Abstract Details

Title Aberrant Iron Deposition in the Progressive MS Spinal Cord Relates to Neurodegeneration

Topic Multiple Sclerosis

Presentation(s) S17 - Multiple Sclerosis: Immunology/Basic Sciences (1:12 PM-1:24 PM)

Poster/Presentation
Number 002

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.

Objective Characterize iron deposition in the MS 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.

Authors/Disclosures
Marco Pisa, MD (Nuffield Department of Clinical Neurosciences, University of Oxford) PRESENTER	Dr. Pisa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck.
Andrew Lockhart, MB, BAO, BCh, MSc (St James Hospital, Dublin)	The institution of Dr. Lockhart has received research support from Oxford-Quinnipiac Partnership.
Aimee Avery (University of Oxford)	No disclosure on file
Thomas M. Angell (University of Oxford)	Mr. Angell has nothing to disclose.
Jonathan Pansieri, PhD (University of Oxford)	The institution of Dr. Pansieri has received research support from UK-MS society. The institution of Dr. Pansieri has received research support from Department of Defense US. Dr. Pansieri has received personal compensation in the range of $0-$499 for serving as a member of the Grant review Panel with French National Agency. Dr. Pansieri has received personal compensation in the range of $500-$4,999 for serving as a recipee of Travel Grant with Brain.
Alex D. Waldman (Emory University School of Medicine)	The institution of Mr. Waldman has received research support from European Charcot Foundation. The institution of Mr. Waldman has received research support from United States Department of Defense. The institution of Mr. Waldman has received research support from MS Treatment, Education, and Research.
Clara Limbaeck (OUH)	No disclosure on file
Gabriele C. De Luca, MD, DPhil, FAAN (University of Oxford)	Dr. De Luca has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Neurology Academy. Dr. De Luca has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Dr. De Luca has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Dr. De Luca has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. The institution of Dr. De Luca has received research support from NIHR, BRC (Oxford). The institution of Dr. De Luca has received research support from National Health and Medical Research (Australia). The institution of Dr. De Luca has received research support from UK MS Society. The institution of Dr. De Luca has received research support from Oxford-Quinnipiac Partnership. The institution of Dr. De Luca has received research support from US Department of Defense. The institution of Dr. De Luca has received research support from Wellcome ISSF (Oxford). The institution of Dr. De Luca has received research support from Bristol Myers Squibb. The institution of Dr. De Luca has received research support from University of Oxford (John Fell Fund). Dr. De Luca has a non-compensated relationship as a Editorial board member with MS Journal that is relevant to AAN interests or activities. Dr. De Luca has a non-compensated relationship as a Vice-Chair of Grant Review Panel with UK MS Society that is relevant to AAN interests or activities. Dr. De Luca has a non-compensated relationship as a Steering Group member with MS Academy that is relevant to AAN interests or activities.