#Grey Matter

Cognitive Impairment, an Early Marker of Poor Long-Term Outcomes

The primary evaluation of disease progression in MS has largely focused on clinical symptoms and the physical function of the patient.1,2 However, the clinical relevance of cognitive impairment in MS is becoming increasingly recognized, especially in the earliest stages of disease.1,2 Nearly half of patients with MS experience cognitive impairment, which most frequently presents as impaired information-processing speed and impaired immediate and delayed memory. Verbal fluency and executive function can also be affected.3 Cognitive impairment may be present in a significant proportion of patients before clinical symptoms appear, sometimes years before, and can serve as an early marker of disease activity.2,4

Significant Impact on Patient Function

Cognitive deficits can impose a heavy burden on the lives of patients with MS. Cognitive impairment may cause limitations in the workplace and social settings irrespective of the level of physical disability.2 Studies indicate that cognitive impairment in patients with MS is implicated in causing reduction of work responsibilities or leaving the workforce. Additionally, these patients are more likely to report higher rates of divorce, low self-esteem, and fewer social activities.6

Impact of Cognitive Impairment on Patient Function2,3,7

Pathogenesis of Cognitive Impairment

Recent advances in MRI technology have revealed that grey matter damage, in addition to white matter damage, plays a significant role in the pathogenesis of cognitive impairment. 3T MRI has demonstrated in studies that T1 hypointense cortical lesions are common in patients with MS and are predictive of worse performance on neuropsychological tests. 7T MRI imaging has provided further evidence that cortical lesions have a strong association with cognitive impairment in this patient population. Recent studies have also revealed that deep grey matter volume, particularly of the thalamus, is lower in patients with MS compared with normal controls and associated with impaired processing speed, working memory, and visuospatial memory.6

Impact of Neurological Reserve on Early Cognitive Impairment
While correlations between MRI findings and cognitive function are robust, the pathophysiological changes underlying cognitive impairment in patients with MS are highly variable. Only 33%–50% of the variability can be explained by MRI findings. Cognitive reserve, the capacity to compensate for pathological damage and maintain neurological function in the presence of disease, may explain individual differences in cognitive deficits and their limited correlation with MRI findings.8 Educational level correlates with levels of cognitive reserve at baseline. Individuals with high cognitive reserve maintain function despite neurological damage and thus are able to withstand greater disease burden prior to cognitive impairment compared with individuals with low cognitive reserve, who cannot compensate for an equivalent amount of neurological damage.9

Based on studies in patients with CIS and early RRMS, it is believed that early intervention against cognitive decline helps preserve intact cognitive functioning and delay impairment in cognitive function.8

Assessing Cognitive Function in Clinical Practice
Initial signs of cognitive impairment are subtle, and standard components of neurological exams do not adequately detect it.2,3

  • The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) battery, which can be completed in 15–30 minutes, is available and recommended for use by Langdon et al. It can be administered by most HCPs without requiring a specially trained or qualified professional. BICAMS is designed for international use and currently validated by 14 countries for a comprehensive cognitive assessment. BICAMS assesses information processing speed (SDMT), immediate verbal recall memory (CVLT-II), and immediate visual recall memory (BVMT-R)1,10
  • The Symbol Digit Modalities Test (SDMT) is a reliable tool that is sensitive to cognitive deficits and takes ≤5 minutes to complete. It can be completed by a trained health care professional and does not require a neurologist to administer.10 Also, robust correlations are seen with MRI metrics, specifically third ventricle widening and thalamus volume loss11
    • When completing the SDMT, the patient is presented with a page that contains a key that pairs the single digits 1–9 with 9 symbols. The patient’s task is to write or orally report the correct number in the spaces within the allotted time12

Example CVLT-II Stimuli13

  • The California Verbal Learning Test-II (CVLT-II) assesses verbal memory, while the Brief Visuospatial Memory Test-Revised (BVMT-R) assesses visuospatial memory. Both tests are associated with high sensitivity with good age- and sex-adjusted normative data available and can be completed in 5–10 minutes1,13
    • When completing the CVLT-II, patients are provided with a list of 16 words, with four items belonging to each of four categories, arranged randomly. The list is read aloud five times in the same order to the patient. Patients are required to recall as many items as possible, in any order, after each reading of the list13

A Scored Version of the SDMT12

    • When completing the BVMT-R, patients are asked to inspect a 2 x 3 stimulus array of abstract geometric figures. The array is removed, and the patient is required to draw the array from memory, with the correct shapes in the correct position13

Example BVMT-R Stimuli13

Additional batteries to assess cognitive function are also available; however, the time and resources it takes to administer them remains a limiting step for their adoption in clinical practice.6

  • Brief Repeatable Battery of Neuropsychological tests (BRB-N) for MS is a battery that takes 1 hour or less to be administered. It can distinguish between MS patients with cognitive impairment versus intact cognition with a sensitivity of 71% and specificity of 94%. There are some limitations to this battery, as some researchers have found this battery to lack measurements of visuospatial ability and executive function. Therefore, other tests are often added to this battery for a more comprehensive assessment6
  • The Minimal Assessment of Cognitive Function in MS (MACFIMS) was developed to include tests that the BRB-N lacks, ensuring a more comprehensive assessment but increasing the test duration to 1.5–2 hours. Although not included in the battery, the panel of experts who developed this test recommended that premorbid cognitive ability, generalized fatigue, and mood disorders, specifically depression, also be measured, as these factors can affect performance on objective cognitive measures6
  • The Paced Auditory Serial Addition Test (PASAT), which is included as part of both BRB-N and MACFIMS batteries, measures cognitive processing speed and working memory. The PASAT stimuli is auditory and utilizes and audio cassette to conduct the test. While this test can be completed in 10–15 minutes, it is associated with several limitations for cognitive monitoring in clinical practice, including limited reliability and poor tolerability by patients1,14

Overcoming Limitations to Adoption of Cognitive Monitoring in Clinical Practice
Practice effects, defined as poorer performance in patients when first tested due to lack of familiarity with the task, have been observed with available cognitive tests, including the SDMT, CVLT-II, BVMT-R, and PASAT.14-17

Computerized testing may serve as an alternative to traditional paper-and-pencil assessments and aim to overcome some limitations associated with them. The Processing Speed Test (PST) is a tablet-based test modeled after the SDMT that enables electronic data from tablet-based tasks to be integrated with electronic medical records. Tools like the PST may help promote cognitive monitoring as standard care for better detection of cognitive decline, develop large datasets from representative samples to advance understanding of prevalence, time course, and risk factors for decline, and promote feasibility of postmarketing studies of the effects of disease-modifying therapies on cognition.1

Observational research has also identified modifiable lifestyle factors that may protect against cognitive decline, such as mental activity, physical exercise, and stress management. However, these treatments are most effective when they are integrated into the context of the patient’s life. Interventions for cognitive rehabilitation may be most effective when tailored to the underlying cause of a patient’s specific deficit, which may differ within the same cognitive domain (eg, memory deficit secondary to diffuse white matter lesions versus focal thalamic lesions). A holistic approach to treatment is necessary to ensure optimal outcomes for each patient in practice and research.1

Conclusions
Cognitive impairment is increasingly recognized and accepted as one of the earliest clinical symptoms of MS, with a significant impact on patient function and overall quality of life.2,6 Cognitive function is not captured using current assessments, such as disability progression (generally measured using the EDSS) as well as no evidence of disease activity-4 (NEDA-4), which includes an assessment of clinical relapses, MRI activity, disability progression, and brain volume loss.18,19 Early and ongoing cognitive assessment using validated tests and management may therefore help improve long-term outcomes. Because cognitive impairment may be missed in a standard neurological exam, early baseline screening and reassessment with the SDMT is recommended.2 Effective use of cognitive assessments, including computerized tests, has the potential to improve clinical outcomes and preserve long-term patient function.1