The neurologist's dilemma: MS is a grey matter disease that standard clinical and MRI measures cannot assess adequately--yes.

MULTIPLE SCLEROSIS MSJ JOURNAL The title statement contains two separate claims: 1. 'MS is a grey matter disease', and 2. '[the grey matter part of] MS cannot be adequately assessed by standard clinical and MRI measures'. The first claim might be understood in more than one sense. For example, 'MS is a grey matter disease' might simply mean 'MS pathology is found in areas that are anatomically referred to as " grey matter " , such as the cortex or the basal ganglia'. Alternatively, it may indicate 'MS (partly, largely or wholly) affects grey matter elements, such as neurons, axons, dendrites, syn-apses, spines, etc.' And finally, the statement may imply 'MS is a disease that starts in the grey matter' (i.e. either in grey matter areas or in grey matter structures, as defined above). The first and second interpretations of the first claim have been supported by solid empirical evidence. Demyelination is found in many (if not all) neocortical areas, as well as in palaeo-and archicortical structures such as the insula and hippocampus, in the basal ganglia, hypo-thalamus, cerebellar cortex and in the spinal cord grey matter. 1,2 Furthermore, in the grey matter of MS patients, neuronal and synapse densities were found to be reduced, and axons and neurites are transected. 3 Whether MS begins in the grey matter is far more difficult to prove. Both white and grey matter demyelination are present from the earliest phases of the disease, 2,4 and definitive conclusions cannot be drawn at present as to whether MS primarily targets neu-ronal or glial elements within the brain. Of course, it is intriguing that the classical hypothesis, which states that MS is caused by an auto-immune, inflammatory demyeli-nating process (with axonal damage as a secondary effect), leaves us with some important explanatory gaps. For example , it does not explain why even the most potent anti-inflammatory drugs, while near-totally abrogating inflammation, are largely incapable of halting disease progression. Moreover, fairly recent in vitro and animal work, as well as human post mortem studies investigating early/ acute demyelinating pathologies have come up with interesting examples of oligodendrocyte and myelin degenera-tion without a concomitant local adaptive immune response, 5 as well as axonal pathology without demyelina-tion. 6 Whether these preliminary findings will prove to be serious, or even fatal, impediments to the classical immu-nopathogenic model of MS is a question that is currently being carefully contemplated by an …