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Researchers Identify 4 Distinct Phenotypes of Cognitive Impairment in MS


Investigators aimed to close the knowledge gap on interindividual variability in cognitive evaluation outcomes by considering both cognitive impairment and mood disorders to better prediction accuracy.

Current criteria for defining cognitive impairment in patients with multiple sclerosis (MS) are broad and exist on a group level, such that patients are defined as either “impaired” or “not impaired.” Information deficits persist on interindividual variability in cognitive evaluation outcomes.

The authors of a recent study in Multiple Sclerosis and Related Disorders aimed to close this knowledge gap in cognitive evaluation by considering both cognitive impairment and mood disorder patient-reported outcomes, “since combining information from different domains could be useful to increase prediction accuracy over and above what can be achieved at the level of single category of markers.”

Cognitive impairment is a common symptom of MS, appearing in 43% to 70% of adults and 30% of children, the authors noted. Their latent class analysis identified 4 distinct phenotypes of cognitive impairment among 872 persons with MS (relapsing-remitting [RRMS] or primary progressive MS [PPMS])—all enrolled in the PROMOPRO-MS initiative—evaluated using the Montreal Cognitive Assessment (MoCA), Symbol Digit Modalities Test (SDMT), Hospital Anxiety and Depression Scale (HADS), with most participants exhibiting severe functioning difficulties.

The 4 phenotypes identified are:

  1. Fewer recall memory difficulties (28.3%)
  2. Mild delayed recall and language deficits with mood disorders (21.2%)
  3. Moderate memory, language, and attention impairments (18.8%)
  4. Severe, widespread memory, language, attention, information processing, and executive function difficulties, without depression and anxiety (31.7%)

Most patients were female (65.3%), the mean (SD) participant age was 54.1 (12.6) years, and the mean (SD) disease duration was 19.3 (12.3) years.

MOCA scores range from 0 to 30, with lower scores indicating greater impairment; HADS scores range from 0 to 3 for each of the 7 items in their depression (HADS-d) and anxiety (HADS-a) subscales, with totals above 8 on each subscale indicating significant anxiety or depression; and SDMT scores range from 0 to 110, with lower scores indicating more neurological dysfunction.

In this study, the mean (SD) and median (interquartile range) scores were as follows:

  • MOCA:
    • Mean: 23.3 (4.3)
    • Median: 24 (21-26.5)
  • SDMT:
    • Mean: 35.3 (15.1)
    • Median: 35.5 (24.5-46.0)
  • HADS-d:
    • Mean: 5.3 (3.6)
    • Median: 5 (2-7)
  • HADS-a:
    • Mean: 6.8 (4.4)
    • Median: 6 (3-10)

Differences seen among the phenotypes are that individuals with phenotype 1 had the highest levels of education, females and persons with RRMS made up most of the participants with phenotype 2, males and persons with PPMS accounted for most of those with phenotype 3, and phenotype 4 comprised older persons who were more “clinically compromised.”

In explaining why their findings are important, the authors noted that their findings can help to advance understanding of cognitive impairment in patients who have MS, which in turn will further clinicians’ ability to tailor interventions.

“Since less is known about the progressive deterioration of cognition in people with multiple sclerosis, a taxonomy of distinct subtypes that consider information from different clustered domains (ie, cognition and mood) represents both a challenge and opportunity for an advanced understanding of cognitive impairments and development of tailored cognitive treatments in MS,” the investigators stated.

Cognitive impairment in MS is a key area for future research, they concluded.


Podda J, Ponzio M, Pedullà L, et al. Predominant cognitive phenotypes in multiple sclerosis: insights from patient-centered outcomes. Mult Scler Relat Disord. Published online March 21, 2021. doi:10.1016/j.msard.2021.102919

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