Articulo

doi:10.1093/brain/awp070

Brain 2009: 132; 1175–1189

| 1175

BRAIN
A JOURNAL OF NEUROLOGY

The relation between inflammation and neurodegeneration in multiple sclerosis brains
Josa M. Frischer,1,* Stephan Bramow,2,* Assunta Dal-Bianco,1 Claudia F. Lucchinetti,3 Helmut Rauschka,4 Manfred Schmidbauer,4 Henning Laursen,5 Per Soelberg Sorensen2 and Hans Lassmann1
1 2 3 4 5 Department ofNeuroimmunology, Center for Brain Research, Medical University of Vienna, Vienna, Austria Danish Multiple Sclerosis Research Center, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark Department of Neurology, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA Department of Neurology, Hospital Hietzing, Vienna, Austria Laboratory of Neuropathology,Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark

*These authors contributed equally to the work. Correspondence to: Prof. Dr Hans Lassmann, MD, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Wien, Austria E-mail: hans.lassmann@meduniwien.ac.at

Some recent studies suggest that in progressive multiple sclerosis, neurodegeneration may occurindependently from inflammation. The aim of our study was to analyse the interdependence of inflammation, neurodegeneration and disease progression in various multiple sclerosis stages in relation to lesional activity and clinical course, with a particular focus on progressive multiple sclerosis. The study is based on detailed quantification of different inflammatory cells in relation to axonal injury in 67multiple sclerosis autopsies from different disease stages and 28 controls without neurological disease or brain lesions. We found that pronounced inflammation in the brain is not only present in acute and relapsing multiple sclerosis but also in the secondary and primary progressive disease. T- and B-cell infiltrates correlated with the activity of demyelinating lesions, while plasma cellinfiltrates were most pronounced in patients with secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS) and even persisted, when T- and B-cell infiltrates declined to levels seen in age matched controls. A highly significant association between inflammation and axonal injury was seen in the global multiple sclerosis population as well as in progressive multiplesclerosis alone. In older patients (median 76 years) with long-disease duration (median 372 months), inflammatory infiltrates declined to levels similar to those found in age-matched controls and the extent of axonal injury, too, was comparable with that in age-matched controls. Ongoing neurodegeneration in these patients, which exceeded the extent found in normal controls, could be attributed toconfounding pathologies such as Alzheimer’s or vascular disease. Our study suggests a close association between inflammation and neurodegeneration in all lesions and disease stages of multiple sclerosis. It further indicates that the disease processes of multiple sclerosis may die out in aged patients with long-standing disease.

Keywords: multiple sclerosis; T cells; B cells; plasma cells; axonal injuryReceived November 25, 2008. Revised and Accepted February 27, 2009. Advance Access publication March 31, 2009 ß 2009 The Author(s) This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/ 2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium,provided the original work is properly cited.

1176

| Brain 2009: 132; 1175–1189

J. M. Frischer et al.

Abbreviations: APP = amyloid precursor protein; EDSS = expanded disability status scale; NAGM = normal appearing grey matter; NAWM = normal appearing white matter; PPMS = primary progressive multiple sclerosis; RRMS = relapsing-remitting multiple sclerosis; SPMS = secondary...