Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system affecting both the brain and spinal cord. It is characterized by inflammation, demyelination, oligodendrocyte loss, axonal and neuronal degeneration, gliosis, and in some instances partial remyelination at the early stages [[1], [2], [3]]. Demyelinating plaques (MS lesions) are typical and result in episodes of neurologic deficit with recovery often followed by relapses and accumulation of sustained disability with the passage of time. MS lesions are characterized by myelin loss and later axonal loss [1,4,5]. MS diagnosis is based on history, neurological examinations and magnetic resonance imaging (MRI) findings, incorporating the dissemination in space and time of MS lesions [6,7]. Due to continued scientific advances, the MS diagnostic McDonald criteria have undergone multiple revisions every few years [[7], [8], [9]]. Additionally, more sensitive imaging methods to distinguish the types of MS lesions are being explored to improve the diagnostic process [10].

The extent of lesions on conventional T2-weighted (T2W) or fluid attenuated inversion recovery (FLAIR) images is currently regarded as the corresponding MRI measure of the disease burden. A strong correlation has been found between the location and extent of hyperintense abnormalities seen on T2W and FLAIR images and the presence of pathological abnormalities of MS [11]. In cross-sectional studies, however, highly variable correlations of lesion load on MRI with clinically established disability of MS patients have been reported [12]. Moreover, the T2 lesion load has been found to be significantly correlated with disability [13]. Although the correlations between changes in T2W imaging and the expanded disability status scale (EDSS) are statistically significant, clinical changes are only partially explained by MRI changes.

Routinely, MR examinations in MS patients not only involve T2W and FLAIR images but also T1-weighted (T1W) images, usually before and after administration of a gadolinium-based contrast agent, to evaluate blood brain barrier disruption. These T1W images often show areas of low signal intensity. These hypointense lesions (including the extreme hypointense regions, i.e., T1 “black holes”) as seen on T1W images represent areas of axonal loss and gliosis [[14], [15], [16]]. On the basis of low magnetization transfer ratios found in hypointense lesions on T1W images, it is speculated that these hypointense lesions represent areas of substantial tissue loss and demyelination [17]. However, this is not particularly quantitative since the loss of signal in the T1W images is highly variable due to the different levels of water content in the lesions.

The problem of identifying lesions in the periventricular region, which is a common site for MS lesions, can be addressed by suppressing the signal from cerebrospinal fluid (CSF) while maintaining heavy T2 weighting as in FLAIR imaging. FLAIR takes advantage of the T1 relaxation rate differences between the tissues and fluid (CSF) by using an inversion pulse that is timed precisely to null the CSF, making it easier to distinguish lesions from CSF. However, the atrophied regions within the lesions will gradually be replaced by fluid [18] and, hence, the response on the FLAIR images is highly dependent on the water content of the lesions potentially causing some lesions to disappear on FLAIR but not on T2W imaging.

In this retrospective work, our goal was to utilize the proton spin density (PD) or water content images, derived from a rapid, multi-parametric acquisition scheme known as strategically acquired gradient echo (STAGE) [19,20] and compare them with white matter (WM) hyperintensities on FLAIR data and with the hypointensities on T1-weighted data. The regions with high PD signal (representing increased fluid content and suggesting tissue rarefaction, or reduced tissue density, and atrophy) were identified; and their volumes determined and correlated with clinical scores across all subjects. Likewise, the volume of all FLAIR lesions (modified by including the high PD regions, which are otherwise suppressed on FLAIR images) and high PD regions were correlated with disease severity scores. The location of the high PD regions was identified, especially to confirm whether they are situated adjacent to the lateral ventricles, suggesting a future ventricular enlargement [21].