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#Atrophy #Early Damage #Imaging #Lesions

Before the 21st century, White Matter (WM) pathology was considered the critical focus of multiple sclerosis (MS) because lesions are more easily seen in the WM of the brain.1 As imaging technology advanced, it has been revealed that Grey Matter (GM) pathology is more important and prevalent than previously realized.2-5 We now know that GM damage is widespread, starts early in disease progression, and is strongly correlated with disability.2-4 In fact, research indicates GM pathology may be more strongly correlated with cognitive and physical impairment than WM pathology.6-8

The Evolution of Our Understanding

Explore the timeline below that highlights just a few of the pivotal discoveries made throughout history that shaped the way we see Grey Matter today:

Icon of the first recognition of GM on the grey matter timeline

1898-1916

The Grey Area

In a disease dominated by White Matter, the existence of Grey Matter demyelination was first recognized by M Sander, M Dinkler, F Schob, and JW Dawson. Unfortunately, the reporting of demyelination was deemed inaccurate, which overshadowed its discovery.4

1962

A Resurgence in Grey

A postmortem histopathology study by Betty Brownell and Trevor Hughes found that 26% of MS lesions were located in or around the cortical and subcortical Grey Matter. It was later revealed that this statistic was a significant understatement.4,9

Icon of brain study on the grey matter timeline
Icon of first commercial magnetic resonance imaging on the grey matter timeline

1980s

Introducing the First Commercial Magnetic Resonance Imaging (MRI)

Icon of first commercial magnetic resonance imaging on the grey matter timeline

T2-weighted imaging
T2 imaging uses a chemical substance called contrast agent gadolinium that is injected into the vein causing longitudinal relaxation. This process allows HCPs to visualize lesions that appear within Grey Matter structures, notably the cortex. Though visualization of Grey Matter is possible, the relaxation times of Grey Matter lesions are longer than White Matter lesions, resulting in poor contrast resolution.10,11

T2-weighted image of a brain
T2-weighted axial view12
Reproduced from Trip SA, Miller DH. Imaging in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2005;76(suppl III):iii11-iii18, with permission from BMJ Publishing Group Ltd.

Fast fluid-attenuated inversion recovery (FLAIR)
FLAIR is a T2-weighted sequence in which the signal from the cerebrospinal fluid (CSF) is suppressed, leading to high lesion contrast.13 This process makes the lesions in the cortex and juxtacortical areas more visible. Though visualizing Grey Matter using FLAIR is preferable to conventional T2-weighted imaging, both methods are inferior to the results found in postmortem studies.4

FLAIR image of a brain
FLAIR axial view12
Reproduced from Trip SA, Miller DH. Imaging in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2005;76(suppl III):iii11-iii18, with permission from BMJ Publishing Group Ltd.

1994

The Superior System—
Double Inversion Recovery (DIR)

Icon of Double Inversion Recovery on the grey matter timeline

DIR is an upgrade to FLAIR in which both CSF and White Matter signals are suppressed, resulting in improved contrast between lesions and increased detection of cortical Grey Matter pathology.4,14 With the help of DIR, Calabrese et al15 made a crucial finding that Grey Matter damage can occur in the earliest stages of disease.

DIR image of a brain
DIR axial view16
Reproduced with permission of Nelson F, Poonawalla AH, Hou P, Huang F, Wolinsky JS, Narayana PA, from Improved identification of intracortical lesions in multiple sclerosis with phase-sensitive inversion recovery in combination with fast double inversion recovery MR imaging, Nelson F, Poonawalla AH, Hou P, Huang F, Wolinsky JS, Narayana PA. AJNR Am J Neuroradiol. 2007;28(9):1645-1649; permission conveyed through Copyright Clearance Center, Inc.
Icon of Double Inversion Recovery on the grey matter timeline
Icon of DIR Enhancement on the grey matter timeline

2005

DIR Enhancement

Icon of DIR Enhancement on the grey matter timeline

About a decade after DIR made its impact, 3-D DIR followed, making it easier to detect intracortical lesions and enhanced the difference between juxtacortical and mixed White Matter/Grey Matter lesions.4

In a study that compared 3-D FLAIR with DIR images in 10 patients, DIR images depicted 80 intracortical lesions where as FLAIR depicted 31, resulting in a 152% relative increase of intracortical lesion detection in DIR over FLAIR.4,17

2007

The Merging of Methods

In an effort to examine Grey Matter damage even closer, a promising technique called phase-sensitive inversion recovery (PSIR) was introduced. PSIR has the ability to depict Grey Matter lesions more clearly than DIR because it generates better contrast than previous imaging methods.4,16

In 2007, Nelson and colleagues16 conducted a study comparing FLAIR images to a combination of PSIR and DIR images in 16 patients with MS. Through this method, they found a 417% increase in cortical lesion detection compared with FLAIR.16

Icon of phase-sensitive inversion recovery (PSIR) on the grey matter timeline
Icon of 7-Tesla MRI on the grey matter timeline

2017-Present

Innovation in Imaging

Approved in late 2017, the 7-Tesla (7T) is an ultra-high field MRI that harnesses high spatial resolution to magnify the visualization of Grey Matter lesions even further.18-20 This enhanced sensitivity makes it possible to determine the connection strength between cortical lesions and disease progression.20,21

In a 2019 study using 7T, Treaba and colleagues21 found that 81% (N=31) of patients developed new Grey Matter lesions per year, which proved to be greater than the development of White Matter lesions.

With more studies visualizing Grey Matter demyelination using 7T MRI, it has been suggested that these technological advances will serve as a powerful tool for understanding Grey Matter damage in the future.4

The Future of Grey

From unknown, to common and widespread, our understanding of Grey Matter pathology has evolved thanks to the progress made in imaging technology.1,4 As a dominant driver of disability, it’s important we continue taking these technological strides toward a future in cortical lesion detection.

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