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Here, we systematically quantified ultrastructural and subcellular characteristics of the axon\u2013myelin unit in MS NAWM and determined how this correlates with low\u2010grade inflammation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Human brain tissue obtained with short postmortem delay and fixation at autopsy enables systematic quantification of ultrastructural characteristics. In this study, we performed high\u2010resolution immunohis tochemistry and quantitative transmission electron microscopy to study inflammation and ultrastructural characteristics of the axon\u2013myelin unit in MS NAWM (n\u00a0=\u00a08) and control white matter (WM) in the optic nerve.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In the MS NAWM, there were more activated and phagocytic microglia cells (HLA<jats:sup>+<\/jats:sup>P2RY12<jats:sup>\u2212<\/jats:sup> and Iba1<jats:sup>+<\/jats:sup>CD68<jats:sup>+<\/jats:sup>) and more T cells (CD3<jats:sup>+<\/jats:sup>) compared to control WM, mainly located in the perivascular space. In MS NAWM compared to control WM, there were, as expected, longer paranodes and juxtaparanodes and larger overlap between paranodes and juxtaparanodes. There was less compact myelin wrapping, a lower g\u2010ratio, and a higher frequency of axonal mitochondria. Changes in myelin and axonal mitochondrial frequency correlated positively with the number of active and phagocytic microglia and lymphocytes in the optic nerve.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>These data suggest that in MS NAWM myelin detachment and uncompact myelin wrapping occurs, potassium channels are unmasked at the nodes of Ranvier, and axonal energy demand is increased, or mitochondrial transport is stagnated, accompanied by increased presence of activated and phagocytic microglia and T cells. These subclinical alterations to the axon\u2013myelin unit in MS NAWM may contribute to disease progression. 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