Cuprizone has grey matter problems…do pathologists?

Although multiple sclerosis (MS) has been considered a white matter disease, MS lesions occur frequently in the gray matter parts of the brain. Gray matter demyelination and atrophy are found during earliest disease stages, and a growing body of evidence demonstrates a positive correlation between gray matter pathology and various measures of motor disability and cognitive impairment. The cuprizone model is classically regarded as white matter demyelination model. However, recent evidence suggests that different gray matter areas are also affected. In this study, we address the vulnerability of white and gray matter forebrain regions in the cuprizone model. While the corpus callosum as interhemispheric white matter tract is affected in this model, other white matter tracts such as the mammillo-thalamic tract, the columns of the fornix, the stria terminalis, the optic tract, or hippocampal fimbria do not present overt demyelination after 5-week cuprizone intoxication. In contrast, gray matter demyelination is widespread in this model. Furthermore, vulnerable white matter tracts display extensive acute axonal damage. These results highlight the relevance of the cuprizone model to study MS-related gray matter pathology and neurodegeneration.

Ooops I didn’t mean to post this and definitely not with a without comment on Saturday…..
…but hey-ho. 

So to make this interesting…. for many years the neuros or more importantly the pathologists told us basic scientists that MS was a disease of the white matter, which causes demyelination of the axons. So animal modellers spent their time investigating white matter damage. 

Problem was either: those lazy pathologists didn’t do the post-mortems and got technicians to do it who happily chopped out brains and then went home in the evening to not think about work and happy to do their job the next day OR those lazy pathologists were blind, because you could easily see grey matter lesions with the naked eye OR they forgot the old literature which they had done with nerve loss………..yes….shocking. 

So next those Pathologists then said to the technicians “there is no myelin in grey matter” so when you do your chemical stain (Luxol fast blue) that stains myelin blue then “differentiate” (remove the stain) the tissues section until the grey matter is white coloured and hey presto……no Grey matter lesions.

Now anti-myelin antibodies come along so you don’t do a differentiation step and grey matter lesions became evident to the Pathologists and they change the world view on MS and so the animal modellers have to change their world view too.

So in a model where chemicals kill oligodendrocytes in mice you get white matter damage, but hey presto because you have myelin forming oligodendrocytes in grey matter, so if you look closely there are grey matter lesions also. This what this paper says 

However, the animal modellers have told us that there are no clinical signs in the cuprizone model…however I bet if you look closely you will find them as I know some groups have, maybe they can do cognition studies.

So the failure to translate treatments from animals to humans……. maybe we should blame it on the pathologists:-), as they can’t make their mind up what’s really going on in MS…….

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