Brain Atrophy Is Associated with Disability Progression in Patients with MS followed in a Clinical Routine

Discussion

This study provides additional insight into brain atrophy progression in a large cohort of patients with CIS and MS followed in a clinical routine as well as the relationship between the development of brain atrophy and DP. The study used retrospectively collected data for 10 years from >1800 individuals who were followed for an average of almost 5 years, and brain volume data were derived from >11,500 MR imaging examinations.

Assessing brain atrophy in the clinical routine may become an important outcome for assessing the effectiveness of disease-modifying treatment. Several reports have shown it to be one of the most reliable biomarkers of neurodegeneration that correlates with physical and cognitive impairment in patients with MS.^{2⇓–4,6,7,15⇓⇓–18} For more than a decade, randomized controlled trials have used brain atrophy measurement as a secondary or tertiary end point to determine the effectiveness of treatment.^8,9,18 However, assessing brain atrophy in a clinical routine can be challenging due to several technical factors related to image acquisition and measurement methods.^2,3,6,7 A recent multicenter, retrospective, real-world study (Multiple Sclerosis and Clinical Outcome and MR Imaging in the United States [MS-MRIUS]) investigated the feasibility of brain atrophy measurement in a clinical routine without MR imaging protocol standardization, using academic and nonacademic centers specialized in treatment and monitoring of MS.¹¹ The MS-MRIUS study showed that 72% of patients with MS had 2D T1WI and only 28% had 3D T1-weighted MR imaging sequences for longitudinal brain atrophy measurement. Scanner/protocol changes occurred in >50% of patients during the 16 months of follow-up.

Image contrast and image resolution are important for a reliable and optimal segmentation of brain volume, and 3D pulse sequences are preferred for measurement of brain atrophy as the criterion standard for brain volumetric imaging because of reduced partial voluming and more accurate coregistration, especially for serial imaging with time, compared with 2D imaging.^2,3,6 In the present study, the main reasons for analysis failures were changes in imaging protocol, poor scan quality, and excessive motion artifacts. Although the scanner and software did not change during a 10-year period of data collection in the present study, subjects were examined on 2 different scanners (1.5T and 3T, On-line Table 1), and minor protocol optimization changes were allowed. Thus, measurement of whole-brain volume changes was not feasible in a substantial number of subjects. These findings are supported by the recent results of the multicenter MS-MRIUS study,¹¹ which found that the feasibility of brain atrophy measurement was substantially lower without the uniformity of scanners, resulting in even larger numbers of failures.

As per the inclusion criteria, all subjects underwent 3D T1WI at every time point of the study; however, longitudinal (PBVC) and cross-sectional–derived (percentage NBV change) whole-brain volume analysis of at least 2 pairs of MR imaging examinations failed in 36.7% and 19.2% of subjects, respectively. The higher prevalence of examination failure with PBVC, compared with the percentage NBV change whole-brain volume analysis, is because SIENA PBVC is a longitudinal registration-based technique requiring concomitant evaluation of the 2 times points,¹³ whereas NBV is a cross-sectional measure performed on every scan separately; then, percentage changes are derived statistically between the 2 time points.¹³ Due to these inherent differences in the 2 methods, the decreased feasibility of PBVC-versus-NBV change measurement was also previously shown in a recent MS clinical trial,¹⁹ and our findings from clinical routine further confirm these findings. In the current study, scanner change was not defined a priori as a failed brain atrophy assessment. It is extremely difficult to ensure consistency of hardware and protocol use in the clinical routine over mid-to-long-term follow-up, even in the controlled setting of a specialized academic MS center. In addition, the results from the present study support previous multicenter findings¹¹ because we were able to obtain reliable LVV measurement in >96% of the study subjects longitudinally.

There is a strong need for developing and validating more simple brain volume measures that are resistant to MR imaging scanner and protocol changes and can be used in a clinical routine.¹¹ The assessment of LVV presents some advantages for calculation of brain atrophy on clinical routine practice scans compared with whole-brain volume measurements.^11,14,20,21 These advantages are mainly because tissue borders of the lateral ventricles have high contrast with respect to the surrounding CSF, and the position of the ventricles centrally to the FOV makes them less likely to be affected by gradient distortions, coregistration, error of tissue segmentation, incomplete head coverage, and wraparound artifacts.^{3,11,14,20,22} Therefore, LVV measurement has the potential to become a meaningful and reliable measure of brain atrophy assessment when scanning protocols cannot be standardized. Several algorithms were introduced for the assessment of LVV. Most of the approaches tend to rely on research quality scans, which are sometimes not obtained in the clinical practice.¹⁴ Contrary to those, NeuroSTREAM has the ability to operate with low-resolution scans, as confirmed in the present and previous studies.^11,14,20

We showed that patients with CIS and MS had higher annualized (first MR imaging to most recent follow-up MR imaging) and cumulative (using all available MR imaging examinations between different time points) brain volume changes compared with HI, using PBVC and percentage LVV change approaches. However, in a subsample of subjects who had PBVC, the percentage NBV change did not differentiate MS from HI; thus, cross-sectional-derived whole-brain volume measures are far from ideal.^2,3,6,7 Patients with CIS showed the highest annualized cumulative percentage LVV change among all the 3 study groups (4.1% for CIS, 2.9% for MS, and 1.9% for HI). One study reported an annualized percentage LVV change of 3.4%,²³ while another study showed an annualized percentage LVV change of 5.5% in patients with RRMS.²⁴ A greater LVV change in patients with CIS who developed clinically definite MS (CDMS), compared with those who remained stable, was found within 1 year of follow-up.^16,25 Recently, it was shown that annualized percentage LVV changes between 3.1% and 3.51% on T2-FLAIR²⁰ correspond to a pathologic whole-brain atrophy rate of 0.4%²⁶ in patients with RRMS and that this LVV pathologic cutoff performs comparably with PBVC for predicting clinical outcomes.²⁰

The annualized LVV rates in patients with MS and CIS, as well as in HI observed in this study, are in line with the suggested LVV pathologic cutoff.²⁰ On the contrary, the annualized rate of whole-brain volume change (found with both longitudinal and cross-sectional–derived approaches) in this study was somewhat above the proposed pathologic cutoff of 0.4%.²⁶ This result can potentially be because most patients in the current study underwent first-generation disease-modifying treatments, which have a weak-to-modest impact on preventing brain atrophy^8,9,27 or they were not treated at all. Moreover, the mean baseline age of patients with MS and HI was around 46 years, which could also have contributed to somewhat accelerated whole-brain atrophy due to an aging effect.^2,3,6,7

We also evaluated brain atrophy in different MS disease subtypes and did not find significant differences in rates among MS disease subtypes during the follow-up. Our results are in line with evidence indicating that brain atrophy rates are independent of MS phenotype.^28,29

Using linear mixed-effects analysis, we showed that all brain volume measures were associated with disease duration, EDSS, MSSS, and DP in patients with MS and CIS. In a subgroup of patients with MS who had PBVC available between the first MR imaging and most recent follow-up, we found that patients with MS with DP had a 33.1% higher LVV yearly increment and 21.9% higher PBVC and NBV change yearly decrease compared with those without DP. Similar findings were found in patients with CIS who converted to CDMS, though the results did not reach significance.

Potential limitations of this study are that it did not consider potential biologic confounders that may have an impact on atrophy assessments, including diurnal fluctuations of brain volume, hydration state, and menstrual cycle^2,3,6,7 or the pseudoatrophy effect of disease-modifying treatments. However, due to the natural composition and size of the sample, we hypothesize that these confounding factors are largely driven when assessing group effects. Incorporating such confounds, though, will almost certainly be required when assessing individual patients, which would be the next step using the proposed MR imaging outcomes. A key strength of this study lies in the large number of subjects examined, with >11,500 MR imaging examinations and the follow-up of almost 5 years.