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Multicenter Study
. 2021 Apr 1;78(4):414-425.
doi: 10.1001/jamaneurol.2020.4920.

Identifying the Distinct Cognitive Phenotypes in Multiple Sclerosis

Ermelinda De Meo  1   2   3 , Emilio Portaccio  4   5 , Antonio Giorgio  6 , Luis Ruano  7   8 , Benedetta Goretti  3 , Claudia Niccolai  5 , Francesco Patti  9 , Clara Grazia Chisari  9 , Paolo Gallo  10 , Paola Grossi  11 , Angelo Ghezzi  12 , Marco Roscio  12 , Flavia Mattioli  13 , Chiara Stampatori  13 , Marta Simone  14 , Rosa Gemma Viterbo  14 , Raffaello Bonacchi  1   2   15 , Maria A Rocca  1   15 , Nicola De Stefano  6 , Massimo Filippi  1   2   15   16 , Maria Pia Amato  3   5
Affiliations
Multicenter Study

Identifying the Distinct Cognitive Phenotypes in Multiple Sclerosis

Ermelinda De Meo et al. JAMA Neurol. .

Abstract

Importance: Cognitive impairment is a common and disabling feature of multiple sclerosis (MS), but a precise characterization of cognitive phenotypes in patients with MS is lacking.

Objectives: To identify cognitive phenotypes in a clinical cohort of patients with MS and to characterize their clinical and magnetic resonance imaging (MRI) features.

Design, setting, and participants: This multicenter cross-sectional study consecutively screened clinically stable patients with MS and healthy control individuals at 8 MS centers in Italy from January 1, 2010, to October 31, 2019. Patients with MS and healthy control individuals who were not using psychoactive drugs and had no history of other neurological or medical disorders, learning disability, severe head trauma, and alcohol or drug abuse were enrolled.

Main outcomes and measures: Participants underwent a neurological examination and a cognitive evaluation with the Rao Brief Repeatable Battery and Stroop Color and Word Test. A subgroup of participants also underwent a brain MRI examination. Latent profile analysis was used on cognitive test z scores to identify cognitive phenotypes. Linear regression and mixed-effects models were used to define clinical and MRI features of each phenotype.

Results: A total of 1212 patients with MS (mean [SD] age, 41.1 [11.1] years; 784 women [64.7%]) and 196 healthy control individuals (mean [SD] age, 40.4 [8.6] years; 130 women [66.3%]) were analyzed in this study. Five cognitive phenotypes were identified: preserved cognition (n = 235 patients [19.4%]), mild-verbal memory/semantic fluency (n = 362 patients [29.9%]), mild-multidomain (n = 236 patients [19.5%]), severe-executive/attention (n = 167 patients [13.8%]), and severe-multidomain (n = 212 patients [17.5%]) involvement. Patients with preserved cognition and mild-verbal memory/semantic fluency were younger (mean [SD] age, 36.5 [9.8] years and 38.2 [11.1] years) and had shorter disease duration (mean [SD] 8.0 [7.3] years and 8.3 [7.6] years) compared with patients with mild-multidomain (mean [SD] age, 42.6 [11.2] years; mean [SD] disease duration, 12.8 [9.6] years; P < .001), severe-executive/attention (mean [SD] age, 42.9 [11.7] years; mean [SD] disease duration, 12.2 [9.5] years; P < .001), and severe-multidomain (mean [SD] age, 44.0 [11.0] years; mean [SD] disease duration, 13.3 [10.2] years; P < .001) phenotypes. Severe cognitive phenotypes prevailed in patients with progressive MS. At MRI evaluation, compared with those with preserved cognition, patients with mild-verbal memory/semantic fluency exhibited decreased mean (SE) hippocampal volume (5.42 [0.68] mL vs 5.13 [0.68] mL; P = .04), patients with the mild-multidomain phenotype had decreased mean (SE) cortical gray matter volume (687.69 [35.40] mL vs 662.59 [35.48] mL; P = .02), patients with severe-executive/attention had higher mean (SE) T2-hyperintense lesion volume (51.33 [31.15] mL vs 99.69 [34.07] mL; P = .04), and 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.

Conclusions and relevance: This study found that by defining homogeneous and clinically meaningful phenotypes, the limitations of the traditional dichotomous classification in MS can be overcome. 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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Portaccio reported receiving personal fees from Biogen, Merck Serono, Genzyme, and Teva outside the submitted work. Dr Ruano reported receiving grants from Biogen and personal fees from Roche and Novartis outside the submitted work. Prof Patti reported receiving grants from RELOAD Onlus Association, University of Catania, Biogen, and Merck; personal fees from Almirall, Bayer, Biogen, Bristol Myers Squibb, Celgene, Merck, Novartis, Roche, Sanofi, and Teva outside the submitted work; and grants from Federazione Italiana Sclerosi Multipla during the conduct of the study. Dr Rocca reported receiving personal fees from Biogen Idec, Novartis, Genzyme, Sanofi, Teva, Merck-Serono, Roche, Celgene, and Bayer outside the submitted work. Prof De Stefano reported receiving personal fees from Immunic Therapeutics, Sanofi Genzyme, Teva, and Biogen as well as grants and personal fees from Merck Serono and Novartis Pharma outside the submitted work. Prof Filippi reported receiving personal fees from Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries; receiving grants from Biogen Idec, Merck-Serono, Novartis, Teva Pharmaceutical Industries, and Roche outside the submitted work; and being editor in chief of Journal of Neurology. Prof Amato reported receiving grants and personal fees from Merck, Biogen, Sanofi Genzyme, Roche, Teva, and Novartis outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Clinical and Demographic Features of Clinical Phenotypes
A-G, Boxplots are represented for each phenotype. H, The histograms show the relative frequencies as percentages of cognitive phenotype within clinical phenotypes from left to right: early relapsing-remitting multiple sclerosis (RRMS), late RRMS, secondary progressive multiple sclerosis (SPMS), and primary progressive multiple sclerosis (PPMS). EDSS indicates Expanded Disability Status Scale.
Figure 2.
Figure 2.. Magnetic Resonance Imaging Features of Cognitive Phenotypes
See this image and copyright information in PMC

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