One of the key results of our study is that in the progressive stage of the disease, active demyelination and neurodegeneration are only seen in patients with pronounced inflammation in the brain. Further, we also show that in aged patients at the late stage of the disease, the inflammatory process may die out and inflammation declines to levels seen in age-matched controls. In this situation, ongoing neurodegeneration is reduced to the levels seen in controls, provided there is no confounding age-related disease, such as Alzheimer's or vascular disease.
Thus, there is no doubt that the pathology of progressive multiple sclerosis is fully consistent with that of a classical inflammatory disease. This contrasts with MRI findings that show only rare Gadolinium (Gd)-enhancing lesions in comparable patients, clearly documenting a dissociation between Gd-enhancement and progressive damage of the grey and white matter (Bielekova et al
; Filippi and Rocca, 2005
; Anderson et al
; Zivadinov and Cox, 2007
; Waxman, 2008
; Young et al
). Furthermore, the question arises, why anti-inflammatory therapies are largely ineffective in the progressive disease stage and in particular in patients with PPMS (Coles et al
; Molyneux et al
). One possible explanation is that in the progressive stage of multiple sclerosis, inflammation becomes trapped within the brain compartment behind a closed or repaired blood–brain barrier. In fact, dissociation between inflammation and blood–brain barrier disturbance in multiple sclerosis patients has been described by using a specific marker, which selectively stained leaky endothelial cells in brain vessels (Hochmeister et al
). Most importantly many vessels with profound perivascular inflammation in the absence of leaky endothelial cells were seen in patients with progressive multiple sclerosis. Furthermore, in the progressive stage of multiple sclerosis, lymph follicle-like structures are formed in the meninges and in the large perivascular spaces. Those lymph-follicle-like structures are associated with rapid disease progression and profound brain damage (Magliozzi et al
). It has been suggested that chronic inflammation within the brains of multiple sclerosis patients creates a microenvironment, which favours homing and retention of inflammatory cells within this compartment (Krumbholz et al
; Meinl et al
Another interesting aspect of inflammation in multiple sclerosis is the difference in the pattern of T-cell, B-cell and plasma cell infiltration. T cells, and to a lesser degree B cells are markers for the activity of the disease process and tissue damage. The more active lesions are, the more of these cells are seen within the tissue. However, there are compartmental differences in the distribution of these cells. T cells are seen in large perivascular cuffs especially in active lesions in the acute and relapsing disease stage but they also infiltrate the CNS parenchyma in high numbers. This is opposite for B cells and even more so for plasma cells. Those cells tend to accumulate predominantly in the connective tissue spaces of the brain, such as the perivascular spaces and the meninges. Furthermore, plasma cells accumulate later in the CNS in relation to disease stage and persist within the brain even at time points, when T-cell and B-cell inflammation is cleared. This may be explained by the existence of a population of long-lived plasma cells, which may accumulate in the CNS in chronic inflammatory conditions. It may also explain the persistence of oligoclonal bands in the CSF in chronic brain inflammation, which may be seen for a prolonged time after recovery (Meinl et al
Regarding neurodegeneration, our study focused on markers for the disturbances of fast axonal transport and the formation of axonal swellings and end-bulbs. Disturbance of fast axonal transport is currently the most accurate and sensitive marker for acute axonal injury, occurring at a short-time window before axonal death, whereas axonal swellings and end-bulbs may persist at sites of damage for an extended period (Li et al
). Thus, the disturbance of fast axonal transport seems to be a suitable marker to identify the acute or progressive damage, which takes place at the time of axonal death. The detection of dying neuronal cell bodies is much more difficult. Neuronal loss has previously been shown to occur in active cortical and deep grey matter lesions (Peterson et al
; Cifelli et al
; Wegner et al
). In some cases with active cortical lesions, associated with profound meningeal inflammation, neuronal apoptosis has been observed (Peterson et al
; Magliozzi et al
). However, in more slowly developing lesions, acute nerve cell destruction is rare or absent, similar to what has been described in the cortex of Alzheimer's disease patients (Stadelmann et al
). Thus, neuronal loss in grey matter may contribute to neurodegeneration in multiple sclerosis.
Understanding the relation between inflammation and neurodegeneration is of key importance for future therapeutic strategies in multiple sclerosis. If inflammation drives subsequent neurodegeneration, proper anti-inflammatory therapies are the best choice to stop the disease and to prevent further clinical deterioration of the patients. If there is a neurodegenerative component, which leads to brain damage independent from inflammation, the effect of anti-inflammatory therapies will be limited and neuroprotective strategies will become the prime target. Clinical experience and magnetic resonance imaging studies suggest that neurodegeneration may become independent from inflammation in the progressive disease (Trapp and Nave, 2008
). We show for the first time in a pathological study that axonal injury is invariably associated with inflammation, especially in progressive multiple sclerosis. Further, in late stages of the disease, inflammation declines in a considerable proportion of the patients to an extent, which is similar to that seen in age-matched controls. This indicates that the inflammatory reaction may die out at late stages of the disease. If there is a neurodegenerative component, which progresses independently from inflammation, one would predict that in such patients axonal injury continues. This was not the case in our study. In contrast, axonal injury in such patients was similar in extent, compared with age-matched controls.
This, however, does not mean that there is no further brain damage in multiple sclerosis patients, when the inflammatory process has stopped. In such patients acute axonal injury does not return to zero, but rather to the levels seen in age-matched controls. Furthermore, confounding pathology is frequently seen in aged multiple sclerosis patients. We have previously shown that Alzheimer's disease lesions develop in multiple sclerosis patients at similar rates compared with those present in a normal aging cohort (Dal-Bianco et al
). In our present study, we could also show that in patients with concomitant multiple sclerosis and Alzheimer's disease, acute axonal injury is more pronounced compared to that in non-Alzheimer's multiple sclerosis patients. The same holds true for patients with concomitant vascular lesions. Thus, in patients with profound multiple sclerosis related brain damage, which exceeds the functional reserve capacity of the nervous tissue, such age related or concomitant brain damage may give rise to further progression of functional deficits, even when the multiple sclerosis related disease process has stopped.