Presented by the New York Academy of Sciences
Cognitive Dysfunction in Multiple Sclerosis: New Approaches to Diagnosis and Treatment
Posted August 25, 2011
Multiple sclerosis (MS) is a degenerative autoimmune disorder that affects the transfer of neural impulses. The immune system destroys the fatty myelin sheath that insulates axons in the central nervous system, the brain, and the optical system, causing signals in these areas to travel less efficiently. As a result, patients usually have problems with movement and vision and have, in up to 70 % of cases, some degree of cognitive impairment.
Although there is no cure for MS, treatments are available to delay and to manage many of the physical symptoms. Cognitive impairments are highly variable, hard to assess, and therefore difficult to treat. During this meeting, Cognitive Dysfunction in Multiple Sclerosis: New Approaches to Diagnosis and Treatment, held from June 21 – 23, 2011 at the New York Academy of Sciences, neurologists, neurobiologists, neuropsychologists, genomics and imaging experts, and patient advocates gathered to discuss cognitive impairments in MS. Over the course of this 2.5 day meeting, researchers discussed the neurobiological underpinnings of cognitive impairment in MS, drug therapies that can improve cognition, tests for diagnosing cognitive impairment in MS, and brain imaging studies to better understand cognitive dysfunction.
Use the tabs above to find a meeting report and multimedia from this event.
Presentations available from:
Peter Arnett, PhD (Penn State University)
Jacqueline T. Bernard, MD (University of Chicago)
Peter Calabresi, MD (Johns Hopkins University School of Medicine)
Patrizia Casaccia, MD, PhD (Mount Sinai School of Medicine)
John DeLuca, PhD (Kessler Foundation Research Center)
Ranjan Dutta, PhD (The Cleveland Clinic)
Massimo Filippi, MD (University San Raffaele, Milan, Italy)
Robert L. Kane, PhD (Washington Neuropsychology Research Group)
Lauren Krupp, PhD (Stony Brook University Medical Center)
Aaron E. Miller, MD (Mount Sinai School of Medicine)
Daniel Pelletier, MD (Yale University School of Medicine)
Stephen M. Rao, PhD (Cleveland Clinic Foundation)
Daniel Reich, MD, PhD (National Institute of Neurological Disorders and Stroke)
Nancy Sicotte, MD (Cedars-Sinai Medical Center)
Stephen G. Waxman, MD, PhD (Yale University School of Medicine and Veterans Affairs Connecticut)
Heather Wishart, PhD (Dartmouth Medical School)
Patient Advocacy Panel Discussion
- 00:011. Introduction; Cynthia Sitcov on the experience of MS
- 07:452. Nicholas LaRocca on the evolution of comprehensive care
- 12:003. Jeffrey Gingold on the impact of MS on cognition
- 15:214. Patient-physician dialog
- 26:025. Defining cognitive dysfunction
- 31:006. Projecting new treatments and targets; Drug treatment for cognitive issues
- 36:407. The stigma of cognitive issues
- 47:348. Manifestation of symptoms; Endpoints in drug development
- 53:009. Conclusio
- 00:011. Overview; Contributors to cognitive deficits in MS
- 03:342. Depression; Potential overlap with MS; Treatment
- 10:363. Anxiety; Studies; Assessing anxiety in MS
- 15:474. Fatigue and exceptions in its association with MS; Studies
- 26:155. Coping as a moderator of cognitive dysfunction; Studies
- 32:046. Summary; Acknowledgements and conclusio
- 00:011. Introduction and overview
- 03:132. Early intervention; Natalizumab; Effects of T cell reduction; Studies
- 07:483. Recent clinical data showing benefit of natalizumab
- 12:234. Optical coherence tomography; Symbol digit modalities test
- 15:545. New study and preliminary data
- 20:136. Predictions, a caveat, and summary; Acknowledgements and conclusio
- 00:011. Introduction
- 05:462. The Griffin Hypothesis; Demyelination; Myelin associated glycoprotein
- 11:053. MAG mouse studies; Summary of in vivo findings
- 18:184. In vitro studies; Summary of results
- 23:355. Treatment of reverse cognitive impairment in MS; Barnes Maze study
- 29:566. Conclusions and future directions; Acknowledgement
- 00:011. Introduction; Cognitive deficits in MS
- 04:122. Learning and memory; Aquisition and retrieval studies
- 08:003. Behavioral approaches; Self-generation, spaced learning, and testing effect
- 18:524. Context and imagery; Studies and preliminary results
- 26:585. White matter tract integrity; Cognitive reserve hypothesis; Aerobic exercise
- 40:076. Summary; Acknowledgements and conclusio
- 00:011. Introduction; Gray matter lesions
- 03:482. New criteria; Future perspectives; Clinical correlations
- 08:553. "Diffuse" GM damage; Prediction of disability
- 10:484. GM atrophy; Cognitive impairment
- 16:365. Cortical reorganization
- 26:476. Cognitive rehabilitation; Conclusions and acknowledgement
- 00:011. Introduction
- 03:302. Challenges; Cognition studies, batteries, and results
- 07:513. Glatiramer acetate trial; Sensitivity of PASAT to treatment effects; DMT summary
- 12:174. Failed cognitive therapies in MS; Trial design challenges
- 19:045. Cholinesterase inhibitor studies; Results
- 25:576. Summary and conclusio
- 00:011. Introduction
- 04:572. Molecular mimicry; Clinical patterns
- 11:473. Conventional MRI in practice; Ultra high field strength MRI
- 17:204. Disease type and disability progression; Conventional wisdom and "benign" MS
- 20:575. Safety, efficacy, and tolerability; Predicting the course; Goal of therapy
- 27:286. Disease-modifying therapy; Immunodulatory treatments
- 34:567. Natalizumab; Fingolimod; Teriflunomide
- 42:298. B-cells and CD20; Rituximab; Alemtuzumab
- 48:409. Design and conduct of clinical trials; Disease modifying therapy
- 55:2810. Summary and conclusio
- 00:011. Introduction and history
- 06:542. Cognitive dysfunction and daily functioning; Correlates
- 10:483. Pathology; CT vs. MRI
- 15:164. MS lesions and focal cognitive impairment; Atrophy of the corpus callosum
- 20:075. Longitudinal perspective; fMRI changes and normal performance
- 30:416. Disease burden; Implications for clinical trials; Acknowledgements and conclusio
- 00:011. Introduction; Gray matter affected in MS; Hippocampal involvement
- 05:162. Cognitive function affected in MS; Hippocampal structure; Study
- 13:403. Adding function to structure; Study
- 21:354. Contributing factors; Second cohort; Hippocampal subregional vulnerability
- 28:085. Assessing change over time; Summary
- 32:346. Acknowledgements and conclusio
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Ranjan Dutta and Bruce D. Trapp
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Filippi M, Rocca MA. Novel MRI approaches to assess patients with multiple sclerosis. Curr. Opin. Neurol. 2010 Jun;23(3):212-7.
Filippi M, Rocca MA. MR imaging of gray matter involvement in multiple sclerosis: implications for understanding disease pathophysiology and monitoring treatment efficacy. AJNR Am. J. Neuroradiol. 2010 Aug;31(7):1171-7.
Lauren B. Krupp
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Aaron E. Miller
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Stephen M. Rao
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Stephen G. Waxman
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Aaron Miller, MD
Aaron Miller is the Director of Clinical Affairs at the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai School of Medicine in New York City. He also serves as Co-director of the Multiple Sclerosis Care Center at Maimonides Medical Center in Brooklyn, NY. He completed his undergraduate degree at Brandeis University, and his medical degree from New York University School of Medicine. He completed a residency in Internal Medicine at Jacobi Hospital Center and a residency in neurology at Bronx Municipal Hospital Center. He also carried out postdoctoral research at Johns Hopkins School of Medicine and Albert Einstein College of Medicine. Miller is a past president of the Consortium for Multiple Sclerosis Centers.
Peter Arnett, PhD
Jacqueline T. Bernard, MD
Pasquale Calabrese, PhD
Peter Calabresi, MD
Patrizia Casaccia, MD, PhD
John DeLuca, PhD
Ranjan Dutta, PhD
Massimo Filippi, MD
Jeffrey N. Gingold
MS Patient Advocate
Robert L. Kane, PhD
Lauren B. Krupp, PhD
Nicholas G. LaRocca, PhD
Aaron E. Miller, MD
Daniel Pelletier, MD
Stephen M. Rao, PhD
Daniel Reich, MD, PhD
Nancy Sicotte, MD
MS Patient Advocate
Bruce D. Trapp, PhD
Stephen G. Waxman, MD, PhD
Heather Wishart, PhD
Sarah Webb, PhD
Before hanging up her labcoat, Sarah Webb earned a PhD in bioorganic chemistry from Indiana University in Bloomington. Based in Brooklyn, NY, she writes about science, health, and technology for many publications including Scientific American, Discover, Science Careers, Science News, Nature Biotechnology, and ACS Chemical Biology.
Basic Multiple Sclerosis biology
In the last 20 years researchers have made progress in understanding the basic biology of Multiple Sclerosis and in developing treatments. As of 1993, no drug treatments were available, but today eight therapies have been approved by the Food and Drug Administration, and several others are in late-stage clinical testing. In his keynote address, Aaron Miller of Mount Sinai School of Medicine outlined the current understanding of the science of MS and described the function both of available therapies and of those currently in testing.
Both genetic and environmental factors interact to cause MS. Several genetic polymorphisms increase the risk of developing MS, and children and siblings are at increased risk compared to the general population. But even among MS patients with identical twins, only 30% of the twins will also develop the disease. MS occurs more often in women and those of caucasian descent. A variety of environmental triggers have been implicated including microbial agents, vitamin D deficiency, or infection with Epstein-Barr virus.
Researchers suspect that a combination of these genetic and environmental factors spurs the autoimmune response underlying MS. The body generates T cells that respond to a particular antigen in the peripheral blood. These foreign proteins (antigens), however, resemble proteins in the central nervous system. Instead of zeroing in on and fighting the invader, the T cells begin to attack the nervous system.
The course of MS symptoms typically follows a distinctive pattern. Up to 85% of those with MS initially have symptoms classified as relapsing-remitting MS. In these cases, symptoms such as fatigue, balance problems, numbness, pain, and vision impairment will flare up intermittently, but in between those periods the symptoms might completely subside. Approximately half of these patients will eventually develop secondary progressive MS: after an initial period of flare-ups and remissions, symptoms will worsen gradually over time or progress between flare-ups. The other 15% of MS cases are a combination of primary progressive disease where symptoms worsen consistently over time (with no distinct relapses or remissions), or progressive relapsing MS, where symptoms continue to worsen between flare-ups. Available treatments target relapsing-remitting MS, and treatments are desperately needed for the progressive forms of the disease, Miller says.
The inflammatory activity accompanying MS leads to changes in the brain, spinal cord, and optic nerve that researchers can observe using magnetic resonance imaging (MRI). New or newly active lesions are typically characterized by perivascular inflammation and disruption to the blood-brain barrier. Contrast agents containing gadolinium (Gd) can cross the disrupted blood brain barrier and thereby enhance the appearance of these active lesions on T1-weighted MRI scans. Lesions in white matter show high contrast with Gd in conventional MRI scans. Increasingly, imaging specialists are observing lesions in gray matter as well as in white, and the development of instruments with increased field strengths (8 Tesla) are allowing researchers to get more detailed views of MS lesions within the brain.
Drug treatments for Multiple Sclerosis
Although there is no cure for MS, doctors typically prescribe some course of drug treatment. Within 15 years of diagnosis, half of all MS patients cannot walk without an aid, but available therapies can delay the progression of the disease. In making treatment decisions, clinicians weigh a number of factors both to predict a patient's prognosis and to balance the safety, efficacy, and tolerability of available therapies, some of which have significant side effects. Potential indicators of a more severe disease course include severe symptoms at the first onset of disease, incomplete recovery from that attack, a large volume or number of T2 lesions (lesions that appear bright in T2-weighted MRI scans) visible in imaging studies, and a short interval between attacks. T2-weighted scans, with their required scan acquisition parameters, are particularly good at revealing pathological edema or inflammation, because water-containing tissues have longer T2 values. T2 values are time constants for describing signal decay in MR imaging.
Three forms of interferon-β are approved for treating MS, all of which modulate the activity of T cells and suppress the expression of various chemokine receptors. Another drug, glatiramer acetate affects the Th2 immune response and spurs the production of anti-inflammatory cytokines.
Natalizumab, another FDA-approved therapy, is a monoclonal antibody that targets the adhesion proteins that immune cells use to cross the blood brain barrier and thereby attack the central nervous system. Another antibody, rituximab, targets CD20, a protein expressed on the surface of B cells, and showed efficacy in a phase II trial.
Fingolimod is the first drug approved for MS that can be taken orally. It targets surface molecules on lymphocytes and directs those cells to internalize the sphingosine I phosphate receptor. That process prevents these cells from being able to leave the lymph nodes. A third phase III trial of the drug was recently completed showing a 54% decrease in relapse compared with placebo.
Most of these drugs have not been tested in head-to-head comparisons, Miller says, so in many cases the relative efficacies of these therapies are not known. In addition, a clinical trial is currently underway to examine whether a combination of glatiramer acetate and interferon-β is more effective than either of these drugs given individually.
Clinical trials, however, have not focused on examining whether any of the drugs that are currently approved or in clinical testing is effective in treating cognitive symptoms in MS. Retrospective studies offer hints that these drugs are having an effect on some of the inflammatory features connected with cognitive impairment, but studying the effect on cognitive impairment is difficult, Miller says. Researchers have to decide on a battery of tests, and even then it can be hard to tease out how other factors such as depression, cognitive reserve, or fatigue might affect those results. Finally, the learning effect—where patient performance on cognitive tests improves over time—can complicate assessments of drugs' effects on cognitive performance.
Cognitive issues in Multiple Sclerosis
In a panel discussion following Miller's talk, he joined Cynthia Sitcov and Jeffrey Gingold, patient advocates, and Nicholas LaRocca of the National Multiple Sclerosis Society to set the stage for the discussion of cognitive impairment and MS. At least 50% and up to 70% of patients with MS suffer some kind of cognitive impairment.
Cognitive impairment in MS is variable, LaRocca said: while one patient might show severe impairment, another patient might appear unaffected. The cognitive areas that are most likely to be affected are memory and the speed of processing. Other problems can involve spatial orientation, Miller said, but people with MS, unlike those with Alzheimer's disease, rarely lose the ability to do skilled activities. An individual with MS often might not notice some of the cognitive symptoms unless a family member points them out. Gingold, who has MS, occasionally experiences word-switching, where he'll unconsciously use an incorrect word when talking. He might not remember the order in which items were said to him, or, when going somewhere, he might get lost or forget why he made the trip.
Peter A. Calabresi, Johns Hopkins University School of Medicine
Ranjan Dutta, the Cleveland Clinic
Bruce D. Trapp, Lerner Research Institute at the Cleveland Clinic Foundation
Patrizia Casaccia, Mount Sinai School of Medicine
- A peptide portion of myelin-associated glycoprotein (MAG) shows promise as a potential MS therapeutic.
- Drugs that improve cognitive function in MS might not necessarily be the same ones that work on physical symptoms.
- Demyelination in the hippocampus follows patterns different from those seen in white or gray matter.
- Myelin appears to regulate gene expression in the hippocampus.
- Histones and mitochondrial proteins are highly acetylated in the neurons of MS patients.
Apparent independence of cognitive and physical symptoms
Treating and even preventing cognitive impairment in MS requires a thorough understanding of the biological mechanisms that cause these problems. Researchers described work to uncover the pathways that lead to neuro-axonal injury and to better understand their relationship to cognitive impairment. They also seek to better understand the changes in the hippocampi of MS patients and the role of histone deacetylation in MS.
Peter Calabresi described the neurobiology of demyelination and the processes that researchers can target therein. The process of demyelination causes a number of biological problems in axons. Damage to myelin increases the energy required for signals to propagate through axons. In addition, myelin damage makes axons more vulnerable to damage from nitric oxide and decreases phosphorylation of cytoskeletal proteins. Demyelinated axons are therefore more likely to experience mitochondrial stress.
Calabresi and his colleagues would like to understand the role of myelin-associated glycoprotein (MAG) in disrupted myelination in MS. Knockout mice that lack this protein can still produce myelin sheaths, but they also show axonal degeneration in nerves in both the peripheral and central nervous systems. In a series of studies in mice, Calabresi and colleagues showed that MAG can protect axons from drug-induced damage in cell culture, possibly through an interaction with the membrane protein β1-integrin. A peptide based on a section of the MAG amino acid sequence could prove useful as an MS therapeutic.
Calabresi also described experiments looking at enzyme inhibitors that could be useful as a treatment for cognitive impairments in MS. N-acetylaspartylglutamic acid (NAAG) is the third most common peptide neurotransmitter and can protect neurons by activating the metabotropic glutamate receptor 3 (mGluR3). Glutamate carboxypeptidase II (GCP II) hydrolyzes NAAG, thereby impeding NAAG's protective function. Calabresi and his colleagues wondered if 2-PMPA, an inhibitor of this enzyme, could protect against impairments in mice with experimental autoimmune encephalomyelitis (EAE), a model syndrome for MS.
Daily treatment with this small molecule did not change the progression of the EAE physical symptoms in the mice. Even with the lack of physical changes, the researchers decided to attempt cognitive studies to look at whether the drug affected the learning in animals with EAE. They used a Barnes maze, a darkened box where mice had to find a target. Two groups of mice with EAE—one group treated with 2-PMPA and one control group—were tested in four trials per day over four days. Both groups of mice took an equivalent amount of time to find the target initially. But by day four, the treated mice found the target more quickly and more efficiently, a 40% improvement over that of the untreated mice.
Because this inhibitor of GCP II showed cognitive benefits without improving physical disability, the results suggest that the drugs that improve cognitive function in MS patients might not be the same treatments that improve physical symptoms. This pathway could represent a promising target for treating cognitive impairment in MS and other neurodegenerative diseases.
Multiple Sclerosis and learning and memory: studies of the hippocampus
Up to 40% of MS patients have memory problems, which suggests that the course of the disease affects neurons within the hippocampus. In their presentations, Ranjan Dutta and Bruce Trapp of the Cleveland Clinic Foundation described their work to better understand the pathology of MS in this section of the brain and to develop possible interventions to slow memory impairment.
Dutta examined hippocampi from the brains of 22 MS patients post mortem to better understand the demyelination pathology and gene expression patterns within this brain structure. Among these patients, axons in 10 of the hippocampi were myelinated, while the other 12 were demyelinated. Neither the myelinated nor the demyelinated hippocami showed any significant loss of neurons, but the gene expression profiles in the demyelinated hippocampi are significantly altered. For example, the expression of the motor proteins, kinesin and dynein, is reduced in demyelinated axons, which could decrease the efficiency of axonal transport, a critical component of memory formation. Several specific structural proteins that mediate signals across synapses also showed decreased expression levels in the demyelinated hippocampi. In these synapses glutamate levels are not as well regulated, which could put these neurons at risk for damage from elevated levels of this neurotransmitter. In addition, the levels of other key molecules such as pCAMKII and pCREB are reduced. Together these results suggest that myelin helps to regulate gene expression in the hippocampus, Dutta said. Bruce Trapp continued the discussion of MS and the hippocampus and described studies that examine the effects of possible remyelination therapies on that section of the brain.
Protein acetylation and cognition in Multiple Sclerosis
Protein acetylation regulates a variety of fundamental biological processes, including memory formation. Acetylation of substrates is modulated by a balance between enzymes depositing acetyl groups (histone acetyltransferases, HATs) and those removing acetyl groups (histone deacetylases, HDACs). The presence of acetyl groups on a protein substrate modifies its function. For instance, acetylation of nucleosomal histones enhances the access of transcription factors to DNA and therefore facilitates transcription, while acetylation of cytoskeletal proteins modulates transport of organelles along the axons. Memory consolidation requires the transcription of genes that are dependent on the transcription factor CREB, and the acetylation of CREB enhances transcription. Previous studies on cognitive impairment in neurodegenerative disorders (e.g., Huntington’s and Alzheimer’s diseases) reported decreased acetylation of substrates in neuronal populations and suggested that blockers of HDAC could be beneficial for treatment of cognitive symptoms. Patrizia Casaccia from Mount Sinai School of Medicine and her colleagues have found that HDAC1 exits the nucleus of neurons in the gray matter from MS patients and that the acetylation state of nucleosomal histones is increased in these patients, which brings into question the validity of treatment with HDAC inhibitors for MS patients. She also mentioned that deacetylation of the histones in early progenitors is crucial for the formation of new myelin during repair from demyelination. Thus, it was suggested that treatment of cognitive impairment should be tailored to the patient’s underlying pathology and that treatment that may be effective in Alzheimer’s disease may not be equally effective for Multiple Sclerosis. One of the newer approved therapies for MS, fingolimod, interferes with the signaling of sphingosine-1-phosphate, a molecule that also acts as an HDAC inhibitor in cells, and in the future it will be important to investigate and understand the effect of fingolimod on histone and other protein deacetylation.
Stephen G. Waxman, Yale University School of Medicine and Veterans Affairs Connecticut
Robert L. Kane, University of Maryland School of Medicine
Lauren Krupp, Stony Brook University Medical Center
Jacqueline T. Bernard, University of Chicago
- Sodium channels appear to play an important role in demyelination and cognitive dysfunction. Drugs that block their activity may have a role in treating these impairments in MS.
- Treating fatigue in MS patients could improve other aspects of cognitive function.
- Carrying out clinical trials to study cognitive impairment is challenging. Trials are often carried out over limited periods, which can be too short to see the cognitive effects of a drug. Another difficulty comes in selecting the patient population: patients need to show sufficient cognitive impairment so that small improvements can be detected.
- Studies with natalizumab suggest potential for curbing cognitive symptoms in MS.
Phenytoinn, modafinil, donepezil, and natalizumab: promising MS pharmacotherapies
More than half of MS patients are unable to work within 10 years of their diagnosis, and for the majority of these individuals, cognitive rather than physical impairments prove more limiting. A few clinical trials are starting to examine how drug therapies for MS and drugs approved for other uses might improve cognition in MS patients. These studies highlight the potential for progress and underscore the challenges in understanding cognitive impairment in MS.
Sodium channels are expressed on the surface of axons, and degenerating axons express more Nav1.6 channels than Nav1.2 channels. These changes in sodium channel expression levels suggest that these pump-like molecules and sodium levels may be important for demyelination and cognitive function in neurodegenerative disease. Stephen Waxman from Yale University School of Medicine and his colleagues have been looking at the effects of phenytoin, an anti-seizure drug that blocks sodium channel activity, in both EAE and MS. Over the short term, 30 days, and over the long term, 180 days, the use of this sodium channel blocker improved cognitive function in mice with EAE. However, when the drug was withdrawn suddenly, more than half of the mice died, suggesting a possible safety issue. Since this finding, Waxman and his colleagues have continued their investigations into the role of sodium channels in axons to find the optimally safe and effective use of this drug to treat MS.
Fatigue is a common cognitive symptom reported by MS patients. Robert Kane and his colleagues at the Washington Neuropsychology Research Group wanted to understand whether modafinil, a treatment for narcolepsy, could prove useful as an adjunct therapy for patients with MS, lessening fatigue and improving cognition. They study enrolled 60 MS patients who were already taking interferon-β-1a and divided them into a group that took modanifil and a control group. The patients then reported their fatigue and their mood and were given a battery of cognitive tests. These tests suggested statistically significant improvements in fatigue, mood, and some of the cognitive tests that required significant effort. The results overall suggest that further efforts to understand and treat fatigue among MS patients could have overall cognitive benefits as well.
Clinical trials to study cognitive effects are inherently challenging to design and implement. Lauren Krupp of Stony Brook University Medical Center described a failed trial of donepezil, a drug used to treat dementia, in MS patients as a case study for understanding these difficulties and for improving future studies. In a few of the large pharmacological studies of new MS drugs, researchers have tried to include cognitive effects as a secondary outcome. Those studies indicate mild cognitive benefits with some treatments such as interferonβ-1a and interferonβ-1b. However, because such studies are carried out over a relatively short period of time, less than four years, the subjects in those trials might not show an MS-induced cognitive decline. Instead, because they become better able to perform the cognitive tasks with repetition, subjects may show improved cognitive performance, which makes results difficult to interpret. The selection of tests is also important: many test batteries include a time-consuming and complicated mixture of tests. The time involved can mean that patients do not complete the study, and the resulting data can be difficult to analyze.
In their study of donezepil Krupp and her colleagues did not find significant memory improvements among their study cohort over 24 weeks based on cognitive testing and self-reports. One problem may have been the choice of this particular drug, Krupp said, which has shown cognitive benefits with patients with Alzheimer's and Parkinson's disease but not in patients with cognitive impairments with other causes. Because the observed cognitive changes are likely to be mild, Krupp also suspects that their study did not include patients with significant enough impairment to show an effect. The need for a reasonable sample size of patients with sufficient cognitive impairment to show a measurable effect requires both multicenter recruitment efforts and a large number of people trained to give these batteries of cognitive tests. She also highlighted the need for new, more effective pharmacological agents that consistently improve cognition based on primary outcomes in randomized clinical trials.
Jacqueline Bernard of the University of Chicago described clinical studies examining whether MS patients treated with natalizumab show cognitive benefits. Natalizumab interferes with cell adhesion processes that allow inflammatory T-cells to cross into the blood brain barrier. Results from a clinical study examining fatigue and cognition in patients with relapsing-remitting MS in a single-arm study with natalizumab showed improvements in overall cognitive efficiency and in procedural reaction time. A variety of other studies examining the effects of natalizumab show reduced damage to brain structures.
In a new study, Bernard and her colleagues are attempting to correlate cognitive performance on the Symbol Digit Modalities Test (SDMT) with a measure of biological changes in the brain. They are also comparing established methods for looking at MS progression in the brain, such as brain and gray matter atrophy from MRI scans, with Optical Coherence Tomography—a measure of neural degeneration on the back of the retina, a quick and non-invasive test. Bernard and her colleagues expect that it may take two years of treatment with natalizumab to see a significant cognitive effect, an issue that they will need to balance with the potential for a life-threatening side effect with this drug, progressive multifocal leukoencephalopathy.
John DeLuca, Kessler Foundation Research Center
Peter Arnett, Pennsylvania State University
Heather Wishart, Dartmouth Medical School
- Cognitive remediation strategies can improve quality of life for MS patients, and the effect is comparable to that of available drug therapies.
- Active coping strategies and cognitive reserve are correlated with better cognitive function in MS patients who are depressed.
- Genome-wide association studies, studies of biological pathways, and those of individual genes such as apolipoprotein E may help explain the heterogeneity of cognitive dysfunction in MS.
Improving memory through learning strategies
To prevent cognitive impairment or to improve cognitive function, researchers need to understand the underlying cognitive problems. In earlier research, John DeLuca of the Kessler Foundation Research Center and his colleagues had asked whether memory difficulties among MS patients resulted from problems with the recall of information or whether the information had been fully learned in the first place. Those studies suggested that learning rather than memory was disrupted among MS patients.
DeLuca and his colleagues have since developed rehabilitation strategies that use learning concepts from cognitive psychology. In a series of studies, they demonstrated the "generation" effect in MS patients using fill-in-the-blank tasks. If a person generates the answer to fill in a sentence himself, he is more likely to remember it, and that strategy helped MS patients perform better on food preparation, financial management, and other day-to-day tasks. Other strategies, such as learning over a spaced period of time and testing oneself on concepts, improved information retention and recall. Combining these techniques—self-generation with spaced learning, for example—increased the overall effect.
These initial cognitive remediation studies show effects of similar magnitude to those observed for cognitive improvement in drug trials. DeLuca and his colleagues are currently working on an NIH-funded cognitive remediation trial to correlate their cognition studies with brain imaging results, both MRI and fMRI, and to describe the effects of these remediation tools. Preliminary data from those trials show increased learning and increased activation in areas of the brain for patients undergoing cognitive remediation.
Coping and depression in patients with Multiple Sclerosis
Much of the focus in understanding disease progression and prognosis has been directed towards the development of better ways to gauge lesion load and atrophy in the brain. These structural changes, however, only account for 40% of the variance in symptoms observed, suggesting that other secondary influences, such as depression, anxiety, and fatigue, also play a role in cognitive dysfunction in MS. Depression is one such influence, affecting 50% of MS patients. Although treating these secondary influences can help improve cognitive function, the overlap in symptoms can make it difficult to distinguish symptoms of anxiety, depression, or fatigue from MS symptoms, said Peter Arnett of Penn State University.
Arnett and his colleagues have looked at cross sectional data to understand how coping strategies might be connected with cognitive dysfunction related to depression. Depressed patients who employ highly adaptive coping strategies show cognitive function and mood scores similar to healthy subjects in the control groups.
Arnett has also examined the effect of cognitive reserve, expecting people whose behavior shows greater resilience to neurological damage to be better able to ward off the cognitive effects of trauma to the brain. In comparing intellectual enrichment with brain atrophy, patients with vocabularies at the 75th percentile showed less substantial effects of cognitive impairment from brain atrophy than patients with vocabularies at the 25th percentile with similar physical changes to the brain. Changing coping strategies and building cognitive reserve could help protect MS patients against some of the cognitive effects of the disease.
Multiple Sclerosis genotypes and cognition
Another approach to understanding the heterogeneity in the cognitive dysfunction in MS may be to examine effects of genotype on individual variations in cognition in this disease. Heather Wishart of Dartmouth Medical School described studies underway to make clearer connections between genotypes, cognitive dysfunction, and MRI imaging data in MS patients. Some of these studies focus on single candidate genetic variations, such as the e4 allele of the apolipoprotein E (APOE) gene, a highly studied gene in human cognition. Other studies underway are taking a broader approach through the study of an entire biological pathway or genome-wide association studies.
Stephen M. Rao, Cleveland Clinic Foundation
Massimo Filippi, Scientific Institute and University "Vita-Salute" San Raffaele
Daniel Pelletier, Yale University School of Medicine
Daniel S. Reich, National Institute of Neurological Disorders and Stroke
Nancy L. Sicotte, Cedars-Sinai Medical Center
- Functional MRI (fMRI) shows that increased neural activity can help early-stage MS patients compensate for demyelination.
- MRI is providing a glimpse into the pathology of gray matter lesions as well as of white matter lesions.
- Proton magnetic resonance spectroscopy allows researchers to analyze the ongoing biochemistry within the living brain of individuals with MS.
- Monitoring MS lesions with MRI over time is providing clues to how lesions originate and evolve.
- Researchers are correlating MRI changes in the hippocampus with cognitive changes to better understand the degenerative effects of MS relative to the effects of secondary factors such as depression.
Imaging and cognitive dysfunction in MS
Cognitive dysfunction in the brain results in part from extensive trauma that interferes with normal brain activity. Understanding the pathology within the human brain has always been challenging because it can be difficult for researchers and clinicians to observe these changes in the patient. Over the last several decades magnetic resonance imaging techniques have provided that vital window into the human brain. New techniques and higher field instruments are helping researchers better understand cognitive dysfunction in MS.
Although MRI is a powerful tool for measuring changes in MS, the correlations between brain changes and cognitive dysfunction are not necessarily straightforward. The number and burden of T2 lesions is a good clinical indicator of cognitive impairment, but these measures show little prediction of physical disability, said Stephen Rao of the Cleveland Clinic.
In his recent studies examining cognitive function with imaging, he and his colleagues have used fMRI to understand the differences in the brain activity in MS patients. When they compared fMRI signals in patients with relapsing remitting MS (RRMS) with the signals in healthy controls, they found that even without observed behavioral differences, MS patients showed increased activation in a number of regions and more communication across the two halves of the brain. Those increases in activity may allow people with early MS to perform normally despite the disease-related changes to their neurons. As the disease progresses, the brain reaches a point where it can no longer compensate for the damage to the brain, and fMRI activity drops off again. These results suggest that this elevated fMRI activity could be useful as a biomarker for monitoring early stage MS in cognitive clinical trials.
Historically, researchers have connected MS with white matter (WM) lesions in the brain. However, recent pathologic and MRI studies have challenged the classic view of MS as a chronic inflammatory-demyelinating condition affecting solely the WM of the central nervous system. Indeed, there is a growing body of evidence showing that a significant portion of MS-related damage affects virtually all gray matter structures. Massimo Filippi and his colleagues at the University "Vita-Salute" San Raffaele are studying gray matter damage in MS and correlating it with the main clinical manifestations of the disease. Gray matter involvement in MS includes focal lesions, diffuse damage to the gray matter, and irreversible tissue loss. Filippi and his colleagues have shown that the involvement of gray matter occurs from the early stages of the disease, progresses with time, and is only moderately correlated with the extent of WM injury. They also demonstrated a correlation between gray matter damage and physical disability and cognitive impairment in MS patients. In addition, Filippi’s group performed several fMRI studies on individuals with MS and showed variable degrees of cortical plasticity, which has the potential to limit the clinical consequences of tissue damage in these patients by compensating for the cognitive effects of such tissue damage. These results suggest that the patients’ disability is likely a result of the balance between structural damage and cortical reorganization rather then a mere reflection of tissue disruption.
Monitoring brain biochemistry in MS
Advances in the development of high field magnetic resonance instruments allow Daniel Pelletier of Yale University School of Medicine to use proton magnetic resonance spectroscopy (1H MRS) to analyze the biochemistry of lesions within the brain. A better understanding of the chemistry within MS lesions could help researchers find signatures of early disease that could serve as biomarkers to monitor progression.
Pelletier and his colleagues segment the brain into voxels (volumetric pixels, a measure of volume in 3D space) and use magnetic resonance spectroscopy to analyze the mixture of molecules within that small section of the brain. With this technique they map the chemical differences between MS-free brains and the brains from those with MS and between white matter lesions and gray matter lesions. Elevated levels of myo-inositol in white matter are correlated with MS, and individuals with MS show higher concentrations of glutamate in both white and grey matter.
In a new study of 68 individuals with MS, Pelletier and his colleagues looked at the concentrations of glutamate in the brain along with tests of cognitive function. They followed patients over 2 years and found that elevated glutamate concentrations are associated with worsening memory and decreasing overall quality of life. In future studies, Pelletier and his colleagues will look at other brain metabolites of interest such as glutathione, GABA, or vitamin C.
Understanding Multiple Sclerosis lesion evolution
Higher field magnetic resonance imaging is also helping Daniel Reich and his colleagues at the NIH's National Institute of Neurological Disorders and Stroke better understand the early formation of MS lesions. Studies of white matter lesions have been categorized based on how and in what shapes the lesions are highlighted by a Gd contrast agent: nodular lesions and ring-shaped lesions. By monitoring brains over time using clinical MR (magnetic resonance) scanners, Reich and his colleagues have shown that these lesions evolve. Nodular lesions appear to form around a central vein where inflammatory factors can cross the blood-brain barrier. In those lesions, researchers can observe the Gd contrast agent leaking into the lesion from the center out to the periphery. However, when the researchers track these patients' scans over time, several days later the same lesion may show leakage of contrast agent from the periphery into the center several days later, a characteristic of the other lesion type: a ring-shaped lesion.
These differences in the movement of the Gd clearly indicate changes in the lesion over time, but the implications of those changes are not so clear. They could indicate growing tissue damage, but they might also suggest the movement of immune factors that eventually stop the growth of the lesion. Further research will be needed to understand the implications of these lesion changes for cognition.
Connecting changes in the hippocampus to cognitive dysfunction
Magnetic resonance imaging is also providing ways to monitor the changes to the hippocampus in living MS patients. Nancy Sicotte of Cedars-Sinai Medical Center described how disease progress in MS modifies the hippocampus and how she and her colleagues distinguish those changes from those of overlapping disease processes such as depression. High resolution MRI studies show atrophy in the hippocampi of MS patients, particularly in the CA1 region. Functional MRI of RRMS patients shows greater activation in the hippocampus during cognitive tasks, and comparisons with the scores on those tasks show that the boost in activation, particularly on the anterior right side, is correlated with performance on those tasks.
Depression also affects the hippocampus, and Sicotte and her colleagues observe atrophy in the CA23 and dentate gyrus of patients with both MS and depression. The effect of MS on the CA1 region is consistent with excitotoxicity from excess glutamate and has been linked with cognitive impairment in MS. Depression causes excess release of glucocorticoids, and the hippocampal subregions CA23 and the dentate gyrus are particularly susceptible to damage from these molecules. These changes in cortisol could provide a neurobiological explanation for the prevalence of depression among MS patients.