Blue image of the brain
#Atrophy #Early Damage #Imaging #Lesions
  • The study: A 5-year longitudinal study published in 2018 examined the correlation between White Matter (WM) lesions and Grey Matter (GM) volume loss in 176 patients with MS1
  • Initial findings: 13 of 14 regions of the brain studied seemed to show a correlation when a limited cross-sectional approach was used1
  • Upon further analysis: No evidence of correlation was found in any of the 14 brain regions studied, after researchers controlled for overall disease burden and lesion load1
  • At the end of 5 years: Evidence of correlation was found in just 1 of 14 brain regions studied, suggesting that WM pathology plays a limited role in GM atrophy1
  • Conclusion: WM pathology and GM pathology are largely independent phenomena in MS1

Multiple sclerosis (MS) is an immune-mediated disease that causes demyelination in the central nervous system (CNS), widespread neurodegeneration, and whole brain volume loss. Until recently, MS was characterized as a disease that primarily affects the myelin-rich White Matter (WM) of the CNS. However, accumulating evidence has made it clear that Grey Matter (GM) pathology plays a major role in driving disease progression.2

But what is the connection between WM and GM pathologies? Are they independent manifestations of disease activity? Or is there a causative relationship? Does WM damage drive GM pathology? A recent study explored these questions in depth and came to some interesting conclusions.

Graphic showing the proximity of cortical white matter and grey matter
Bonilha L, Gleichgerrcht E, Nesland T, Rorden C, Fridriksson J. Gray matter axonal connectivity maps. Front Psychiatry. 2015;6:35. doi: 10.3389/fpsyt.2015.00035 Licensed under CC BY 4.0

Correlation vs Causation

For years, the relationship between WM and GM disease activity was unclear. Some previous research suggested that WM pathology may play a causative role in triggering GM damage. In several studies, researchers reported that GM atrophy appeared to be a result of damage to WM tracts that extend to connecting GM.3,4 Evidence suggested that axonal damage in active WM lesions may result in anterograde and retrograde degeneration of axons connecting to the thalamus and basal ganglia.4

In one study, investigators reported a correlation between the extent of WM lesions and deterioration of the thalamus in patients with relapsing-remitting MS (RRMS) and clinically isolated syndrome (CIS).5,6 Furthermore, conventional cross-sectional MRI examination in patients with MS has shown an association between total GM volume and total WM volume in T1- and T2-weighted lesions.7-9

Although some studies suggested a correlation between WM and GM damage, they did not conclusively show a causative relationship.

Conclusions from these studies suggest that GM atrophy is secondary to WM damage. In patients with RRMS, there is GM volume loss in the frontal and parietal cortical regions, which correlates with the increase in T2-weighted WM lesion volume.10,11 In a study of GM atrophy, investigators found that patients with increasing WM lesion burden had greater GM volume loss compared with patients who did not see an increase in WM lesion burden.11

Although the studies described above argue that there is a correlation between the extent of WM lesions and GM atrophy, they did not conclusively show a causative relationship. In fact, new studies suggest that the 2 pathologies are largely independent.12-15

Evidence Indicating Grey Matter Pathology Is Independent

A postmortem study of cadavers with MS revealed that there was greater demyelination in GM tissue than in WM tissue in different regions of the CNS.12 In addition, most leukocortical lesions (a type of MS lesion that extends from GM into WM) occurred in GM independently from WM. Also, widespread cortical demyelination was sometimes observed in areas with little to no WM demyelination.13 Furthermore, other MRI studies have confirmed the existence of intracortical lesions at very early stages of the disease in patients with CIS.14 Finally, using double inversion recovery (DIR) MRI sequence, results from a study in patients with normal-appearing WM at clinical onset revealed the presence of cortical lesions at least 6 months to a few years prior to when conventional MRI-sensitive lesions were visible in the WM.15

GM lesions have been found in the earliest stages of MS—even in patients with minimal WM damage.

Lending credence to an independent GM pathology is a recent identification of a subtype of MS, known as myelocortical MS (MCMS). MCMS is characterized by neuronal degeneration without demyelination in the WM. When researchers at the Cleveland Clinic compared brain tissue of postmortem cadavers with MS, they found GM (cortical) lesions but no trace of WM demyelinated lesions in 12 cadavers.16 This was compared with 12 other postmortem cadavers with typical MS in whom both cortical and WM lesions were detected. Furthermore, the percentage of cortical lesion area was not significantly different for both MCMS and typical MS cadavers. Although there was no WM demyelination, there was a greater reduction in GM neuronal density in cadavers with MCMS than in typical MS cadavers. Notably, cadavers were similar in other respects, including disease duration and degree of physical disability as measured by the Expanded Disability Status Scale.16

A Deeper Examination: The Results of a Recent 5-Year Longitudinal Study

To investigate the notion that GM volume loss could be caused by WM pathology, a longitudinal 5-year study (n=176) was initiated by Dr Tom Fuchs of the Department of Neurology, Buffalo Neuroimaging Analysis Center. Throughout the study, Fuchs et al sought to define the extent to which new lesions in connected WM tracts contributed to atrophy of specific GM regions.1 In contrast to the cross-sectional approach, the longitudinal approach characterizes the association between WM lesions and GM atrophy over time. This aims to elucidate any direct relationship between both MS pathologies.

"These findings point toward independent mechanisms…" —Fuchs et al1

As part of the study, researchers conducted an MRI analysis of specific regions of GM with connecting WM tract. Because WM and GM damages are not mutually exclusive and damages can occur simultaneously due to a common underlying disease factor, researchers controlled for disease progression by measuring total brain volume loss and lesion burden‒a critical aspect that previous studies have failed to account for. They then quantified disruptions to WM tracts caused by lesions, to parse out the extent to which accumulation of WM damage contributes to volume loss in connecting GM. They focused on specific GM regions and reasoned that if these regions are directly influenced by the associated WM pathology, there would be a parallel increase in WM lesions and GM atrophy beyond what could be explained by a general progression of MS pathology.

The investigators first duplicated and confirmed results from previous cross-sectional studies reporting a significant correlation between WM lesion and GM atrophy in 13 of 14 brain regions assessed. They then controlled for overall disease burden and multiple comparisons and found that this correlation was nullified in all GM regions. Later, in their longitudinal analysis, they found a significant correlation between WM tract disruption and regional GM atrophy in only 1 of 14 GM regions (the right putamen) after controlling for disease burden and multiple comparisons. This study indicates that WM lesions are not the primary driving force of GM atrophy.1

"WM tract disruption accounts for a small percentage of atrophy in connected subcortical gray matter when controlling for overall disease burden and is not the primary driver in most cases." —Fuchs et al1

Using this more robust methodology, researchers concluded that WM and GM pathologies are mostly independent, with WM damage having limited value in explaining GM atrophy. Fuchs et al also suggested that incorporating GM measures in future clinical research could be helpful.


Taken together, the studies outlined above carefully assesses WM and GM damages in MS and reveal that although there are common underlying mechanisms that lead to disease progression in both pathologies (ie, inflammation17), GM atrophy is not directly caused by or dependent upon WM demyelination.

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