapse”, though patients with nonrelapsing (primary or secondary progressive) MS develop new lesions, albeit less frequently (Petzold, 2008)
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