By Susan Gauthier, DO, MSW

Associate Professor of Clinical Neurology, Weill Cornell Medical College

Dr. Gauthier reports she receives grant/research support from Genzyme, Mallinckrodt, and Novartis.

SYNOPSIS: In this MRI and histopathological study, the investigators showed that cortical T1w/T2w ratio was unrelated to myelin density, but had a strong correlation with dendritic density. Furthermore, abnormal values within the posterior cingulate cortex correlated with impairment in cognitive domains.

SOURCE: Righart R, et al. Cortical pathology in multiple sclerosis detected by the T1/T2-weighted ratio from routine magnetic resonance imaging. Ann Neurol 2017; Aug. 18. doi: 10.1002/ana.25020 [Epub ahead of print].

Multiple sclerosis (MS) is a complicated disease with both inflammatory (relapsing) and degenerative (progressive) stages. Traditionally, studies have focused on pathological changes within the white matter (WM) as the trigger for secondary neuronal loss and sustained clinical progression in MS. However, recent evidence has suggested that primary gray matter (GM) pathology contributes significantly to the progressive process. Cortical demyelination has been appreciated only recently through histopathological studies and in vivo exploration with high-field MRI. MRI studies using magnetization transfer imaging (MTR) and double inversion recovery have revealed that routine clinical MRI sequences are grossly underestimating the lesion load within MS patients. The ability to study cortical pathology with routine clinical MRI could allow for the exploration of cortical pathology among much larger populations and provide a pathway to determine the influence of cortical lesions on the natural course of the disease.

Righart et al used a conventional 3T MRI to obtain three-dimensional (3D) gradient-echo T1weighted (w) and high-resolution T2w sequences to create a cortical map of the T1w/T2w signal. Previous work has suggested that cortical T1w/T2w ratio is reflective of myelin; however, this conclusion was drawn through indirect evidence, and no direct histological comparison has ever been reported. In this study, cortical T1w/T2w ratios from 168 MS patients (either clinically isolated syndrome or relapsing-remitting) were compared to 80 age-matched healthy controls (HC). The T1w/T2w ratio values were sampled at the mid-thickness surface, which is midway between the WM and GM surfaces, using FreeSurfer software, which provides cortical GM surface thickness maps. The investigators compared T1w/T2w ratios within the whole cortex and derived regional differences through voxel-wise general linear models. In addition, researchers collected clinical parameters such as EDSS, MSFC, as well as cognitive testing focused on the core cognitive deficits generally found in MS. Lastly, the study included a postmortem analysis of nine progressive MS patients to provide histopathological validation for cortical T1w/T2w ratio.

The investigators found that the T1w/T2w ratio across the whole cortex was lower in MS compared to HC. Four regional clusters were identified: left and right medial occipital cortex as well as the right and left posterior cingulate cortex. Given the integral role of the posterior cingulate in memory and attention, the T1w/T2w ratio in this region was associated with clinical metrics to provide a functional relevance to the MRI metric. Wordlist retrieval correlated with T1w/T2w ratio within this region after appropriately controlling for multiple comparisons, age, cortical thickness, and WM lesions. In the postmortem analysis, the strongest correlation of cortical T1w/T2w ratio was determined to be with dendrite density (P = 0.0008), and no trends were found with myelin density, axonal density, or cortical thickness. The average T1w/T2w ratio within the posterior cingulate cortex was plotted across all populations studied (HC, in vivo imaging, and postmortem) and suggested a declining slope associated with advancing disease stage.

COMMENTARY

Cortical T1w/T2w ratio has a strong advantage over high-field imaging, given that these sequences are commonly acquired as routine standard of care. Many investigators in the field have categorized cortical T1w/T2w ratio as a measurement of myelin based on the knowledge that the T1w signal is predominantly dependent on myelin and reported patterns tended to follow classic studies of cortical myelination. Given the ease of obtaining these data and the interpretation that the data reflect myelin, a number of studies are now starting to emerge using this MRI metric.

Righart et al emphasized the importance of proper histopathological validation and demonstrated the failure of using indirect means to interpret the tissue-specificity of MR signal intensity. Interestingly, they highlighted the role of dendritic density in MS, which has been under-recognized as a contributing factor in disease progression. As the authors noted, significant dendritic damage has been reported to be independent of cortical demyelination and, combined with the current observation, raises the question of the role of dendritic damage in MS disease pathogenesis and, importantly, the potential role in cognitive dysfunction. Although cortical T1w/T2w ratio can be derived from routine imaging, significant methodological development is still needed (because of challenges with cortical segmentation), and more data are required to elucidate the influence of change in cortical T1w/T2w on the disease course of MS.