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Tool May Identify Risk of Transition to Secondary Progressive MS
SAN DIEGO—A new statistical model may be able to estimate a patient’s current risk of progressing from relapsing-remitting multiple sclerosis (MS) to secondary progressive MS. If future investigations prove the model robust, it eventually may help select high-risk patients for clinical trials and aid in the design of trials in which secondary progressive MS is an outcome, said Helen Tedeholm, MSci, a doctoral student at the University of Gothenburg in Sweden.
At the 65th Annual Meeting of the American Academy of Neurology, Ms. Tedeholm and colleagues presented their study of 157 untreated patients diagnosed with relapsing-remitting MS according to the Poser criteria. All patients had had a distinct second relapse of the disease and were followed up for more than 45 years.
The researchers created Poisson regression models with secondary progressive MS as an outcome using previously validated clinical characteristics as variables. The variables were confirmed for each patient as they arose at any time during the course of relapsing-remitting MS.
Of the original cohort, 118 patients developed secondary progressive MS. The risk of secondary progressive MS peaked when the patients were approximately age 30. Three of the variables that the investigators tested—current age, severity of the last relapse, and time since the last relapse—were independently significant predictors of transition to secondary progressive MS.
Ms. Tedeholm and colleagues developed a statistical model that included information from the second relapse onward, as well as the time and clinical characteristics of relapses. The risk of transition to secondary progressive MS increased sharply with a relapse with a high severity score, but it decreased with a relapse with a low severity score.
By applying the model to individual patients, the researchers calculated their current risk of developing secondary progressive MS. Among the study participants, 40 had the highest risk of progressive MS (greater than 0.14 events/year), and 41 had the lowest risk (less than 0.015 events/year).
—Erik Greb
Senior Associate Editor
Suggested Reading
Martinelli-Boneschi F, Esposito F, Brambilla P, et al. A genome-wide association study in progressive multiple sclerosis. Mult Scler. 2012;18(10):1384-1394. Roudbari SA, Ansar MM, Yousefzad A. Smoking as a risk factor for development of secondary progressive multiple sclerosis: A study in IRAN, Guilan. J Neurol Sci. 2013 Apr 26 [Epub ahead of print].
SAN DIEGO—A new statistical model may be able to estimate a patient’s current risk of progressing from relapsing-remitting multiple sclerosis (MS) to secondary progressive MS. If future investigations prove the model robust, it eventually may help select high-risk patients for clinical trials and aid in the design of trials in which secondary progressive MS is an outcome, said Helen Tedeholm, MSci, a doctoral student at the University of Gothenburg in Sweden.
At the 65th Annual Meeting of the American Academy of Neurology, Ms. Tedeholm and colleagues presented their study of 157 untreated patients diagnosed with relapsing-remitting MS according to the Poser criteria. All patients had had a distinct second relapse of the disease and were followed up for more than 45 years.
The researchers created Poisson regression models with secondary progressive MS as an outcome using previously validated clinical characteristics as variables. The variables were confirmed for each patient as they arose at any time during the course of relapsing-remitting MS.
Of the original cohort, 118 patients developed secondary progressive MS. The risk of secondary progressive MS peaked when the patients were approximately age 30. Three of the variables that the investigators tested—current age, severity of the last relapse, and time since the last relapse—were independently significant predictors of transition to secondary progressive MS.
Ms. Tedeholm and colleagues developed a statistical model that included information from the second relapse onward, as well as the time and clinical characteristics of relapses. The risk of transition to secondary progressive MS increased sharply with a relapse with a high severity score, but it decreased with a relapse with a low severity score.
By applying the model to individual patients, the researchers calculated their current risk of developing secondary progressive MS. Among the study participants, 40 had the highest risk of progressive MS (greater than 0.14 events/year), and 41 had the lowest risk (less than 0.015 events/year).
—Erik Greb
Senior Associate Editor
Suggested Reading
Martinelli-Boneschi F, Esposito F, Brambilla P, et al. A genome-wide association study in progressive multiple sclerosis. Mult Scler. 2012;18(10):1384-1394. Roudbari SA, Ansar MM, Yousefzad A. Smoking as a risk factor for development of secondary progressive multiple sclerosis: A study in IRAN, Guilan. J Neurol Sci. 2013 Apr 26 [Epub ahead of print].
SAN DIEGO—A new statistical model may be able to estimate a patient’s current risk of progressing from relapsing-remitting multiple sclerosis (MS) to secondary progressive MS. If future investigations prove the model robust, it eventually may help select high-risk patients for clinical trials and aid in the design of trials in which secondary progressive MS is an outcome, said Helen Tedeholm, MSci, a doctoral student at the University of Gothenburg in Sweden.
At the 65th Annual Meeting of the American Academy of Neurology, Ms. Tedeholm and colleagues presented their study of 157 untreated patients diagnosed with relapsing-remitting MS according to the Poser criteria. All patients had had a distinct second relapse of the disease and were followed up for more than 45 years.
The researchers created Poisson regression models with secondary progressive MS as an outcome using previously validated clinical characteristics as variables. The variables were confirmed for each patient as they arose at any time during the course of relapsing-remitting MS.
Of the original cohort, 118 patients developed secondary progressive MS. The risk of secondary progressive MS peaked when the patients were approximately age 30. Three of the variables that the investigators tested—current age, severity of the last relapse, and time since the last relapse—were independently significant predictors of transition to secondary progressive MS.
Ms. Tedeholm and colleagues developed a statistical model that included information from the second relapse onward, as well as the time and clinical characteristics of relapses. The risk of transition to secondary progressive MS increased sharply with a relapse with a high severity score, but it decreased with a relapse with a low severity score.
By applying the model to individual patients, the researchers calculated their current risk of developing secondary progressive MS. Among the study participants, 40 had the highest risk of progressive MS (greater than 0.14 events/year), and 41 had the lowest risk (less than 0.015 events/year).
—Erik Greb
Senior Associate Editor
Suggested Reading
Martinelli-Boneschi F, Esposito F, Brambilla P, et al. A genome-wide association study in progressive multiple sclerosis. Mult Scler. 2012;18(10):1384-1394. Roudbari SA, Ansar MM, Yousefzad A. Smoking as a risk factor for development of secondary progressive multiple sclerosis: A study in IRAN, Guilan. J Neurol Sci. 2013 Apr 26 [Epub ahead of print].
How Prevalent Is Pain in MS?
Pain in multiple sclerosis (MS) is common, occurring in 63% of patients with the disease, researchers reported in the May issue of Pain. Headache and extremity neuropathic pain are the most common pain syndromes in patients with MS.
Peter Foley, MRCP, and colleagues based their findings on a systematic review and meta-analysis of 17 prospective studies (5,319 patients) that explored pain prevalence in definite MS. The percentage of females in the studies ranged from 55% to 96%, mean age ranged from 31 to 54, mean disease duration ranged from 2.5 to 23 years, and between 30% and 100% of subjects had relapsing-remitting MS (RRMS).
The researchers found a pooled overall pain prevalence of 62.8%. They quantified a prevalence of 43% for headache, 26% for extremity neuropathic pain, 20% for back pain, 15% for painful spasms, 16% for painful Lhermitte sign, and 3.8% for trigeminal neuralgia. The prevalence of pain at MS disease milestones—prior to onset, at onset, and at relapse—and during longitudinal follow-up was “poorly described,” according to Dr. Foley, from the Division of Clinical Neurosciences, University of Edinburgh.
Among the studies that were reviewed, one investigated pain prevalence soon after MS diagnosis and found a 73.5% prevalence of any pain, with a mean disease duration at assessment of 30.5 months. A separate study analyzed headache during relapse and found a prevalence of 38.9%. In addition, two studies prospectively examined overall pain evolution with disease progression—one study found a nonsignificant reduction in prevalence of pain over time in early MS, while another found an increasing prevalence of pain over time in later MS, particularly in those with worsening disability.
“Pain seems to affect approximately 63% of people with MS,” Dr. Foley told Neurology Reviews. “People with MS suffer from a complex variety of pain problems, with both neuropathic and nociceptive mechanisms, and we now have a clearer idea of how common these different pain problems are in MS. Looking at pain overall in these studies, although there was significant variability between studies, we didn’t find that patient disability scores, disease duration, gender mix, or mix of people with progressive MS and RRMS in the studies significantly affected the prevalence of pain.
“Because pain is so common, and seems to affect all groups of people with MS, doctors should strongly consider asking their patients about pain,” Dr. Foley concluded. “Future research studies using standardized designs might give us further evidence to identify who is most at risk of pain, and how this might relate to inflammatory, degenerative, or other processes in MS.”
—Colby Stong
Editor
Suggested Reading
Foley PL, Vesterinen HM, Laird BJ, et al. Prevalence and natural history of pain in adults with multiple sclerosis: systematic review and meta-analysis. Pain. 2013;154(5):632-642.
Pain in multiple sclerosis (MS) is common, occurring in 63% of patients with the disease, researchers reported in the May issue of Pain. Headache and extremity neuropathic pain are the most common pain syndromes in patients with MS.
Peter Foley, MRCP, and colleagues based their findings on a systematic review and meta-analysis of 17 prospective studies (5,319 patients) that explored pain prevalence in definite MS. The percentage of females in the studies ranged from 55% to 96%, mean age ranged from 31 to 54, mean disease duration ranged from 2.5 to 23 years, and between 30% and 100% of subjects had relapsing-remitting MS (RRMS).
The researchers found a pooled overall pain prevalence of 62.8%. They quantified a prevalence of 43% for headache, 26% for extremity neuropathic pain, 20% for back pain, 15% for painful spasms, 16% for painful Lhermitte sign, and 3.8% for trigeminal neuralgia. The prevalence of pain at MS disease milestones—prior to onset, at onset, and at relapse—and during longitudinal follow-up was “poorly described,” according to Dr. Foley, from the Division of Clinical Neurosciences, University of Edinburgh.
Among the studies that were reviewed, one investigated pain prevalence soon after MS diagnosis and found a 73.5% prevalence of any pain, with a mean disease duration at assessment of 30.5 months. A separate study analyzed headache during relapse and found a prevalence of 38.9%. In addition, two studies prospectively examined overall pain evolution with disease progression—one study found a nonsignificant reduction in prevalence of pain over time in early MS, while another found an increasing prevalence of pain over time in later MS, particularly in those with worsening disability.
“Pain seems to affect approximately 63% of people with MS,” Dr. Foley told Neurology Reviews. “People with MS suffer from a complex variety of pain problems, with both neuropathic and nociceptive mechanisms, and we now have a clearer idea of how common these different pain problems are in MS. Looking at pain overall in these studies, although there was significant variability between studies, we didn’t find that patient disability scores, disease duration, gender mix, or mix of people with progressive MS and RRMS in the studies significantly affected the prevalence of pain.
“Because pain is so common, and seems to affect all groups of people with MS, doctors should strongly consider asking their patients about pain,” Dr. Foley concluded. “Future research studies using standardized designs might give us further evidence to identify who is most at risk of pain, and how this might relate to inflammatory, degenerative, or other processes in MS.”
—Colby Stong
Editor
Suggested Reading
Foley PL, Vesterinen HM, Laird BJ, et al. Prevalence and natural history of pain in adults with multiple sclerosis: systematic review and meta-analysis. Pain. 2013;154(5):632-642.
Pain in multiple sclerosis (MS) is common, occurring in 63% of patients with the disease, researchers reported in the May issue of Pain. Headache and extremity neuropathic pain are the most common pain syndromes in patients with MS.
Peter Foley, MRCP, and colleagues based their findings on a systematic review and meta-analysis of 17 prospective studies (5,319 patients) that explored pain prevalence in definite MS. The percentage of females in the studies ranged from 55% to 96%, mean age ranged from 31 to 54, mean disease duration ranged from 2.5 to 23 years, and between 30% and 100% of subjects had relapsing-remitting MS (RRMS).
The researchers found a pooled overall pain prevalence of 62.8%. They quantified a prevalence of 43% for headache, 26% for extremity neuropathic pain, 20% for back pain, 15% for painful spasms, 16% for painful Lhermitte sign, and 3.8% for trigeminal neuralgia. The prevalence of pain at MS disease milestones—prior to onset, at onset, and at relapse—and during longitudinal follow-up was “poorly described,” according to Dr. Foley, from the Division of Clinical Neurosciences, University of Edinburgh.
Among the studies that were reviewed, one investigated pain prevalence soon after MS diagnosis and found a 73.5% prevalence of any pain, with a mean disease duration at assessment of 30.5 months. A separate study analyzed headache during relapse and found a prevalence of 38.9%. In addition, two studies prospectively examined overall pain evolution with disease progression—one study found a nonsignificant reduction in prevalence of pain over time in early MS, while another found an increasing prevalence of pain over time in later MS, particularly in those with worsening disability.
“Pain seems to affect approximately 63% of people with MS,” Dr. Foley told Neurology Reviews. “People with MS suffer from a complex variety of pain problems, with both neuropathic and nociceptive mechanisms, and we now have a clearer idea of how common these different pain problems are in MS. Looking at pain overall in these studies, although there was significant variability between studies, we didn’t find that patient disability scores, disease duration, gender mix, or mix of people with progressive MS and RRMS in the studies significantly affected the prevalence of pain.
“Because pain is so common, and seems to affect all groups of people with MS, doctors should strongly consider asking their patients about pain,” Dr. Foley concluded. “Future research studies using standardized designs might give us further evidence to identify who is most at risk of pain, and how this might relate to inflammatory, degenerative, or other processes in MS.”
—Colby Stong
Editor
Suggested Reading
Foley PL, Vesterinen HM, Laird BJ, et al. Prevalence and natural history of pain in adults with multiple sclerosis: systematic review and meta-analysis. Pain. 2013;154(5):632-642.
Could Stem Cells Reduce Inflammatory Lesions in Patients With MS?
ORLANDO—An international group of researchers has begun to study whether mesenchymal stem cells (MSCs) could reduce inflammatory lesions in patients with multiple sclerosis (MS). Pilot clinical trials have demonstrated that MSCs are safe, but their patient populations have been too small to prove the treatment’s efficacy, according to a presentation given at the Fifth Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS (ACTRIMS).
MSCs can be derived from bone marrow or placenta, said Mark Freedman, MD, Professor of Neurology at the University of Ottawa. Various anti-inflammatory models showed that the cells have immunologic properties, and they can release growth factors that might offer neuroprotection, he added. Human MSCs promoted the differentiation of myelin-expressing cells in a mouse model of experimental autoimmune encephalomyelitis.
An International Study of MSCs’ Efficacy
Dr. Freedman and Antonio Uccelli, MD, Associate Professor of Medical Sciences at the University of Genoa, led a group that established a consensus protocol for a clinical trial to test the efficacy of MSCs for patients with relapsing-remitting, secondary progressive, or primary progressive MS who continue to have active relapses or enhancing MRI lesions despite receiving treatment. Research groups in 12 countries will participate in the protocol, which was published in the April 2010 Multiple Sclerosis Journal. The investigators will aspirate bone marrow from each patient and culture MSCs from it. The researchers will create enough cells for the trial and additional cells that can be studied for their immunologic properties.
Patients will be randomized to sham treatment or to a standard IV dose of one to two million MSCs per kilogram. Participants in the treatment arm will receive MSCs cultured from their own bone marrow. The study’s primary outcomes are safety and the reduction in the number and volume of new enhancing lesions over six months. After six months, the investigators will administer MSCs to patients in the sham group. All patients will be followed for one year so that the researchers can examine the crossover effect in the patients who received delayed treatment.
In addition to efficacy, the investigators plan to study the endurance of MSCs’ effect over time and whether MSCs can promote CNS repair. Several exploratory outcome measures, such as effects on reparative signals on MRI, neurophysiology, cognition, or clinical capability “are key to deciding whether these cells are capable of doing the wonderful things that you’ve heard about,” said Dr. Freedman.
Pilot Studies Indicate That MSCs Are Safe
An “intriguing” proof-of-concept study published in the February 2012 Lancet Neurology suggested that MSCs could promote recovery in patients with secondary progressive MS and optic nerve lesions, said Dr. Freedman. The investigators gave 10 patients an IV infusion of approximately two million autologous MSCs per kilogram. The cells had been derived from the patients’ bone marrow and cultured with fetal bovine serum. During the 10-month follow-up, patients’ visual acuity and visual evoked response latency improved. In addition, the diameter of patients’ optic nerves increased. “There were trends on the general MRIs of the brain to having fewer T2 lesions and less atrophy,” added Dr. Freedman.
A recent case study also suggested a potential benefit of MSCs for patients with MS. Researchers in China preconditioned a patient with cyclophosphamide and subsequently administered 10 million MSCs intrathecally and 20 million MSCs IV. On day three, the patient had sensory impairment, but muscle strength increased by day nine. The patient’s neurologic signs improved by day 52, and the patient became mobile. The Expanded Disability Status Scale (EDSS) score decreased to 6.5, and the MRI showed improvement.
Results of other small studies have been less clear. Israeli researchers gave 15 patients with MS intrathecal and IV doses of autologous MSCs. Some of the patients in this study developed headache and fever, which were interpreted as side effects of intrathecal administration. Patients’ EDSS decreased slightly, but not significantly, from a mean of approximately 6.
In a phase 1 study, Iranian researchers gave infusions of MSCs to 10 patients with progressive MS and followed them for various periods of time. EDSS declined from 4.5 to 2.5 for some patients, but other patients got worse. At least six patients had continued attacks that required the administration of steroids. The treatment “certainly didn’t turn off the disease,” said Dr. Freedman.
“We’re all in agreement that these cells are easy to get and easy to culture,” he added. The current, large-scale study will provide more clarity about the therapeutic potential of MSCs.
—Erik Greb
Senior Associate Editor
Suggested Reading
Auletta JJ, Bartholomew AM, Maziarz RT, et al. The potential of mesenchymal stromal cells as a novel cellular therapy for multiple sclerosis. Immunotherapy. 2012;4(5):529-547.
Connick P, Kolappan M, Crawley C, et al. Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study. Lancet Neurol. 2012;11(2):150-156.
Freedman MS, Bar-Or A, Atkins HL, et al. The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis: consensus report of the International MSCT Study Group. Mult Scler. 2010;16(4):503-510.
Uccelli A, Laroni A, Freedman MS. Mesenchymal stem cells as treatment for MS—progress to date. Mult Scler. 2013;19(5):515-519.
ORLANDO—An international group of researchers has begun to study whether mesenchymal stem cells (MSCs) could reduce inflammatory lesions in patients with multiple sclerosis (MS). Pilot clinical trials have demonstrated that MSCs are safe, but their patient populations have been too small to prove the treatment’s efficacy, according to a presentation given at the Fifth Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS (ACTRIMS).
MSCs can be derived from bone marrow or placenta, said Mark Freedman, MD, Professor of Neurology at the University of Ottawa. Various anti-inflammatory models showed that the cells have immunologic properties, and they can release growth factors that might offer neuroprotection, he added. Human MSCs promoted the differentiation of myelin-expressing cells in a mouse model of experimental autoimmune encephalomyelitis.
An International Study of MSCs’ Efficacy
Dr. Freedman and Antonio Uccelli, MD, Associate Professor of Medical Sciences at the University of Genoa, led a group that established a consensus protocol for a clinical trial to test the efficacy of MSCs for patients with relapsing-remitting, secondary progressive, or primary progressive MS who continue to have active relapses or enhancing MRI lesions despite receiving treatment. Research groups in 12 countries will participate in the protocol, which was published in the April 2010 Multiple Sclerosis Journal. The investigators will aspirate bone marrow from each patient and culture MSCs from it. The researchers will create enough cells for the trial and additional cells that can be studied for their immunologic properties.
Patients will be randomized to sham treatment or to a standard IV dose of one to two million MSCs per kilogram. Participants in the treatment arm will receive MSCs cultured from their own bone marrow. The study’s primary outcomes are safety and the reduction in the number and volume of new enhancing lesions over six months. After six months, the investigators will administer MSCs to patients in the sham group. All patients will be followed for one year so that the researchers can examine the crossover effect in the patients who received delayed treatment.
In addition to efficacy, the investigators plan to study the endurance of MSCs’ effect over time and whether MSCs can promote CNS repair. Several exploratory outcome measures, such as effects on reparative signals on MRI, neurophysiology, cognition, or clinical capability “are key to deciding whether these cells are capable of doing the wonderful things that you’ve heard about,” said Dr. Freedman.
Pilot Studies Indicate That MSCs Are Safe
An “intriguing” proof-of-concept study published in the February 2012 Lancet Neurology suggested that MSCs could promote recovery in patients with secondary progressive MS and optic nerve lesions, said Dr. Freedman. The investigators gave 10 patients an IV infusion of approximately two million autologous MSCs per kilogram. The cells had been derived from the patients’ bone marrow and cultured with fetal bovine serum. During the 10-month follow-up, patients’ visual acuity and visual evoked response latency improved. In addition, the diameter of patients’ optic nerves increased. “There were trends on the general MRIs of the brain to having fewer T2 lesions and less atrophy,” added Dr. Freedman.
A recent case study also suggested a potential benefit of MSCs for patients with MS. Researchers in China preconditioned a patient with cyclophosphamide and subsequently administered 10 million MSCs intrathecally and 20 million MSCs IV. On day three, the patient had sensory impairment, but muscle strength increased by day nine. The patient’s neurologic signs improved by day 52, and the patient became mobile. The Expanded Disability Status Scale (EDSS) score decreased to 6.5, and the MRI showed improvement.
Results of other small studies have been less clear. Israeli researchers gave 15 patients with MS intrathecal and IV doses of autologous MSCs. Some of the patients in this study developed headache and fever, which were interpreted as side effects of intrathecal administration. Patients’ EDSS decreased slightly, but not significantly, from a mean of approximately 6.
In a phase 1 study, Iranian researchers gave infusions of MSCs to 10 patients with progressive MS and followed them for various periods of time. EDSS declined from 4.5 to 2.5 for some patients, but other patients got worse. At least six patients had continued attacks that required the administration of steroids. The treatment “certainly didn’t turn off the disease,” said Dr. Freedman.
“We’re all in agreement that these cells are easy to get and easy to culture,” he added. The current, large-scale study will provide more clarity about the therapeutic potential of MSCs.
—Erik Greb
Senior Associate Editor
Suggested Reading
Auletta JJ, Bartholomew AM, Maziarz RT, et al. The potential of mesenchymal stromal cells as a novel cellular therapy for multiple sclerosis. Immunotherapy. 2012;4(5):529-547.
Connick P, Kolappan M, Crawley C, et al. Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study. Lancet Neurol. 2012;11(2):150-156.
Freedman MS, Bar-Or A, Atkins HL, et al. The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis: consensus report of the International MSCT Study Group. Mult Scler. 2010;16(4):503-510.
Uccelli A, Laroni A, Freedman MS. Mesenchymal stem cells as treatment for MS—progress to date. Mult Scler. 2013;19(5):515-519.
ORLANDO—An international group of researchers has begun to study whether mesenchymal stem cells (MSCs) could reduce inflammatory lesions in patients with multiple sclerosis (MS). Pilot clinical trials have demonstrated that MSCs are safe, but their patient populations have been too small to prove the treatment’s efficacy, according to a presentation given at the Fifth Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS (ACTRIMS).
MSCs can be derived from bone marrow or placenta, said Mark Freedman, MD, Professor of Neurology at the University of Ottawa. Various anti-inflammatory models showed that the cells have immunologic properties, and they can release growth factors that might offer neuroprotection, he added. Human MSCs promoted the differentiation of myelin-expressing cells in a mouse model of experimental autoimmune encephalomyelitis.
An International Study of MSCs’ Efficacy
Dr. Freedman and Antonio Uccelli, MD, Associate Professor of Medical Sciences at the University of Genoa, led a group that established a consensus protocol for a clinical trial to test the efficacy of MSCs for patients with relapsing-remitting, secondary progressive, or primary progressive MS who continue to have active relapses or enhancing MRI lesions despite receiving treatment. Research groups in 12 countries will participate in the protocol, which was published in the April 2010 Multiple Sclerosis Journal. The investigators will aspirate bone marrow from each patient and culture MSCs from it. The researchers will create enough cells for the trial and additional cells that can be studied for their immunologic properties.
Patients will be randomized to sham treatment or to a standard IV dose of one to two million MSCs per kilogram. Participants in the treatment arm will receive MSCs cultured from their own bone marrow. The study’s primary outcomes are safety and the reduction in the number and volume of new enhancing lesions over six months. After six months, the investigators will administer MSCs to patients in the sham group. All patients will be followed for one year so that the researchers can examine the crossover effect in the patients who received delayed treatment.
In addition to efficacy, the investigators plan to study the endurance of MSCs’ effect over time and whether MSCs can promote CNS repair. Several exploratory outcome measures, such as effects on reparative signals on MRI, neurophysiology, cognition, or clinical capability “are key to deciding whether these cells are capable of doing the wonderful things that you’ve heard about,” said Dr. Freedman.
Pilot Studies Indicate That MSCs Are Safe
An “intriguing” proof-of-concept study published in the February 2012 Lancet Neurology suggested that MSCs could promote recovery in patients with secondary progressive MS and optic nerve lesions, said Dr. Freedman. The investigators gave 10 patients an IV infusion of approximately two million autologous MSCs per kilogram. The cells had been derived from the patients’ bone marrow and cultured with fetal bovine serum. During the 10-month follow-up, patients’ visual acuity and visual evoked response latency improved. In addition, the diameter of patients’ optic nerves increased. “There were trends on the general MRIs of the brain to having fewer T2 lesions and less atrophy,” added Dr. Freedman.
A recent case study also suggested a potential benefit of MSCs for patients with MS. Researchers in China preconditioned a patient with cyclophosphamide and subsequently administered 10 million MSCs intrathecally and 20 million MSCs IV. On day three, the patient had sensory impairment, but muscle strength increased by day nine. The patient’s neurologic signs improved by day 52, and the patient became mobile. The Expanded Disability Status Scale (EDSS) score decreased to 6.5, and the MRI showed improvement.
Results of other small studies have been less clear. Israeli researchers gave 15 patients with MS intrathecal and IV doses of autologous MSCs. Some of the patients in this study developed headache and fever, which were interpreted as side effects of intrathecal administration. Patients’ EDSS decreased slightly, but not significantly, from a mean of approximately 6.
In a phase 1 study, Iranian researchers gave infusions of MSCs to 10 patients with progressive MS and followed them for various periods of time. EDSS declined from 4.5 to 2.5 for some patients, but other patients got worse. At least six patients had continued attacks that required the administration of steroids. The treatment “certainly didn’t turn off the disease,” said Dr. Freedman.
“We’re all in agreement that these cells are easy to get and easy to culture,” he added. The current, large-scale study will provide more clarity about the therapeutic potential of MSCs.
—Erik Greb
Senior Associate Editor
Suggested Reading
Auletta JJ, Bartholomew AM, Maziarz RT, et al. The potential of mesenchymal stromal cells as a novel cellular therapy for multiple sclerosis. Immunotherapy. 2012;4(5):529-547.
Connick P, Kolappan M, Crawley C, et al. Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study. Lancet Neurol. 2012;11(2):150-156.
Freedman MS, Bar-Or A, Atkins HL, et al. The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis: consensus report of the International MSCT Study Group. Mult Scler. 2010;16(4):503-510.
Uccelli A, Laroni A, Freedman MS. Mesenchymal stem cells as treatment for MS—progress to date. Mult Scler. 2013;19(5):515-519.
PEGylated Interferon Beta-1a May Reduce Annualized Relapse Rate in Patients With MS
SAN DIEGO—A drug formulation made of polyethylene glycol chains attached to interferon beta-1a (PEGylated interferon beta-1a) may reduce annualized relapse rate significantly for patients with relapsing-remitting multiple sclerosis (MS), researchers reported at the 65th Annual Meeting of the American Academy of Neurology. The drug may also prolong the time to first relapse and reduce the accumulation of disability.
In a phase III pivotal clinical trial, annualized relapse rate was 27.5% lower for patients with MS who received PEGylated interferon beta-1a once every four weeks, compared with patients who received placebo, said Peter Calabresi, MD, Professor of Neurology at the Johns Hopkins Multiple Sclerosis Center in Baltimore. Annualized relapse rate was 35.6% lower among patients receiving the drug every two weeks, compared with patients receiving placebo.
The hazard ratio of a prolonged time to first relapse was 0.61 for patients who received the drug every two weeks and 0.74 for patients who received the drug every four weeks. At one year, disability accumulation was significantly reduced among active patients, compared with controls. The hazard ratio for reduced disability accumulation was 0.62 for all treated patients.
Comparing Two Dosing Frequencies With Placebo
Dr. Calabresi and colleagues enrolled approximately 1,500 patients with relapsing-remitting MS in a two-year, multicenter, randomized, double-blind study. Eligible patients were younger than 65 and had an Expanded Disability Status Scale (EDSS) score of 5 or lower. The trial’s primary end point was annualized relapse rate at one year. Secondary end points included the proportions of patients who relapsed during one year, the proportions of patients with disability progression over one year, and new and newly enlarging T2 hyperintense lesions. The trial was conducted at sites located in India, North America, Western and Eastern Europe, and other countries.
Equal numbers of patients were randomized to receive placebo, 125 µg of PEGylated interferon beta-1a subcutaneously once every four weeks, or 125 µg of PEGylated interferon beta-1a subcutaneously once every two weeks. The treatment groups were well balanced in terms of age, gender, and race. Most patients had an EDSS score lower than 4, and MRI activity was well distributed.
PEGylated Interferon Beta-1a Reduced MRI Activity
At one year, patients receiving PEGylated interferon beta-1a every four weeks had a 28% reduction in new and newly enlarging T2 lesions, compared with controls. Patients receiving the drug every two weeks had a 67% reduction in T2 lesions, compared with controls.
Participants who received PEGylated interferon beta-1a every four weeks had a 36% reduction in gadolinium-enhancing lesions, compared with participants receiving placebo. This result was not statistically significant, but was “a strong trend,” said Dr. Calabresi. Participants who received PEGylated interferon beta-1a every two weeks had an 86% reduction in gadolinium-enhancing lesions, compared with controls, and this result was highly significant.
Researchers observed neutralizing antibodies in less than 1% of patients in both treatment arms. Adverse events were similar in both treatment groups, and the majority of adverse events were mild or moderate. Common adverse events included injection-site reactions, influenza-like illness, and pyrexia. Slightly more active patients than controls dropped out of the trial because of adverse events.
“At year one of the placebo-controlled component of the trial, which was [the time of our] preplanned primary analysis, PEGylated interferon had an effect on the clinical and radiologic measures and seemed to offer the safety profile of presently available interferon beta-1a molecules,” concluded Dr. Calabresi.
—Erik Greb
Senior Associate Editor
Suggested Reading
Hu X, Miller L, Richman S, et al. A novel PEGylated interferon beta-1a for multiple sclerosis: safety, pharmacology, and biology. J Clin Pharmacol. 2012;52(6):798-808.
Kieseier BC, Calabresi PA. PEGylation of interferon-b-1a: a promising strategy in multiple sclerosis. CNS Drugs. 2012;26(3):205-214.
Shirani A, Zhao Y, Karim ME, et al. Association between use of interferon beta and progression of disability in patients with relapsing-remitting multiple sclerosis. JAMA. 2012;308(3):247-256.
SAN DIEGO—A drug formulation made of polyethylene glycol chains attached to interferon beta-1a (PEGylated interferon beta-1a) may reduce annualized relapse rate significantly for patients with relapsing-remitting multiple sclerosis (MS), researchers reported at the 65th Annual Meeting of the American Academy of Neurology. The drug may also prolong the time to first relapse and reduce the accumulation of disability.
In a phase III pivotal clinical trial, annualized relapse rate was 27.5% lower for patients with MS who received PEGylated interferon beta-1a once every four weeks, compared with patients who received placebo, said Peter Calabresi, MD, Professor of Neurology at the Johns Hopkins Multiple Sclerosis Center in Baltimore. Annualized relapse rate was 35.6% lower among patients receiving the drug every two weeks, compared with patients receiving placebo.
The hazard ratio of a prolonged time to first relapse was 0.61 for patients who received the drug every two weeks and 0.74 for patients who received the drug every four weeks. At one year, disability accumulation was significantly reduced among active patients, compared with controls. The hazard ratio for reduced disability accumulation was 0.62 for all treated patients.
Comparing Two Dosing Frequencies With Placebo
Dr. Calabresi and colleagues enrolled approximately 1,500 patients with relapsing-remitting MS in a two-year, multicenter, randomized, double-blind study. Eligible patients were younger than 65 and had an Expanded Disability Status Scale (EDSS) score of 5 or lower. The trial’s primary end point was annualized relapse rate at one year. Secondary end points included the proportions of patients who relapsed during one year, the proportions of patients with disability progression over one year, and new and newly enlarging T2 hyperintense lesions. The trial was conducted at sites located in India, North America, Western and Eastern Europe, and other countries.
Equal numbers of patients were randomized to receive placebo, 125 µg of PEGylated interferon beta-1a subcutaneously once every four weeks, or 125 µg of PEGylated interferon beta-1a subcutaneously once every two weeks. The treatment groups were well balanced in terms of age, gender, and race. Most patients had an EDSS score lower than 4, and MRI activity was well distributed.
PEGylated Interferon Beta-1a Reduced MRI Activity
At one year, patients receiving PEGylated interferon beta-1a every four weeks had a 28% reduction in new and newly enlarging T2 lesions, compared with controls. Patients receiving the drug every two weeks had a 67% reduction in T2 lesions, compared with controls.
Participants who received PEGylated interferon beta-1a every four weeks had a 36% reduction in gadolinium-enhancing lesions, compared with participants receiving placebo. This result was not statistically significant, but was “a strong trend,” said Dr. Calabresi. Participants who received PEGylated interferon beta-1a every two weeks had an 86% reduction in gadolinium-enhancing lesions, compared with controls, and this result was highly significant.
Researchers observed neutralizing antibodies in less than 1% of patients in both treatment arms. Adverse events were similar in both treatment groups, and the majority of adverse events were mild or moderate. Common adverse events included injection-site reactions, influenza-like illness, and pyrexia. Slightly more active patients than controls dropped out of the trial because of adverse events.
“At year one of the placebo-controlled component of the trial, which was [the time of our] preplanned primary analysis, PEGylated interferon had an effect on the clinical and radiologic measures and seemed to offer the safety profile of presently available interferon beta-1a molecules,” concluded Dr. Calabresi.
—Erik Greb
Senior Associate Editor
Suggested Reading
Hu X, Miller L, Richman S, et al. A novel PEGylated interferon beta-1a for multiple sclerosis: safety, pharmacology, and biology. J Clin Pharmacol. 2012;52(6):798-808.
Kieseier BC, Calabresi PA. PEGylation of interferon-b-1a: a promising strategy in multiple sclerosis. CNS Drugs. 2012;26(3):205-214.
Shirani A, Zhao Y, Karim ME, et al. Association between use of interferon beta and progression of disability in patients with relapsing-remitting multiple sclerosis. JAMA. 2012;308(3):247-256.
SAN DIEGO—A drug formulation made of polyethylene glycol chains attached to interferon beta-1a (PEGylated interferon beta-1a) may reduce annualized relapse rate significantly for patients with relapsing-remitting multiple sclerosis (MS), researchers reported at the 65th Annual Meeting of the American Academy of Neurology. The drug may also prolong the time to first relapse and reduce the accumulation of disability.
In a phase III pivotal clinical trial, annualized relapse rate was 27.5% lower for patients with MS who received PEGylated interferon beta-1a once every four weeks, compared with patients who received placebo, said Peter Calabresi, MD, Professor of Neurology at the Johns Hopkins Multiple Sclerosis Center in Baltimore. Annualized relapse rate was 35.6% lower among patients receiving the drug every two weeks, compared with patients receiving placebo.
The hazard ratio of a prolonged time to first relapse was 0.61 for patients who received the drug every two weeks and 0.74 for patients who received the drug every four weeks. At one year, disability accumulation was significantly reduced among active patients, compared with controls. The hazard ratio for reduced disability accumulation was 0.62 for all treated patients.
Comparing Two Dosing Frequencies With Placebo
Dr. Calabresi and colleagues enrolled approximately 1,500 patients with relapsing-remitting MS in a two-year, multicenter, randomized, double-blind study. Eligible patients were younger than 65 and had an Expanded Disability Status Scale (EDSS) score of 5 or lower. The trial’s primary end point was annualized relapse rate at one year. Secondary end points included the proportions of patients who relapsed during one year, the proportions of patients with disability progression over one year, and new and newly enlarging T2 hyperintense lesions. The trial was conducted at sites located in India, North America, Western and Eastern Europe, and other countries.
Equal numbers of patients were randomized to receive placebo, 125 µg of PEGylated interferon beta-1a subcutaneously once every four weeks, or 125 µg of PEGylated interferon beta-1a subcutaneously once every two weeks. The treatment groups were well balanced in terms of age, gender, and race. Most patients had an EDSS score lower than 4, and MRI activity was well distributed.
PEGylated Interferon Beta-1a Reduced MRI Activity
At one year, patients receiving PEGylated interferon beta-1a every four weeks had a 28% reduction in new and newly enlarging T2 lesions, compared with controls. Patients receiving the drug every two weeks had a 67% reduction in T2 lesions, compared with controls.
Participants who received PEGylated interferon beta-1a every four weeks had a 36% reduction in gadolinium-enhancing lesions, compared with participants receiving placebo. This result was not statistically significant, but was “a strong trend,” said Dr. Calabresi. Participants who received PEGylated interferon beta-1a every two weeks had an 86% reduction in gadolinium-enhancing lesions, compared with controls, and this result was highly significant.
Researchers observed neutralizing antibodies in less than 1% of patients in both treatment arms. Adverse events were similar in both treatment groups, and the majority of adverse events were mild or moderate. Common adverse events included injection-site reactions, influenza-like illness, and pyrexia. Slightly more active patients than controls dropped out of the trial because of adverse events.
“At year one of the placebo-controlled component of the trial, which was [the time of our] preplanned primary analysis, PEGylated interferon had an effect on the clinical and radiologic measures and seemed to offer the safety profile of presently available interferon beta-1a molecules,” concluded Dr. Calabresi.
—Erik Greb
Senior Associate Editor
Suggested Reading
Hu X, Miller L, Richman S, et al. A novel PEGylated interferon beta-1a for multiple sclerosis: safety, pharmacology, and biology. J Clin Pharmacol. 2012;52(6):798-808.
Kieseier BC, Calabresi PA. PEGylation of interferon-b-1a: a promising strategy in multiple sclerosis. CNS Drugs. 2012;26(3):205-214.
Shirani A, Zhao Y, Karim ME, et al. Association between use of interferon beta and progression of disability in patients with relapsing-remitting multiple sclerosis. JAMA. 2012;308(3):247-256.
New and Noteworthy Information—May 2013
Living in the stroke belt as an adolescent is significantly associated with a high risk of stroke, according to research published online ahead of print April 24 in Neurology. Researchers examined data for 24,544 stroke-free participants in the Reasons for Geographic and Racial Differences in Stroke study. Stroke belt exposure was calculated by combinations of stroke belt birthplace, current residence, and proportion of years in the stroke belt during discrete age categories. Risk of stroke was significantly associated with proportion of life in the stroke belt and with all other exposure periods except birth, ages 31 to 45, and current residence. After adjustment for risk factors, the risk of stroke remained significantly associated only with proportion of residence in the stroke belt during adolescence.
Increased levels of trimethylamine-N-oxide (TMAO), a proatherosclerotic metabolite, are associated with an increased risk of stroke, myocardial infarction, or death, according to research published in the April 25 New England Journal of Medicine. Investigators measured TMAO, choline, and betaine levels in patients who had eaten two hard-boiled eggs and deuterium [d9]-labeled phosphatidylcholine before and after suppressing intestinal microbiota with antibiotics. They also examined the relationship between fasting plasma levels of TMAO and major adverse cardiovascular events during three years of follow-up. Increased plasma levels of TMAO were associated with an increased risk of a major adverse cardiovascular event. An elevated TMAO level predicted an increased risk of major adverse cardiovascular events after adjustment for traditional risk factors, as well as in lower-risk subgroups.
A single-nucleotide polymorphism (SNP) in the ABCA7 gene was significantly linked with an increased risk of Alzheimer’s disease among African Americans, according to research published in the April 10 JAMA. African Americans with this mutation have nearly double the risk of Alzheimer’s disease, but the SNP is not associated with the disease among Europeans. The effect size for the SNP in ABCA7 was comparable with that of the APOE ε4–determining SNP rs429358. Investigators examined data for 5,896 African Americans (1,968 with Alzheimer’s disease and 3,928 controls) who were 60 or older. Data were collected between 1989 and 2011 at multiple sites. The team assessed the association of Alzheimer’s disease with genotyped and imputed SNPs in case–control and in family-based data sets.
The FDA has approved the Precision Spectra Spinal Cord Stimulator (SCS) System, which is designed to provide improved pain relief to patients with chronic pain. The system, manufactured by Boston Scientific (Natick, Massachusetts), includes Illumina 3D software intended to improve physicians’ control of the stimulation field. It is based on a proprietary computer model that takes into account 3-D anatomical structures, including the conductivity of the spinal cord and surrounding tissue. The physician can select a desired location on the spinal cord and prompt the programming software to create a customized stimulation field to mask the patient’s pain. Previous SCS systems included 16 contacts, but the Precision Spectra system includes 32 contacts and is designed to offer more coverage of the spinal cord.
Framingham risk scores may be better than a dementia risk score for assessing individuals’ risk of cognitive decline and targeting modifiable risk factors, according to research published in the April 2 Neurology. Researchers examined data for participants in the Whitehall II longitudinal cohort study. Subjects’ mean age at baseline was 55.6. The investigators compared the Framingham general cardiovascular disease risk score and the Framingham stroke risk score with the Cardiovascular Risk Factors, Aging, and Dementia risk score. Patients underwent cognitive tests of reasoning, memory, verbal fluency, vocabulary, and global cognition three times over 10 years. Compared with the dementia risk score, cardiovascular and stroke risk scores showed slightly stronger associations with 10-year cognitive decline. The differences were statistically significant for semantic fluency and global cognitive scores.
Children born to women who used valproate during pregnancy may have a significantly increased risk of autism spectrum disorder and childhood autism, according to research published in the April 24 JAMA. Investigators used national registers to identify Danish children exposed to valproate during pregnancy and diagnosed with autism spectrum disorders. The researchers analyzed the risks associated with all autism spectrum disorders, as well as childhood autism, and adjusted for potential confounders. The estimated absolute risk after 14 years of follow-up was 1.53% for autism spectrum disorder and 0.48% for childhood autism. The 508 children exposed to valproate had an absolute risk of 4.42% for autism spectrum disorder and an absolute risk of 2.50% for childhood autism. Results changed slightly after considering only the children born to women with epilepsy.
The antisense oligonucleotide ISIS 333611 is a safe treatment for amyotrophic lateral sclerosis (ALS), according to a trial published online ahead of print March 29 in Lancet Neurology. Investigators studied 32 patients with SOD1-positive ALS in a randomized, placebo-controlled, phase I trial. The researchers delivered the drug by intrathecal infusion using an external pump over 11.5 hours at increasing doses (0.15 mg, 0.50 mg, 1.50 mg, and 3.00 mg). Approximately 88% of patients in the placebo group had adverse events, compared with 83% in the active group. The most common events were post-lumbar puncture syndrome, back pain, and nausea. The investigators found no dose-limiting toxic effects or safety or tolerability concerns related to ISIS 333611. No serious adverse events occurred in patients given ISIS 333611.
Thalamic atrophy in patients with clinically isolated syndrome (CIS) is associated with the development of clinically definite multiple sclerosis (MS), according to a study published online ahead of print April 23 in Radiology. Using MRI, researchers assessed 216 patients with CIS at baseline, six months, one year, and two years. MRI measures of progression included new and enlarged T2 lesions and changes in whole-brain, tissue-specific global, and regional gray matter volumes. In mixed-effect model analysis, the lateral ventricle volume, accumulation of new total T2 and new enlarging T2 lesions increase, and thalamic and whole-brain volume decrease were associated with development of clinically definite MS. In multivariate regression analysis, decrease in thalamic volumes and increase in lateral ventricle volumes were associated with the development of clinically definite MS.
Functional MRI (fMRI) can identify pain caused by heat in healthy persons, according to research published in the April 11 New England Journal of Medicine. In four studies of 114 participants, investigators developed an fMRI-based measure that predicts pain intensity, tested its sensitivity and specificity to pain versus warmth, assessed its specificity relative to social pain, and assessed the responsiveness of the measure to the analgesic remifentanil. The neurologic signature distinguished painful heat from nonpainful warmth, pain anticipation, and pain recall with sensitivity and specificity of 94% or more. The signature discriminated between painful heat and nonpainful warmth with 93% sensitivity and specificity. It also distinguished between physical pain and social pain with 85% sensitivity and 73% specificity. The strength of the signature response was substantially reduced after remifentanil administration.
Family history of late-onset Alzheimer’s disease is associated with an increased prevalence of an abnormal cerebral beta-amyloid and tau protein phenotype in patients with mild cognitive impairment (MCI), according to a study published on April 17 in PLOS One. Investigators studied 257 participants (ages 55 to 89) in the Alzheimer’s Disease Neuroimaging Initiative. Subjects were categorized as cognitively normal, having MCI, or having Alzheimer’s disease. Among patients with MCI, CSF Ab42 was lower, t-tau was higher, and t-tau–Ab42 ratio was higher in patients with a family history of Alzheimer’s disease than in patients without. A significant residual effect of family history on pathologic markers in MCI remained after adjusting for APOE e4. The effect of family history was not significant in patients with Alzheimer’s disease.
Most potential migraine triggers are so variable that it may not be possible to identify them without formal experimentation, according to a study published in the April issue of Headache. Investigators examined the similarity of day-to-day weather conditions over four years, as well as the similarity of ovarian hormones and perceived stress over a median of 89 days in nine patients with headache and regular menstrual cycles. A threshold of 90% similarity using Gower’s index identified similar days for comparison. The day-to-day variability in the three headache triggers was substantial enough that finding two naturally similar days for which to contrast the effect of a fourth trigger (eg, drinking wine) occurred infrequently. Fluctuations in weather patterns resulted in a median of 2.3 similar days each year.
Elevated low-density lipoprotein (LDL) cholesterol and altered cholesterol homeostasis may promote neurodegeneration, atherosclerosis, and Alzheimer’s disease by disrupting chromosome segregation, according to research published on April 12 in PLOS One. In a study of mice, investigators observed that high dietary cholesterol induced aneuploidy. In a separate study, the accumulation of intracellular cholesterol was associated with the accumulation of aneuploid fibroblasts, neurons, and glia in patients with Niemann-Pick C1. The researchers also observed that oxidized LDL, LDL, and cholesterol, but not high-density lipoprotein (HDL), induced chromosome mis-segregation and aneuploidy in cultured cells, including neuronal precursors. LDL-induced aneuploidy required the LDL receptor, but not Ab. Cholesterol treatment disrupted the structure of the mitotic spindle, providing a cell biologic mechanism for its aneugenic activity, and ethanol or calcium chelation attenuated lipoprotein-induced chromosome mis-segregation.
The incidence of dementia in central Stockholm may have decreased from the late 1980s to the early 2000s, according to research published online ahead of print April 17 in Neurology. Investigators analyzed data from two cross-sectional surveys of people ages 75 or older. One study was conducted from 1987 to 1989 and included 1,700 participants; the other was conducted from 2001 to 2004 and included 1,575 subjects. The team inferred the incidence of dementia according to its relationship with prevalence and survival. The adjusted odds ratio of dementia in the later study versus the earlier study was 1.17. The multiadjusted hazard ratio of death in the later study versus the earlier study was 0.71 in subjects with dementia, 0.68 in those without dementia, and 0.66 in all participants.
—Erik Greb
Senior Associate Editor
Living in the stroke belt as an adolescent is significantly associated with a high risk of stroke, according to research published online ahead of print April 24 in Neurology. Researchers examined data for 24,544 stroke-free participants in the Reasons for Geographic and Racial Differences in Stroke study. Stroke belt exposure was calculated by combinations of stroke belt birthplace, current residence, and proportion of years in the stroke belt during discrete age categories. Risk of stroke was significantly associated with proportion of life in the stroke belt and with all other exposure periods except birth, ages 31 to 45, and current residence. After adjustment for risk factors, the risk of stroke remained significantly associated only with proportion of residence in the stroke belt during adolescence.
Increased levels of trimethylamine-N-oxide (TMAO), a proatherosclerotic metabolite, are associated with an increased risk of stroke, myocardial infarction, or death, according to research published in the April 25 New England Journal of Medicine. Investigators measured TMAO, choline, and betaine levels in patients who had eaten two hard-boiled eggs and deuterium [d9]-labeled phosphatidylcholine before and after suppressing intestinal microbiota with antibiotics. They also examined the relationship between fasting plasma levels of TMAO and major adverse cardiovascular events during three years of follow-up. Increased plasma levels of TMAO were associated with an increased risk of a major adverse cardiovascular event. An elevated TMAO level predicted an increased risk of major adverse cardiovascular events after adjustment for traditional risk factors, as well as in lower-risk subgroups.
A single-nucleotide polymorphism (SNP) in the ABCA7 gene was significantly linked with an increased risk of Alzheimer’s disease among African Americans, according to research published in the April 10 JAMA. African Americans with this mutation have nearly double the risk of Alzheimer’s disease, but the SNP is not associated with the disease among Europeans. The effect size for the SNP in ABCA7 was comparable with that of the APOE ε4–determining SNP rs429358. Investigators examined data for 5,896 African Americans (1,968 with Alzheimer’s disease and 3,928 controls) who were 60 or older. Data were collected between 1989 and 2011 at multiple sites. The team assessed the association of Alzheimer’s disease with genotyped and imputed SNPs in case–control and in family-based data sets.
The FDA has approved the Precision Spectra Spinal Cord Stimulator (SCS) System, which is designed to provide improved pain relief to patients with chronic pain. The system, manufactured by Boston Scientific (Natick, Massachusetts), includes Illumina 3D software intended to improve physicians’ control of the stimulation field. It is based on a proprietary computer model that takes into account 3-D anatomical structures, including the conductivity of the spinal cord and surrounding tissue. The physician can select a desired location on the spinal cord and prompt the programming software to create a customized stimulation field to mask the patient’s pain. Previous SCS systems included 16 contacts, but the Precision Spectra system includes 32 contacts and is designed to offer more coverage of the spinal cord.
Framingham risk scores may be better than a dementia risk score for assessing individuals’ risk of cognitive decline and targeting modifiable risk factors, according to research published in the April 2 Neurology. Researchers examined data for participants in the Whitehall II longitudinal cohort study. Subjects’ mean age at baseline was 55.6. The investigators compared the Framingham general cardiovascular disease risk score and the Framingham stroke risk score with the Cardiovascular Risk Factors, Aging, and Dementia risk score. Patients underwent cognitive tests of reasoning, memory, verbal fluency, vocabulary, and global cognition three times over 10 years. Compared with the dementia risk score, cardiovascular and stroke risk scores showed slightly stronger associations with 10-year cognitive decline. The differences were statistically significant for semantic fluency and global cognitive scores.
Children born to women who used valproate during pregnancy may have a significantly increased risk of autism spectrum disorder and childhood autism, according to research published in the April 24 JAMA. Investigators used national registers to identify Danish children exposed to valproate during pregnancy and diagnosed with autism spectrum disorders. The researchers analyzed the risks associated with all autism spectrum disorders, as well as childhood autism, and adjusted for potential confounders. The estimated absolute risk after 14 years of follow-up was 1.53% for autism spectrum disorder and 0.48% for childhood autism. The 508 children exposed to valproate had an absolute risk of 4.42% for autism spectrum disorder and an absolute risk of 2.50% for childhood autism. Results changed slightly after considering only the children born to women with epilepsy.
The antisense oligonucleotide ISIS 333611 is a safe treatment for amyotrophic lateral sclerosis (ALS), according to a trial published online ahead of print March 29 in Lancet Neurology. Investigators studied 32 patients with SOD1-positive ALS in a randomized, placebo-controlled, phase I trial. The researchers delivered the drug by intrathecal infusion using an external pump over 11.5 hours at increasing doses (0.15 mg, 0.50 mg, 1.50 mg, and 3.00 mg). Approximately 88% of patients in the placebo group had adverse events, compared with 83% in the active group. The most common events were post-lumbar puncture syndrome, back pain, and nausea. The investigators found no dose-limiting toxic effects or safety or tolerability concerns related to ISIS 333611. No serious adverse events occurred in patients given ISIS 333611.
Thalamic atrophy in patients with clinically isolated syndrome (CIS) is associated with the development of clinically definite multiple sclerosis (MS), according to a study published online ahead of print April 23 in Radiology. Using MRI, researchers assessed 216 patients with CIS at baseline, six months, one year, and two years. MRI measures of progression included new and enlarged T2 lesions and changes in whole-brain, tissue-specific global, and regional gray matter volumes. In mixed-effect model analysis, the lateral ventricle volume, accumulation of new total T2 and new enlarging T2 lesions increase, and thalamic and whole-brain volume decrease were associated with development of clinically definite MS. In multivariate regression analysis, decrease in thalamic volumes and increase in lateral ventricle volumes were associated with the development of clinically definite MS.
Functional MRI (fMRI) can identify pain caused by heat in healthy persons, according to research published in the April 11 New England Journal of Medicine. In four studies of 114 participants, investigators developed an fMRI-based measure that predicts pain intensity, tested its sensitivity and specificity to pain versus warmth, assessed its specificity relative to social pain, and assessed the responsiveness of the measure to the analgesic remifentanil. The neurologic signature distinguished painful heat from nonpainful warmth, pain anticipation, and pain recall with sensitivity and specificity of 94% or more. The signature discriminated between painful heat and nonpainful warmth with 93% sensitivity and specificity. It also distinguished between physical pain and social pain with 85% sensitivity and 73% specificity. The strength of the signature response was substantially reduced after remifentanil administration.
Family history of late-onset Alzheimer’s disease is associated with an increased prevalence of an abnormal cerebral beta-amyloid and tau protein phenotype in patients with mild cognitive impairment (MCI), according to a study published on April 17 in PLOS One. Investigators studied 257 participants (ages 55 to 89) in the Alzheimer’s Disease Neuroimaging Initiative. Subjects were categorized as cognitively normal, having MCI, or having Alzheimer’s disease. Among patients with MCI, CSF Ab42 was lower, t-tau was higher, and t-tau–Ab42 ratio was higher in patients with a family history of Alzheimer’s disease than in patients without. A significant residual effect of family history on pathologic markers in MCI remained after adjusting for APOE e4. The effect of family history was not significant in patients with Alzheimer’s disease.
Most potential migraine triggers are so variable that it may not be possible to identify them without formal experimentation, according to a study published in the April issue of Headache. Investigators examined the similarity of day-to-day weather conditions over four years, as well as the similarity of ovarian hormones and perceived stress over a median of 89 days in nine patients with headache and regular menstrual cycles. A threshold of 90% similarity using Gower’s index identified similar days for comparison. The day-to-day variability in the three headache triggers was substantial enough that finding two naturally similar days for which to contrast the effect of a fourth trigger (eg, drinking wine) occurred infrequently. Fluctuations in weather patterns resulted in a median of 2.3 similar days each year.
Elevated low-density lipoprotein (LDL) cholesterol and altered cholesterol homeostasis may promote neurodegeneration, atherosclerosis, and Alzheimer’s disease by disrupting chromosome segregation, according to research published on April 12 in PLOS One. In a study of mice, investigators observed that high dietary cholesterol induced aneuploidy. In a separate study, the accumulation of intracellular cholesterol was associated with the accumulation of aneuploid fibroblasts, neurons, and glia in patients with Niemann-Pick C1. The researchers also observed that oxidized LDL, LDL, and cholesterol, but not high-density lipoprotein (HDL), induced chromosome mis-segregation and aneuploidy in cultured cells, including neuronal precursors. LDL-induced aneuploidy required the LDL receptor, but not Ab. Cholesterol treatment disrupted the structure of the mitotic spindle, providing a cell biologic mechanism for its aneugenic activity, and ethanol or calcium chelation attenuated lipoprotein-induced chromosome mis-segregation.
The incidence of dementia in central Stockholm may have decreased from the late 1980s to the early 2000s, according to research published online ahead of print April 17 in Neurology. Investigators analyzed data from two cross-sectional surveys of people ages 75 or older. One study was conducted from 1987 to 1989 and included 1,700 participants; the other was conducted from 2001 to 2004 and included 1,575 subjects. The team inferred the incidence of dementia according to its relationship with prevalence and survival. The adjusted odds ratio of dementia in the later study versus the earlier study was 1.17. The multiadjusted hazard ratio of death in the later study versus the earlier study was 0.71 in subjects with dementia, 0.68 in those without dementia, and 0.66 in all participants.
—Erik Greb
Senior Associate Editor
Living in the stroke belt as an adolescent is significantly associated with a high risk of stroke, according to research published online ahead of print April 24 in Neurology. Researchers examined data for 24,544 stroke-free participants in the Reasons for Geographic and Racial Differences in Stroke study. Stroke belt exposure was calculated by combinations of stroke belt birthplace, current residence, and proportion of years in the stroke belt during discrete age categories. Risk of stroke was significantly associated with proportion of life in the stroke belt and with all other exposure periods except birth, ages 31 to 45, and current residence. After adjustment for risk factors, the risk of stroke remained significantly associated only with proportion of residence in the stroke belt during adolescence.
Increased levels of trimethylamine-N-oxide (TMAO), a proatherosclerotic metabolite, are associated with an increased risk of stroke, myocardial infarction, or death, according to research published in the April 25 New England Journal of Medicine. Investigators measured TMAO, choline, and betaine levels in patients who had eaten two hard-boiled eggs and deuterium [d9]-labeled phosphatidylcholine before and after suppressing intestinal microbiota with antibiotics. They also examined the relationship between fasting plasma levels of TMAO and major adverse cardiovascular events during three years of follow-up. Increased plasma levels of TMAO were associated with an increased risk of a major adverse cardiovascular event. An elevated TMAO level predicted an increased risk of major adverse cardiovascular events after adjustment for traditional risk factors, as well as in lower-risk subgroups.
A single-nucleotide polymorphism (SNP) in the ABCA7 gene was significantly linked with an increased risk of Alzheimer’s disease among African Americans, according to research published in the April 10 JAMA. African Americans with this mutation have nearly double the risk of Alzheimer’s disease, but the SNP is not associated with the disease among Europeans. The effect size for the SNP in ABCA7 was comparable with that of the APOE ε4–determining SNP rs429358. Investigators examined data for 5,896 African Americans (1,968 with Alzheimer’s disease and 3,928 controls) who were 60 or older. Data were collected between 1989 and 2011 at multiple sites. The team assessed the association of Alzheimer’s disease with genotyped and imputed SNPs in case–control and in family-based data sets.
The FDA has approved the Precision Spectra Spinal Cord Stimulator (SCS) System, which is designed to provide improved pain relief to patients with chronic pain. The system, manufactured by Boston Scientific (Natick, Massachusetts), includes Illumina 3D software intended to improve physicians’ control of the stimulation field. It is based on a proprietary computer model that takes into account 3-D anatomical structures, including the conductivity of the spinal cord and surrounding tissue. The physician can select a desired location on the spinal cord and prompt the programming software to create a customized stimulation field to mask the patient’s pain. Previous SCS systems included 16 contacts, but the Precision Spectra system includes 32 contacts and is designed to offer more coverage of the spinal cord.
Framingham risk scores may be better than a dementia risk score for assessing individuals’ risk of cognitive decline and targeting modifiable risk factors, according to research published in the April 2 Neurology. Researchers examined data for participants in the Whitehall II longitudinal cohort study. Subjects’ mean age at baseline was 55.6. The investigators compared the Framingham general cardiovascular disease risk score and the Framingham stroke risk score with the Cardiovascular Risk Factors, Aging, and Dementia risk score. Patients underwent cognitive tests of reasoning, memory, verbal fluency, vocabulary, and global cognition three times over 10 years. Compared with the dementia risk score, cardiovascular and stroke risk scores showed slightly stronger associations with 10-year cognitive decline. The differences were statistically significant for semantic fluency and global cognitive scores.
Children born to women who used valproate during pregnancy may have a significantly increased risk of autism spectrum disorder and childhood autism, according to research published in the April 24 JAMA. Investigators used national registers to identify Danish children exposed to valproate during pregnancy and diagnosed with autism spectrum disorders. The researchers analyzed the risks associated with all autism spectrum disorders, as well as childhood autism, and adjusted for potential confounders. The estimated absolute risk after 14 years of follow-up was 1.53% for autism spectrum disorder and 0.48% for childhood autism. The 508 children exposed to valproate had an absolute risk of 4.42% for autism spectrum disorder and an absolute risk of 2.50% for childhood autism. Results changed slightly after considering only the children born to women with epilepsy.
The antisense oligonucleotide ISIS 333611 is a safe treatment for amyotrophic lateral sclerosis (ALS), according to a trial published online ahead of print March 29 in Lancet Neurology. Investigators studied 32 patients with SOD1-positive ALS in a randomized, placebo-controlled, phase I trial. The researchers delivered the drug by intrathecal infusion using an external pump over 11.5 hours at increasing doses (0.15 mg, 0.50 mg, 1.50 mg, and 3.00 mg). Approximately 88% of patients in the placebo group had adverse events, compared with 83% in the active group. The most common events were post-lumbar puncture syndrome, back pain, and nausea. The investigators found no dose-limiting toxic effects or safety or tolerability concerns related to ISIS 333611. No serious adverse events occurred in patients given ISIS 333611.
Thalamic atrophy in patients with clinically isolated syndrome (CIS) is associated with the development of clinically definite multiple sclerosis (MS), according to a study published online ahead of print April 23 in Radiology. Using MRI, researchers assessed 216 patients with CIS at baseline, six months, one year, and two years. MRI measures of progression included new and enlarged T2 lesions and changes in whole-brain, tissue-specific global, and regional gray matter volumes. In mixed-effect model analysis, the lateral ventricle volume, accumulation of new total T2 and new enlarging T2 lesions increase, and thalamic and whole-brain volume decrease were associated with development of clinically definite MS. In multivariate regression analysis, decrease in thalamic volumes and increase in lateral ventricle volumes were associated with the development of clinically definite MS.
Functional MRI (fMRI) can identify pain caused by heat in healthy persons, according to research published in the April 11 New England Journal of Medicine. In four studies of 114 participants, investigators developed an fMRI-based measure that predicts pain intensity, tested its sensitivity and specificity to pain versus warmth, assessed its specificity relative to social pain, and assessed the responsiveness of the measure to the analgesic remifentanil. The neurologic signature distinguished painful heat from nonpainful warmth, pain anticipation, and pain recall with sensitivity and specificity of 94% or more. The signature discriminated between painful heat and nonpainful warmth with 93% sensitivity and specificity. It also distinguished between physical pain and social pain with 85% sensitivity and 73% specificity. The strength of the signature response was substantially reduced after remifentanil administration.
Family history of late-onset Alzheimer’s disease is associated with an increased prevalence of an abnormal cerebral beta-amyloid and tau protein phenotype in patients with mild cognitive impairment (MCI), according to a study published on April 17 in PLOS One. Investigators studied 257 participants (ages 55 to 89) in the Alzheimer’s Disease Neuroimaging Initiative. Subjects were categorized as cognitively normal, having MCI, or having Alzheimer’s disease. Among patients with MCI, CSF Ab42 was lower, t-tau was higher, and t-tau–Ab42 ratio was higher in patients with a family history of Alzheimer’s disease than in patients without. A significant residual effect of family history on pathologic markers in MCI remained after adjusting for APOE e4. The effect of family history was not significant in patients with Alzheimer’s disease.
Most potential migraine triggers are so variable that it may not be possible to identify them without formal experimentation, according to a study published in the April issue of Headache. Investigators examined the similarity of day-to-day weather conditions over four years, as well as the similarity of ovarian hormones and perceived stress over a median of 89 days in nine patients with headache and regular menstrual cycles. A threshold of 90% similarity using Gower’s index identified similar days for comparison. The day-to-day variability in the three headache triggers was substantial enough that finding two naturally similar days for which to contrast the effect of a fourth trigger (eg, drinking wine) occurred infrequently. Fluctuations in weather patterns resulted in a median of 2.3 similar days each year.
Elevated low-density lipoprotein (LDL) cholesterol and altered cholesterol homeostasis may promote neurodegeneration, atherosclerosis, and Alzheimer’s disease by disrupting chromosome segregation, according to research published on April 12 in PLOS One. In a study of mice, investigators observed that high dietary cholesterol induced aneuploidy. In a separate study, the accumulation of intracellular cholesterol was associated with the accumulation of aneuploid fibroblasts, neurons, and glia in patients with Niemann-Pick C1. The researchers also observed that oxidized LDL, LDL, and cholesterol, but not high-density lipoprotein (HDL), induced chromosome mis-segregation and aneuploidy in cultured cells, including neuronal precursors. LDL-induced aneuploidy required the LDL receptor, but not Ab. Cholesterol treatment disrupted the structure of the mitotic spindle, providing a cell biologic mechanism for its aneugenic activity, and ethanol or calcium chelation attenuated lipoprotein-induced chromosome mis-segregation.
The incidence of dementia in central Stockholm may have decreased from the late 1980s to the early 2000s, according to research published online ahead of print April 17 in Neurology. Investigators analyzed data from two cross-sectional surveys of people ages 75 or older. One study was conducted from 1987 to 1989 and included 1,700 participants; the other was conducted from 2001 to 2004 and included 1,575 subjects. The team inferred the incidence of dementia according to its relationship with prevalence and survival. The adjusted odds ratio of dementia in the later study versus the earlier study was 1.17. The multiadjusted hazard ratio of death in the later study versus the earlier study was 0.71 in subjects with dementia, 0.68 in those without dementia, and 0.66 in all participants.
—Erik Greb
Senior Associate Editor
Edward Fox, MD, Discusses the Extension Study of Alemtuzumab for MS
Research Helps Clarify the Role of Vitamin D in Multiple Sclerosis
LYON, FRANCE—Researchers are uncovering an increasing amount of evidence that vitamin D plays a role in multiple sclerosis (MS), according to a review presented at the 28th Congress of the European Committee for Treatment and Research in MS. Recent findings indicate that vitamin D may be influential during interactions between genes and the environment and may have long-term epigenetic effects.
Sreeram Ramagopalan, postdoctoral fellow at Oxford University in the United Kingdom, described the results of various investigations that shed further light on how vitamin D levels may affect gene expression and, ultimately, the risk of developing MS.
A Threshold Effect on Activation of the Vitamin D Receptor
To investigate the relationship between vitamin D receptor binding and vitamin D levels in serum, Dr. Ramagopalan and his colleagues examined nine healthy individuals. Using flow sorting and chromatin immunoprecipitation sequencing, the researchers observed a strong correlation between serum hydroxyvitamin D levels and vitamin D receptor binding in the subjects' CD4+ T-cells. "There seems to be a threshold effect on activation of the vitamin D receptor," said Dr. Ramagopalan.
Healthy individuals with serum 25-hydroxyvitamin D levels greater than 75 nmol/L had a mean of approximately 4,500 vitamin D receptor binding sites. Individuals with serum vitamin D levels lower than 75 nmol/L had a mean of approximately 500 binding sites.
A hierarchical clustering analysis revealed that individuals with serum hydroxyvitamin D levels greater than 75 nmol/L tended to have intronic and intragenic binding sites. Promoter-based binding sites were more common in subjects with lower levels of hydroxyvitamin D. The Vitamin D Council recommends a minimum serum vitamin D level of 75 nmol/L for health, noted Dr. Ramagopalan.
Further testing indicated that vitamin D receptor binding sites were highly enriched for genes associated with MS in individuals with serum hydroxyvitamin D levels greater than 75 nmol/L. The investigators found no enrichment for vitamin D receptor binding sites in individuals who had serum hydroxyvitamin D levels lower than 75 nmol/L. In addition, the researchers detected "a big difference in gene expression, and this also related to MS-associated genes," between individuals with serum hydroxyvitamin D levels above and below 75 nmol/L, said Dr. Ramagopalan.
Methylation May Affect Vitamin D's Influence on MS
Dr. Ramagopalan and his colleagues are examining sets of twins as part of ongoing studies of the epigenetics of MS. Each set includes one twin with MS and one without. Recently, the investigators studied DNA methylation in the twins' CD4+ T-cells using an Illumina 27k array, which covers approximately 0.1% of DNA methylone. They found "about 120 differentially methylated regions or methylation-variable positions," including hypomethylation and hypermethylation in the affected twins, said Dr. Ramagopalan.
After examining three of these twin pairs to determine whether vitamin D receptor binding was affected by DNA methylation, the group found that methylation at promoter sites correlated with the absence of vitamin D receptor binding. Conversely, lack of methylation correlated with high levels of vitamin D receptor binding. Methylation associated with MS also appeared to affect vitamin D receptor binding. In affected twins, hypermethylation correlated with little or no vitamin D receptor binding. "Methylation associated with MS may affect the influence of vitamin D in patients with MS," said Dr. Ramagopalan.
Vitamin D May Influence the Expression of Thousands of Genes
These results extend and complement the findings of Dr. Ramagopalan's previous studies. In 2010, he and his colleagues investigated whether the vitamin D receptor was more or less likely to bind to genes associated with 47 diseases. The researchers found that genes associated with autoimmune diseases such as type 1 diabetes, Crohn's disease, MS, and colorectal cancer were unusually enriched for vitamin D receptor binding sites.
At the time, approximately 10 genes were associated with MS, and more have been associated with the disease since then. In the group's updated analysis, performed in 2012, 80% of the more than 60 MS-associated genes had vitamin D receptor binding near them.
The vitamin D receptor tends to bind to intragenic or intronic binding sites, and Dr. Ramagopalan's group wanted to understand how this tendency affects gene expression. The investigators found that vitamin D receptors bound to strong enhancer sites and active promoter sites at more than 60 times the rate that would result from chance. "This suggested that the binding of vitamin D receptors to these regions should influence gene expression," said Dr. Ramagopalan. The investigators also found that when the Epstein–Barr virus protein EBNA-3 was knocked out, vitamin D was associated with the differential expression of approximately 4,000 genes.
In subsequent studies, the researchers exposed in utero mice to vitamin D deficiency. The number and type of genes expressed were different in these mice, compared with control mice. Genes that were upregulated in mice exposed to vitamin D deficiency were also upregulated in their offspring, and the same correspondence was true for genes that were downregulated in the parent mice. "This suggests that vitamin D impacts gene expression until adulthood, and this impact also lasts until the next generation," said Dr. Ramagopalan. "We're actively trying to study the mechanism and how this potentially may relate to complex disease."
Senior Associate Editor
Suggested Reading
Ban M, Caillier S, Mero IL, et al. No evidence of association between mutant alleles of the CYP27B1 gene and multiple sclerosis. Ann Neurol. 2012 Dec 13 [Epub ahead of print].
Disanto G, Sandve GK, Berlanga-Taylor AJ, et al. Vitamin D receptor binding, chromatin states and association with multiple sclerosis. Hum Mol Genet. 2012;21(16):3575-3586.
LYON, FRANCE—Researchers are uncovering an increasing amount of evidence that vitamin D plays a role in multiple sclerosis (MS), according to a review presented at the 28th Congress of the European Committee for Treatment and Research in MS. Recent findings indicate that vitamin D may be influential during interactions between genes and the environment and may have long-term epigenetic effects.
Sreeram Ramagopalan, postdoctoral fellow at Oxford University in the United Kingdom, described the results of various investigations that shed further light on how vitamin D levels may affect gene expression and, ultimately, the risk of developing MS.
A Threshold Effect on Activation of the Vitamin D Receptor
To investigate the relationship between vitamin D receptor binding and vitamin D levels in serum, Dr. Ramagopalan and his colleagues examined nine healthy individuals. Using flow sorting and chromatin immunoprecipitation sequencing, the researchers observed a strong correlation between serum hydroxyvitamin D levels and vitamin D receptor binding in the subjects' CD4+ T-cells. "There seems to be a threshold effect on activation of the vitamin D receptor," said Dr. Ramagopalan.
Healthy individuals with serum 25-hydroxyvitamin D levels greater than 75 nmol/L had a mean of approximately 4,500 vitamin D receptor binding sites. Individuals with serum vitamin D levels lower than 75 nmol/L had a mean of approximately 500 binding sites.
A hierarchical clustering analysis revealed that individuals with serum hydroxyvitamin D levels greater than 75 nmol/L tended to have intronic and intragenic binding sites. Promoter-based binding sites were more common in subjects with lower levels of hydroxyvitamin D. The Vitamin D Council recommends a minimum serum vitamin D level of 75 nmol/L for health, noted Dr. Ramagopalan.
Further testing indicated that vitamin D receptor binding sites were highly enriched for genes associated with MS in individuals with serum hydroxyvitamin D levels greater than 75 nmol/L. The investigators found no enrichment for vitamin D receptor binding sites in individuals who had serum hydroxyvitamin D levels lower than 75 nmol/L. In addition, the researchers detected "a big difference in gene expression, and this also related to MS-associated genes," between individuals with serum hydroxyvitamin D levels above and below 75 nmol/L, said Dr. Ramagopalan.
Methylation May Affect Vitamin D's Influence on MS
Dr. Ramagopalan and his colleagues are examining sets of twins as part of ongoing studies of the epigenetics of MS. Each set includes one twin with MS and one without. Recently, the investigators studied DNA methylation in the twins' CD4+ T-cells using an Illumina 27k array, which covers approximately 0.1% of DNA methylone. They found "about 120 differentially methylated regions or methylation-variable positions," including hypomethylation and hypermethylation in the affected twins, said Dr. Ramagopalan.
After examining three of these twin pairs to determine whether vitamin D receptor binding was affected by DNA methylation, the group found that methylation at promoter sites correlated with the absence of vitamin D receptor binding. Conversely, lack of methylation correlated with high levels of vitamin D receptor binding. Methylation associated with MS also appeared to affect vitamin D receptor binding. In affected twins, hypermethylation correlated with little or no vitamin D receptor binding. "Methylation associated with MS may affect the influence of vitamin D in patients with MS," said Dr. Ramagopalan.
Vitamin D May Influence the Expression of Thousands of Genes
These results extend and complement the findings of Dr. Ramagopalan's previous studies. In 2010, he and his colleagues investigated whether the vitamin D receptor was more or less likely to bind to genes associated with 47 diseases. The researchers found that genes associated with autoimmune diseases such as type 1 diabetes, Crohn's disease, MS, and colorectal cancer were unusually enriched for vitamin D receptor binding sites.
At the time, approximately 10 genes were associated with MS, and more have been associated with the disease since then. In the group's updated analysis, performed in 2012, 80% of the more than 60 MS-associated genes had vitamin D receptor binding near them.
The vitamin D receptor tends to bind to intragenic or intronic binding sites, and Dr. Ramagopalan's group wanted to understand how this tendency affects gene expression. The investigators found that vitamin D receptors bound to strong enhancer sites and active promoter sites at more than 60 times the rate that would result from chance. "This suggested that the binding of vitamin D receptors to these regions should influence gene expression," said Dr. Ramagopalan. The investigators also found that when the Epstein–Barr virus protein EBNA-3 was knocked out, vitamin D was associated with the differential expression of approximately 4,000 genes.
In subsequent studies, the researchers exposed in utero mice to vitamin D deficiency. The number and type of genes expressed were different in these mice, compared with control mice. Genes that were upregulated in mice exposed to vitamin D deficiency were also upregulated in their offspring, and the same correspondence was true for genes that were downregulated in the parent mice. "This suggests that vitamin D impacts gene expression until adulthood, and this impact also lasts until the next generation," said Dr. Ramagopalan. "We're actively trying to study the mechanism and how this potentially may relate to complex disease."
Senior Associate Editor
LYON, FRANCE—Researchers are uncovering an increasing amount of evidence that vitamin D plays a role in multiple sclerosis (MS), according to a review presented at the 28th Congress of the European Committee for Treatment and Research in MS. Recent findings indicate that vitamin D may be influential during interactions between genes and the environment and may have long-term epigenetic effects.
Sreeram Ramagopalan, postdoctoral fellow at Oxford University in the United Kingdom, described the results of various investigations that shed further light on how vitamin D levels may affect gene expression and, ultimately, the risk of developing MS.
A Threshold Effect on Activation of the Vitamin D Receptor
To investigate the relationship between vitamin D receptor binding and vitamin D levels in serum, Dr. Ramagopalan and his colleagues examined nine healthy individuals. Using flow sorting and chromatin immunoprecipitation sequencing, the researchers observed a strong correlation between serum hydroxyvitamin D levels and vitamin D receptor binding in the subjects' CD4+ T-cells. "There seems to be a threshold effect on activation of the vitamin D receptor," said Dr. Ramagopalan.
Healthy individuals with serum 25-hydroxyvitamin D levels greater than 75 nmol/L had a mean of approximately 4,500 vitamin D receptor binding sites. Individuals with serum vitamin D levels lower than 75 nmol/L had a mean of approximately 500 binding sites.
A hierarchical clustering analysis revealed that individuals with serum hydroxyvitamin D levels greater than 75 nmol/L tended to have intronic and intragenic binding sites. Promoter-based binding sites were more common in subjects with lower levels of hydroxyvitamin D. The Vitamin D Council recommends a minimum serum vitamin D level of 75 nmol/L for health, noted Dr. Ramagopalan.
Further testing indicated that vitamin D receptor binding sites were highly enriched for genes associated with MS in individuals with serum hydroxyvitamin D levels greater than 75 nmol/L. The investigators found no enrichment for vitamin D receptor binding sites in individuals who had serum hydroxyvitamin D levels lower than 75 nmol/L. In addition, the researchers detected "a big difference in gene expression, and this also related to MS-associated genes," between individuals with serum hydroxyvitamin D levels above and below 75 nmol/L, said Dr. Ramagopalan.
Methylation May Affect Vitamin D's Influence on MS
Dr. Ramagopalan and his colleagues are examining sets of twins as part of ongoing studies of the epigenetics of MS. Each set includes one twin with MS and one without. Recently, the investigators studied DNA methylation in the twins' CD4+ T-cells using an Illumina 27k array, which covers approximately 0.1% of DNA methylone. They found "about 120 differentially methylated regions or methylation-variable positions," including hypomethylation and hypermethylation in the affected twins, said Dr. Ramagopalan.
After examining three of these twin pairs to determine whether vitamin D receptor binding was affected by DNA methylation, the group found that methylation at promoter sites correlated with the absence of vitamin D receptor binding. Conversely, lack of methylation correlated with high levels of vitamin D receptor binding. Methylation associated with MS also appeared to affect vitamin D receptor binding. In affected twins, hypermethylation correlated with little or no vitamin D receptor binding. "Methylation associated with MS may affect the influence of vitamin D in patients with MS," said Dr. Ramagopalan.
Vitamin D May Influence the Expression of Thousands of Genes
These results extend and complement the findings of Dr. Ramagopalan's previous studies. In 2010, he and his colleagues investigated whether the vitamin D receptor was more or less likely to bind to genes associated with 47 diseases. The researchers found that genes associated with autoimmune diseases such as type 1 diabetes, Crohn's disease, MS, and colorectal cancer were unusually enriched for vitamin D receptor binding sites.
At the time, approximately 10 genes were associated with MS, and more have been associated with the disease since then. In the group's updated analysis, performed in 2012, 80% of the more than 60 MS-associated genes had vitamin D receptor binding near them.
The vitamin D receptor tends to bind to intragenic or intronic binding sites, and Dr. Ramagopalan's group wanted to understand how this tendency affects gene expression. The investigators found that vitamin D receptors bound to strong enhancer sites and active promoter sites at more than 60 times the rate that would result from chance. "This suggested that the binding of vitamin D receptors to these regions should influence gene expression," said Dr. Ramagopalan. The investigators also found that when the Epstein–Barr virus protein EBNA-3 was knocked out, vitamin D was associated with the differential expression of approximately 4,000 genes.
In subsequent studies, the researchers exposed in utero mice to vitamin D deficiency. The number and type of genes expressed were different in these mice, compared with control mice. Genes that were upregulated in mice exposed to vitamin D deficiency were also upregulated in their offspring, and the same correspondence was true for genes that were downregulated in the parent mice. "This suggests that vitamin D impacts gene expression until adulthood, and this impact also lasts until the next generation," said Dr. Ramagopalan. "We're actively trying to study the mechanism and how this potentially may relate to complex disease."
Senior Associate Editor
Suggested Reading
Ban M, Caillier S, Mero IL, et al. No evidence of association between mutant alleles of the CYP27B1 gene and multiple sclerosis. Ann Neurol. 2012 Dec 13 [Epub ahead of print].
Disanto G, Sandve GK, Berlanga-Taylor AJ, et al. Vitamin D receptor binding, chromatin states and association with multiple sclerosis. Hum Mol Genet. 2012;21(16):3575-3586.
Suggested Reading
Ban M, Caillier S, Mero IL, et al. No evidence of association between mutant alleles of the CYP27B1 gene and multiple sclerosis. Ann Neurol. 2012 Dec 13 [Epub ahead of print].
Disanto G, Sandve GK, Berlanga-Taylor AJ, et al. Vitamin D receptor binding, chromatin states and association with multiple sclerosis. Hum Mol Genet. 2012;21(16):3575-3586.
New and Noteworthy Information—April 2013
Greater dietary fiber intake is significantly associated with a lower risk of first stroke, according to a study published online ahead of print March 28 in Stroke. Investigators searched several electronic databases for healthy participant studies published between January 1990 and May 2012 that reported fiber intake and incidence of first hemorrhagic or ischemic stroke. The group identified eight cohort studies from the United States, Europe, Australia, and Japan that met their inclusion criteria. Total dietary fiber intake was inversely associated with risk of hemorrhagic plus ischemic stroke. The researchers found evidence of heterogeneity between the studies. Soluble fiber intake of 4 g/day was not associated with stroke risk reduction, and the investigators found evidence of low heterogeneity on this point between the studies.
In women who have episodic migraine, the ratio of high molecular weight to low molecular weight ictal adiponectin (ADP) may be associated with migraine severity and predict acute treatment response, according to a study published in the March Headache. Investigators collected peripheral blood specimens from women with episodic migraine before and after acute abortive treatment with sumatriptan and naproxen sodium or placebo. In all participants, increases in the ratio of high molecular weight to low molecular weight ADP were associated with increases in pain severity. For every 0.25-μg/mL increase in low molecular weight ADP, pain severity decreased by 0.20. In treatment responders, total ADP levels were reduced at 30, 60, and 120 minutes after treatment, compared with onset.
The FDA has approved Tecfidera (dimethyl fumarate) capsules to treat adults with relapsing forms of multiple sclerosis (MS). In two clinical trials, patients with MS who took dimethyl fumarate had fewer relapses compared with people who received placebo. In one of the trials, patients who took dimethyl fumarate experienced a worsening of disability less often than patients who took a placebo. Dimethyl fumarate may decrease a person's white blood cell count, but the drug was not associated with a significant increase in infections in clinical trials. Before starting treatment, and annually thereafter, the FDA recommends that a patient's white blood cell count be assessed by a health care provider. Flushing and stomach problems were the most common adverse reactions reported. Tecfidera is manufactured by Biogen Idec (Weston, Massachusetts).
Mild cognitive impairment (MCI) at the time of Parkinson's disease diagnosis may predict a highly increased risk for early dementia, according to a study published online ahead of print March 25 in JAMA Neurology. Researchers examined data for a population-based cohort of 182 patients with incident Parkinson's disease who were monitored for three years. Significantly more patients with MCI than without MCI at baseline (27.0% versus 0.7%) progressed to dementia during follow-up. Mild cognitive impairment at the one-year visit was associated with a similar progression rate to dementia (ie, 27.8%) and reversion rate to normal cognition (ie, 19.4%). Among the 22 patients with persistent MCI at baseline and the one-year visit, 10 developed dementia and two reverted to normal cognition by the end of the study.
Higher consumption of green tea and coffee may reduce the risk of cardiovascular disease and stroke, according to a study published online ahead of print March 14 in Stroke. Investigators studied 82,369 Japanese persons between ages 45 and 74 without cardiovascular disease or cancer. Green tea and coffee consumption was assessed by a self-administered questionnaire at baseline. Compared with seldom drinking green tea, the multivariable-adjusted hazard ratios of all strokes were 0.86 and 0.80 in individuals who drank two to three and four or more cups of green tea per day, respectively. Compared with seldom drinking coffee, the multivariable-adjusted hazard ratios of all strokes were 0.89, 0.80, and 0.81 for individuals who drank coffee three to six times per week, once daily, and twice or more daily, respectively.
Updated Guidelines for the Management of Acute Cervical Spine and Spinal Cord Injuries recommend against the use of steroids, including methylprednisolone, in acute spinal cord injury in the first 24 to 48 hours after injury. The use of steroids previously was recommended for this indication with consideration of the risk–reward profile, as evaluated by the physician. In the first new treatment guidelines in a decade, which were issued by the Joint Section on Disorders of the Spine and Peripheral Nerves of the Congress of Neurological Surgeons and the American Association of Neurological Surgeons, the standard has been revised based on the lack of medical evidence supporting the benefits of these drugs in the clinical setting. The report cites strong evidence that "high-dose steroids are associated with harmful side effects, including death."
Abnormalities in cortical surface area may indicate an individual's predisposition to developing migraine, and abnormalities in cortical thickness may result from migraine-related processes, according to research published online ahead of print March 26 in Radiology. Investigators took T2-weighted and three-dimensional T1-weighted MRIs of the brain for 63 migraineurs and 18 controls. They estimated cortical thickness and cortical surface area. Compared with control subjects, patients with migraine had reduced cortical thickness and surface area in pain-processing regions. These reductions were greater in regions involved in executive functions and visual-motion processing. Cortical thickness and cortical surface area abnormalities had minimal areas of overlap. Cortical thickness and surface area abnormalities were related to aura and white matter hyperintensities, but not to disease duration and attack frequency.
Primary stroke centers are more likely to administer t-PA than noncertified hospitals, according to research published online ahead of print March 26 in the Journal of the American Heart Association. Investigators analyzed data obtained from the Nationwide Inpatient Sample between 2004 and 2009 for patients age 18 or older with a primary diagnosis of acute ischemic stroke. IV t-PA was administered to 3.1% of patients overall. The drug was given to 2.2% of patients at noncertified hospitals and to 6.7% of patients at primary stroke centers. Between 2004 and 2009, t-PA administration increased from 1.4% to 3.3% of patients at noncertified hospitals and from 6.0% to 7.6% of patients at primary stroke centers. In a multivariable model, evaluation at a primary stroke center was significantly associated with t-PA use.
Control and prevention of risk factors such as hypertension earlier in life may limit or delay neuropathologic brain changes such as Alzheimer's disease with aging, researchers reported in a study published online ahead of print March 18 in JAMA Neurology. The investigators studied 118 cognitively normal adults ages 47 to 89. Participants were classified as having hypertension if they reported a medical diagnosis of hypertension or if blood pressure exceeded 140 mm Hg systolic/90 mm Hg diastolic on seven occasions. Participants underwent Ab PET imaging with radiotracer fluorine 18–labeled florbetapir, were genotyped for apolipoprotein E, and were classified as ε4+ or ε4−. Subjects with hypertension and at least one ε4 allele had significantly more amyloid burden than those with one or no risk factors.
Physicians can discontinue chronic antipsychotic medication for many elderly adults with Alzheimer's dementia and neuropsychiatric symptoms without causing detrimental effects on their behavior, according to a review published online March 28 in the Cochrane Database of Systematic Reviews. Investigators examined data from nine randomized controlled trials that compared antipsychotic withdrawal strategies with continuation of antipsychotics in patients with dementia. Although neurologists have concerns about the potential adverse events of antipsychotics, it is not clear whether withdrawal is beneficial for patients' cognition or psychomotor status. In two studies of patients whose agitation or psychosis had previously responded well to antipsychotic treatment, discontinuation was associated with an increased risk of relapse or shorter time to relapse. Two studies suggested that patients with severe neuropsychiatric symptoms at baseline could benefit from continuing their antipsychotic medication.
Greater exposure to pathogens associated with stroke risk and atherosclerosis may correlate with poorer cognitive performance, according to research published in the March 26 Neurology. Investigators tested for various pathogens (eg, Chlamydia pneumonia and Helicobacter pylori) in 1,625 participants in the Northern Manhattan Study. The researchers assessed patients' cognitive performance at baseline and at annual follow-up visits. Higher infectious burden index was associated with worse cognition. Each standard deviation in infectious burden correlated with a 0.77-point decline in Mini-Mental State Examination (MMSE) score. Adjustment for risk factors weakened the effect, however. Infectious burden was associated with an MMSE score of 24 or lower. Infectious burden was not associated with cognitive decline over time. Past infections may contribute to cognitive impairment, said the researchers.
Smoking cessation was associated with a decreased risk of cardiovascular disease events, and subsequent weight gain did not modify this association, researchers reported in the March 13 JAMA. Investigators analyzed data collected from 1984 through 2011 in the Framingham Offspring Study. Participants' self-reported smoking status was recorded during four-year examinations. Median four-year weight gain was 2.7 kg for recent smoking quitters without diabetes, 3.6 kg for recent quitters with diabetes, and 0.9 kg for long-term quitters. After adjustment for cardiovascular risk factors, compared with smokers, recent smoking quitters had a hazard ratio for cardiovascular disease of 0.47, and long-term quitters had a hazard ratio of 0.46. The results changed minimally after further adjustment for weight change. Similar point estimates for participants with diabetes did not reach statistical significance.
Women who enter menopause prematurely after bilateral ovariectomy may have a significantly increased risk for cognitive decline and dementia, according to a study published online ahead of print March 9 in Brain. The investigators studied rats 10 weeks after they had undergone bilateral ovariectomy and found that long-term estrogen deprivation dramatically increased the hippocampal CA3 region's sensitivity to ischemic stress, which correlated with a worse cognitive outcome. Long-term ovariectomized rats had robust hyperinduction of Alzheimer's disease-related proteins in the CA3 region. Following ischemic stress, amyloid-precursor protein processing switched from nonamyloidogenic to amyloidogenic. Replacement of 17β-estradiol at the end of the estrogen-deprivation period could not prevent CA3 hypersensitivity and amyloidogenesis, but if 17β-estradiol was initiated at ovariectomy and maintained throughout the estrogen deprivation period, it completely prevented these events.
Senior Associate Editor
Greater dietary fiber intake is significantly associated with a lower risk of first stroke, according to a study published online ahead of print March 28 in Stroke. Investigators searched several electronic databases for healthy participant studies published between January 1990 and May 2012 that reported fiber intake and incidence of first hemorrhagic or ischemic stroke. The group identified eight cohort studies from the United States, Europe, Australia, and Japan that met their inclusion criteria. Total dietary fiber intake was inversely associated with risk of hemorrhagic plus ischemic stroke. The researchers found evidence of heterogeneity between the studies. Soluble fiber intake of 4 g/day was not associated with stroke risk reduction, and the investigators found evidence of low heterogeneity on this point between the studies.
In women who have episodic migraine, the ratio of high molecular weight to low molecular weight ictal adiponectin (ADP) may be associated with migraine severity and predict acute treatment response, according to a study published in the March Headache. Investigators collected peripheral blood specimens from women with episodic migraine before and after acute abortive treatment with sumatriptan and naproxen sodium or placebo. In all participants, increases in the ratio of high molecular weight to low molecular weight ADP were associated with increases in pain severity. For every 0.25-μg/mL increase in low molecular weight ADP, pain severity decreased by 0.20. In treatment responders, total ADP levels were reduced at 30, 60, and 120 minutes after treatment, compared with onset.
The FDA has approved Tecfidera (dimethyl fumarate) capsules to treat adults with relapsing forms of multiple sclerosis (MS). In two clinical trials, patients with MS who took dimethyl fumarate had fewer relapses compared with people who received placebo. In one of the trials, patients who took dimethyl fumarate experienced a worsening of disability less often than patients who took a placebo. Dimethyl fumarate may decrease a person's white blood cell count, but the drug was not associated with a significant increase in infections in clinical trials. Before starting treatment, and annually thereafter, the FDA recommends that a patient's white blood cell count be assessed by a health care provider. Flushing and stomach problems were the most common adverse reactions reported. Tecfidera is manufactured by Biogen Idec (Weston, Massachusetts).
Mild cognitive impairment (MCI) at the time of Parkinson's disease diagnosis may predict a highly increased risk for early dementia, according to a study published online ahead of print March 25 in JAMA Neurology. Researchers examined data for a population-based cohort of 182 patients with incident Parkinson's disease who were monitored for three years. Significantly more patients with MCI than without MCI at baseline (27.0% versus 0.7%) progressed to dementia during follow-up. Mild cognitive impairment at the one-year visit was associated with a similar progression rate to dementia (ie, 27.8%) and reversion rate to normal cognition (ie, 19.4%). Among the 22 patients with persistent MCI at baseline and the one-year visit, 10 developed dementia and two reverted to normal cognition by the end of the study.
Higher consumption of green tea and coffee may reduce the risk of cardiovascular disease and stroke, according to a study published online ahead of print March 14 in Stroke. Investigators studied 82,369 Japanese persons between ages 45 and 74 without cardiovascular disease or cancer. Green tea and coffee consumption was assessed by a self-administered questionnaire at baseline. Compared with seldom drinking green tea, the multivariable-adjusted hazard ratios of all strokes were 0.86 and 0.80 in individuals who drank two to three and four or more cups of green tea per day, respectively. Compared with seldom drinking coffee, the multivariable-adjusted hazard ratios of all strokes were 0.89, 0.80, and 0.81 for individuals who drank coffee three to six times per week, once daily, and twice or more daily, respectively.
Updated Guidelines for the Management of Acute Cervical Spine and Spinal Cord Injuries recommend against the use of steroids, including methylprednisolone, in acute spinal cord injury in the first 24 to 48 hours after injury. The use of steroids previously was recommended for this indication with consideration of the risk–reward profile, as evaluated by the physician. In the first new treatment guidelines in a decade, which were issued by the Joint Section on Disorders of the Spine and Peripheral Nerves of the Congress of Neurological Surgeons and the American Association of Neurological Surgeons, the standard has been revised based on the lack of medical evidence supporting the benefits of these drugs in the clinical setting. The report cites strong evidence that "high-dose steroids are associated with harmful side effects, including death."
Abnormalities in cortical surface area may indicate an individual's predisposition to developing migraine, and abnormalities in cortical thickness may result from migraine-related processes, according to research published online ahead of print March 26 in Radiology. Investigators took T2-weighted and three-dimensional T1-weighted MRIs of the brain for 63 migraineurs and 18 controls. They estimated cortical thickness and cortical surface area. Compared with control subjects, patients with migraine had reduced cortical thickness and surface area in pain-processing regions. These reductions were greater in regions involved in executive functions and visual-motion processing. Cortical thickness and cortical surface area abnormalities had minimal areas of overlap. Cortical thickness and surface area abnormalities were related to aura and white matter hyperintensities, but not to disease duration and attack frequency.
Primary stroke centers are more likely to administer t-PA than noncertified hospitals, according to research published online ahead of print March 26 in the Journal of the American Heart Association. Investigators analyzed data obtained from the Nationwide Inpatient Sample between 2004 and 2009 for patients age 18 or older with a primary diagnosis of acute ischemic stroke. IV t-PA was administered to 3.1% of patients overall. The drug was given to 2.2% of patients at noncertified hospitals and to 6.7% of patients at primary stroke centers. Between 2004 and 2009, t-PA administration increased from 1.4% to 3.3% of patients at noncertified hospitals and from 6.0% to 7.6% of patients at primary stroke centers. In a multivariable model, evaluation at a primary stroke center was significantly associated with t-PA use.
Control and prevention of risk factors such as hypertension earlier in life may limit or delay neuropathologic brain changes such as Alzheimer's disease with aging, researchers reported in a study published online ahead of print March 18 in JAMA Neurology. The investigators studied 118 cognitively normal adults ages 47 to 89. Participants were classified as having hypertension if they reported a medical diagnosis of hypertension or if blood pressure exceeded 140 mm Hg systolic/90 mm Hg diastolic on seven occasions. Participants underwent Ab PET imaging with radiotracer fluorine 18–labeled florbetapir, were genotyped for apolipoprotein E, and were classified as ε4+ or ε4−. Subjects with hypertension and at least one ε4 allele had significantly more amyloid burden than those with one or no risk factors.
Physicians can discontinue chronic antipsychotic medication for many elderly adults with Alzheimer's dementia and neuropsychiatric symptoms without causing detrimental effects on their behavior, according to a review published online March 28 in the Cochrane Database of Systematic Reviews. Investigators examined data from nine randomized controlled trials that compared antipsychotic withdrawal strategies with continuation of antipsychotics in patients with dementia. Although neurologists have concerns about the potential adverse events of antipsychotics, it is not clear whether withdrawal is beneficial for patients' cognition or psychomotor status. In two studies of patients whose agitation or psychosis had previously responded well to antipsychotic treatment, discontinuation was associated with an increased risk of relapse or shorter time to relapse. Two studies suggested that patients with severe neuropsychiatric symptoms at baseline could benefit from continuing their antipsychotic medication.
Greater exposure to pathogens associated with stroke risk and atherosclerosis may correlate with poorer cognitive performance, according to research published in the March 26 Neurology. Investigators tested for various pathogens (eg, Chlamydia pneumonia and Helicobacter pylori) in 1,625 participants in the Northern Manhattan Study. The researchers assessed patients' cognitive performance at baseline and at annual follow-up visits. Higher infectious burden index was associated with worse cognition. Each standard deviation in infectious burden correlated with a 0.77-point decline in Mini-Mental State Examination (MMSE) score. Adjustment for risk factors weakened the effect, however. Infectious burden was associated with an MMSE score of 24 or lower. Infectious burden was not associated with cognitive decline over time. Past infections may contribute to cognitive impairment, said the researchers.
Smoking cessation was associated with a decreased risk of cardiovascular disease events, and subsequent weight gain did not modify this association, researchers reported in the March 13 JAMA. Investigators analyzed data collected from 1984 through 2011 in the Framingham Offspring Study. Participants' self-reported smoking status was recorded during four-year examinations. Median four-year weight gain was 2.7 kg for recent smoking quitters without diabetes, 3.6 kg for recent quitters with diabetes, and 0.9 kg for long-term quitters. After adjustment for cardiovascular risk factors, compared with smokers, recent smoking quitters had a hazard ratio for cardiovascular disease of 0.47, and long-term quitters had a hazard ratio of 0.46. The results changed minimally after further adjustment for weight change. Similar point estimates for participants with diabetes did not reach statistical significance.
Women who enter menopause prematurely after bilateral ovariectomy may have a significantly increased risk for cognitive decline and dementia, according to a study published online ahead of print March 9 in Brain. The investigators studied rats 10 weeks after they had undergone bilateral ovariectomy and found that long-term estrogen deprivation dramatically increased the hippocampal CA3 region's sensitivity to ischemic stress, which correlated with a worse cognitive outcome. Long-term ovariectomized rats had robust hyperinduction of Alzheimer's disease-related proteins in the CA3 region. Following ischemic stress, amyloid-precursor protein processing switched from nonamyloidogenic to amyloidogenic. Replacement of 17β-estradiol at the end of the estrogen-deprivation period could not prevent CA3 hypersensitivity and amyloidogenesis, but if 17β-estradiol was initiated at ovariectomy and maintained throughout the estrogen deprivation period, it completely prevented these events.
Senior Associate Editor
Greater dietary fiber intake is significantly associated with a lower risk of first stroke, according to a study published online ahead of print March 28 in Stroke. Investigators searched several electronic databases for healthy participant studies published between January 1990 and May 2012 that reported fiber intake and incidence of first hemorrhagic or ischemic stroke. The group identified eight cohort studies from the United States, Europe, Australia, and Japan that met their inclusion criteria. Total dietary fiber intake was inversely associated with risk of hemorrhagic plus ischemic stroke. The researchers found evidence of heterogeneity between the studies. Soluble fiber intake of 4 g/day was not associated with stroke risk reduction, and the investigators found evidence of low heterogeneity on this point between the studies.
In women who have episodic migraine, the ratio of high molecular weight to low molecular weight ictal adiponectin (ADP) may be associated with migraine severity and predict acute treatment response, according to a study published in the March Headache. Investigators collected peripheral blood specimens from women with episodic migraine before and after acute abortive treatment with sumatriptan and naproxen sodium or placebo. In all participants, increases in the ratio of high molecular weight to low molecular weight ADP were associated with increases in pain severity. For every 0.25-μg/mL increase in low molecular weight ADP, pain severity decreased by 0.20. In treatment responders, total ADP levels were reduced at 30, 60, and 120 minutes after treatment, compared with onset.
The FDA has approved Tecfidera (dimethyl fumarate) capsules to treat adults with relapsing forms of multiple sclerosis (MS). In two clinical trials, patients with MS who took dimethyl fumarate had fewer relapses compared with people who received placebo. In one of the trials, patients who took dimethyl fumarate experienced a worsening of disability less often than patients who took a placebo. Dimethyl fumarate may decrease a person's white blood cell count, but the drug was not associated with a significant increase in infections in clinical trials. Before starting treatment, and annually thereafter, the FDA recommends that a patient's white blood cell count be assessed by a health care provider. Flushing and stomach problems were the most common adverse reactions reported. Tecfidera is manufactured by Biogen Idec (Weston, Massachusetts).
Mild cognitive impairment (MCI) at the time of Parkinson's disease diagnosis may predict a highly increased risk for early dementia, according to a study published online ahead of print March 25 in JAMA Neurology. Researchers examined data for a population-based cohort of 182 patients with incident Parkinson's disease who were monitored for three years. Significantly more patients with MCI than without MCI at baseline (27.0% versus 0.7%) progressed to dementia during follow-up. Mild cognitive impairment at the one-year visit was associated with a similar progression rate to dementia (ie, 27.8%) and reversion rate to normal cognition (ie, 19.4%). Among the 22 patients with persistent MCI at baseline and the one-year visit, 10 developed dementia and two reverted to normal cognition by the end of the study.
Higher consumption of green tea and coffee may reduce the risk of cardiovascular disease and stroke, according to a study published online ahead of print March 14 in Stroke. Investigators studied 82,369 Japanese persons between ages 45 and 74 without cardiovascular disease or cancer. Green tea and coffee consumption was assessed by a self-administered questionnaire at baseline. Compared with seldom drinking green tea, the multivariable-adjusted hazard ratios of all strokes were 0.86 and 0.80 in individuals who drank two to three and four or more cups of green tea per day, respectively. Compared with seldom drinking coffee, the multivariable-adjusted hazard ratios of all strokes were 0.89, 0.80, and 0.81 for individuals who drank coffee three to six times per week, once daily, and twice or more daily, respectively.
Updated Guidelines for the Management of Acute Cervical Spine and Spinal Cord Injuries recommend against the use of steroids, including methylprednisolone, in acute spinal cord injury in the first 24 to 48 hours after injury. The use of steroids previously was recommended for this indication with consideration of the risk–reward profile, as evaluated by the physician. In the first new treatment guidelines in a decade, which were issued by the Joint Section on Disorders of the Spine and Peripheral Nerves of the Congress of Neurological Surgeons and the American Association of Neurological Surgeons, the standard has been revised based on the lack of medical evidence supporting the benefits of these drugs in the clinical setting. The report cites strong evidence that "high-dose steroids are associated with harmful side effects, including death."
Abnormalities in cortical surface area may indicate an individual's predisposition to developing migraine, and abnormalities in cortical thickness may result from migraine-related processes, according to research published online ahead of print March 26 in Radiology. Investigators took T2-weighted and three-dimensional T1-weighted MRIs of the brain for 63 migraineurs and 18 controls. They estimated cortical thickness and cortical surface area. Compared with control subjects, patients with migraine had reduced cortical thickness and surface area in pain-processing regions. These reductions were greater in regions involved in executive functions and visual-motion processing. Cortical thickness and cortical surface area abnormalities had minimal areas of overlap. Cortical thickness and surface area abnormalities were related to aura and white matter hyperintensities, but not to disease duration and attack frequency.
Primary stroke centers are more likely to administer t-PA than noncertified hospitals, according to research published online ahead of print March 26 in the Journal of the American Heart Association. Investigators analyzed data obtained from the Nationwide Inpatient Sample between 2004 and 2009 for patients age 18 or older with a primary diagnosis of acute ischemic stroke. IV t-PA was administered to 3.1% of patients overall. The drug was given to 2.2% of patients at noncertified hospitals and to 6.7% of patients at primary stroke centers. Between 2004 and 2009, t-PA administration increased from 1.4% to 3.3% of patients at noncertified hospitals and from 6.0% to 7.6% of patients at primary stroke centers. In a multivariable model, evaluation at a primary stroke center was significantly associated with t-PA use.
Control and prevention of risk factors such as hypertension earlier in life may limit or delay neuropathologic brain changes such as Alzheimer's disease with aging, researchers reported in a study published online ahead of print March 18 in JAMA Neurology. The investigators studied 118 cognitively normal adults ages 47 to 89. Participants were classified as having hypertension if they reported a medical diagnosis of hypertension or if blood pressure exceeded 140 mm Hg systolic/90 mm Hg diastolic on seven occasions. Participants underwent Ab PET imaging with radiotracer fluorine 18–labeled florbetapir, were genotyped for apolipoprotein E, and were classified as ε4+ or ε4−. Subjects with hypertension and at least one ε4 allele had significantly more amyloid burden than those with one or no risk factors.
Physicians can discontinue chronic antipsychotic medication for many elderly adults with Alzheimer's dementia and neuropsychiatric symptoms without causing detrimental effects on their behavior, according to a review published online March 28 in the Cochrane Database of Systematic Reviews. Investigators examined data from nine randomized controlled trials that compared antipsychotic withdrawal strategies with continuation of antipsychotics in patients with dementia. Although neurologists have concerns about the potential adverse events of antipsychotics, it is not clear whether withdrawal is beneficial for patients' cognition or psychomotor status. In two studies of patients whose agitation or psychosis had previously responded well to antipsychotic treatment, discontinuation was associated with an increased risk of relapse or shorter time to relapse. Two studies suggested that patients with severe neuropsychiatric symptoms at baseline could benefit from continuing their antipsychotic medication.
Greater exposure to pathogens associated with stroke risk and atherosclerosis may correlate with poorer cognitive performance, according to research published in the March 26 Neurology. Investigators tested for various pathogens (eg, Chlamydia pneumonia and Helicobacter pylori) in 1,625 participants in the Northern Manhattan Study. The researchers assessed patients' cognitive performance at baseline and at annual follow-up visits. Higher infectious burden index was associated with worse cognition. Each standard deviation in infectious burden correlated with a 0.77-point decline in Mini-Mental State Examination (MMSE) score. Adjustment for risk factors weakened the effect, however. Infectious burden was associated with an MMSE score of 24 or lower. Infectious burden was not associated with cognitive decline over time. Past infections may contribute to cognitive impairment, said the researchers.
Smoking cessation was associated with a decreased risk of cardiovascular disease events, and subsequent weight gain did not modify this association, researchers reported in the March 13 JAMA. Investigators analyzed data collected from 1984 through 2011 in the Framingham Offspring Study. Participants' self-reported smoking status was recorded during four-year examinations. Median four-year weight gain was 2.7 kg for recent smoking quitters without diabetes, 3.6 kg for recent quitters with diabetes, and 0.9 kg for long-term quitters. After adjustment for cardiovascular risk factors, compared with smokers, recent smoking quitters had a hazard ratio for cardiovascular disease of 0.47, and long-term quitters had a hazard ratio of 0.46. The results changed minimally after further adjustment for weight change. Similar point estimates for participants with diabetes did not reach statistical significance.
Women who enter menopause prematurely after bilateral ovariectomy may have a significantly increased risk for cognitive decline and dementia, according to a study published online ahead of print March 9 in Brain. The investigators studied rats 10 weeks after they had undergone bilateral ovariectomy and found that long-term estrogen deprivation dramatically increased the hippocampal CA3 region's sensitivity to ischemic stress, which correlated with a worse cognitive outcome. Long-term ovariectomized rats had robust hyperinduction of Alzheimer's disease-related proteins in the CA3 region. Following ischemic stress, amyloid-precursor protein processing switched from nonamyloidogenic to amyloidogenic. Replacement of 17β-estradiol at the end of the estrogen-deprivation period could not prevent CA3 hypersensitivity and amyloidogenesis, but if 17β-estradiol was initiated at ovariectomy and maintained throughout the estrogen deprivation period, it completely prevented these events.
Senior Associate Editor
Stuart Cook, MD, Discusses the CMSC Joint Statement on Adding MRI to the Lublin–Reingold Classification of MS
FROM AAN'S 2013 ANNUAL MEETING—Early Detection of PML May Improve Survival and Reduce Disability in MS
SAN DIEGO—Early detection of progressive multifocal leukoencephalopathy (PML) may reduce mortality and disability levels in patients with multiple sclerosis (MS), according to a study presented at the 65th Annual Meeting of the American Academy of Neurology. The research could have implications for patients with MS who receive natalizumab, which increases the risk of PML.
Tuan Dong-Si, MD, Medical Director at Biogen Idec in Weston, Massachusetts, and colleagues examined 319 individuals with MS who were treated with natalizumab and diagnosed with PML. The investigators compared patients who had symptoms of PML at the time of diagnosis with patients who had no symptoms of PML but were diagnosed with the disease by brain scans and spinal fluid tests for John Cunningham virus. Patients' level of disability was assessed before the PML diagnosis, at the time of the diagnosis, six months after the diagnosis, and one year after the diagnosis.
Twenty-one participants had no PML symptoms at the time of their diagnosis, and 298 individuals had symptoms. The study's preliminary data suggest that patients who have no symptoms at diagnosis may have improved survival and less disability than those who had developed symptoms before their diagnosis, according to Dr. Dong-Si.
At the time of PML diagnosis, individuals without symptoms had an average score of 67 on the Karnofsky Performance Scale. In contrast, participants with symptoms had an average score of 54. One year after PML diagnosis, the average Karnofsky score of patients with no symptoms at diagnosis was 70, compared with 47 for patients with symptoms at diagnosis.
Karnofsky scores lower than 50 indicate that the patient may not be able to care for himself or herself and may require institutional care. A Karnofsky score of 70 suggests that the person can care for himself or herself, but may not be able to engage in normal activities or work. A Karnofsky score of 50 indicates that a person may require considerable assistance and frequent medical care.
As of January 1, 2013, all 21 participants with no symptoms at the time of PML diagnosis were alive, compared with 77% of those with symptoms at the time of diagnosis. "These results suggest that the consequences of PML infection can be mitigated by early detection of the disease," said Dr. Dong-Si.
SAN DIEGO—Early detection of progressive multifocal leukoencephalopathy (PML) may reduce mortality and disability levels in patients with multiple sclerosis (MS), according to a study presented at the 65th Annual Meeting of the American Academy of Neurology. The research could have implications for patients with MS who receive natalizumab, which increases the risk of PML.
Tuan Dong-Si, MD, Medical Director at Biogen Idec in Weston, Massachusetts, and colleagues examined 319 individuals with MS who were treated with natalizumab and diagnosed with PML. The investigators compared patients who had symptoms of PML at the time of diagnosis with patients who had no symptoms of PML but were diagnosed with the disease by brain scans and spinal fluid tests for John Cunningham virus. Patients' level of disability was assessed before the PML diagnosis, at the time of the diagnosis, six months after the diagnosis, and one year after the diagnosis.
Twenty-one participants had no PML symptoms at the time of their diagnosis, and 298 individuals had symptoms. The study's preliminary data suggest that patients who have no symptoms at diagnosis may have improved survival and less disability than those who had developed symptoms before their diagnosis, according to Dr. Dong-Si.
At the time of PML diagnosis, individuals without symptoms had an average score of 67 on the Karnofsky Performance Scale. In contrast, participants with symptoms had an average score of 54. One year after PML diagnosis, the average Karnofsky score of patients with no symptoms at diagnosis was 70, compared with 47 for patients with symptoms at diagnosis.
Karnofsky scores lower than 50 indicate that the patient may not be able to care for himself or herself and may require institutional care. A Karnofsky score of 70 suggests that the person can care for himself or herself, but may not be able to engage in normal activities or work. A Karnofsky score of 50 indicates that a person may require considerable assistance and frequent medical care.
As of January 1, 2013, all 21 participants with no symptoms at the time of PML diagnosis were alive, compared with 77% of those with symptoms at the time of diagnosis. "These results suggest that the consequences of PML infection can be mitigated by early detection of the disease," said Dr. Dong-Si.
SAN DIEGO—Early detection of progressive multifocal leukoencephalopathy (PML) may reduce mortality and disability levels in patients with multiple sclerosis (MS), according to a study presented at the 65th Annual Meeting of the American Academy of Neurology. The research could have implications for patients with MS who receive natalizumab, which increases the risk of PML.
Tuan Dong-Si, MD, Medical Director at Biogen Idec in Weston, Massachusetts, and colleagues examined 319 individuals with MS who were treated with natalizumab and diagnosed with PML. The investigators compared patients who had symptoms of PML at the time of diagnosis with patients who had no symptoms of PML but were diagnosed with the disease by brain scans and spinal fluid tests for John Cunningham virus. Patients' level of disability was assessed before the PML diagnosis, at the time of the diagnosis, six months after the diagnosis, and one year after the diagnosis.
Twenty-one participants had no PML symptoms at the time of their diagnosis, and 298 individuals had symptoms. The study's preliminary data suggest that patients who have no symptoms at diagnosis may have improved survival and less disability than those who had developed symptoms before their diagnosis, according to Dr. Dong-Si.
At the time of PML diagnosis, individuals without symptoms had an average score of 67 on the Karnofsky Performance Scale. In contrast, participants with symptoms had an average score of 54. One year after PML diagnosis, the average Karnofsky score of patients with no symptoms at diagnosis was 70, compared with 47 for patients with symptoms at diagnosis.
Karnofsky scores lower than 50 indicate that the patient may not be able to care for himself or herself and may require institutional care. A Karnofsky score of 70 suggests that the person can care for himself or herself, but may not be able to engage in normal activities or work. A Karnofsky score of 50 indicates that a person may require considerable assistance and frequent medical care.
As of January 1, 2013, all 21 participants with no symptoms at the time of PML diagnosis were alive, compared with 77% of those with symptoms at the time of diagnosis. "These results suggest that the consequences of PML infection can be mitigated by early detection of the disease," said Dr. Dong-Si.