Memory Deficits Precede Processing Speed Decline in Modern Multiple Sclerosis Care

Evolving Cognitive Phenotypes in Multiple Sclerosis

Cognitive impairment remains a debilitating manifestation of multiple sclerosis, frequently serving as a primary driver of vocational disability and reduced quality of life. For decades, clinical practice has been guided by the understanding that slowed information processing speed is the hallmark cognitive deficit, often assessed through standardized tools like the Symbol Digit Modalities Test [1, 2]. While molecular biomarkers such as neurofilament light chain have been linked to these processing speed outcomes, the underlying drivers of cognitive decline continue to be a focus of intensive research [3, 4]. Current management increasingly relies on a combination of high-efficacy disease-modifying therapies and non-pharmacological interventions, such as exercise and cognitive rehabilitation, to preserve functional capacity [5, 6]. However, as the diagnostic and therapeutic landscape has transformed over the last twenty years, the relevance of historical cognitive models in today's clinical environment requires urgent re-evaluation. Recent findings offer fresh insights into how these cognitive profiles have changed for patients in the modern era, suggesting that clinicians may need to rethink how they screen for cognitive decline.

The Decline of the Speed-Centric Model

For more than 30 years, the clinical understanding of cognitive impairment in multiple sclerosis has been dominated by a speed-centric model. This framework posits that slowed information processing speed is the principal cognitive deficit in the disease, acting as a primary driver presumed responsible for downstream deficits in other domains, including memory. However, this foundational model was established before the widespread availability of modern disease-modifying therapies. Because these early observations were made prior to the current era of high-efficacy treatment, their continued application to contemporary patients has remained largely unquestioned, even when it conflicts with everyday clinical experience. To address this discrepancy, researchers conducted a comprehensive re-evaluation of the speed-centric model by analyzing data from patients diagnosed and treated between 2001 and 2025. By examining large clinical cohorts and comparing them against historical data, the investigators sought to determine if the cognitive profiles of today's patients still align with benchmarks set in the late 20th century. The findings demonstrate that the speed-centric model of cognitive dysfunction is inaccurate for the modern diagnostic and treatment era. The traditional expectation of primary processing speed decline no longer matches the objective performance of current patients, indicating that physicians must adjust their diagnostic expectations.

Memory Impairment in Early Relapsing-Remitting Disease

To investigate the initial manifestations of cognitive decline, researchers analyzed a case-control cohort consisting of 170 persons with early relapsing-remitting disease (defined as 5.0 years or less since diagnosis) and 45 neurologically healthy controls. The results indicated a distinct divergence from historical expectations. Patients with early relapsing-remitting disease performed worse than controls on memory assessments but showed no significant deficit in cognitive speed. For practicing neurologists, this suggests that memory impairment now frequently emerges as an isolated or primary cognitive symptom, rather than a secondary consequence of slowed information processing. Longitudinal data further challenged the traditional speed-centric framework. Over a 6-year follow-up period, cognitive speed among these patients remained normal and stable, even as they experienced a subtle but measurable decline in memory performance. When the investigators compared these results to four historical studies of early relapsing-remitting disease diagnosed under older criteria, they found that the effect sizes for case-control differences in the modern cohort were much lower for cognitive speed than in previous decades. In contrast, the effect sizes for memory deficits remained comparable to those observed in historical cohorts. This indicates that while modern disease management successfully preserves processing speed, it has not mitigated the persistence of memory impairment.

Objective Performance Across Large Clinical Cohorts

The researchers expanded their investigation through an independent clinical cohort of 1004 consecutive patients aged 18 to 65 years with relapse-onset multiple sclerosis, all of whom underwent standard-of-care cognitive screenings between 2018 and 2025. Data captured during the first of three independent periods (n = 642) revealed that rates of poor performance, defined as the 7.5th percentile or lower, did not differ from normative expectations for cognitive speed (8.4%) or attention (9.0%). However, these same patients exhibited elevated rates of impairment in verbal memory (23.8%) and visuospatial memory (14.8%). This confirms that memory deficits frequently occur in the absence of the processing speed delays traditionally associated with the disease. This pattern of preserved processing speed alongside memory dysfunction remained consistent across subsequent groups. Patients evaluated during the second (n = 123) and third (n = 239) periods demonstrated memory deficits despite maintaining normal cognitive speed on co-normed tasks (assessments calibrated against the exact same healthy reference group to ensure direct statistical comparability). The objective cognitive speed among current patients was remarkably similar to healthy normative expectations, yielding a z-score mean (standard deviation) of 0.03 (1.14) and a median (interquartile range) of 0.00 (-0.67, 0.67). Because a z-score of 0.00 represents the exact average of the healthy population, this indicates that the median patient in this modern cohort shows no speed deficit whatsoever. These findings highlight a significant shift in the clinical presentation of cognitive symptoms. The objective cognitive speed in this modern cohort was significantly better than results reported in historical comparisons from 20 to 25 years ago. For clinicians, these data from over 1,000 contemporary patients dictate a change in diagnostic focus, as memory impairment is now the more prevalent and clinically relevant concern.

Patient-Reported Outcomes and Disease Subtypes

The researchers supplemented objective neuropsychological testing with patient-reported outcomes to capture the subjective experience of cognitive decline across the total clinical cohort. These self-reports indicated that the most severe disease-related difficulties occurred in expressive language, specifically word-finding. These linguistic challenges were followed in severity by deficits in working memory (the ability to hold and manipulate information temporarily) and episodic memory (the recall of specific personal events). This hierarchy of subjective complaints aligns with the objective findings, suggesting that patients are acutely aware of their memory and language limitations even when traditional measures of processing speed remain within normal limits. When analyzing the relationship between mood and perceived cognitive function, the study found that a small difference in executive function and speed was fully explained by mood in patients with relapsing-remitting disease. Clinically, this suggests that when patients with this subtype report feeling cognitively slow, the symptom may be a manifestation of underlying affective distress, such as depression or anxiety, rather than a primary neurocognitive deficit. Furthermore, the researchers noted a significant historical shift in patient experiences. Current patient-reported attention and executive deficits were lower than those reported 35 years ago, a finding that stands in contrast to the fact that memory difficulties have remained comparable over the same period. This divergence suggests that while modern disease management successfully preserves executive networks, memory remains a persistent clinical challenge. The study also identified a clear distinction in cognitive profiles based on disease subtype, noting that the traditional speed-centric model still holds relevance for specific populations. Deficits in attention, executive function, and cognitive speed were specifically observed in patients with secondary-progressive disease, a stage characterized by a gradual worsening of symptoms following an initial relapsing-remitting course. For these patients, the classic presentation of slowed information processing remains a primary clinical feature. However, for the broader population of modern patients with relapse-onset disease, the findings emphasize that memory and language should be the primary focus of cognitive assessment.

Clinical Implications for Screening and Research

The findings suggest that clinical reliance on processing speed as the primary indicator of cognitive health in multiple sclerosis may lead to the underdiagnosis of significant impairments. While tools like the Symbol Digit Modalities Test are standard for assessing cognitive speed, the researchers demonstrated that memory deficits remain prevalent in the modern era, even when speed scores are perfectly normal. In the first period of the clinical cohort involving 642 patients, the rate of poor performance on cognitive speed was only 8.4 percent, which aligns with normative expectations. However, deficits were significantly elevated for verbal memory at 23.8 percent and visuospatial memory at 14.8 percent. These data indicate that clinicians must incorporate dedicated memory assessments into routine screenings to capture the nearly one in four patients who struggle with memory despite maintaining normal processing speed. Beyond screening, the study identifies a specific neurocognitive mechanism that warrants prioritized attention in both clinical management and drug development. The researchers highlighted working memory maintenance (the active retention of information over short periods to guide behavior) as a critical target for further investigation. This focus is essential because current disease-modifying therapies, while highly effective at reducing relapse rates and preserving processing speed, have not yet provided reliable treatments for memory dysfunction. The authors argue that the field requires new, testable models of memory impairment informed by contemporary cognitive neuroscience. By shifting the focus from speed to the preservation of working memory, the medical community can begin developing targeted interventions to address the persistent memory challenges that impact the daily lives of patients in the modern treatment era.

References

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