Some recent studies suggest that in progressive multiple sclerosis, neurodegeneration may occur independently 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 67 multiple 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 cell infiltrates 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 multiple sclerosis 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 to confounding 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.

Although spontaneous remyelination does occur in multiple sclerosis lesions, its extent within the global population with this disease is presently unknown. We have systematically analysed the incidence and distribution of completely remyelinated lesions (so-called shadow plaques) or partially remyelinated lesions (shadow plaque areas) in 51 autopsies of patients with different clinical courses and disease durations. The extent of remyelination was variable between cases. In 20% of the patients, the extent of remyelination was extensive with 60-96% of the global lesion area remyelinated. Extensive remyelination was found not only in patients with relapsing multiple sclerosis, but also in a subset of patients with progressive disease. Older age at death and longer disease duration were associated with significantly more remyelinated lesions or lesion areas. No correlation was found between the extent of remyelination and either gender or age at disease onset. These results suggest that the variable and patient-dependent extent of remyelination must be considered in the design of future clinical trials aimed at promoting CNS repair.

Neocortical demyelination in the forebrain has recently been identified as an important pathological feature of multiple sclerosis (MS). Here we describe that the cerebellar cortex is a major predilection site for demyelination, in particular in patients with primary and secondary progressive MS. In these patients, on average, 38.7% of cerebellar cortical area is affected, reaching in extreme examples up to 92%. Cerebellar cortical demyelination occurs mainly in a band-like manner, affecting multiple folia. The lesions are characterized by primary demyelination with relative axonal and neuronal preservation, although some axonal spheroids and a moderate reduction of Purkinje cells are present. Although cortical demyelination sometimes occurs together with demyelination in the adjacent white matter (leukocortical lesions), in most instances, the cortex was affected independently from white matter lesions. We found no correlation between demyelination in the cortex and the white matter, and in some cases, extensive cortical demyelination was present in the near absence of white matter lesions. Our data identify cortical demyelination as a potential substrate of cerebellar dysfunction in MS. Brain Pathol 2007;17:38-44. INTRODUCTIONMultiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system, which leads to large confluent demyelinated plaques in the white matter (15). However, recent studies show that in addition to focal white matter plaques, there is also widespread damage in the gray matter and a diffuse and global injury in the normal appearing white matter (6,9,11). With the introduction of new and sensitive staining techniques for myelin, extensive cerebral cortical demyelination in MS brains recently became apparent (2,17). Cortical lesions are prominent in patients with primary and secondary progressive MS (PPMS and SPMS, respectively) (11), and the majority of cortical demyelination occurs in the form of widespread and band-like subpial lesions, which appear to be related to an inflammatory process within the meninges (3, 11). Cortical demyelination has so far only been investigated in the forebrain. Here we describe that cortical demyelination is even more prominent in the cerebellum. PATIENTS AND METHODSAutopsy material. The study was performed on autopsy material from 40 MS patients, eight neurologically normal patients without cerebellar pathology and 34 patients with focal or diffuse cerebellar hypoxia (Tables 1 and 2). The MS cohort consisted of patients with acute MS (AMS; Marburg's type, n = 5), relapsing/remitting MS (RRMS; n = 3), SPMS (n = 19), PPMS (n = 10) and progressive MS, where clinical records were insufficient to differentiate between SPMS and PPMS (UPMS; n = 3). Patient demographics are given in Table 1. Clinical courses were determined by retrospective chart reviews, performed by a neurologist (PSS, CFL, HR and MS) blinded to the outcome of the neuropathological analysis.Neuropathological evaluation. Autopsy material was fixed in buffered formalin. ...