ACTRIMS 2016

NEW ORLEANS – Research from Australia shows that disability in multiple sclerosis (MS) is independent of past damage, even in people whose disease is moderately advanced, with further disease progression varying widely in severity.

The findings should prompt a rethink of the policy of ceasing treatment when MS-related disability becomes more advanced.

Brian Hoyle/Frontline Medical News

“Our main findings were that moderately advanced multiple sclerosis is indeed independent of previous disease, but still extremely variable. Higher relapse rates later in disease increased the risk of disability worsening. More promisingly, more time spent on therapy later in disease lowered the risk of disability progression to EDSS [Expanded Disability Status Scale] 6 or 6.5,” Nathaniel Lizak said in an interview at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

The study sought to identify factors that modified progression in early and moderately advanced MS. Three prior cohort studies had not shed light on the variability in disease trajectory during moderately advanced MS.

“We wanted to examine how much variability there was later in disease, what determined this variability, and to confirm whether later disease was really independent of previous disease, as was suggested in previous studies,” said Mr. Lizak of Monash University, Clayton, Australia, and the University of Melbourne. The influences of relapse rate and proportion of time treated prior to and during each disability time period, age, and disease duration at baseline on the progression to moderate MS disability (EDSS 6 or 6.5) were assessed. The hypothesis was that, even at a later stage of MS, disease progression varies from patient to patient, and that some patients can benefit from immunomodulatory therapy.

The time between EDSS steps 3-6 (n = 1,560, 71% female, 40.9±9.9 years old at baseline), 4-6 (n = 1,504, 69% female, 43.0±9.6 years old at baseline), and 6-6.5 (n = 1,231, 67% female, 46.5±10.2 years old at baseline) were analyzed for the 32,336 patients included in the MSBase large, international, observational MS cohort study who met the inclusion criteria. Median disease duration at baseline was 9.4, 11.1, and 14.0 years in the same respective order.

Pre- and postbaseline disability trajectories showed large coefficients of variance and did not correlate. The probability of reaching the outcome EDSS was independent of prebaseline variables, but was increased if relapse during any particular EDSS was more frequent (hazard ratios, 1.58-3.07; P less than .001). At each measured stage of MS, higher-efficacy therapies were beneficial and lowered the risk of progression (HR, 0.27-0.68; P less than .02).

Some countries, such as New Zealand, by policy don’t allow patients to receive treatments if they display moderate or significant disability. In other places this can be common practice because of concerns with treatment-related side effects or affordability. The main driver of this practice is that the clinical trials of most MS therapies that have validated these medications specifically recruited patients with low disability scores. So, according to Mr. Lizak, the evidence exists only for therapies at lower disability scores.

“These results are important as they show that there is still hope. Reaching disability landmarks of EDSS 3, 4, and 6 does not guarantee continuous worsening of disability. Doctors still have the ability to reduce their patients’ risk of attaining further disability, even at later stages of disease,” said Mr. Lizak.

The hope is that the data will change clinical practice to encourage more therapy even when substantial disability has accumulated.

“Translating results into everyday practice is difficult, and doctors must always weigh the risks and benefits. We hope that our work will influence the clinical decision to, where in doubt, favor high-efficacy treatments at later disease stages. That’s not to say that patients should be blindly treated, as side effects always merit consideration. But we hope our work will inform neurologists that there is evidence supporting treating patients with more advanced disability. Where, by practice or policy, treatments are not provided to patients who have accumulated significant disability, we hope to change such clinical practice,” said Mr. Lizak.

The study did not require funding. Mr. Lizak had no disclosures.

NEW ORLEANS – Research from Australia shows that disability in multiple sclerosis (MS) is independent of past damage, even in people whose disease is moderately advanced, with further disease progression varying widely in severity.

The findings should prompt a rethink of the policy of ceasing treatment when MS-related disability becomes more advanced.

Brian Hoyle/Frontline Medical News

“Our main findings were that moderately advanced multiple sclerosis is indeed independent of previous disease, but still extremely variable. Higher relapse rates later in disease increased the risk of disability worsening. More promisingly, more time spent on therapy later in disease lowered the risk of disability progression to EDSS [Expanded Disability Status Scale] 6 or 6.5,” Nathaniel Lizak said in an interview at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

The study sought to identify factors that modified progression in early and moderately advanced MS. Three prior cohort studies had not shed light on the variability in disease trajectory during moderately advanced MS.

“We wanted to examine how much variability there was later in disease, what determined this variability, and to confirm whether later disease was really independent of previous disease, as was suggested in previous studies,” said Mr. Lizak of Monash University, Clayton, Australia, and the University of Melbourne. The influences of relapse rate and proportion of time treated prior to and during each disability time period, age, and disease duration at baseline on the progression to moderate MS disability (EDSS 6 or 6.5) were assessed. The hypothesis was that, even at a later stage of MS, disease progression varies from patient to patient, and that some patients can benefit from immunomodulatory therapy.

The time between EDSS steps 3-6 (n = 1,560, 71% female, 40.9±9.9 years old at baseline), 4-6 (n = 1,504, 69% female, 43.0±9.6 years old at baseline), and 6-6.5 (n = 1,231, 67% female, 46.5±10.2 years old at baseline) were analyzed for the 32,336 patients included in the MSBase large, international, observational MS cohort study who met the inclusion criteria. Median disease duration at baseline was 9.4, 11.1, and 14.0 years in the same respective order.

Pre- and postbaseline disability trajectories showed large coefficients of variance and did not correlate. The probability of reaching the outcome EDSS was independent of prebaseline variables, but was increased if relapse during any particular EDSS was more frequent (hazard ratios, 1.58-3.07; P less than .001). At each measured stage of MS, higher-efficacy therapies were beneficial and lowered the risk of progression (HR, 0.27-0.68; P less than .02).

Some countries, such as New Zealand, by policy don’t allow patients to receive treatments if they display moderate or significant disability. In other places this can be common practice because of concerns with treatment-related side effects or affordability. The main driver of this practice is that the clinical trials of most MS therapies that have validated these medications specifically recruited patients with low disability scores. So, according to Mr. Lizak, the evidence exists only for therapies at lower disability scores.

“These results are important as they show that there is still hope. Reaching disability landmarks of EDSS 3, 4, and 6 does not guarantee continuous worsening of disability. Doctors still have the ability to reduce their patients’ risk of attaining further disability, even at later stages of disease,” said Mr. Lizak.

The hope is that the data will change clinical practice to encourage more therapy even when substantial disability has accumulated.

“Translating results into everyday practice is difficult, and doctors must always weigh the risks and benefits. We hope that our work will influence the clinical decision to, where in doubt, favor high-efficacy treatments at later disease stages. That’s not to say that patients should be blindly treated, as side effects always merit consideration. But we hope our work will inform neurologists that there is evidence supporting treating patients with more advanced disability. Where, by practice or policy, treatments are not provided to patients who have accumulated significant disability, we hope to change such clinical practice,” said Mr. Lizak.

The study did not require funding. Mr. Lizak had no disclosures.

NEW ORLEANS – Research from Australia shows that disability in multiple sclerosis (MS) is independent of past damage, even in people whose disease is moderately advanced, with further disease progression varying widely in severity.

The findings should prompt a rethink of the policy of ceasing treatment when MS-related disability becomes more advanced.

Brian Hoyle/Frontline Medical News

“Our main findings were that moderately advanced multiple sclerosis is indeed independent of previous disease, but still extremely variable. Higher relapse rates later in disease increased the risk of disability worsening. More promisingly, more time spent on therapy later in disease lowered the risk of disability progression to EDSS [Expanded Disability Status Scale] 6 or 6.5,” Nathaniel Lizak said in an interview at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

The study sought to identify factors that modified progression in early and moderately advanced MS. Three prior cohort studies had not shed light on the variability in disease trajectory during moderately advanced MS.

“We wanted to examine how much variability there was later in disease, what determined this variability, and to confirm whether later disease was really independent of previous disease, as was suggested in previous studies,” said Mr. Lizak of Monash University, Clayton, Australia, and the University of Melbourne. The influences of relapse rate and proportion of time treated prior to and during each disability time period, age, and disease duration at baseline on the progression to moderate MS disability (EDSS 6 or 6.5) were assessed. The hypothesis was that, even at a later stage of MS, disease progression varies from patient to patient, and that some patients can benefit from immunomodulatory therapy.

The time between EDSS steps 3-6 (n = 1,560, 71% female, 40.9±9.9 years old at baseline), 4-6 (n = 1,504, 69% female, 43.0±9.6 years old at baseline), and 6-6.5 (n = 1,231, 67% female, 46.5±10.2 years old at baseline) were analyzed for the 32,336 patients included in the MSBase large, international, observational MS cohort study who met the inclusion criteria. Median disease duration at baseline was 9.4, 11.1, and 14.0 years in the same respective order.

Pre- and postbaseline disability trajectories showed large coefficients of variance and did not correlate. The probability of reaching the outcome EDSS was independent of prebaseline variables, but was increased if relapse during any particular EDSS was more frequent (hazard ratios, 1.58-3.07; P less than .001). At each measured stage of MS, higher-efficacy therapies were beneficial and lowered the risk of progression (HR, 0.27-0.68; P less than .02).

Some countries, such as New Zealand, by policy don’t allow patients to receive treatments if they display moderate or significant disability. In other places this can be common practice because of concerns with treatment-related side effects or affordability. The main driver of this practice is that the clinical trials of most MS therapies that have validated these medications specifically recruited patients with low disability scores. So, according to Mr. Lizak, the evidence exists only for therapies at lower disability scores.

“These results are important as they show that there is still hope. Reaching disability landmarks of EDSS 3, 4, and 6 does not guarantee continuous worsening of disability. Doctors still have the ability to reduce their patients’ risk of attaining further disability, even at later stages of disease,” said Mr. Lizak.

The hope is that the data will change clinical practice to encourage more therapy even when substantial disability has accumulated.

“Translating results into everyday practice is difficult, and doctors must always weigh the risks and benefits. We hope that our work will influence the clinical decision to, where in doubt, favor high-efficacy treatments at later disease stages. That’s not to say that patients should be blindly treated, as side effects always merit consideration. But we hope our work will inform neurologists that there is evidence supporting treating patients with more advanced disability. Where, by practice or policy, treatments are not provided to patients who have accumulated significant disability, we hope to change such clinical practice,” said Mr. Lizak.

The study did not require funding. Mr. Lizak had no disclosures.

NEW ORLEANS – Protein profiling of cerebrospinal fluid and MRI has revealed the involvement of exacerbated gray matter demyelination and brain atrophy in the progression of multiple sclerosis.

The pattern of the cerebrospinal fluid (CSF) biomarkers, which correspond to the extent of gray matter damage, have potential value in stratifying patients in terms of disease severity from the onset of multiple sclerosis (MS), Roberta Magliozzi, Ph.D., of the University of Verona (Italy) said at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

Brian Hoyle/Frontline Medical News

Gray matter atrophy and the accumulation of cortical lesions are central to the progressive clinical deterioration that occurs in MS. The damage involves a “compartmentalized immune response” featuring meningeal infiltration of certain immune cells, which is associated with increased cortical demyelination and meningeal inflammation. The gray matter damage and inflammation are harbingers of earlier onset and rapid progression of neurological damage in MS, and a more severe disease outcome.

“We sought to find a combination of CSF biomarkers [and] neuropathological and early neuroimaging correlates of disease progression in order to predict onset and rate of MS progression,” Dr. Magliozzi explained.

The investigators assessed gray matter damage with MRI and analyzed CSF proteins in 36 MS patients and 12 healthy controls and also acquired and analyzed meningeal and CSF samples after death from 20 individuals with secondary progressive MS (SPMS) and 10 healthy individuals to detect inflammatory mediators associated with meningeal infiltration that were released to the CSF.

MS patients with meningeal infiltration displayed more extensive gray matter demyelination and more rapid disease progression. They also demonstrated a “pronounced proinflammatory CSF profile” featuring overexpression of an array of molecules associated with chronic inflammation. Patients with less gray matter damage displayed a pattern of increased regulatory molecules. Consistent with the patient data, similar expression patterns were evident in the meninges and CSF samples of postmortem SPMS cases with a higher level of meningeal inflammation and gray matter demyelination.

“Meningeal infiltrates may represent the main source of intrathecal inflammatory activity mediating the gradient of cortical tissue injury since early disease stages and in progressive MS,” Dr. Magliozzi said.

The markedly different CSF profiles in patients with more and less extensive gray matter damage may be an exploitable characteristic to stratify patients early in the course of MS, with benefits in disease prognosis and monitoring, and treatment that is more rationally geared to the patient’s condition.

“The results indicate that we may be able to get an image-based functional profile of patients in relapse, which would be a phenomenal finding,” Dr. Jerry Wolinsky of the University of Texas Health Science Center at Houston, commented in a press conference following the presentation.

The study was funded by Progressive MS Alliance. Dr. Magliozzi had no disclosures.

NEW ORLEANS – Protein profiling of cerebrospinal fluid and MRI has revealed the involvement of exacerbated gray matter demyelination and brain atrophy in the progression of multiple sclerosis.

The pattern of the cerebrospinal fluid (CSF) biomarkers, which correspond to the extent of gray matter damage, have potential value in stratifying patients in terms of disease severity from the onset of multiple sclerosis (MS), Roberta Magliozzi, Ph.D., of the University of Verona (Italy) said at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

Brian Hoyle/Frontline Medical News

Gray matter atrophy and the accumulation of cortical lesions are central to the progressive clinical deterioration that occurs in MS. The damage involves a “compartmentalized immune response” featuring meningeal infiltration of certain immune cells, which is associated with increased cortical demyelination and meningeal inflammation. The gray matter damage and inflammation are harbingers of earlier onset and rapid progression of neurological damage in MS, and a more severe disease outcome.

“We sought to find a combination of CSF biomarkers [and] neuropathological and early neuroimaging correlates of disease progression in order to predict onset and rate of MS progression,” Dr. Magliozzi explained.

The investigators assessed gray matter damage with MRI and analyzed CSF proteins in 36 MS patients and 12 healthy controls and also acquired and analyzed meningeal and CSF samples after death from 20 individuals with secondary progressive MS (SPMS) and 10 healthy individuals to detect inflammatory mediators associated with meningeal infiltration that were released to the CSF.

MS patients with meningeal infiltration displayed more extensive gray matter demyelination and more rapid disease progression. They also demonstrated a “pronounced proinflammatory CSF profile” featuring overexpression of an array of molecules associated with chronic inflammation. Patients with less gray matter damage displayed a pattern of increased regulatory molecules. Consistent with the patient data, similar expression patterns were evident in the meninges and CSF samples of postmortem SPMS cases with a higher level of meningeal inflammation and gray matter demyelination.

“Meningeal infiltrates may represent the main source of intrathecal inflammatory activity mediating the gradient of cortical tissue injury since early disease stages and in progressive MS,” Dr. Magliozzi said.

The markedly different CSF profiles in patients with more and less extensive gray matter damage may be an exploitable characteristic to stratify patients early in the course of MS, with benefits in disease prognosis and monitoring, and treatment that is more rationally geared to the patient’s condition.

“The results indicate that we may be able to get an image-based functional profile of patients in relapse, which would be a phenomenal finding,” Dr. Jerry Wolinsky of the University of Texas Health Science Center at Houston, commented in a press conference following the presentation.

The study was funded by Progressive MS Alliance. Dr. Magliozzi had no disclosures.

NEW ORLEANS – Protein profiling of cerebrospinal fluid and MRI has revealed the involvement of exacerbated gray matter demyelination and brain atrophy in the progression of multiple sclerosis.

The pattern of the cerebrospinal fluid (CSF) biomarkers, which correspond to the extent of gray matter damage, have potential value in stratifying patients in terms of disease severity from the onset of multiple sclerosis (MS), Roberta Magliozzi, Ph.D., of the University of Verona (Italy) said at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

Brian Hoyle/Frontline Medical News

Gray matter atrophy and the accumulation of cortical lesions are central to the progressive clinical deterioration that occurs in MS. The damage involves a “compartmentalized immune response” featuring meningeal infiltration of certain immune cells, which is associated with increased cortical demyelination and meningeal inflammation. The gray matter damage and inflammation are harbingers of earlier onset and rapid progression of neurological damage in MS, and a more severe disease outcome.

“We sought to find a combination of CSF biomarkers [and] neuropathological and early neuroimaging correlates of disease progression in order to predict onset and rate of MS progression,” Dr. Magliozzi explained.

The investigators assessed gray matter damage with MRI and analyzed CSF proteins in 36 MS patients and 12 healthy controls and also acquired and analyzed meningeal and CSF samples after death from 20 individuals with secondary progressive MS (SPMS) and 10 healthy individuals to detect inflammatory mediators associated with meningeal infiltration that were released to the CSF.

MS patients with meningeal infiltration displayed more extensive gray matter demyelination and more rapid disease progression. They also demonstrated a “pronounced proinflammatory CSF profile” featuring overexpression of an array of molecules associated with chronic inflammation. Patients with less gray matter damage displayed a pattern of increased regulatory molecules. Consistent with the patient data, similar expression patterns were evident in the meninges and CSF samples of postmortem SPMS cases with a higher level of meningeal inflammation and gray matter demyelination.

“Meningeal infiltrates may represent the main source of intrathecal inflammatory activity mediating the gradient of cortical tissue injury since early disease stages and in progressive MS,” Dr. Magliozzi said.

The markedly different CSF profiles in patients with more and less extensive gray matter damage may be an exploitable characteristic to stratify patients early in the course of MS, with benefits in disease prognosis and monitoring, and treatment that is more rationally geared to the patient’s condition.

“The results indicate that we may be able to get an image-based functional profile of patients in relapse, which would be a phenomenal finding,” Dr. Jerry Wolinsky of the University of Texas Health Science Center at Houston, commented in a press conference following the presentation.

The study was funded by Progressive MS Alliance. Dr. Magliozzi had no disclosures.

NEW ORLEANS – Findings last year from the ORATORIO trial showed for the first time that a pharmaceutical agent – ocrelizumab – was effective for slowing the rate of progression in patients with primary progressive multiple sclerosis, but there is as much to learn from the many failed trials and treatments as from this recent success, according to experts at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

“Insofar as we have seen failure after failure in studying progressive MS, we’ve also learned from the studies themselves how best to redesign the studies and how to target the right kind of patients to be able to see a therapeutic effect once that appropriate drug came along,” Dr. John Rinker II said in an interview at the meeting sponsored by the Americas Committee for Treatment and Research in Multiple Sclerosis.

Dr. Rinker of the University of Alabama at Birmingham chaired a session on “the treatment pipeline” in MS, and noted in the interview that the lessons learned from failed trials could potentially be used to “re-look at some of these older drugs that had been failures in the past and, using a different trial methodology, maybe find some success in the future.”

sworcester@frontlinemedcom.com

NEW ORLEANS – Findings last year from the ORATORIO trial showed for the first time that a pharmaceutical agent – ocrelizumab – was effective for slowing the rate of progression in patients with primary progressive multiple sclerosis, but there is as much to learn from the many failed trials and treatments as from this recent success, according to experts at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

“Insofar as we have seen failure after failure in studying progressive MS, we’ve also learned from the studies themselves how best to redesign the studies and how to target the right kind of patients to be able to see a therapeutic effect once that appropriate drug came along,” Dr. John Rinker II said in an interview at the meeting sponsored by the Americas Committee for Treatment and Research in Multiple Sclerosis.

Dr. Rinker of the University of Alabama at Birmingham chaired a session on “the treatment pipeline” in MS, and noted in the interview that the lessons learned from failed trials could potentially be used to “re-look at some of these older drugs that had been failures in the past and, using a different trial methodology, maybe find some success in the future.”

sworcester@frontlinemedcom.com

NEW ORLEANS – Findings last year from the ORATORIO trial showed for the first time that a pharmaceutical agent – ocrelizumab – was effective for slowing the rate of progression in patients with primary progressive multiple sclerosis, but there is as much to learn from the many failed trials and treatments as from this recent success, according to experts at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

“Insofar as we have seen failure after failure in studying progressive MS, we’ve also learned from the studies themselves how best to redesign the studies and how to target the right kind of patients to be able to see a therapeutic effect once that appropriate drug came along,” Dr. John Rinker II said in an interview at the meeting sponsored by the Americas Committee for Treatment and Research in Multiple Sclerosis.

Dr. Rinker of the University of Alabama at Birmingham chaired a session on “the treatment pipeline” in MS, and noted in the interview that the lessons learned from failed trials could potentially be used to “re-look at some of these older drugs that had been failures in the past and, using a different trial methodology, maybe find some success in the future.”

sworcester@frontlinemedcom.com

New Orleans – A “Lessons from the Bench” session at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis addressed the ongoing debate regarding the relative importance of neurodegeneration vs. inflammation in progressive multiple sclerosis.

In an interview, session chair Dr. Benjamin Segal discussed the research presented – on topics ranging from immunological biomarkers that could also prove to be therapeutic targets, to immune- and central nervous system–related susceptibility alleles identified in genome wide association studies – and how the findings could lead to new and improved treatments.

“These types of studies give us insights into the immune pathways that are dysregulated in the different diseases and how they may be similar or different from one another. Ultimately all of these scientific studies hopefully will translate into treatments in the future,” said Dr. Segal of the University of Michigan, Ann Arbor.

New Orleans – A “Lessons from the Bench” session at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis addressed the ongoing debate regarding the relative importance of neurodegeneration vs. inflammation in progressive multiple sclerosis.

In an interview, session chair Dr. Benjamin Segal discussed the research presented – on topics ranging from immunological biomarkers that could also prove to be therapeutic targets, to immune- and central nervous system–related susceptibility alleles identified in genome wide association studies – and how the findings could lead to new and improved treatments.

“These types of studies give us insights into the immune pathways that are dysregulated in the different diseases and how they may be similar or different from one another. Ultimately all of these scientific studies hopefully will translate into treatments in the future,” said Dr. Segal of the University of Michigan, Ann Arbor.

New Orleans – A “Lessons from the Bench” session at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis addressed the ongoing debate regarding the relative importance of neurodegeneration vs. inflammation in progressive multiple sclerosis.

In an interview, session chair Dr. Benjamin Segal discussed the research presented – on topics ranging from immunological biomarkers that could also prove to be therapeutic targets, to immune- and central nervous system–related susceptibility alleles identified in genome wide association studies – and how the findings could lead to new and improved treatments.

“These types of studies give us insights into the immune pathways that are dysregulated in the different diseases and how they may be similar or different from one another. Ultimately all of these scientific studies hopefully will translate into treatments in the future,” said Dr. Segal of the University of Michigan, Ann Arbor.

NEW ORLEANS – A decline in levels of anti-müllerian hormone as women approach menopause – a phenomenon dubbed ovarian decline – appears associated with clinical disability and brain atrophy in women with multiple sclerosis, according to the findings of a study of more than 400 women with multiple sclerosis followed up for a decade.

This “accumulation of disability” may explain the often rapid transition from a benign disease course to secondary progressive multiple sclerosis (MS) in women as they approach menopause, Dr. Jennifer S. Graves reported at a meeting held by at the Americas Committee for Treatment and Research in Multiple Sclerosis.

Earlier in life, females often have a more benign initial course of MS than males. The mean age of onset of primary progressive MS and secondary progressive MS are both approximately 45 years. The mean age of menopause is 51 years. Ovarian aging involves up to a 10-year period of decline in ovarian function. After age 50, “women catch up in terms of disability with males” with MS, said Dr. Graves of the University of California, San Francisco. One explanation could be that ovarian aging contributes to the development of progressive disease.

The objective was to determine if ovarian decline as measured by the levels of anti-müllerian hormone (AMH) is associated with clinical disability or brain atrophy in women with MS. The cohort of 412 female patients with MS (mean age, 43 years) was from the UCSF EPIC (Expression, Proteomics, Imaging, Clinical) study, which has followed more than 500 people with MS since 2004 with the aim of identifying factors that drive the disease. Also included were 180 healthy controls with the exact same mean age. AMH levels were measured using an ultrasensitive enzyme-linked immunosorbent assay at baseline and at years 3, 5, 8, 9, and 10. Brain magnetic resonance imaging data also were acquired.

When the data were adjusted for chronologic age, women with MS and healthy controls displayed similar AMH levels (P = .97), implying a normal follicular reserve and rate of ovarian decline in those with MS. White matter volume was associated with AMH levels at baseline (P = .047). The association did not persist when adjusted for age as well as disease duration and body mass index (P = .24), while ovarian reserve was associated with normalized gray matter volume (P = .049) and MS functional composite z scores (P = .036) at baseline. Scrutiny of the follow-up period revealed that a twofold decrease in AMH was associated with a 1.85-mm³ decrease in gray matter volume (P = .060) in MS patients. Almost a third of the MS patients had undetectable levels of AMH, which was associated with a 0.60-point higher expanded disability status scale score (P =.039)

The results support the hypothesized association of ovarian decline with increased severity of MS. Furthermore, AMH may be a useful biomarker of MS progression, said Dr. Graves. “The advantage of this biomarker would be that it captures biological activity in women in their 40s, and so could let you know of imminent change.”

Validation of the findings needs to be done.

The study was funded by the National Institutes of Health, National MS Society, Race to Erase MS, Foundation for the Cedars-Sinai Medical Center, Biogen, and Genentech. Dr. Graves had no relevant financial disclosures.

NEW ORLEANS – A decline in levels of anti-müllerian hormone as women approach menopause – a phenomenon dubbed ovarian decline – appears associated with clinical disability and brain atrophy in women with multiple sclerosis, according to the findings of a study of more than 400 women with multiple sclerosis followed up for a decade.

This “accumulation of disability” may explain the often rapid transition from a benign disease course to secondary progressive multiple sclerosis (MS) in women as they approach menopause, Dr. Jennifer S. Graves reported at a meeting held by at the Americas Committee for Treatment and Research in Multiple Sclerosis.

Earlier in life, females often have a more benign initial course of MS than males. The mean age of onset of primary progressive MS and secondary progressive MS are both approximately 45 years. The mean age of menopause is 51 years. Ovarian aging involves up to a 10-year period of decline in ovarian function. After age 50, “women catch up in terms of disability with males” with MS, said Dr. Graves of the University of California, San Francisco. One explanation could be that ovarian aging contributes to the development of progressive disease.

The objective was to determine if ovarian decline as measured by the levels of anti-müllerian hormone (AMH) is associated with clinical disability or brain atrophy in women with MS. The cohort of 412 female patients with MS (mean age, 43 years) was from the UCSF EPIC (Expression, Proteomics, Imaging, Clinical) study, which has followed more than 500 people with MS since 2004 with the aim of identifying factors that drive the disease. Also included were 180 healthy controls with the exact same mean age. AMH levels were measured using an ultrasensitive enzyme-linked immunosorbent assay at baseline and at years 3, 5, 8, 9, and 10. Brain magnetic resonance imaging data also were acquired.

When the data were adjusted for chronologic age, women with MS and healthy controls displayed similar AMH levels (P = .97), implying a normal follicular reserve and rate of ovarian decline in those with MS. White matter volume was associated with AMH levels at baseline (P = .047). The association did not persist when adjusted for age as well as disease duration and body mass index (P = .24), while ovarian reserve was associated with normalized gray matter volume (P = .049) and MS functional composite z scores (P = .036) at baseline. Scrutiny of the follow-up period revealed that a twofold decrease in AMH was associated with a 1.85-mm³ decrease in gray matter volume (P = .060) in MS patients. Almost a third of the MS patients had undetectable levels of AMH, which was associated with a 0.60-point higher expanded disability status scale score (P =.039)

The results support the hypothesized association of ovarian decline with increased severity of MS. Furthermore, AMH may be a useful biomarker of MS progression, said Dr. Graves. “The advantage of this biomarker would be that it captures biological activity in women in their 40s, and so could let you know of imminent change.”

Validation of the findings needs to be done.

The study was funded by the National Institutes of Health, National MS Society, Race to Erase MS, Foundation for the Cedars-Sinai Medical Center, Biogen, and Genentech. Dr. Graves had no relevant financial disclosures.

NEW ORLEANS – A decline in levels of anti-müllerian hormone as women approach menopause – a phenomenon dubbed ovarian decline – appears associated with clinical disability and brain atrophy in women with multiple sclerosis, according to the findings of a study of more than 400 women with multiple sclerosis followed up for a decade.

This “accumulation of disability” may explain the often rapid transition from a benign disease course to secondary progressive multiple sclerosis (MS) in women as they approach menopause, Dr. Jennifer S. Graves reported at a meeting held by at the Americas Committee for Treatment and Research in Multiple Sclerosis.

Earlier in life, females often have a more benign initial course of MS than males. The mean age of onset of primary progressive MS and secondary progressive MS are both approximately 45 years. The mean age of menopause is 51 years. Ovarian aging involves up to a 10-year period of decline in ovarian function. After age 50, “women catch up in terms of disability with males” with MS, said Dr. Graves of the University of California, San Francisco. One explanation could be that ovarian aging contributes to the development of progressive disease.

The objective was to determine if ovarian decline as measured by the levels of anti-müllerian hormone (AMH) is associated with clinical disability or brain atrophy in women with MS. The cohort of 412 female patients with MS (mean age, 43 years) was from the UCSF EPIC (Expression, Proteomics, Imaging, Clinical) study, which has followed more than 500 people with MS since 2004 with the aim of identifying factors that drive the disease. Also included were 180 healthy controls with the exact same mean age. AMH levels were measured using an ultrasensitive enzyme-linked immunosorbent assay at baseline and at years 3, 5, 8, 9, and 10. Brain magnetic resonance imaging data also were acquired.

When the data were adjusted for chronologic age, women with MS and healthy controls displayed similar AMH levels (P = .97), implying a normal follicular reserve and rate of ovarian decline in those with MS. White matter volume was associated with AMH levels at baseline (P = .047). The association did not persist when adjusted for age as well as disease duration and body mass index (P = .24), while ovarian reserve was associated with normalized gray matter volume (P = .049) and MS functional composite z scores (P = .036) at baseline. Scrutiny of the follow-up period revealed that a twofold decrease in AMH was associated with a 1.85-mm³ decrease in gray matter volume (P = .060) in MS patients. Almost a third of the MS patients had undetectable levels of AMH, which was associated with a 0.60-point higher expanded disability status scale score (P =.039)

The results support the hypothesized association of ovarian decline with increased severity of MS. Furthermore, AMH may be a useful biomarker of MS progression, said Dr. Graves. “The advantage of this biomarker would be that it captures biological activity in women in their 40s, and so could let you know of imminent change.”

Validation of the findings needs to be done.

The study was funded by the National Institutes of Health, National MS Society, Race to Erase MS, Foundation for the Cedars-Sinai Medical Center, Biogen, and Genentech. Dr. Graves had no relevant financial disclosures.

NEW ORLEANS – Exercise can be beneficial in transiently improving cognitive impairment in people with multiple sclerosis.

Research presented at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis has extended the exercise benefit to cognitive impairment, as measured by reaction time in 24 subjects. The benefit, which was transient, also was evident in 14 subjects who were thermosensitive and displayed elevated core body temperature during exercise. Although preliminary, the data are sufficiently evocative to warrant randomized controlled trials (RCTs).

Brian Hoyle/Frontline Medical News

Cognitive impairment is prevalent in MS, being present in upward of 50% of affected individuals. Exercise may or may not be beneficial in cognitive improvement, given the inconsistent results from three RCTs that have been done. The different types of exercise used in the studies could be one reason for the uncertainty.

For people with MS who are fully ambulatory, treadmill walking could be the best form of exercise. But it’s not known how long and at what intensity someone should walk to realize any cognitive benefit. The investigators, led by Brian M. Sandroff, Ph.D., a postdoctoral fellow at the Kessler Foundation, West Orange, N.J., designed the study to assess these unknowns.

The study compared the influence of light, moderate, and vigorous treadmill walking on what is known as inhibitory control – a mental ability to react to stimuli. A period of quiet rest also was included prior to treadmill walking to assess the effects of no walking. The four conditions were tested in random order by the 24 participants with MS who had an Expanded Disability Status Scale (EDSS) score greater than or equal to 4, indicative of minimal or moderate disability. Prior to and soon after 20 minutes of treadmill walking, the reaction time of each participant was judged using a modified flanker task. The test requires a subject to respond to specific relevant information or ignore irrelevant information. The time for a correct response was the reaction time.

Light, moderate, and vigorous treadmill walking similarly and significantly improved reaction time, compared with quiet rest. To assess whether an increase in core body temperature might negate the exercise-related benefit, core body temperature was assessed in 14 thermosensitive MS patients (EDSS less than or equal to 4.0). Core body temperature was recorded every 10 seconds using an ingested sensor capsule and wireless data recorder during 20 minutes of vigorous treadmill exercise and 20 minutes of quiet rest. The core temperature of the subjects rose significantly by about 0.6° C during exercise. But this did not affect the exercise-related improved reaction time.

“There have been no published studies comparing the acute (transient) versus chronic effects of exercise on cognition in MS. We have hypothesized that the acute effects of single bouts of exercise on cognition will be both additive and cumulative over time, when delivered in a longitudinal intervention – much like the effects of a single bout of aerobic exercise on aerobic fitness. In this example, you get small, transient improvements in aerobic fitness after a single session of aerobic exercise; these small improvements add up with continued training, and eventually result in a meaningful improvement,” Dr. Sandroff said in an interview.

The researchers are planning an RCT on the longer-term effects of treadmill walking exercise training on cognition and brain structure/function.

The study was not funded by an external grant. Dr. Sandroff had no relevant financial disclosures.

NEW ORLEANS – Exercise can be beneficial in transiently improving cognitive impairment in people with multiple sclerosis.

Research presented at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis has extended the exercise benefit to cognitive impairment, as measured by reaction time in 24 subjects. The benefit, which was transient, also was evident in 14 subjects who were thermosensitive and displayed elevated core body temperature during exercise. Although preliminary, the data are sufficiently evocative to warrant randomized controlled trials (RCTs).

Brian Hoyle/Frontline Medical News

Cognitive impairment is prevalent in MS, being present in upward of 50% of affected individuals. Exercise may or may not be beneficial in cognitive improvement, given the inconsistent results from three RCTs that have been done. The different types of exercise used in the studies could be one reason for the uncertainty.

For people with MS who are fully ambulatory, treadmill walking could be the best form of exercise. But it’s not known how long and at what intensity someone should walk to realize any cognitive benefit. The investigators, led by Brian M. Sandroff, Ph.D., a postdoctoral fellow at the Kessler Foundation, West Orange, N.J., designed the study to assess these unknowns.

The study compared the influence of light, moderate, and vigorous treadmill walking on what is known as inhibitory control – a mental ability to react to stimuli. A period of quiet rest also was included prior to treadmill walking to assess the effects of no walking. The four conditions were tested in random order by the 24 participants with MS who had an Expanded Disability Status Scale (EDSS) score greater than or equal to 4, indicative of minimal or moderate disability. Prior to and soon after 20 minutes of treadmill walking, the reaction time of each participant was judged using a modified flanker task. The test requires a subject to respond to specific relevant information or ignore irrelevant information. The time for a correct response was the reaction time.

Light, moderate, and vigorous treadmill walking similarly and significantly improved reaction time, compared with quiet rest. To assess whether an increase in core body temperature might negate the exercise-related benefit, core body temperature was assessed in 14 thermosensitive MS patients (EDSS less than or equal to 4.0). Core body temperature was recorded every 10 seconds using an ingested sensor capsule and wireless data recorder during 20 minutes of vigorous treadmill exercise and 20 minutes of quiet rest. The core temperature of the subjects rose significantly by about 0.6° C during exercise. But this did not affect the exercise-related improved reaction time.

“There have been no published studies comparing the acute (transient) versus chronic effects of exercise on cognition in MS. We have hypothesized that the acute effects of single bouts of exercise on cognition will be both additive and cumulative over time, when delivered in a longitudinal intervention – much like the effects of a single bout of aerobic exercise on aerobic fitness. In this example, you get small, transient improvements in aerobic fitness after a single session of aerobic exercise; these small improvements add up with continued training, and eventually result in a meaningful improvement,” Dr. Sandroff said in an interview.

The researchers are planning an RCT on the longer-term effects of treadmill walking exercise training on cognition and brain structure/function.

The study was not funded by an external grant. Dr. Sandroff had no relevant financial disclosures.

NEW ORLEANS – Exercise can be beneficial in transiently improving cognitive impairment in people with multiple sclerosis.

Research presented at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis has extended the exercise benefit to cognitive impairment, as measured by reaction time in 24 subjects. The benefit, which was transient, also was evident in 14 subjects who were thermosensitive and displayed elevated core body temperature during exercise. Although preliminary, the data are sufficiently evocative to warrant randomized controlled trials (RCTs).

Brian Hoyle/Frontline Medical News

Cognitive impairment is prevalent in MS, being present in upward of 50% of affected individuals. Exercise may or may not be beneficial in cognitive improvement, given the inconsistent results from three RCTs that have been done. The different types of exercise used in the studies could be one reason for the uncertainty.

For people with MS who are fully ambulatory, treadmill walking could be the best form of exercise. But it’s not known how long and at what intensity someone should walk to realize any cognitive benefit. The investigators, led by Brian M. Sandroff, Ph.D., a postdoctoral fellow at the Kessler Foundation, West Orange, N.J., designed the study to assess these unknowns.

The study compared the influence of light, moderate, and vigorous treadmill walking on what is known as inhibitory control – a mental ability to react to stimuli. A period of quiet rest also was included prior to treadmill walking to assess the effects of no walking. The four conditions were tested in random order by the 24 participants with MS who had an Expanded Disability Status Scale (EDSS) score greater than or equal to 4, indicative of minimal or moderate disability. Prior to and soon after 20 minutes of treadmill walking, the reaction time of each participant was judged using a modified flanker task. The test requires a subject to respond to specific relevant information or ignore irrelevant information. The time for a correct response was the reaction time.

Light, moderate, and vigorous treadmill walking similarly and significantly improved reaction time, compared with quiet rest. To assess whether an increase in core body temperature might negate the exercise-related benefit, core body temperature was assessed in 14 thermosensitive MS patients (EDSS less than or equal to 4.0). Core body temperature was recorded every 10 seconds using an ingested sensor capsule and wireless data recorder during 20 minutes of vigorous treadmill exercise and 20 minutes of quiet rest. The core temperature of the subjects rose significantly by about 0.6° C during exercise. But this did not affect the exercise-related improved reaction time.

“There have been no published studies comparing the acute (transient) versus chronic effects of exercise on cognition in MS. We have hypothesized that the acute effects of single bouts of exercise on cognition will be both additive and cumulative over time, when delivered in a longitudinal intervention – much like the effects of a single bout of aerobic exercise on aerobic fitness. In this example, you get small, transient improvements in aerobic fitness after a single session of aerobic exercise; these small improvements add up with continued training, and eventually result in a meaningful improvement,” Dr. Sandroff said in an interview.

The researchers are planning an RCT on the longer-term effects of treadmill walking exercise training on cognition and brain structure/function.

The study was not funded by an external grant. Dr. Sandroff had no relevant financial disclosures.