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. 2014 Jun 4;85(12):1386–1395. doi: 10.1136/jnnp-2014-307712

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Inflammation, neurodegeneration and iron in the deep grey matter (DGM) of patients with multiple sclerosis (MS). The figure shows photomicrographs of the caudate nucleus of a control patient (left panel), the NADGM (normal-appearing putamen) of a patient with 30 months of relapsing/remitting MS (middle panel) and an active DGM lesion (an actively demyelinating lesion in the putamen/globus pallidus) of a patient who had secondary progressive MS with attacks and a total disease duration of 444 months (right panel). An original magnification of 200× applies for all of the pictures (see 50 µm scale bar), excluding the insets. The scale bar in insets equals 10 µm. (A) H&E staining: reduced neuronal density in the NADGM and active lesioned DGM compared with control DGM. (B) CD3-positive T cell infiltration is absent in control patients and present in the NADGM of MS patients. Perivascular and parenchymal T cells are accumulated in the DGM with active lesions. (C) Ionised calcium-binding adapter molecule 1 (IBA-1) immunoreactivity is found on thin ramified microglial processes in the DGM of control patients and on microglial nodules in the NADGM of MS patients, and is massively increased in active DGM lesion areas. (D) The p22-phox subunit of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase reacts similarly to the microglial activation marker IBA-1 and is increasingly expressed on microglia in the NADGM with expression peaks in the active lesion areas. (E) In contrast to its expression in the white matter or cortical grey matter, inducible nitric oxide synthase (iNOS) is expressed under baseline conditions in the DGM of control patients. iNOS immunoreactivity is significantly increased in the NADGM of MS patients compared with controls and is mainly expressed on cells with macrophage morphology. The highest expression levels of iNOS are found on microglia in the active lesion areas. (F) Only exceptional amyloid precursor protein (APP)-reactive axonal spheroids are found in the DGM of control patients, whereas they are significantly more frequent in the NADGM of MS patients. The highest counts for APP-positive axonal spheroids are observed in active lesions. (G) E06, which is an oxidised phospholipid-reactive footprint of oxidative stress, is found in an age-dependent manner in neuronal lipofuscin granules within the DGM of control patients. Both neurons and oligodendrocytes, which are reactive for E06, as well as the total E06-reactive area, are significantly enriched in the NADGM of MS patients compared with that of controls. Note that the H&E-depicted neuronal loss in line A is associated with increased neuronal E06 reactivity in the NADGM of MS patients in line G. Inset: Neuron with cytoplasmic E06 reactivity. In active DGM lesions, severe signs of oxidative injury are observed in axons, neurons and oligodendrocytes. Inset: Neuron with cytoplasmic E06 reactivity. Scale bar: 10 µm. (H) In control patients and in the NADGM of MS patients, Turnbull blue-reactive iron is found primarily in oligodendrocytes and myelin fibres. Upon demyelination, iron reactivity decreases and shows a shift towards microglial cells, as shown in the rim of an actively demyelinating DGM lesion. The insets show oligodendrocytes in the DGM of controls and NADGM of MS patients and microglial cells in active DGM lesions. Scale bar size: 10 µm. NADGM, normal-appearing deep grey matter.