Longitudinal Network Changes and Conversion to Cognitive Impairment in Multiple Sclerosis

Abstract

Objective: To characterize functional network changes related to conversion to cognitive impairment in a large sample of patients with multiple sclerosis (MS) over a period of 5 years.

Methods: Two hundred twenty-seven patients with MS and 59 healthy controls of the Amsterdam MS cohort underwent neuropsychological testing and resting-state fMRI at 2 time points (time interval 4.9 ± 0.9 years). At both baseline and follow-up, patients were categorized as cognitively preserved (CP; n = 123), mildly impaired (MCI; z < -1.5 on ≥2 cognitive tests, n = 32), or impaired (CI; z < -2 on ≥2 tests, n = 72), and longitudinal conversion between groups was determined. Network function was quantified with eigenvector centrality, a measure of regional network importance, which was computed for individual resting-state networks at both time points.

Results: Over time, 18.9% of patients converted to a worse phenotype; 22 of 123 patients who were CP (17.9%) converted from CP to MCI, 10 of 123 from CP to CI (8.1%), and 12 of 32 patients with MCI converted to CI (37.5%). At baseline, default-mode network (DMN) centrality was higher in CI individuals compared to controls (p = 0.05). Longitudinally, ventral attention network (VAN) importance increased in CP, driven by stable CP and CP-to-MCI converters (p < 0.05).

Conclusions: Of all patients, 19% worsened in their cognitive status over 5 years. Conversion from intact cognition to impairment is related to an initial disturbed functioning of the VAN, then shifting toward DMN dysfunction in CI. Because the VAN normally relays information to the DMN, these results could indicate that in MS normal processes crucial for maintaining overall network stability are progressively disrupted as patients clinically progress.

Figure 1. Longitudinal Change in VAN Importance Is Related to Cognitive Conversion in MS

(A) Delta ventral attention network (VAN) z scores (means and 95% confidence intervals) for each of the cognitive converter groups showing a significant increase in VAN importance over time in the cognitively preserved (CP)→CP and CP→mildly cognitively impaired (MCI) groups (false discovery rate corrected). (B) Sample size and reliable change index (RCI) for the average cognition score per converter group. (C) Lateral and top view of the VAN, projected onto a standard brain. CI = cognitively impaired; MS = multiple sclerosis.

Figure 2. Positive Relationship Between Baseline Average Cognition and Longitudinal VAN Change in MS

Residual scatterplot of average cognition at baseline (z scores) and change from baseline to follow-up in ventral attention network (VAN) centrality (delta, also z scores). Positive relationship indicates that individuals with higher average cognition at baseline generally showed a stronger increase in VAN importance over time. Partial correlation coefficient (r = 0.18, p = 0.006) was corrected for age, sex, education, and time interval between visits. MS = multiple sclerosis.