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Cognitive reserve may help the brain resist the effects of MS on thinking

By Erik Greb

credit: SDI Productions/Getty Images

During the past few decades, research has made clear that multiple sclerosis causes not only physical disability but also cognitive problems. Patients with MS commonly report memory lapses and word-finding difficulties, to cite only the most frequent complaints. Such clinical observations have prompted many investigators to examine how MS affects cognitive functions such as memory and processing speed. Yet patients with similar disease activity and disease duration sometimes have different levels of cognitive deficit.


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Researchers have advanced the theory of cognitive reserve to explain this observation. Yaakov Stern, PhD, professor of neuropsychology at Columbia University Medical Center in New York, and colleagues were among the first to develop the theory when they observed that people with higher educational attainment lived longer without developing clinical signs of dementia. The theory has since been adopted by specialists in MS.

Defining and measuring cognitive reserve

“Cognitive reserve is the influence of the environment in protecting against clinical manifestation of neurologic damage,” said John DeLuca, PhD, senior vice president for research and training at Kessler Foundation in West Orange, N.J. “It’s the idea that a lifetime of cognitively enriching activities creates a brain that is more resistant to the effects of the disease – not to the disease itself, but to the effects of the disease.”

Enriching activities can be physical, cultural, intellectual, or spiritual, said Bianca Weinstock-Guttman, MD, professor of neurology at the State University of New York at Buffalo. Data suggest that these activities improve cognition, activities of daily living, and quality of life, she added.

The efficiency of brain function is one component of cognitive reserve, which can be understood as a patient’s maximum capacity for cognition, according to James F. Sumowski, PhD, associate professor of neurology at the Icahn School of Medicine at Mount Sinai in New York. The amount of a patient’s cognitive reserve depends mainly on genetics, the environment in which he or she spent the formative years, and education, he added.

Dr. John DeLuca

Dr. Bianca Weinstock-Guttman

Research suggests that personality, early life environment, and cognitive reserve are linked. Roy et al. found that childhood enrichment activities and a higher degree of conscientiousness have a synergistic effect on cognitive processing speed. “These data support using psychological interventions to foster reserve and adaptive personality characteristics to benefit patients with longstanding MS,” said Dr. Weinstock-Guttman.

Neurologists do not measure cognitive reserve directly, but through proxies. The traditional means is to administer the North American Reading Test or the Wechsler Test of Adult Reading, which require patients to read aloud lists of words of increasing sophistication. The ability to read such lists is believed to withstand aging and neurologic diseases such as MS. The persistence of this ability allows clinicians to estimate a patient’s premorbid vocabulary and IQ, said Dr. Sumowski. These tests, however, do not measure a patient’s current cognitive reserve, he added. If these word lists are not available, clinicians use other proxies such as years of education and occupational attainment to measure cognitive reserve.

 

The benefits of cognitive reserve

As MS progresses and brain atrophy increases, patients with higher cognitive reserve are less likely to have evident cognitive decline than patients with low cognitive reserve, said Dr. DeLuca. Conversely, patients with low cognitive reserve at diagnosis are at higher risk of cognitive decline than patients with high cognitive reserve. The same degree of atrophy on MRI thus may result in different outcomes between patients. But the effects of cognitive reserve are less evident at lower levels of brain atrophy, said Dr. DeLuca.

In a study published in Neurology in 2013, Sumowski et al. examined 62 patients with MS using MRI. The investigators also estimated participants’ cognitive reserve, based on their early life cognitive leisure, and assessed their cognitive status. They found that cognitive reserve protected patients against disease-related cognitive decline independently of, and in addition to, the effects of brain reserve, which they defined as maximal lifetime brain volume. Cognitive reserve “delays the negative effects of disease on cognition,” said Dr. Sumowski.

Therefore, there are probably things that protect some people from the negative effects of disease on cognition, and we want to identify those things.

A recent functional MRI study by Fuchs et al. showed that higher premorbid verbal intelligence, which the investigators considered a proxy for cognitive reserve, predicted relative preservation of functional connectivity despite accumulation of gray-matter atrophy. Furthermore, preserved functional connectivity attenuated the effect of white-matter tract disruption on cognitive processing speed and visuospatial memory. “These data suggest that preserved functional connectivity explains cognitive reserve in people with MS, thus helping to maintain cognitive capacity despite structural damage,” said Dr. Weinstock-Guttman.

Although the relationship has not been studied widely, evidence suggests that cognitive reserve can protect against physical disability, as well. “Interestingly, a recent meta-analysis of cognitive reserve literature substantiated a significant impact of cognitive reserve on preserving physical ability and cognitive functioning, but cognitive reserve did not moderate the relationship between Expanded Disability Status Scale [score] and cognitive performance,” said Dr. Weinstock-Guttman.

Part of the clinical value of the concept of cognitive reserve is that it enables clinicians to identify patients with MS who are at risk of greater cognitive decline. It also indicates that a given number of lesions or a given amount of atrophy is not necessarily associated with a distinctly defined cognitive decrement, said Dr. Sumowski. “Therefore, there are probably things that protect some people from the negative effects of disease on cognition, and we want to identify those things.”

Can cognitive reserve be modified?

Whether a patient’s amount of cognitive reserve can be modified is a central focus of research. “A person with high cognitive reserve to begin with can potentially still build cognitive reserve,” said Dr. DeLuca. “A person with low cognitive reserve to begin with can likely also build up cognitive reserve. But we’re not sure about whether they can build it to the same degree.”

Recommendations may differ from patient to patient. One approach is for a clinician to ask, “What are you missing in your life that you used to do?” said Dr. DeLuca. “Get them to do something that they like, to get back into it. Join a book club, for example…. The point is becoming socially and cognitively active. It should be a prescription.”

Although clinicians encourage patients with MS to engage in cognitively stimulating activities, no high-quality studies have examined which types of interventions could increase cognitive reserve, said Dr. DeLuca. The literature on aging and dementia suggests that a range of cognitively stimulating activities (e.g., reading books, solving puzzles, socializing, and playing cards) can be beneficial, but these studies are observational rather than interventional.

“Most available studies are based on cross-sectional cohorts,” said Dr. Weinstock-Guttman. “Longitudinal studies of specific interventions, including active exercise programs, cognitive rehabilitation, and mindfulness programs, should be considered within specific age and disability groups to better understand the benefit of a single intervention versus the combined effect of multiple interventions in improving cognitive reserve, and ultimately well-being, in patients with MS.”

Although clinicians should recommend stimulating activities, “we don’t have evidence that doing those things is going to improve outcomes,” said Dr. Sumowski. Patients who report that they engage in cognitively stimulating activities have better outcomes, but investigators have not conducted causal research to determine whether such activities can change outcomes. “We either have to do those studies … or we can focus on modifiable factors that we know are related to brain health generally.” Shifting the focus from building cognitive reserve to preserving cognitive reserve will lead to clearer clinical recommendations, said Dr. Sumowski.

One mechanism by which a patient can preserve his or her cognitive reserve is to reduce the negative effects of MS on the brain. The importance of providing timely therapeutic interventions that decrease the risk for underlying pathology (e.g., lesion burden and atrophy) is indisputable, said Dr. Weinstock-Guttman.

The other main mechanism for preserving cognitive reserve is to maintain general brain health. Focusing on brain health provides targets for intervention that are based on good evidence, said Dr. Sumowski. These targets include modifiable factors such as diet, obesity, cardiovascular health, sleep, and depression.

All clinicians who treat patients with MS should focus “not just on disease-modifying therapies, but on the idea that the environment can change brain function to lessen the possibility of cognitive decline later on.”

Seeking the neural basis of reserve

Many aspects of cognitive reserve remain to be clarified. Whether it can be improved and which specific interventions could improve or maintain it are open questions. Cognitive reserve is measured by proxy, and the best way to measure it has yet to be determined, said Dr. DeLuca. The effect of any given proxy also is uncertain. “Does verbal intelligence as a proxy have a greater effect on certain cognitive variables such as processing speed or memory, whereas another proxy such as years of education may be more aligned with other aspects of cognition? It’s unclear,” said Dr. DeLuca. Furthermore, neurologists do not yet know whether a combination of various proxies would provide a better measure than one proxy alone.

In addition, the ways in which interventions could preserve or increase cognitive reserve must be clarified. Research into imaging techniques, such as functional MRI, that can reveal the underlying brain network changes resulting from various interventions, as well as their correlations with cognitive outcomes, will be beneficial, said Dr. Weinstock-Guttman.

“We don’t understand completely how cognitive reserve is instantiated in the brain,” said Dr. Sumowski. The theory is that cognitive reserve is associated with efficient information processing, but the manifestation of this efficiency is unknown. “Do [patients with cognitive reserve] have more synapses? Do they have more dendritic spines that are leading to more synapses? We don’t know exactly what the basis of reserve is in the brain. If we can identify the neural basis of reserve, maybe there are mechanisms to help preserve those connections.”

Another unanswered question is whether cognitive reserve influences cognition in general or whether patients have reserves for particular domains. “If you have reserve for processing speed, is it the same as reserve for language? Or are they all just different abilities that have their own capacities?” said Dr. Sumowski. “Usually, it’s thought that reserve is one entity, but it could be that people have different reserve for different types of functions.”

As investigators examine these questions, all clinicians who treat patients with MS should focus “not just on disease-modifying therapies, but on the idea that the environment can change brain function to lessen the possibility of cognitive decline later on,” said Dr. DeLuca. Maintaining cognitive stimulation could enable patients to continue working and improve their everyday lives. “Despite the fact that there’s lots of research to be done, it is something that we can do right now to potentially help patients.”