Abstract
ObjectiveConventional magnetic resonance imaging (MRI) of the multiple sclerosis spinal cord is limited by low specificity regarding the underlying pathological processes, and new MRI metrics assessing microscopic damage are required. We aim to show for the first time that neurite orientation dispersion (i.e., variability in axon/dendrite orientations) is a new biomarker that uncovers previously undetected layers of complexity of multiple sclerosis spinal cord pathology. Also, we validate against histology a clinically viable MRI technique for dispersion measurement (neurite orientation dispersion and density imaging, NODDI), to demonstrate the strong potential of the new marker.MethodsWe related quantitative metrics from histology and MRI in four post mortem spinal cord specimens (two controls; two progressive multiple sclerosis cases). The samples were scanned at high field, obtaining maps of neurite density and orientation dispersion from NODDI and routine diffusion tensor imaging (DTI) indices. Histological procedures provided markers of astrocyte, microglia, myelin and neurofilament density, as well as neurite dispersion.ResultsWe report from both NODDI and histology a trend toward lower neurite dispersion in demyelinated lesions, indicative of reduced neurite architecture complexity. Also, we provide unequivocal evidence that NODDI‐derived dispersion matches its histological counterpart (P < 0.001), while DTI metrics are less specific and influenced by several biophysical substrates.InterpretationNeurite orientation dispersion detects a previously undescribed and potentially relevant layer of microstructural complexity of multiple sclerosis spinal cord pathology. Clinically feasible techniques such as NODDI may play a key role in clinical trial and practice settings, as they provide histologically meaningful dispersion indices.
Highlights
We aim to show that neurite orientation dispersion, namely the variability of neurite orientations, is a new sensitive and specific biomarker of multiple sclerosis spinal cord pathology
Through the combination of state-of-the-art histology[33] and post mortem NODDI26,27 magnetic resonance imaging (MRI), we show for the first time that neurite orientation dispersion is a marker of microstructural pathology, as it detects trends of reduced geometrical complexity of neurite architecture within multiple sclerosis lesions
We present quantitative maps (Table 1) from neurite orientation dispersion and density imaging (NODDI) (IVF, neurite density index (NDI), and orientation dispersion index (ODI)), diffusion tensor imaging (DTI) (FA, AD, RD, and MD) and histology (CV, MSF, NSF, ASF, lGSF) at the same resolution and from the same locations (Figs. 2 and 3)
Summary
Multiple sclerosis is a central nervous system disease characterized by a complex pathophysiology,[1] the fundamental features of which have been derived from the analysis of post mortem tissue.[2,3,4,5] Spinal cord pathology is an important determinant of permanent neurological disability with cardinal characteristics being inflammatory demyelination, synaptic, neuronal and axonal loss.[6,7,8,9,10,11] The precise nature of how these pathological alterations impact clinical phenotypes remains unknown. Conventional magnetic resonance imaging (MRI) provides the unique opportunity to decipher the impact of multiple sclerosis spinal cord pathology on clinical outcomes in vivo. New quantitative MRI methods that assess functionally relevant microstructure noninvasively and relate to changes at the microscopic level are urgently needed
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