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Cognitive Impairment in MS (PART 3: current treatment options, MRI role)
Current Treatment Options
Researchers recently evaluated four pharmacological interventions intended to reverse cognitive impairment in patients with MS in large-scale (n > 40), double-blind, placebo-controlled clinical studies. Researchers likely chose the compounds—ginkgo biloba, donepezil, rivastigmine, and memantine—due to anecdotal evidence and clinical success in treating memory impairment in patients with Alzheimer’s disease (AD).16 Two of these drugs, donepezil and rivastigmine, are designed to increase brain levels of acetylcholine (ACh), a neurotransmitter (or chemical messenger) that facilitates learning and memory processes. The third, memantine, which prevents abnormal activation of signaling pathways between neurons in the brain, has demonstrated success in treating early AD. AD studies using ginkgo biloba, a plant often used in traditional Chinese medicine and reported to affect neurotransmitter signaling and neuroprotection, have shown mixed results; some demonstrate cognitive-enhancing effects, while others show no effect compared to placebo. Unfortunately none of these compounds demonstrated beneficial, reproducible improvements in cognitive function in clinical trials with MS.16
Cognitive rehabilitation therapy is a nonpharmacological method of improving a specific cognitive skill through practice and training. The brain is a dynamic organ, and practicing a specific cognitive task strengthens the communication between neurons required for that task. Results from trials focusing on cognitive rehabilitation in MS are mixed.17 Researchers did find, however, that neurocognitive rehabilitation alleviates fatigue in patients with MS, and this also might help restore cognitive facilities such as attention span and working (short-term) memory.
If a patient has irreversible cognitive deficits, the focus shifts from restoration to compensation. Coping strategies might be both emotion-focused and problem-focused. Emotion-focused strategies, which help a patient regulate the emotional consequences of cognitive deficits, include accepting the deficit and obtaining social support from peers or trained professionals. Problem-focused strategies alleviate some of the stress that cognitive impairment places on the individual through solutions to specific problems, such as using a tape recorder in meetings or lectures to aid in recall. A 2010 study demonstrated that patients with MS are unlikely to use positive coping strategies. Instead, many avoid situations in which their cognitive impairment might be evident or obvious to others.18 This is particularly true if the patient had deficits in attention and executive functioning, which indicates that educating patients with MS on the benefits of positive coping strategies is an important and unmet need.
In addition, researchers found that physical activity affects cognition in some patients with MS. Reported benefits of yoga in populations of patients with MS include reduced fatigue and improved attention.19 A 2011 study demonstrated a positive correlation between physical activity and cognitive processing speed in ambulatory patients with MS.20 While definite conclusions cannot be drawn from these studies, the positive association between physical activity and cognitive function (which also has been demonstrated in healthy and AD populations) suggests that physical activity might be an efficacious nonpharmacological treatment for cognitive impairment in MS.
The Role of Imaging
The search for a marker or specific cause of cognitive impairment in patients with MS has proven unsuccessful, and not knowing the exact mechanism(s) makes it extremely difficult to develop a treatment. The advancement of brain-imaging techniques and the development of more sophisticated experimental disease models have allowed for a more thorough understanding of pathogenesis in MS, but the exact cause or trigger is still unknown. Less than five years ago, researchers identified a cell that significantly contributes to MS development and progression. These T helper 17 immune cells are thought to contribute to CNS inflammation and are located within the brain lesions of people with MS. Despite recent advances, much work is still required to understand the cause of MS, the triggers for disease pathogenesis, and the mechanisms behind loss of myelin and neuronal degeneration.
Before the advent of magnetic resonance imaging (MRI) in the 1980s and computed tomography (CT) scans in the 1970s, only extremely crude brain-imaging techniques (such as plain X-rays) were available. Makeshift temperature tests were commonly used to assist in making an MS diagnosis, as uninsulated neurons conduct poorly at elevated temperatures. Thus, in bygone eras, many patients who presented with symptoms suggestive of MS were told to go home and get into a hot bathtub, and if their condition worsened significantly, then the diagnosis was confirmed as well as possible. Thankfully, diagnostic tools in neurology have improved, and techniques such as MRI can safely and accurately aid in diagnosing MS.
MRI uses a powerful magnet without harmful radiation to view successive sections of the brain and spinal cord with remarkable detail in any desired plane, much as one would slice a loaf of bread or a vegetable. Areas of the brain that appear “bright” or “hyperintense” on MRI images, called T2 hyperintense areas or simply T2 lesions, are thought to correspond to regions of inflammation, swelling, or injury. Dye is injected into the bloodstream of a patient, and leakage of dye into the brain indicates disruption of the protective barrier between the brain and the blood. This disruption occurs in patients with MS due to active inflammation, and immune cells rush into the brain to do battle with what is mistakenly perceived as an adversary.
MRI has become integral to the initial diagnostic workup of patients with MS. However, when it comes to the prediction of clinical status, course, or outcome, MRI has proven to be a surprisingly poor indicator.21 Perhaps the injury that results in clinical symptoms happens in a more general way throughout the brain, and the number of hyperintense lesions seen on MRI is not directly related to the severity of a patient’s deficits. Alternatively, it is possible that the brain is particularly good at routing neural impulses around regions actively under attack by the immune system. Although MRI highlights sites of inflammation, it does not show the compensatory mechanisms mediated by brain changes in signal routing or electrochemical boosting. Nowhere has the lack of a correlation between MRI findings and disability been more pronounced than in the poor prediction of cognitive impairment. Whatever the cause, the clinical-MRI paradox (the lack of correlation between findings on MRI and the level of clinical disability) has played a role in slowing the development of novel and potent therapies, especially those targeting cognitive preservation or improvement.
Researchers have investigated a number of related neuroimaging techniques in an effort to overcome the limitations of standard MRI in predicting cognitive performance. General measurements of either whole-brain or regional atrophy (brain shrinkage), the final outcome of demyelination and neuronal injury throughout the brain, correlate with cognitive impairment better than MRI imaging does. Two other techniques that indicate tissue damage have been used with some preliminary success in correlating with cognitive impairment in MS: magnetization transfer imaging, which measures how charged aspects of water interact with charges at the molecular level in the brain, and diffusion tensor imaging, which measures how water diffuses through the brain.
We recently had preliminary success, which is not yet published, in correlating the cognitive function of human MS patients with magnetic resonance spectroscopy (MRS). Unlike MRI, which determines the structural integrity of the brain based on the water distribution, MRS measures chemical compounds in specific areas of the brain. Since the brain’s hippocampus has a prominent role in learning and memory functions, we used MRS to investigate the chemistry of this brain region in people with MS. We found very strong positive correlations between cognitive function and levels of N-acetylaspartylglutamate (NAAG), an abundant signaling molecule in the brain. Specifically, higher NAAG levels were correlated with improved cognitive function. Although human studies of this chemical await the development of a drug that safely elevates NAAG levels in humans, we found that elevating the levels of NAAG in an animal model of MS resulted in a two-fold improvement in learning and memory functions compared to untreated animals. There may be hope on the horizon for the development of pharmacological interventions for MS cognitive impairment.
PART 4: http://activemsers.wssnoc.net/showthread.php?t=1166
PART 1: http://activemsers.wssnoc.net/showthread.php?t=1163
PART 2: http://activemsers.wssnoc.net/showthread.php?t=1164
Researchers recently evaluated four pharmacological interventions intended to reverse cognitive impairment in patients with MS in large-scale (n > 40), double-blind, placebo-controlled clinical studies. Researchers likely chose the compounds—ginkgo biloba, donepezil, rivastigmine, and memantine—due to anecdotal evidence and clinical success in treating memory impairment in patients with Alzheimer’s disease (AD).16 Two of these drugs, donepezil and rivastigmine, are designed to increase brain levels of acetylcholine (ACh), a neurotransmitter (or chemical messenger) that facilitates learning and memory processes. The third, memantine, which prevents abnormal activation of signaling pathways between neurons in the brain, has demonstrated success in treating early AD. AD studies using ginkgo biloba, a plant often used in traditional Chinese medicine and reported to affect neurotransmitter signaling and neuroprotection, have shown mixed results; some demonstrate cognitive-enhancing effects, while others show no effect compared to placebo. Unfortunately none of these compounds demonstrated beneficial, reproducible improvements in cognitive function in clinical trials with MS.16
Cognitive rehabilitation therapy is a nonpharmacological method of improving a specific cognitive skill through practice and training. The brain is a dynamic organ, and practicing a specific cognitive task strengthens the communication between neurons required for that task. Results from trials focusing on cognitive rehabilitation in MS are mixed.17 Researchers did find, however, that neurocognitive rehabilitation alleviates fatigue in patients with MS, and this also might help restore cognitive facilities such as attention span and working (short-term) memory.
If a patient has irreversible cognitive deficits, the focus shifts from restoration to compensation. Coping strategies might be both emotion-focused and problem-focused. Emotion-focused strategies, which help a patient regulate the emotional consequences of cognitive deficits, include accepting the deficit and obtaining social support from peers or trained professionals. Problem-focused strategies alleviate some of the stress that cognitive impairment places on the individual through solutions to specific problems, such as using a tape recorder in meetings or lectures to aid in recall. A 2010 study demonstrated that patients with MS are unlikely to use positive coping strategies. Instead, many avoid situations in which their cognitive impairment might be evident or obvious to others.18 This is particularly true if the patient had deficits in attention and executive functioning, which indicates that educating patients with MS on the benefits of positive coping strategies is an important and unmet need.
In addition, researchers found that physical activity affects cognition in some patients with MS. Reported benefits of yoga in populations of patients with MS include reduced fatigue and improved attention.19 A 2011 study demonstrated a positive correlation between physical activity and cognitive processing speed in ambulatory patients with MS.20 While definite conclusions cannot be drawn from these studies, the positive association between physical activity and cognitive function (which also has been demonstrated in healthy and AD populations) suggests that physical activity might be an efficacious nonpharmacological treatment for cognitive impairment in MS.
The Role of Imaging
The search for a marker or specific cause of cognitive impairment in patients with MS has proven unsuccessful, and not knowing the exact mechanism(s) makes it extremely difficult to develop a treatment. The advancement of brain-imaging techniques and the development of more sophisticated experimental disease models have allowed for a more thorough understanding of pathogenesis in MS, but the exact cause or trigger is still unknown. Less than five years ago, researchers identified a cell that significantly contributes to MS development and progression. These T helper 17 immune cells are thought to contribute to CNS inflammation and are located within the brain lesions of people with MS. Despite recent advances, much work is still required to understand the cause of MS, the triggers for disease pathogenesis, and the mechanisms behind loss of myelin and neuronal degeneration.
Before the advent of magnetic resonance imaging (MRI) in the 1980s and computed tomography (CT) scans in the 1970s, only extremely crude brain-imaging techniques (such as plain X-rays) were available. Makeshift temperature tests were commonly used to assist in making an MS diagnosis, as uninsulated neurons conduct poorly at elevated temperatures. Thus, in bygone eras, many patients who presented with symptoms suggestive of MS were told to go home and get into a hot bathtub, and if their condition worsened significantly, then the diagnosis was confirmed as well as possible. Thankfully, diagnostic tools in neurology have improved, and techniques such as MRI can safely and accurately aid in diagnosing MS.
MRI uses a powerful magnet without harmful radiation to view successive sections of the brain and spinal cord with remarkable detail in any desired plane, much as one would slice a loaf of bread or a vegetable. Areas of the brain that appear “bright” or “hyperintense” on MRI images, called T2 hyperintense areas or simply T2 lesions, are thought to correspond to regions of inflammation, swelling, or injury. Dye is injected into the bloodstream of a patient, and leakage of dye into the brain indicates disruption of the protective barrier between the brain and the blood. This disruption occurs in patients with MS due to active inflammation, and immune cells rush into the brain to do battle with what is mistakenly perceived as an adversary.
MRI has become integral to the initial diagnostic workup of patients with MS. However, when it comes to the prediction of clinical status, course, or outcome, MRI has proven to be a surprisingly poor indicator.21 Perhaps the injury that results in clinical symptoms happens in a more general way throughout the brain, and the number of hyperintense lesions seen on MRI is not directly related to the severity of a patient’s deficits. Alternatively, it is possible that the brain is particularly good at routing neural impulses around regions actively under attack by the immune system. Although MRI highlights sites of inflammation, it does not show the compensatory mechanisms mediated by brain changes in signal routing or electrochemical boosting. Nowhere has the lack of a correlation between MRI findings and disability been more pronounced than in the poor prediction of cognitive impairment. Whatever the cause, the clinical-MRI paradox (the lack of correlation between findings on MRI and the level of clinical disability) has played a role in slowing the development of novel and potent therapies, especially those targeting cognitive preservation or improvement.
Researchers have investigated a number of related neuroimaging techniques in an effort to overcome the limitations of standard MRI in predicting cognitive performance. General measurements of either whole-brain or regional atrophy (brain shrinkage), the final outcome of demyelination and neuronal injury throughout the brain, correlate with cognitive impairment better than MRI imaging does. Two other techniques that indicate tissue damage have been used with some preliminary success in correlating with cognitive impairment in MS: magnetization transfer imaging, which measures how charged aspects of water interact with charges at the molecular level in the brain, and diffusion tensor imaging, which measures how water diffuses through the brain.
We recently had preliminary success, which is not yet published, in correlating the cognitive function of human MS patients with magnetic resonance spectroscopy (MRS). Unlike MRI, which determines the structural integrity of the brain based on the water distribution, MRS measures chemical compounds in specific areas of the brain. Since the brain’s hippocampus has a prominent role in learning and memory functions, we used MRS to investigate the chemistry of this brain region in people with MS. We found very strong positive correlations between cognitive function and levels of N-acetylaspartylglutamate (NAAG), an abundant signaling molecule in the brain. Specifically, higher NAAG levels were correlated with improved cognitive function. Although human studies of this chemical await the development of a drug that safely elevates NAAG levels in humans, we found that elevating the levels of NAAG in an animal model of MS resulted in a two-fold improvement in learning and memory functions compared to untreated animals. There may be hope on the horizon for the development of pharmacological interventions for MS cognitive impairment.
PART 4: http://activemsers.wssnoc.net/showthread.php?t=1166
PART 1: http://activemsers.wssnoc.net/showthread.php?t=1163
PART 2: http://activemsers.wssnoc.net/showthread.php?t=1164