A new classification of cognitive deficits in patients with multiple sclerosis (MS) may be helpful in defining clinical disability, support clinicians in treatment choices, and help tailor cognitive rehabilitation strategies, according to study results published in JAMA Neurology.

While cognitive dysfunction is common among patients with MS, the heterogeneity of cognitive deficits in these patients prevents a clear assessment of neuroanatomical substrates and personalized rehabilitation strategies. The objective of the current study was to define cognitive phenotypes in a clinical cohort of patients with MS and to characterize their clinical and MRI features.

The cross-sectional study included 1212 patients (mean age, 41.1 years; 64.7% women) with MS and 196 healthy controls (mean age, 40.4 years; 66.3% women) from 8 Italian centers from January 1, 2010, to October 31, 2019. No participants were using psychoactive drugs and none had a history of other neurological or medical disorders, learning disabilities, severe head trauma, or alcohol or drug abuse.

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All study participants completed neuropsychological evaluations using the Rao Brief Repeatable Battery and the Stroop Color and Word Test. At the time of neuropsychological evaluation, 172 patients with MS and 50 healthy control group participants had a brain MRI examination.

The study researchers used latent profile analysis (LPA) on cognitive test z scores to identify cognitive phenotypes, and they used statistical analysis to compare demographic and clinical parameters and radiographic features of each phenotype.

Using LPA, they identified these 5 cognitive phenotypes as compared with healthy control group participants:

  • Preserved cognition: 235 patients (19.4%) who showed no substantial difference
  • Mild-verbal memory/semantic fluency: 362 patients (29.9%) who had only a mild decrease in the Selective Reminding Test and Word List Generation
  • Mild-multidomain: 236 patients (19.5%) who had a mild decrease in the Selective Reminding Test, Symbol Digit Modalities Test, Stroop Color and Word Test, and Paced Auditory Serial Addition Test
  • Severe-executive/attention: 167 patients (13.8%) who had severely decreased performance in the Stroop Color and Word Test and Paced Auditory Serial Addition Test
  • Severe multidomain: 212 patients (17.5%) who had severely decreased performance in the Selective Reminding Test, Stroop Color and Word Test, Symbol Digit Modalities Test, Paced Auditory Serial Addition Test, and Word List Generation

Patients with preserved cognition and mild-verbal memory/semantic fluency phenotypes were younger and had shorter disease duration (mean age, 36.5 years and 38.2 years, respectively; mean disease duration, 8.0 years and 8.3 years, respectively), compared with patients with mild-multidomain (mean age, 42.6 years; mean disease duration, 12.8 years; P <.001), severe-executive/attention (mean age, 42.9 years; mean disease duration, 12.2 years; P <.001), and severe–multidomain (mean age, 44.0 years; mean disease duration, 13.3 years; P <.001) phenotypes.

The relative frequencies of severe-executive/attention (11%, 14%, and 19%, respectively) and severe-multidomain (12%, 18%, and 36%, respectively) phenotypes progressively increased from early relapsing-remitting MS to late relapsing-remitting MS to secondary progressive MS.

On MRI evaluation, compared with patients with preserved cognition, those with mild-verbal memory/semantic fluency had decreased hippocampal volume, those with mild-multidomain phenotype had decreased cortical gray matter, those with severe-executive/attention had higher mean T2 hyperintense lesion volume, and those with severe multidomain phenotype had decreased volume in most brain structures.

The study had several limitations, including the cross-sectional design, the data being based on a clinical sample that may not be representative of the general MS population, and MRI examination being completed in only a subgroup of patients.

“These phenotypes can represent a more meaningful measure of the cognitive status of patients with MS and can help define clinical disability, support clinicians in treatment choices, and tailor cognitive rehabilitation strategies,” concluded the study researchers.


De Meo E, Portaccio E, Giorgio A, et al. Identifying the distinct cognitive phenotypes in multiple sclerosis. JAMA Neurol. Published online January 4, 2021. doi:10.1001/jamaneurol.2020.4920