Cognitive clinico-radiological paradox in early stages of multiple sclerosis

Abstract

Objective: To investigate whether the strength of the association between magnetic resonance imaging (MRI) metrics and cognitive outcomes differs between various multiple sclerosis subpopulations.

Methods: A total of 1052 patients were included in this large cross-sectional study. Brain MRI (T1 and T2 lesion volume and brain parenchymal fraction) and neuropsychological assessment (Brief International Cognitive Assessment for Multiple Sclerosis and Paced Auditory Serial Addition Test) were performed.

Results: Weak correlations between cognitive domains and MRI measures were observed in younger patients (age≤30 years; absolute Spearman's rho = 0.05-0.21), with short disease duration (<2 years; rho = 0.01-0.21), low Expanded Disability Status Scale [EDSS] (≤1.5; rho = 0.08-0.18), low T2 lesion volume (lowest quartile; <0.59 mL; rho = 0.01-0.20), and high brain parenchymal fraction (highest quartile; >86.66; rho = 0.01-0.16). Stronger correlations between cognitive domains and MRI measures were observed in older patients (age>50 years; rho = 0.24-0.50), with longer disease duration (>15 years; rho = 0.26-0.53), higher EDSS (≥5.0; rho = 0.23-0.39), greater T2 lesion volume (highest quartile; >5.33 mL; rho = 0.16-0.32), and lower brain parenchymal fraction (lowest quartile; <83.71; rho = 0.13-0.46). The majority of these observed results were confirmed by significant interactions (P ≤ 0.01) using continuous variables.

Interpretation: The association between structural brain damage and functional cognitive impairment is substantially weaker in multiple sclerosis patients with a low disease burden. Therefore, disease stage should be taken into consideration when interpreting associations between structural and cognitive measures in clinical trials, research studies, and clinical practice.

Figure 1

The strength of associations between brain MRI (brain parenchymal fraction, T1 and T2 lesion volume) and cognitive measures (Symbol Digit Modalities Test, three‐second interval Paced Auditory Serial Addition Test, Brief Visuospatial Memory Test Revised, California Verbal Learning Test Second Edition) in multiple sclerosis subpopulations. Subgroups of patients stratified by (A) age, (B) disease duration, (C) Expanded Disability Status Scale, (D) T2 lesion volume, or (E) brain parenchymal fraction were used for graphical purposes (the primary analysis of interaction models was performed using continuous variables).

Figure 2

(A‐B) The threshold concept of brain pathology for the manifestation of a cognitive decline in multiple sclerosis patients. (C) The strength of associations between brain parenchymal fraction and Symbol Digit Modalities Test scores in patients within the lowest and the highest quartile of T2 lesion volume.