The Prioritized Research Agenda Dissemination Advancement (PRADA) project is a collaborative effort to identify and prioritize research questions that are most important to people affected by MS.
PRADA was launched with a focus on the topic of "MS Symptoms and their Treatment and Management." Questions on this topic were were contributed through the iConquerMS Our Questions Have Power program, and selected through a process that intentionally incorporates the perspectives of groups that have been historically underrepresented in research.
The PRADA project has produced a people-powered research agenda shaped directly by the iConquerMS community. These priorities are now being shared with researchers, funders, and partners to help influence study design, funding decisions, and future MS research efforts.
PRADA was designed to be repeated, and a new topic will be coming soon. We are grateful to Bristol Myers Squibb and EMD Serono for providing the funding that made this project possible.
How are lesion locations in the brain and spinal cord linked to specific MS symptoms, and can this information be used to support individualized symptom treatment?
Why this question matters: Having this information could help people with MS better understand the underlying cause of the symptoms they are experiencing, or predict which symptoms they may experience in the future. It could also provide the potential for location-specific treatments, such as transcranial direct current stimulation, a non-invasive treatment involving mild electrical currents.
Background: MS symptoms can sometimes be linked to specific lesion locations based on the functions carried out at that location. For example, optic nerve lesions can cause problems with vision. Not all symptoms and lesion locations can be easily mapped, however. Factors that complicate this mapping include symptoms involving functions that are distributed throughout the central nervous system, lesions affecting a circuit that routes messages through the nervous system, lesions in locations that don't result in definitive symptoms, and lesions located in the gray matter which are harder to detect on MRI images. New research techniques are being applied to imaging and clinical databases to map relationships between lesion locations and more complex symptoms. Continued research in this area and translation to individual cases could provide the answers that people with MS are looking for.
What factors affect the severity of, or protect against, MS-associated fatigue?
Why this question matters: Fatigue is a very common symptom in MS, and is often a disabling one. Understanding what affects the severity of fatigue, as well as why some people with MS don’t experience it, could point to treatments and strategies for reducing fatigue, including personalized approaches.
Background: Fatigue is known to be made worse by MS-related factors such as depression, medications, and MS symptoms that cause sleep disturbances. The severity of fatigue has also been correlated with higher disability and lower cognitive (thinking) processing speed. Several mechanisms related to nerve degeneration and/or inflammation underlying MS fatigue and affecting its severity have been proposed. These mechanisms include impacts on how well axons (long-distance nerve segments) transmit signals, the production of neurotransmitters (chemical messengers) within the brain, and energy supply. However, the specific causes have not been fully determined.
Does age contribute to MS symptoms stabilizing and/or decreasing as people get older? If so, in what age range does this typically occur?
Why this question matters: The answer to this question would help people with MS know what to expect as they get older, and also help inform the question of whether or not to discontinue DMTs later in life.
Background: The immune system changes with aging (a process that is called immunosenescence), which includes a shift to a more inflammatory state. Therefore it might be expected that symptoms would become worse in older years. Changes associated with normal aging would also be expected to contribute to worsening of certain symptoms. Some studies have published changes in disability rates over time using general disability scales, but data on the course of individual symptoms is lacking.
Why are some people with MS negatively affected by high temperatures, and why are some negatively affected by low temperatures?
Why this question matters: Understanding the factors affecting temperature sensitivity could lead to strategies, methods, or therapies for helping people with MS to function well in different conditions and climates.
Background: Higher internal (core) body temperatures have been found to slow or block signal conduction in demyelinated axons. However, the exact mechanism underlying this impaired transmission is unknown. One proposed explanation is that new sodium channels (structures in the walls of axons that help with signal transmission) created to compensate for the lack of myelin are more sensitive to temperature. There are also open questions about whether heat sensitivity is dependent on increases in core temperature, or whether skin exposure to sunlight or other sources of heat that don’t increase core temperature can also impair function. Anxiety about ambient temperatures may also compound this effect.
Cold sensitivity has been associated with the presence of lesions in the hypothalamus (part of the gray matter in the brain) which interfere with autonomic (involuntary) responses and can lead to hypothermia. There is some evidence that lowering the core temperature may also interfere with neural conduction, although again the mechanisms are not understood.
Can high doses of vitamin D3 (for example, 40,000 IU/day as in the Coimbra protocol) help to reduce MS symptoms?
Why this question matters: Low levels of serum vitamin D have been associated with a higher risk of developing MS, with anti-inflammatory effects being proposed as the basis for its protective effect against autoimmunity. The Coimbra protocol of high-level vitamin D supplementation (~40,000 IU/day) was developed to treat vitamin D resistance, a syndrome which has been hypothesized to be present in a subset of people with MS or other chronic diseases.
Background: A systematic review of vitamin D supplementation trials found inconclusive evidence for effects on outcomes such as symptoms (e.g., fatigue or depression), relapse rates or disability. However, none of the trials used daily doses of vitamin D approaching the levels specified in the Coimbra protocol.
Can MS symptoms be affected (worsened, stabilized or improved) by consuming specific ingredients or following specific diets?
Why this question matters: Diet has been shown to affect the risk and severity of many health conditions. For example, the autoimmune response in celiac disease is triggered by eating gluten. It has been hypothesized that certain ingredients in the diet of people with MS could similarly trigger or enhance an inflammatory response in the central nervous system that leads to worsening of symptoms. This effect could be the result of various mechanisms, including changes in the bacteria residing in the digestive system (microbiome), production of antioxidants, and communications between the brain and digestive system (gut-brain axis).
Background: Several types of diets have been studied for their effect on MS, including variations of a paleo diet (such as the Wahls diet), ketogenic diets, and low-fat diets (such as the Swank diet). Individual supplements such as vitamin D and fish oil (omega-3 fatty acids) have also been investigated. While some studies have reported positive effects on MS symptoms such as fatigue and depression, conclusive support for any specific diet or supplement is lacking. Moreover, the specific mechanism(s) linking specific dietary strategies to outcomes are unknown.
Are cognitive burden or fatigue associated with worsening of MS symptoms such as pain and difficulty walking? If so, what causes this to happen?
Why this question matters: Cognitive fatigue is a common and often disabling symptom in MS. Understanding how cognitive burden and fatigue can worsen other MS symptoms could lead to the development of strategies or therapies that support cognitive functioning without worsening in other areas.
Background: Several studies have documented that cognitive burden can interfere with other functions in MS using dual-tasking experiments (e.g., performing cognitive tests while walking on a treadmill). However, research on the effect of cognitive burden on other MS symptoms is lacking. Imaging studies are beginning to uncover associations between cognitive fatigue and damage to certain brain structures and connections. More work is needed to understand the drivers of cognitive fatigue and impacts on other functions and symptoms.
How effective are available or supportive treatments or medications in treating and preventing symptoms such as dizziness, lightheadedness, vertigo and other equilibrium issues in MS?
Why this question matters: Dizziness, lightheadedness and vertigo are complex symptoms that may have their origin in MS lesions, disturbances in the vestibular system (a sensory system in the inner ear), or even psychological symptoms such as anxiety. Balance disorders are common in MS and can increase the risk of falls and have a significant impact on quality of life.
Background: A number of approaches have been explored for treating dizziness and vertigo in MS, including head-turning maneuvers to reposition stones in the inner ear, vestibular physical therapy, therapies such as noisy galvanic vestibular stimulation, and mental health medications and therapies. Observational and comparative effectiveness trials have been conducted to assess the efficacy of some of these treatments, but additional research is needed to determine the best approach on an individualized basis.
To what extent is mental health therapy routinely recommended as part of the standard care plan for individuals with MS, considering the high prevalence of depression and anxiety in this population?
Why this question matters: Mental health concerns including depression and anxiety are common in people with MS and can significantly affect quality of life, disease management, and overall health outcomes. Understanding the extent to which mental health therapy is being recommended can reveal important gaps in care delivery and help ensure comprehensive treatment that addresses both physical and psychological needs.
Background: Studies conducted to date highlight significant gaps between the mental health needs of people with multiple sclerosis (PwMS) and the support they receive. Surveys and interviews of healthcare providers indicate varying levels of depression screening as a routine practice. Frequency of mental health recommendations and referrals may also vary based on country/region.
Do Hispanics as a group have different MS symptoms than non-Hispanic people? What about other people of diverse racial and ethnic groups, e.g., African Americans, Asian Americans, or Native Americans?
Why this question matters: Understanding ethnic variations in the presentation of MS symptoms can improve diagnosis accuracy and tailor treatment plans. Certain ethnic groups may experience earlier disability progression, greater motor or visual symptoms, or differences in lesion location. Identifying differences allows clinicians to offer culturally informed, equitable care and better counseling on what to expect.
Background: Recent research reveals that differences in MS risk and severity do exist among racial and ethnic groups; however, less is known about the differences in the frequencies of specific symptoms across groups. Prior studies have reported higher symptom burden for specific groups; for example a higher rate of optic neuritis in Hispanic/Latinx people, particularly those with Native ancestry, and greater mobility impairment in Black/African Americans.