The CogEx trial – Cognitive rehabilitation and aerobic exercise for cognitive impairment in people with progressive multiple sclerosis: A randomised,blinded,sham-controlled trial

Cognitive dysfunction affects between 80% and 90% of people with progressive multiple sclerosis (MS), twice the rate seen in relapsing-remitting disease. ¹ The implications of this for individuals with the more advanced form of MS are considerable because cognitive dysfunction is associated with difficulties maintaining employment, sustaining relationships and carrying out activities of daily living. Adding to these concerns has been the uncertainty of whether cognitive deficits in progressive MS are treatable.

The impetus to tackle this pressing clinical need emerged as one of the priorities of the Progressive MS Alliance, a global collaboration of MS organisations, researchers, health professionals, the pharmaceutical industry, companies, trusts, foundations, donors and people affected by progressive MS, working together to address the unmet needs of people with progressive MS. ²

Over the last few years, a number of studies of cognitive rehabilitation (CR) have given rise to cautious optimism that deficits in processing speed, memory and executive function in people with MS may to a degree be reversible. The findings with respect to exercise are more equivocal. The CR and exercise studies are, however, heavily weighted towards people with relapsing-remitting multiple sclerosis (RRMS) and are beset with methodological limitations including small sample size, single-centre samples and the inclusion of participants who are not cognitively impaired. The few studies focusing on people with progressive MS share these pitfalls.

The CogEx trail – Cognitive rehabilitation and aerobic exercise for cognitive impairment in people with progressive multiple sclerosis: A randomised, blinded, sham-controlled trial – was an attempt to address the dearth of progressive MS cognition studies while avoiding the limitations highlighted above. ³ CogEx brought together a multidisciplinary team (neurology, psychiatry, neuropsychology, physiotherapy, exercise physiology) from 11 centres in six countries (Canada, Italy, the United States, the United Kingdom, Belgium and Denmark). The study enrolled 311 people with progressive MS and administered the interventions twice a week for 12 weeks (24 therapy sessions in total).

In recognition of the potentially greater challenge of reversing cognitive deficits in progressive as opposed to relapsing-remitting disease, one of the four treatment arms entailed a combination of CR plus aerobic exercise given sequentially. The hypothesis was that this combined intervention would prove superior to CR and sham exercise, exercise and sham CR and sham CR plus sham exercise. The primary outcome measure was processing speed, the quintessential cognitive deficit in people with MS, which was measured by the Symbol Digit Modalities Test (SDMT) at 12 weeks post-interventions.

The results failed to support the central hypothesis that CR and aerobic exercise would have a synergistically beneficial effect on processing speed. Indeed, the primary outcome did not differ across the four treatment arms, a result attributed to the sham exercise turning out to be an active intervention. Designed to avoid stressing the cardiovascular system, the stretching and balance exercises led to an unexpected improvement in the 6-minute walk test, a secondary outcome measure. Improvement in ambulation in turn has been shown to enhance processing speed in people with MS. ⁴

Looking beyond the disappointment of a failed primary hypothesis, there is much in the CogEx data to encourage people with progressive disease. A change in group score of four or more points on the SDMT is associated with real-world benefits. ⁵ This improvement threshold was reached by almost two-thirds of the participants at 12 weeks and maintained by almost half the group 6 months after the interventions ended. The magnitude of this change suggests it cannot alone be explained by practice effects or regression to the mean. The conclusion is that CR and exercise alone may therefore improve cognition in advanced MS, something that was not known prior to CogEx.

There is another plausible explanation that may have contributed to the improvement in processing speed. Some participants informed the investigators that the 3-month intervention period provided more physical, intellectual and social activity – an enriched lifestyle – than they had experienced in many years. This in turn could have boosted their cognition. This explanation is supported by a study in people with predominantly RRMS that revealed an association between what the authors called a positive lifestyle (exercise, social or intellectual engagement and healthy nutritional choices) and processing speed. ⁶ The protective effects of an enriched environment on mitigating cognitive decline in progressive MS were first described in 2012. ⁷ The CogEx findings suggest that enhancing enrichment in multiple ways might offer additional remedial benefits, specific to processing speed in this group as well.

The CogEx imaging data are still being analysed. They will hopefully provide a mechanistic understanding of why some people with advanced MS improved cognitively, whereas others did not. This line of inquiry suggests one direction for the post-CogEx research agenda; the development of a Sequential, Multiple Assignment, Randomised Trial (SMART). It is becoming clear that a ‘one size fits all’ approach to improving cognition in people with all forms of MS misses the mark. What is needed are individually tailored interventions that derive direction from specific characteristics – demographics, symptom profiles, biomarkers of disease activity – that define the potential for positive change. These will vary between people and are yet to be clearly defined, although a study like CogEx has the potential to begin providing clues. Moreover, future research methodologies have to be flexible enough to accommodate an individual being randomised more than once within the trial, something a SMART design allows for, as the interventions are finessed in response to improvement or failure to improve.

Looking back at the CogEx trial, it would be remiss not to mention the effects of the COVID pandemic on participants, investigators and the many research assistants tasked with collecting a trove of data. A number of people were infected by the virus. Thankfully none died. A lot of money, unbudgeted for, had to be spent on personal protective equipment. The study was forced to suspend enrolment and interventions multiple times according to each country’s approach to managing an unprecedented global healthcare emergency. Nevertheless, the study endured because all involved were aware of the unique opportunity it afforded to make a difference to the lives of people with progressive MS, many of whom had despaired of what they saw as the MS therapeutic bandwagon bypassing them in favour of those with relapsing-remitting forms of the disease. The study was not without its limitations, which the investigators acknowledge. But the results offer cautious hope that even in the face of neural degeneration, cognitive decline may be arrested and perhaps, even to a degree, reversed.