Aberrant Iron Deposition in the Progressive MS Spinal Cord Relates to Neurodegeneration
Marco Pisa1, Andrew Lockhart1, Aimee Avery1, Thomas Angell1, Jonathan Pansieri1, Alex Waldman1, Clara Limbaeck2, Gabriele De Luca1
1Nuffield Department of Clinical Neurosciences, University of Oxford, 2Neuropathology, Oxford University Hospital NHS Fundation Trust
Objective:
Characterize iron deposition in the MS spinal cord
Background:
Iron accumulates in microglia-macrophages at the edge of multiple sclerosis (MS) plaques in the brain. Iron-rimmed brain lesions strongly predict disability accumulation, supporting iron metabolism is crucial in MS pathology. Little is known about iron accumulation in the spinal cord.
Design/Methods:
Autopsy cervical, thoracic and lumbar spinal cord samples from 9 controls and 46 MS donors were labelled for iron (DAB-enhanced Turnbull), myelin (PLP), axons (Palmgren silver), microglia-macrophages (TMEM119, Iba1, CD68), astroglia (GFAP), and oligodendroglia (OLIG2). Soluble-CD163 was quantified in post-mortem CSF.
Results:
Iron was found in oligodendrocyte throughout the parenchyma and subpial area in controls. In MS plaques, iron-rich foamy macrophages were common in acute (50%) and chronic active (56.4%) lesions, displaying a striking perivascular pattern rather than accumulating at the lesion's edge. In non-lesional areas, iron-rich microglia-macrophages were also commonly found MS compared with controls, and correlated with Iba-1- and CD68-macrophage inflammation (both ρ>0.3, p=0.001). In non-lesional areas, 44.7% of samples showed iron-positive axons compared to only 13% of controls (p 0.005). Iron-positive axons and glia correlated with axonal counts (ρ -0.24, p=0.013 and ρ -0.27, p=0.005, respectively) and cord area (ρ -0.26, p=0.009 and ρ -0.25, p=0.013). MS cases also exhibited an astrocytic subpial pattern (32.6% vs. 2.4% in controls, p<0.001) that associated with higher glial and axonal iron staining. The presence of iron-rich axonal and/or microglia-macrophage associated with higher CSF sCD163 levels.
Conclusions:
In the spinal cord, non-heme iron is almost restricted to oligodendrocytes in controls, while in MS a pathological accumulation of iron in axons, microglia-macrophages, and subpial astrocytes was observed in non-lesional WM. Iron accumulation in axons and microglia-macrophages associated with lower axonal densities and spinal cord atrophy. Our findings point to a diffuse dysregulation of iron metabolism in the spinal cord outside demyelinating plaques, which relates to neurodegeneration.