More Severe Cognitive, Physical Phenotypes Observed in Progressive Multiple Sclerosis

January 26, 2021
Victoria Johnson
Victoria Johnson

Victoria Johnson, Assistant Editor for NeurologyLive, joined the MJH Life Sciences team in October 2020. Follow her on Twitter @_vic_j or email her at

Researchers sought to redefine dichotomous classifications of MS and identified meaningful classifications.

A recent study worked to define homogenous and clinically meaningful phenotypes of multiple sclerosis (MS) to improve measures and definitions over traditional dichotomous classifications. Ultimately, after assessing 1212 patients, the study identified 5 cognitive phenotypes. 

Preserved cognition was observed in 235 patients (19.4%), mild-verbal memory/semantic fluency was seen in 362 patients (29.9%), mild-multidomain involvement in 236 patients (19.5%), severe-executive attention in 167 patients (13.8%). and severe-multidomain in 212 patients (17.5%). Study author Maria A. Rocca, MD, head, neuroimaging of CNS white matter unit, Institute of Experimental Neurology, IRCCS Ospedale San Raffaele, and colleagues wrote that “in this cross-sectional study, we propose a classification of cognitive functions in patients with MS that is based on the identification of distinct cognitive phenotypes.” 

The group applied latent profile analysis (LPA) to a set of neuropsychological data they pulled from a large cohort of patients with MS, and then utilized validated evaluations to characterize the MRI features.

“This approach allowed us to identify the latent variables replacing single test measures, which can be affected by multiple cognitive functions, and to capture the shared variance across cognitive tests, likely reflecting purer measures of cognitive domains,” Rocca et al. wrote. “Moreover, by using z scores rather than a dichotomous classification, we found that the cognitive function was more properly represented as a continuum.”

READ MORE: New Study Clarifies Gray Matter Atrophy in MS Phenotypes

Rocca and colleagues classified MS phenotypes from their population of patients who had a mean age of 41.1 years (standard deviation [SD], 11.1), 64.7% (784) of which were women. The authors included 196 healthy controls with a mean age of 40.4 years (SD, 8.6), 66.3% (130) of which were women. All participants underwent neurological examinations and cognitive evaluations with the Rao Brief Repeatable Battery and Stroop Color and Word Test, with some undergoing MRI examinations. LPA was used on cognitive test z-scores to stratify cognitive phenotypes.

They found that patients with preserved cognition had an average age of 36.5 years (SD, 9.8) and an average disease duration of 8.0 years (SD, 7.3). Patients with mild-verbal memory semantic fluency had an average age of 38.2 years (SD, 11.1) and an average disease duration of 8.3 years (SD, 7.6). These patients were younger with a shorter disease duration than other phenotypes – patients with mild-multidomain had an average age of 42.6 years (SD, 11.2) and a mean disease duration of 12.8 years (SD, 9.6; P <.001), patients with severe-executive/attention had an average age of 42.9 years (SD, 11.7) and an average disease duration of 12.2 years (SD, 9.5; P <.001), and patients with severe-multidomain had an average age of 44.0 years (SD, 11.0) and an average disease duration of 13.3 years (SD, 10.2; P <.001). Patients with the severe–multidomain phenotype had extensive brain damage, with decreased volume in all the brain structures explored, except for nucleus pallidus, amygdala, and caudate nucleus.

Rocca and colleagues also identified that patients with progressive MS had a greater incidence of severe cognitive phenotypes, with severe multidomain phenotypes found in 36% of patients with secondary MS and 21% with primary progressive MS, as compared to 12% of patients with relapsing-remitting MS.

The MRI evaluations showed that compared to those with preserved cognition (5.42 mL; standard error [SE], 0.68), patients with mild-verbal memory/semantic fluency exhibited decreased mean hippocampal volume (5.13 mL; SE, 0.68; P = .04). Patients with the mild-multidomain phenotype had decreased mean cortical gray matter volume (662.59 mL; SE, 35.48) when compared to those with preserved cognition (687.69 mL; SE, 35.40; P = .02). Patients with severe-executive/attention had higher mean T2-hyperintense lesion volume (99.69 mL; SE, 34.07) when compared to those with preserved cognition (51.33 mL; SE, 31.15; P = .04).

Patients with the severe-multidomain phenotype had a median Expanded Disability Status Scale (EDSS) score of 3.0 (range, 0.0–8.0), significantly higher than other phenotypes (P ≤.001). Patients with preserved cognition had a median EDSS score of 1.5 (range, 0.0–7.0), signifying lower physical disability than those with mild-verbal memory/semantic fluency (median EDSS, 2.0; range, 0.0–7.5; P <.001), mild-multidomain (median EDSS, 2.0; range, 0.0–8.0; P <.001), severe-executive/attention (median EDSS, 2.0; range, 0.0–8.0; P = .001), and severe-multidomain (median EDSS, 3.0; range, 0.0–8.0; P <.001) phenotypes.

“The data-driven cognitive phenotypes presented in this study can overcome the limitations of the traditional dichotomous classification in MS and have the potential to represent a more meaningful measure of the cognitive status of patients with MS. This new categorization of cognitive deficits may integrate the EDSS score in defining clinical disability, support clinicians in treatment choices, and help tailor cognitive rehabilitation strategies,” Rocca and colleagues concluded.

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