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Original Investigation
January 4, 2021

Identifying the Distinct Cognitive Phenotypes in Multiple Sclerosis

Author Affiliations
  • 1Neuroimaging Research Unit, Division of Neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy
  • 2Institute of Experimental Neurology, Vita-Salute San Raffaele University, Milan, Italy
  • 3Section Neurosciences, Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, University of Florence, Florence, Italy
  • 4Department of Neurology, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
  • 5Department of Neurorehabilitation, IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy
  • 6Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy
  • 7EPIUnit, Instituto de Saúde Pública de Universidade do Porto, Porto, Portugal
  • 8Neurology Department, Centro Hospitalar de Entre Douro e Vouga, Santa Maria da Feira, Portugal
  • 9Department of Neurology, University of Catania, Catania, Italy
  • 10Department of Neurology, University of Padova, Padova, Italy
  • 11Neuroimmunology Center, Cardiocerebrovascular, Azienda Socio Sanitaria Territoriale (ASST) of Crema, Crema, Italy
  • 12Gallarate Hospital, Varese, Italy
  • 13Neuropsychology Unit, ASST Spedali Civili Brescia, Brescia, Italy
  • 14Child and Adolescence Neuropsychiatry Unit, Department of Basic Medical Sciences, Neuroscience and Sense Organs University Aldo Moro Bari, Bari, Italy
  • 15Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
  • 16Neurophysiology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
JAMA Neurol. Published online January 4, 2021. doi:10.1001/jamaneurol.2020.4920
Key Points

Question  Given the heterogeneity of cognitive function in patients with multiple sclerosis (MS), can distinct cognitive phenotypes be identified for clinical and research purposes?

Findings  In this cross-sectional study of 1212 patients with MS and 196 healthy control individuals, 5 cognitive phenotypes (preserved cognition, mild–verbal memory/semantic fluency, mild–multidomain, severe–executive/attention, and severe–multidomain) were identified by using a data-driven approach to cognitive evaluations. Each phenotype was characterized by specific clinical and magnetic resonance imaging features.

Meaning  Findings of this study suggest that this new categorization of cognitive deficits in MS may integrate the Expanded Disability Status Scale score in defining clinical disability, support clinicians in treatment choices, and help tailor cognitive rehabilitation strategies.


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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