Thursday, 24 December 2015

White first then grey or confusion then clarity

Bodini B, Chard D, Altmann DR, Tozer D, Miller DH, Thompson AJ, Wheeler-Kingshott C, Ciccarelli O. White and gray matter damage in primary progressive MS: The chicken or the egg? Neurology. 2015. pii: 10.1212/WNL.0000000000002237. [Epub ahead of print]

OBJECTIVE:The temporal relationship between white matter (WM) and gray matter (GM) damage in vivo in early primary progressive multiple sclerosis (PPMS) was investigated testing 2 hypotheses: (1) WM tract abnormalities predict subsequent changes in the connected cortex ("primary WM damage model"); and (2) cortical abnormalities predict later changes in connected WM tracts ("primary GM damage model").
METHODS:Forty-seven patients with early PPMS and 18 healthy controls had conventional and magnetization transfer imaging at baseline; a subgroup of 35 patients repeated the protocol after 2 years. Masks of the corticospinal tracts, genu of the corpus callosum and optic radiations, and of connected cortical regions, were used for extracting the mean magnetization transfer ratio (MTR). Multiple regressions within each of 5 tract-cortex pairs were performed, adjusting for the dependent variable's baseline MTR; tract lesion load and MTR, spinal cord area, age, and sex were examined for potential confounding.
RESULTS:The baseline MTR of most regions was lower in patients than in healthy controls. The tract-cortex pair relationships in the primary WM damage model were significant for the bilateral motor pair and right visual pair, while those in the primary GM damage model were only significant for the right motor pair. Lower lesion MTR at baseline was associated with lower MTR in the same tract normal-appearing WM at 2 years in 3 tracts.
CONCLUSION: These results are consistent with the hypothesis that in early PPMS, cortical damage is for the most part a sequela of normal-appearing WM pathology, which, in turn, is predicted by abnormalities within WM lesions
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So this study asks in PPMS what happens first, white matter damage? or grey matter damage?. They think that the white matter damage results in subsequent grey matter damage, but if I chop a nerve in two you would them expect the nerve cell body to reflect this a bit later. The sad thing is that these PPMSers are just been watched and not treated.

However what do other people thing so another group get on their magnet and  what do they find the chicken, egg or the turkey?

Steenwijk MD, Geurts JJ, Daams M, Tijms BM, Wink AM, Balk LJ, Tewarie PK, Uitdehaag BM, Barkhof F, Vrenken H, Pouwels PJ.Cortical atrophy patterns in multiple sclerosis are non-random and clinically relevant Brain. 2015. pii: awv337. [Epub ahead of print]
Grey matter atrophy is common in multiple sclerosis. However, in contrast with other neurodegenerative diseases, it is unclear whether grey matter atrophy in multiple sclerosis is a diffuse 'global' process or develops, instead, according to distinct anatomical patterns. Using source-based morphometry we searched for anatomical patterns of co-varying cortical thickness and assessed their relationships with white matter pathology, physical disability and cognitive functioning. Magnetic resonance imaging was performed at 3 T in 208 patients with long-standing multiple sclerosis(141 females; age = 53.7 ± 9.6 years; disease duration = 20.2 ± 7.1 years) and 60 age- and sex-matched healthy controls. Spatial independent component analysis was performed on cortical thickness maps derived from 3D T1-weighted images across all subjects to identify co-varying patterns. The loadings, which reflect the presence of each cortical thickness pattern in a subject, were compared between patients with multiple sclerosis and healthy controls with generalized linear models. Stepwise linear regression analyses were used to assess whether white matter pathology was associated with these loadings and to identify the cortical thickness patterns that predict measures of physical and cognitive dysfunction. Ten cortical thickness patterns were identified, of which six had significantly lower loadings in patients with multiple sclerosis than in controls: the largest loading differences corresponded to the pattern predominantly involving the bilateral temporal pole and entorhinal cortex, and the pattern involving the bilateral posterior cingulate cortex. In patients with multiple sclerosis, overall white matter lesion load was negatively associated with the loadings of these two patterns. The final model for physical dysfunction as measured with Expanded Disability Status Scale score (adjusted R2 = 0.297; P < 0.001) included the predictors age, overall white matter lesion load, the loadings of two cortical thickness patterns (bilateral sensorimotor cortex and bilateral insula), and global cortical thickness. The final model predicting average cognition (adjusted R2 = 0.469; P < 0.001) consisted of age, the loadings of two cortical thickness patterns (bilateral posterior cingulate cortex and bilateral temporal pole), overall white matter lesion load and normal-appearing white matter integrity. Although white matter pathology measures were part of the final clinical regression models, they explained limited incremental variance (to a maximum of 4%). Several cortical atrophy patterns relevant for multiple sclerosis were found. This suggests that cortical atrophy in multiple sclerosis occurs largely in a non-random manner and develops (at least partly) according to distinct anatomical patterns. In addition, these cortical atrophy patterns showed stronger associations with clinical (especially cognitive) dysfunction than global cortical atrophy.

So in this study they say white matter is not really the story and they find grey matter damage in certain regions 

However maybe you can go abit further and rather than rely on MRI outcomes were we are not 100% certain what they mean and actually do some histology and actually trace the paths of the nerves. Abit of histology will tell you exactly where the grey matter lesions are. 


Jürgens T, Jafari M, Kreutzfeldt M, Bahn E, Brück W, Kerschensteiner M, Merkler D. Reconstruction of single cortical projection neurons reveals primary spine loss in multiple sclerosis.
Brain. 2015. pii: awv353. [Epub ahead of print]

Grey matter pathology has emerged as an important contributor to long-term disability in multiple sclerosis. To better understand where and how neuronal damage in the grey matter is initiated, we used high resolution confocal microscopy of Golgi-Cox impregnated tissue sections and reconstructed single cortical projection neurons in autopsies from eight patients with long-standing relapsing-remitting or secondary progressive multiple sclerosis and eight control patients without neurological disease. Analysis of several hundred individual neurons located in the insular, frontotemporal and occipital lobe revealed a widespread and pronounced loss of dendritic spines in multiple sclerosis cortex that occurs independent of cortical demyelination and axon loss. The presence of a primary synaptic pathology in the normal-appearing cortex of multiple sclerosis patients challenges current disease concepts and has important implications for our understanding of disease progression.


So here they find that it is the synaptic processess in the  the cortex that go before demyelination or axonal damage, is this the white matter problem thats causing this? or is this the primary pathology

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