Image of stained glass showing brain affected by multiple sclerosis

Grey Matter: Essential to Understanding MS

Why Grey Matters in Multiple Sclerosis

Damage to Grey Matter in MS–Prevalent and Important

Recent advancements in imaging technology have revealed that Grey Matter pathology in multiple sclerosis (MS) is more important and prevalent than previously realized.1-4

Accumulating evidence from numerous longitudinal and imaging studies has shown that Grey Matter damage2-4:

  • is widespread
  • starts early in disease progression
  • and is strongly correlated with disability

Strongly Correlated With Disability

Several cross-sectional studies have demonstrated that Grey Matter pathology is significantly correlated with both cognitive impairment and physical disability in MS patients.8

Among the negative outcomes associated with Grey Matter pathology are9:

  • Cognitive decline
  • Fatigue
  • Motor deficits
  • Ocular motility disturbances
  • Painful syndromes

View references on Grey Matter pathology.

 

Why Grey Matters in Multiple Sclerosis

The Impact of Grey Matter Atrophy

A Dominant Driver of Disability

Physical Disability
In a 4-year longitudinal study (n=87), Grey Matter atrophy was correlated with sustained worsening of physical disability in MS patients.6

In a 2018 study of patients with multiple sclerosis (N=71), Grey Matter volume (cortical and deep grey) had the strongest association with the extent of walking disability.10

Recent findings from a 10-year follow-up study (n=152) suggest that confirmed disability progression (CDP) and Grey Matter atrophy may be inextricably linked.11

In a 2-year longitudinal study with more than 1200 patients with multiple sclerosis, researchers found that Deep Grey Matter volume loss was a dominant driver of disability accumulation across all MS phenotypes.12

  • A post hoc analysis of atrophy in more than 40 different regions of the brain (n=1214) found that the thalamus was a better predictor of future disability than any other region12

Cognitive Disability
Data from several cross-sectional studies indicate that Grey Matter damage is significantly correlated with cognitive dysfunction, which can occur early in the course of disease.5,6,8,9,12-14

  • Even in patients with little or no physical disability, early cognitive deficits have been observed15

In a clinical trial with 67 patients with probable MS,

54%

of patients exhibited signs of cognitive decline16

Fatigue

  • Fatigue is a common and debilitating symptom of MS, affecting nearly 80% of patients—with more than half describing it as one of the worst symptoms of the disease17
  • Studies have shown that fatigue has a major impact on quality of life, adversely affecting a patient’s ability to work and socialize17

In a retrospective MRI study of 1214 patients with MS,

Patients With Lower Deep Grey Matter Volume at Baseline Had Increased Rates of Physical Disability Progression12

Chart showing that patients with lower DGM volume at baseline had increased rates of MS disease progression
Eshaghi A, Prados F, Brownlee W, et al; on behalf of the MAGNIMS study group. Annals of Neurology. John Wiley and Sons. © 2018 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.
CIS=clinically isolated syndrome; RRMS=relapsing-remitting multiple sclerosis; SPMS=secondary progressive multiple sclerosis; EDSS=Expanded Disability Status Scale; DGM=Deep Grey Matter.

 

The Importance of Spinal Cord Grey Matter

Grey Matter volume loss in the spinal cord was found to be predictive of disease progression18

  • In an observational study of disability progression (N=113), spinal cord Grey Matter area was more strongly correlated with disability than all other variables examined

Chart: Relative Contributions of Pathology to EDSS
Schlaeger R, Papinutto N, Panara V, et al. Annals of Neurology. John Wiley and Sons.
© 2014 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.

 

A Stronger Correlation Than White Matter?

Research indicates that Grey Matter pathology may be more strongly correlated with cognitive and physical impairment than White Matter pathology.12,13,19

Imaging studies that examined a number of key MRI parameters found that Grey Matter atrophy was the single strongest MRI correlate of both clinical disability and cognitive impairment in MS patients.13,19

Long Term

59%

reduced odds of more severe EDSS

A 20-year longitudinal study (n=73) found that Grey Matter atrophy was more strongly correlated with clinical disability over time compared with White Matter atrophy.19

In the same study, patients were 59% less likely to be in a more severe Expanded Disability Status Scale (EDSS) category for every 1 standard deviation increase in their Grey Matter volume.19

“. . .these data suggest that GM atrophy has more clinical relevance in the long term than either lesion load or WM atrophy . . . ”
—Fisniku et al19

Short Term
Grey Matter atrophy explained physical disability better than White Matter atrophy or even whole brain volume loss.12

  • Deep Grey Matter volume loss was especially predictive in determining time-to-EDSS progression12

View references on Grey Matter atrophy.

Why Grey Matters in Multiple Sclerosis

The Impact of Grey Matter Lesions

Driving Both Physical and Cognitive Disability

In a 5-year, prospective, longitudinal study (n=312), MS patients with high cortical lesion load had the worst physical and cognitive prognosis compared with all other patient groups.13

  • 92% of patients with high cortical lesion load experienced significant cognitive impairment at study end compared to 23% of patients with low cortical lesion load
  • 86% of patients with high cortical lesion load experienced worsening of physical disability at study end compared to 42% of patients with low cortical lesion load

In a 3-year prospective study (n=107), cortical lesion volume was found to be a strong independent predictor of declining physical disability.14

86%

of patients with a high cortical Grey Matter lesion load experienced disability progression after 5 years13

A Stronger Correlation Than White Matter?

Research indicates that Grey Matter pathology may be more strongly correlated with cognitive and physical impairment than White Matter pathology.12,13,19

In a 5-year longitudinal study (n=312), cortical lesion load was a stronger predictor of physical and cognitive decline than White Matter lesion load.13

“. . .our data strengthen the concept that disability progression in multiple sclerosis is more related to GM than to WM pathology, in all disease phenotypes.”13

View references on Grey Matter lesions.

Is Grey Matter Pathology Independent?

The Relationship Between Grey and White Matter Pathologies

Grey Matter Disease Activity Appears to Be Distinct From White Matter Pathology

In multiple sclerosis (MS), the relationship between Grey Matter and White Matter pathologies in the central nervous system has not been clear.21 However, evidence suggests that the 2 pathologies can be separate and distinct.21-23

Using postmortem, in vivo MRI, and MR spectroscopy techniques, researchers have examined MS activity and observed that Grey Matter pathology and White Matter pathology appear to be largely independent processes.22,23

  • In a longitudinal, cross-sectional study (N=89) that examined the spatiotemporal topographic distribution of pathology in MS patients, researchers found no direct anatomical overlap between White Matter lesions and Grey Matter pathology23,24
  • In a comparison of postmortem MRI and histopathologic data in 6 MS patients, the process of Grey Matter demyelination was determined to be largely independent of White Matter demyelination, occurring in different regions and to different degrees22

MRI pictures: Cortical atrophy can be present in the absence of visible white or grey matter lesions
Reprinted by permission from Springer Nature. Nature Reviews Neuroscience. Exploring the origins of grey matter damage in multiple sclerosis. Massimiliano Calabrese, Roberta Magliozzi, Olga Ciccarelli, Jeroen J. G. Geurts, Richard Reynolds et al. © 2015.

Cortical atrophy can be present in the absence of visible White Matter or Grey Matter lesions.23

In a 5-year prospective study (n=312), MS patients who experienced disease progression had significant increases in the volume and number of cortical lesions, but no significant increase in the volume or number of White Matter lesions.13

View references on Grey Matter independent pathology.

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