Jeff Evans

The full results of the CLOSURE I trial to reduce the risk of stroke in patients with patent foramen ovale who had a previous cryptogenic stroke are now published in the March 15 issue of the New England Journal of Medicine (N. Engl. J. Med. 2012;366:991-9). The results are not substantially different from our report on the results of the trial when they were presented at the American Heart Association scientific sessions in 2010 (See related story on the sidebar).

The percentages of patients who experienced the primary end points of transient ischemic attack, stroke, or the composite of the two were slightly different in the two reports, but this did not alter the results of the statistical analyses or the conclusions drawn by the investigators.

The full results of the CLOSURE I trial to reduce the risk of stroke in patients with patent foramen ovale who had a previous cryptogenic stroke are now published in the March 15 issue of the New England Journal of Medicine (N. Engl. J. Med. 2012;366:991-9). The results are not substantially different from our report on the results of the trial when they were presented at the American Heart Association scientific sessions in 2010 (See related story on the sidebar).

The percentages of patients who experienced the primary end points of transient ischemic attack, stroke, or the composite of the two were slightly different in the two reports, but this did not alter the results of the statistical analyses or the conclusions drawn by the investigators.

The full results of the CLOSURE I trial to reduce the risk of stroke in patients with patent foramen ovale who had a previous cryptogenic stroke are now published in the March 15 issue of the New England Journal of Medicine (N. Engl. J. Med. 2012;366:991-9). The results are not substantially different from our report on the results of the trial when they were presented at the American Heart Association scientific sessions in 2010 (See related story on the sidebar).

The percentages of patients who experienced the primary end points of transient ischemic attack, stroke, or the composite of the two were slightly different in the two reports, but this did not alter the results of the statistical analyses or the conclusions drawn by the investigators.

A pharmacotherapeutic approach that harnesses the amyloid-beta clearing effects of the apolipoprotein E gene while also activating microglia to clear amyloid plaques from the brains of mouse models of Alzheimer’s disease could become a new treatment strategy to test clinically.

The protein product of the APOE gene – the most influential genetic risk factor for late-onset Alzheimer’s disease in humans – normally acts to help build high-density lipoprotein (HDL) particles that promote the degradation of soluble forms of amyloid-beta, which is thought by many researchers to cause the cognitive dysfunction associated with Alzheimer’s. However, efforts that seek to induce the expression of the APOE gene must also ensure that its protein product is lipidated by associated proteins in order for it to clear soluble amyloid-beta.

Paige E. Cramer and Gary E. Landreth, Ph.D., of Case Western Reserve University, Cleveland, and their colleagues took that approach in experiments by inducing the expression of APOE in mouse models of Alzheimer’s disease with the retinoid X receptor agonist bexarotene (Targretin). The drug already is approved by the Food and Drug Administration for the treatment of cutaneous T-cell lymphoma; it is known to cross the blood-brain barrier and has a favorable safety profile.

The investigators used an agonist of the retinoid X receptor (RXR) because the receptor increases the expression of APOE and the lipid transporters ABCA1 and ABCG1 while also stimulating the secretion of highly lipidated HDL particles that are necessary for the clearance of soluble amyloid-beta. RXR agonists such as bexarotene also convert microglia and macrophages into an alternative activation state that helps to clear amyloid-beta plaques.

Unlike interventional approaches to Alzheimer’s therapy that have used vaccines or inhibitors of beta- and gamma-secretase, Dr. Landreth and his colleagues stimulated the normal, physiological clearance mechanisms for soluble amyloid-beta and amyloid-beta plaques.

“There’s no precedent for this,” Dr. Landreth said in an interview.

Photo (c)Science/AAAS

Dr. Landreth emphasized that the oncologically effective dose that they used in the experiments is “way too high to treat Alzheimer’s disease or other CNS diseases,” noting that “it may be unsafe to administer this drug to an AD patient at anywhere near the dosages we’ve reported.”

Within 24 hours of giving bexarotene to transgenic mice expressing mutations in several genes known to be associated with early-onset Alzheimer’s in humans, the investigators found that brain interstitial fluid levels of amyloid-beta had dropped by 25%, followed by a return to baseline by 84 hours. However, the drug had no effect on amyloid-beta levels in mice bred without APOE, which indicated that the clearance of amyloid-beta required APOE (Science 2012 Feb. 9 [doi:10.1126/science.1217697]).

During a 14-day treatment period, the investigators observed a sustained 30% reduction in soluble amyloid-beta levels and a 75% reduction in amyloid-beta plaques. They also found abundant microglia laden with amyloid-beta beginning 3 days after treatment with bexarotene, as well as a progressive enhancement of the expression of APOE, ABCA1, ABCG1, and elevated HDL levels in the hippocampus and cortex of the mice.

Treatment of older, 11-month-old mice with greater plaque deposition, compared with 2- and 6-month-old mice, led to significantly reduced levels of both soluble and insoluble amyloid-beta as well as a 50% decline in the number of plaques and a simultaneous increase in the expression of APOE, ABCA1, and ABCG1 and HDL levels.

Although soluble amyloid-beta levels were continuously reduced during a 3-month period of daily treatment with bexarotene, the researchers surprisingly found no change in amyloid plaque burden at the end of treatment. This raises the question, “Do plaques matter?” Dr. Landreth said.

Treatment with bexarotene also restored cognition and memory in both 6- and 11-month-old transgenic mice during treatment periods lasting 7 days and 3 months.

“The ability of bexarotene to rapidly reverse a broad range of deficits suggests that RXR agonists may be of therapeutic utility in the treatment of AD and its antecedent phases,” Dr. Landreth and his associates wrote.

They plan to perform additional preclinical work to determine how small of a dose of bexarotene is necessary to get the same effects observed in the experiments. This will help to determine what dose to give to normal human subjects in a pilot, proof-of-mechanism clinical study that Dr. Landreth said he and his colleagues would like to conduct in the next few months.

Dr. Landreth and Ms. Cramer hold a U.S. provisional patent application for bexarotene as a potential therapy for Alzheimer’s disease and have founded ReXceptor Inc. The researchers received support from the Blanchette Hooker Rockefeller Foundation, the Thome Foundation, the Roby and Taft Funds for Alzheimer’s Research, the National Institutes of Health, the Charles F. and Joanne Knight Alzheimer’s Disease Research Center at Washington University in St. Louis, and the Marian S. Ware Alzheimer Program

A pharmacotherapeutic approach that harnesses the amyloid-beta clearing effects of the apolipoprotein E gene while also activating microglia to clear amyloid plaques from the brains of mouse models of Alzheimer’s disease could become a new treatment strategy to test clinically.

The protein product of the APOE gene – the most influential genetic risk factor for late-onset Alzheimer’s disease in humans – normally acts to help build high-density lipoprotein (HDL) particles that promote the degradation of soluble forms of amyloid-beta, which is thought by many researchers to cause the cognitive dysfunction associated with Alzheimer’s. However, efforts that seek to induce the expression of the APOE gene must also ensure that its protein product is lipidated by associated proteins in order for it to clear soluble amyloid-beta.

Paige E. Cramer and Gary E. Landreth, Ph.D., of Case Western Reserve University, Cleveland, and their colleagues took that approach in experiments by inducing the expression of APOE in mouse models of Alzheimer’s disease with the retinoid X receptor agonist bexarotene (Targretin). The drug already is approved by the Food and Drug Administration for the treatment of cutaneous T-cell lymphoma; it is known to cross the blood-brain barrier and has a favorable safety profile.

The investigators used an agonist of the retinoid X receptor (RXR) because the receptor increases the expression of APOE and the lipid transporters ABCA1 and ABCG1 while also stimulating the secretion of highly lipidated HDL particles that are necessary for the clearance of soluble amyloid-beta. RXR agonists such as bexarotene also convert microglia and macrophages into an alternative activation state that helps to clear amyloid-beta plaques.

Unlike interventional approaches to Alzheimer’s therapy that have used vaccines or inhibitors of beta- and gamma-secretase, Dr. Landreth and his colleagues stimulated the normal, physiological clearance mechanisms for soluble amyloid-beta and amyloid-beta plaques.

“There’s no precedent for this,” Dr. Landreth said in an interview.

Photo (c)Science/AAAS

Dr. Landreth emphasized that the oncologically effective dose that they used in the experiments is “way too high to treat Alzheimer’s disease or other CNS diseases,” noting that “it may be unsafe to administer this drug to an AD patient at anywhere near the dosages we’ve reported.”

Within 24 hours of giving bexarotene to transgenic mice expressing mutations in several genes known to be associated with early-onset Alzheimer’s in humans, the investigators found that brain interstitial fluid levels of amyloid-beta had dropped by 25%, followed by a return to baseline by 84 hours. However, the drug had no effect on amyloid-beta levels in mice bred without APOE, which indicated that the clearance of amyloid-beta required APOE (Science 2012 Feb. 9 [doi:10.1126/science.1217697]).

During a 14-day treatment period, the investigators observed a sustained 30% reduction in soluble amyloid-beta levels and a 75% reduction in amyloid-beta plaques. They also found abundant microglia laden with amyloid-beta beginning 3 days after treatment with bexarotene, as well as a progressive enhancement of the expression of APOE, ABCA1, ABCG1, and elevated HDL levels in the hippocampus and cortex of the mice.

Treatment of older, 11-month-old mice with greater plaque deposition, compared with 2- and 6-month-old mice, led to significantly reduced levels of both soluble and insoluble amyloid-beta as well as a 50% decline in the number of plaques and a simultaneous increase in the expression of APOE, ABCA1, and ABCG1 and HDL levels.

Although soluble amyloid-beta levels were continuously reduced during a 3-month period of daily treatment with bexarotene, the researchers surprisingly found no change in amyloid plaque burden at the end of treatment. This raises the question, “Do plaques matter?” Dr. Landreth said.

Treatment with bexarotene also restored cognition and memory in both 6- and 11-month-old transgenic mice during treatment periods lasting 7 days and 3 months.

“The ability of bexarotene to rapidly reverse a broad range of deficits suggests that RXR agonists may be of therapeutic utility in the treatment of AD and its antecedent phases,” Dr. Landreth and his associates wrote.

They plan to perform additional preclinical work to determine how small of a dose of bexarotene is necessary to get the same effects observed in the experiments. This will help to determine what dose to give to normal human subjects in a pilot, proof-of-mechanism clinical study that Dr. Landreth said he and his colleagues would like to conduct in the next few months.

Dr. Landreth and Ms. Cramer hold a U.S. provisional patent application for bexarotene as a potential therapy for Alzheimer’s disease and have founded ReXceptor Inc. The researchers received support from the Blanchette Hooker Rockefeller Foundation, the Thome Foundation, the Roby and Taft Funds for Alzheimer’s Research, the National Institutes of Health, the Charles F. and Joanne Knight Alzheimer’s Disease Research Center at Washington University in St. Louis, and the Marian S. Ware Alzheimer Program

A pharmacotherapeutic approach that harnesses the amyloid-beta clearing effects of the apolipoprotein E gene while also activating microglia to clear amyloid plaques from the brains of mouse models of Alzheimer’s disease could become a new treatment strategy to test clinically.

The protein product of the APOE gene – the most influential genetic risk factor for late-onset Alzheimer’s disease in humans – normally acts to help build high-density lipoprotein (HDL) particles that promote the degradation of soluble forms of amyloid-beta, which is thought by many researchers to cause the cognitive dysfunction associated with Alzheimer’s. However, efforts that seek to induce the expression of the APOE gene must also ensure that its protein product is lipidated by associated proteins in order for it to clear soluble amyloid-beta.

Paige E. Cramer and Gary E. Landreth, Ph.D., of Case Western Reserve University, Cleveland, and their colleagues took that approach in experiments by inducing the expression of APOE in mouse models of Alzheimer’s disease with the retinoid X receptor agonist bexarotene (Targretin). The drug already is approved by the Food and Drug Administration for the treatment of cutaneous T-cell lymphoma; it is known to cross the blood-brain barrier and has a favorable safety profile.

The investigators used an agonist of the retinoid X receptor (RXR) because the receptor increases the expression of APOE and the lipid transporters ABCA1 and ABCG1 while also stimulating the secretion of highly lipidated HDL particles that are necessary for the clearance of soluble amyloid-beta. RXR agonists such as bexarotene also convert microglia and macrophages into an alternative activation state that helps to clear amyloid-beta plaques.

Unlike interventional approaches to Alzheimer’s therapy that have used vaccines or inhibitors of beta- and gamma-secretase, Dr. Landreth and his colleagues stimulated the normal, physiological clearance mechanisms for soluble amyloid-beta and amyloid-beta plaques.

“There’s no precedent for this,” Dr. Landreth said in an interview.

Photo (c)Science/AAAS

Dr. Landreth emphasized that the oncologically effective dose that they used in the experiments is “way too high to treat Alzheimer’s disease or other CNS diseases,” noting that “it may be unsafe to administer this drug to an AD patient at anywhere near the dosages we’ve reported.”

Within 24 hours of giving bexarotene to transgenic mice expressing mutations in several genes known to be associated with early-onset Alzheimer’s in humans, the investigators found that brain interstitial fluid levels of amyloid-beta had dropped by 25%, followed by a return to baseline by 84 hours. However, the drug had no effect on amyloid-beta levels in mice bred without APOE, which indicated that the clearance of amyloid-beta required APOE (Science 2012 Feb. 9 [doi:10.1126/science.1217697]).

During a 14-day treatment period, the investigators observed a sustained 30% reduction in soluble amyloid-beta levels and a 75% reduction in amyloid-beta plaques. They also found abundant microglia laden with amyloid-beta beginning 3 days after treatment with bexarotene, as well as a progressive enhancement of the expression of APOE, ABCA1, ABCG1, and elevated HDL levels in the hippocampus and cortex of the mice.

Treatment of older, 11-month-old mice with greater plaque deposition, compared with 2- and 6-month-old mice, led to significantly reduced levels of both soluble and insoluble amyloid-beta as well as a 50% decline in the number of plaques and a simultaneous increase in the expression of APOE, ABCA1, and ABCG1 and HDL levels.

Although soluble amyloid-beta levels were continuously reduced during a 3-month period of daily treatment with bexarotene, the researchers surprisingly found no change in amyloid plaque burden at the end of treatment. This raises the question, “Do plaques matter?” Dr. Landreth said.

Treatment with bexarotene also restored cognition and memory in both 6- and 11-month-old transgenic mice during treatment periods lasting 7 days and 3 months.

“The ability of bexarotene to rapidly reverse a broad range of deficits suggests that RXR agonists may be of therapeutic utility in the treatment of AD and its antecedent phases,” Dr. Landreth and his associates wrote.

They plan to perform additional preclinical work to determine how small of a dose of bexarotene is necessary to get the same effects observed in the experiments. This will help to determine what dose to give to normal human subjects in a pilot, proof-of-mechanism clinical study that Dr. Landreth said he and his colleagues would like to conduct in the next few months.

Dr. Landreth and Ms. Cramer hold a U.S. provisional patent application for bexarotene as a potential therapy for Alzheimer’s disease and have founded ReXceptor Inc. The researchers received support from the Blanchette Hooker Rockefeller Foundation, the Thome Foundation, the Roby and Taft Funds for Alzheimer’s Research, the National Institutes of Health, the Charles F. and Joanne Knight Alzheimer’s Disease Research Center at Washington University in St. Louis, and the Marian S. Ware Alzheimer Program

An MR spectroscopic imaging technique has the potential to predict the prognosis and response to treatment of patients with low-grade infiltrating gliomas that harbor mutations in the gene encoding isocitrate dehydrogenase 1, according to ex vivo and in vivo imaging studies.

The approach takes advantage of experimental results that show the production and accumulation of 2-hydroxyglutarate (2HG) is a consequence of new enzymatic activity of mutant IDH1 variants that are present in more than 70% of patients with low-grade gliomas and have a better than 5-year survival rate than do wild-type IDH1 gliomas. The metabolite is found in a high enough concentration for new MR spectroscopic methods to differentiate it in vivo from the overlapping spectra of metabolites with similar chemical shifts.

The studies suggest great potential for such imaging tests if the biological rationale for such an approach can be verified in animal studies and much larger validation studies, Dr. Patrick Y. Wen said in an interview.

"Being able to measure 2HG in patients noninvasively with MR spectroscopy opens up a whole lot of options. You could diagnose patients. It would help in the diagnosis of the tumor itself, and it would give you an idea of the type of tumor and the prognosis. There are also companies making drugs against IDH, and so you could now noninvasively identify those patients who would be suitable for these drugs," said Dr. Wen, director of the division of neuro-oncology at Brigham and Women’s Hospital, Boston. He was not involved in the studies.

In one study, Adam Elkhaled and his colleagues at the University of California, San Francisco, examined 104 tissue samples from 52 patients who had previously been diagnosed with World Health Organization grade II glioma but were presenting for surgical resection because of suspected disease recurrence (Sci. Transl. Med. 2012 Jan. 11 [Epub doi:10.1126/scitranslmed.3002796]).

They used proton high-resolution magic angle spinning nuclear MR spectroscopy to evaluate the samples for the presence of 2HG. Spectra were positive for 2HG in 33 of 38 patients with evaluable samples (58 of 66 tissue specimens), which translated to a concordance of 86% between the presence of 2HG in tissue samples (51 of 59) and positive IDH1 mutation status (32 of 38).

The investigators found positive correlations in the tissue specimens between 2HG levels and other metabolites that are commonly associated with tumor, as well as with common findings in tumor tissue histopathology, such as mitotic activity, relative tumor content, and cellular density, which "implies that in vivo levels of 2HG may be able to contribute not only to the classification of glioma but also to characterizing the spatial extent of infiltrative lesions," Mr. Elkhaled and his colleagues wrote. The results also suggest that the presence of 2HG may help in "determining the extent of recurrent tumor in an in vivo setting," especially when differentiating tumor from treatment effects.

Dr. Ovidiu C. Andronesi of Massachusetts General Hospital, Boston, and colleagues took these ex vivo findings a step further by applying a two-dimensional correlation MR spectroscopy technique that is able to resolve 2HG from similar metabolites, such as glutamate and glutamine (Sci. Transl. Med. 2012 Jan. 11 [Epub doi:10.1126/scitranslmed.3002693]).

In a preliminary study, they applied the technique to determine the presence of 2HG and measure its level relative to the amounts of glutamate and glutamine present in vivo in two glioma patients with an IDH1 mutation and eight control patients with wild-type IDH1 (including four with primary glioblastoma and four healthy volunteers). The two-dimensional technique correctly identified 2HG in the two patients with IDH1 mutations and did not find 2HG – as expected – in the patients with wild-type IDH1.

Pharmaceutical companies are interested in developing inhibitors of mutated IDH1, Dr. Andronesi and his associates noted, because 2HG might act as an oncometabolite that competitively inhibits enzymes involved in altering histone proteins and DNA methylation, as well as enzymes that affect the level of hypoxia-inducible factor 1, which may be involved in tumor angiogenesis and growth.

Many patients’ low-grade gliomas eventually recur, but not all will get another biopsy, which is where Dr. Wen thought the ability to monitor 2HG levels noninvasively would be of value, particularly in measuring its levels in patients taking inhibitors of mutant IDH. He noted that falling 2HG levels in these patients could be a biomarker response, which "opens up a whole number of options that have never previously been possible in brain tumors because we haven’t had such a biomarker before."

Both studies were funded by grants from the National Institutes of Health. Dr. Andronesi also received support from the Harvard Catalyst (the Harvard Clinical and Translational Science Center).

Dr. Andronesi and a coauthor have applied for a patent for the two-dimensional MRS method they used in their study. No other authors for either study reported having relevant disclosures. Dr. Wen said that he had no relevant disclosures.

An MR spectroscopic imaging technique has the potential to predict the prognosis and response to treatment of patients with low-grade infiltrating gliomas that harbor mutations in the gene encoding isocitrate dehydrogenase 1, according to ex vivo and in vivo imaging studies.

The approach takes advantage of experimental results that show the production and accumulation of 2-hydroxyglutarate (2HG) is a consequence of new enzymatic activity of mutant IDH1 variants that are present in more than 70% of patients with low-grade gliomas and have a better than 5-year survival rate than do wild-type IDH1 gliomas. The metabolite is found in a high enough concentration for new MR spectroscopic methods to differentiate it in vivo from the overlapping spectra of metabolites with similar chemical shifts.

The studies suggest great potential for such imaging tests if the biological rationale for such an approach can be verified in animal studies and much larger validation studies, Dr. Patrick Y. Wen said in an interview.

"Being able to measure 2HG in patients noninvasively with MR spectroscopy opens up a whole lot of options. You could diagnose patients. It would help in the diagnosis of the tumor itself, and it would give you an idea of the type of tumor and the prognosis. There are also companies making drugs against IDH, and so you could now noninvasively identify those patients who would be suitable for these drugs," said Dr. Wen, director of the division of neuro-oncology at Brigham and Women’s Hospital, Boston. He was not involved in the studies.

In one study, Adam Elkhaled and his colleagues at the University of California, San Francisco, examined 104 tissue samples from 52 patients who had previously been diagnosed with World Health Organization grade II glioma but were presenting for surgical resection because of suspected disease recurrence (Sci. Transl. Med. 2012 Jan. 11 [Epub doi:10.1126/scitranslmed.3002796]).

They used proton high-resolution magic angle spinning nuclear MR spectroscopy to evaluate the samples for the presence of 2HG. Spectra were positive for 2HG in 33 of 38 patients with evaluable samples (58 of 66 tissue specimens), which translated to a concordance of 86% between the presence of 2HG in tissue samples (51 of 59) and positive IDH1 mutation status (32 of 38).

The investigators found positive correlations in the tissue specimens between 2HG levels and other metabolites that are commonly associated with tumor, as well as with common findings in tumor tissue histopathology, such as mitotic activity, relative tumor content, and cellular density, which "implies that in vivo levels of 2HG may be able to contribute not only to the classification of glioma but also to characterizing the spatial extent of infiltrative lesions," Mr. Elkhaled and his colleagues wrote. The results also suggest that the presence of 2HG may help in "determining the extent of recurrent tumor in an in vivo setting," especially when differentiating tumor from treatment effects.

Dr. Ovidiu C. Andronesi of Massachusetts General Hospital, Boston, and colleagues took these ex vivo findings a step further by applying a two-dimensional correlation MR spectroscopy technique that is able to resolve 2HG from similar metabolites, such as glutamate and glutamine (Sci. Transl. Med. 2012 Jan. 11 [Epub doi:10.1126/scitranslmed.3002693]).

In a preliminary study, they applied the technique to determine the presence of 2HG and measure its level relative to the amounts of glutamate and glutamine present in vivo in two glioma patients with an IDH1 mutation and eight control patients with wild-type IDH1 (including four with primary glioblastoma and four healthy volunteers). The two-dimensional technique correctly identified 2HG in the two patients with IDH1 mutations and did not find 2HG – as expected – in the patients with wild-type IDH1.

Pharmaceutical companies are interested in developing inhibitors of mutated IDH1, Dr. Andronesi and his associates noted, because 2HG might act as an oncometabolite that competitively inhibits enzymes involved in altering histone proteins and DNA methylation, as well as enzymes that affect the level of hypoxia-inducible factor 1, which may be involved in tumor angiogenesis and growth.

Many patients’ low-grade gliomas eventually recur, but not all will get another biopsy, which is where Dr. Wen thought the ability to monitor 2HG levels noninvasively would be of value, particularly in measuring its levels in patients taking inhibitors of mutant IDH. He noted that falling 2HG levels in these patients could be a biomarker response, which "opens up a whole number of options that have never previously been possible in brain tumors because we haven’t had such a biomarker before."

Both studies were funded by grants from the National Institutes of Health. Dr. Andronesi also received support from the Harvard Catalyst (the Harvard Clinical and Translational Science Center).

Dr. Andronesi and a coauthor have applied for a patent for the two-dimensional MRS method they used in their study. No other authors for either study reported having relevant disclosures. Dr. Wen said that he had no relevant disclosures.

An MR spectroscopic imaging technique has the potential to predict the prognosis and response to treatment of patients with low-grade infiltrating gliomas that harbor mutations in the gene encoding isocitrate dehydrogenase 1, according to ex vivo and in vivo imaging studies.

The approach takes advantage of experimental results that show the production and accumulation of 2-hydroxyglutarate (2HG) is a consequence of new enzymatic activity of mutant IDH1 variants that are present in more than 70% of patients with low-grade gliomas and have a better than 5-year survival rate than do wild-type IDH1 gliomas. The metabolite is found in a high enough concentration for new MR spectroscopic methods to differentiate it in vivo from the overlapping spectra of metabolites with similar chemical shifts.

The studies suggest great potential for such imaging tests if the biological rationale for such an approach can be verified in animal studies and much larger validation studies, Dr. Patrick Y. Wen said in an interview.

"Being able to measure 2HG in patients noninvasively with MR spectroscopy opens up a whole lot of options. You could diagnose patients. It would help in the diagnosis of the tumor itself, and it would give you an idea of the type of tumor and the prognosis. There are also companies making drugs against IDH, and so you could now noninvasively identify those patients who would be suitable for these drugs," said Dr. Wen, director of the division of neuro-oncology at Brigham and Women’s Hospital, Boston. He was not involved in the studies.

In one study, Adam Elkhaled and his colleagues at the University of California, San Francisco, examined 104 tissue samples from 52 patients who had previously been diagnosed with World Health Organization grade II glioma but were presenting for surgical resection because of suspected disease recurrence (Sci. Transl. Med. 2012 Jan. 11 [Epub doi:10.1126/scitranslmed.3002796]).

They used proton high-resolution magic angle spinning nuclear MR spectroscopy to evaluate the samples for the presence of 2HG. Spectra were positive for 2HG in 33 of 38 patients with evaluable samples (58 of 66 tissue specimens), which translated to a concordance of 86% between the presence of 2HG in tissue samples (51 of 59) and positive IDH1 mutation status (32 of 38).

The investigators found positive correlations in the tissue specimens between 2HG levels and other metabolites that are commonly associated with tumor, as well as with common findings in tumor tissue histopathology, such as mitotic activity, relative tumor content, and cellular density, which "implies that in vivo levels of 2HG may be able to contribute not only to the classification of glioma but also to characterizing the spatial extent of infiltrative lesions," Mr. Elkhaled and his colleagues wrote. The results also suggest that the presence of 2HG may help in "determining the extent of recurrent tumor in an in vivo setting," especially when differentiating tumor from treatment effects.

Dr. Ovidiu C. Andronesi of Massachusetts General Hospital, Boston, and colleagues took these ex vivo findings a step further by applying a two-dimensional correlation MR spectroscopy technique that is able to resolve 2HG from similar metabolites, such as glutamate and glutamine (Sci. Transl. Med. 2012 Jan. 11 [Epub doi:10.1126/scitranslmed.3002693]).

In a preliminary study, they applied the technique to determine the presence of 2HG and measure its level relative to the amounts of glutamate and glutamine present in vivo in two glioma patients with an IDH1 mutation and eight control patients with wild-type IDH1 (including four with primary glioblastoma and four healthy volunteers). The two-dimensional technique correctly identified 2HG in the two patients with IDH1 mutations and did not find 2HG – as expected – in the patients with wild-type IDH1.

Pharmaceutical companies are interested in developing inhibitors of mutated IDH1, Dr. Andronesi and his associates noted, because 2HG might act as an oncometabolite that competitively inhibits enzymes involved in altering histone proteins and DNA methylation, as well as enzymes that affect the level of hypoxia-inducible factor 1, which may be involved in tumor angiogenesis and growth.

Many patients’ low-grade gliomas eventually recur, but not all will get another biopsy, which is where Dr. Wen thought the ability to monitor 2HG levels noninvasively would be of value, particularly in measuring its levels in patients taking inhibitors of mutant IDH. He noted that falling 2HG levels in these patients could be a biomarker response, which "opens up a whole number of options that have never previously been possible in brain tumors because we haven’t had such a biomarker before."

Both studies were funded by grants from the National Institutes of Health. Dr. Andronesi also received support from the Harvard Catalyst (the Harvard Clinical and Translational Science Center).

Dr. Andronesi and a coauthor have applied for a patent for the two-dimensional MRS method they used in their study. No other authors for either study reported having relevant disclosures. Dr. Wen said that he had no relevant disclosures.

Two different approaches to treating spinocerebellar ataxia type 1 – aerobic exercise or delivery of vascular endothelial growth factor – appeared to halt or slow the dysfunction of vulnerable cerebellar and brain stem cells in separate studies of a mouse model that closely mirrors the human disease.

The studies also shed light on how the poly-glutamine repeat mutation found in the AXTN1 gene of patients with spinocerebellar ataxia type 1 (SCA1) affects the transcription of particular genes that may contribute to the disease’s hallmark pathology of atrophy and loss of Purkinje neurons from the cerebellar cortex.

Patients with SCA1 most often initially experience problems with gait and balance, followed later by other motor difficulties, cognitive impairment, and sometimes sensory neuropathy, dystonia, and muscle atrophy and fasciculations.

Exercise Increased Life Span

The researchers, led by John D. Fryer, Ph.D., at Baylor College of Medicine, Houston, found that a regimen of relatively light exercise 5 days per week at an early age extended the life of mice with SCA1 by up to 6 weeks but did not improve their motor performance. This exercise led to a sustained increase in the level of epidermal growth factor (EGF) in the brain stem but not in the cerebellum (Science 2011;334:690-3).

The investigators also looked at how exercise affected the function of a transcriptional repressor protein called Capicua (Cic) that interacts with the ATXN1 gene’s protein product (ataxin 1) and lies downstream of EGF signaling.

Levels of Cic in SCA1 mice declined in the brainstem but not in the cerebellum after the exercise training period. Similarly, when brainstem neuronal cultures from SCA1 mice were exposed to EGF, levels of Cic declined. This suggested that a reduction of Cic itself might improve the survival of the SCA1 mice.

Further experiments showed that genetically reducing the level of Cic by 50% in SCA1 mice significantly improved their motor coordination, learning, and memory deficits; curbed the loss of Purkinje cells at 40 weeks of age; and extended their life span.

Genetic reduction of Cic improved motor coordination, according to Dr. Fryer and his coauthors. However, exercise on its own or in the amount undertaken in the first group of SCA1 mice did not improve motor coordination, judging from the observation that it lowered Cic levels only in the brainstem rather than in the cerebellum.

The investigators suggested that the deleterious effects of mutant ataxin 1 may be moderated by lower levels of Cic because the mutant protein appeared to cause a simultaneous increase or decrease in Cic’s transcriptional repression of certain genes. Based on these results, the researchers thought that therapeutics aimed at lowering Cic levels or disrupting the interaction between Cic and mutant ataxin 1 "could potentially ameliorate the disease."

Because the effect of exercise on life span lasted long after the mice stopped exercising, they suggested that "SCA1 individuals might benefit from an exercise program early in disease course." They described the exercise regimen as being "quite gentle," so they could not rule out "the possibility that more intense or longer-duration exercise could cause a sustained EGF increase and Cic decrease in the cerebellum that could lead to motor improvements."

Dr. S. H. Subramony, codirector of the ataxia clinic in the movement disorder center at the University of Florida, Gainesville, said in an interview that the study gives greater weight for the potential use of exercise training in neurodegenerative diseases. Exercise training has not been studied, to his knowledge, in individuals with SCA1. "I think we increasingly recognize that physical activity has numerous biochemical effects, many beneficial, including changes in gene transcription."

There is evolving evidence that suggests exercise in general increases life span, "so whether there is a specific effect of exercise on SCA1 pathogenesis or a general effect is not clear to me because they do not show a SCA1-specific effect in terms of motor performance and pathology in the cerebellum, but the parallel biochemical evidence suggests that it might" said Dr. Subramony, who was not involved with the study.

It remains to be clarified whether exercise needs to start before the onset of symptoms or can be begun after or how intense it needs to be, noted Dr. Subramony, who also is director of the neuromuscular division in the department of neurology at the university.

Another Growth Factor at Work in SCA1

Another study on SCA1 mice supports the notion that mutant ataxin 1 has a toxic gain of function in repressing the transcription of certain genes. Marija Cvetanovic, Ph.D., of Northwestern University, Chicago, found that another growth factor, vascular endothelial growth factor (VEGF), also is transcriptionally repressed by mutant ataxin 1.

Dr. Cvetanovic and her associates found that the expression of the gene for VEGF, an angiogenic and neurotrophic growth factor, was downregulated in the cerebellar Purkinje neurons of SCA1 mice before they showed any behavioral or pathologic signs of the disease. Mutant ataxin 1 directly repressed the expression of VEGF mRNA in the mice. The mutation of a site on the protein known to be crucial for its toxicity stopped its ability to repress the transcription of VEGF; this demonstrated that the repression of VEGF correlates with the in vivo toxicity of the mutant protein (Nat. Med. 2011;17:1445-7).

The researchers observed that VEGF repression induced hypoxia and also limited angiogenesis in the cerebellum of SCA1 mice by significantly decreasing cerebellar microvessel density and total vessel length. Inhibition of VEGF signaling in cerebellar neuronal cultures also decreased neurite length and increased cell death.

However, the genetic overexpression of VEGF beginning during embryonic development in SCA1 mice enhanced their motor performance at 13 weeks and 6 months of age and improved their cerebellar pathology. In other SCA1 mice, continuous intracerebroventricular delivery of VEGF after the onset of disease led to similar improvements.

"Our findings suggest a role for VEGF in SCA1 pathogenesis and indicate that restoring VEGF levels may be a potentially useful treatment in patients with SCA1," the researchers concluded.

When asked to comment on this research, Dr. Subramony called the VEGF study "elegant," but noted that studies of growth factors for other diseases have had generally disappointing results in translating murine data to humans. Another concern for translating the study to humans is in getting the molecule to enough of the affected area in human brains, which is less of a problem with very small mouse brains.

In addition, the literature suggests that mutant ataxin 1 causes dysregulation of many genes, not just VEGF, so "the possibility remains that just replacing VEGF may not rescue the disease in a more comprehensive manner because we know that a number of other genetic alterations take place in these tissues because of the mutation," he said.

"From a clinical perspective, it may be easier to translate the exercise study to humans because it is easier to put patients through an exercise program than to give them a novel molecule" such as VEGF, which to Dr. Subramony’s knowledge has not been studied in a human trial for any disease.

The exercise study was supported by grants from the National Institutes of Health (NIH). Dr. Fryer performed the research for the exercise study at Baylor, but he is now at the Mayo Clinic in Jacksonville, Fla. The VEGF study was supported by grants from the NIH, the U.S. National Organization for Rare Disorders, the U.S. Brain Research Foundation, and the U.S. National Ataxia Foundation. None of the authors of that study had relevant financial disclosures. Dr. Subramony said that he serves on the speakers bureau for Athena Diagnostics and receives research funding from the National Ataxia Foundation.

Two different approaches to treating spinocerebellar ataxia type 1 – aerobic exercise or delivery of vascular endothelial growth factor – appeared to halt or slow the dysfunction of vulnerable cerebellar and brain stem cells in separate studies of a mouse model that closely mirrors the human disease.

The studies also shed light on how the poly-glutamine repeat mutation found in the AXTN1 gene of patients with spinocerebellar ataxia type 1 (SCA1) affects the transcription of particular genes that may contribute to the disease’s hallmark pathology of atrophy and loss of Purkinje neurons from the cerebellar cortex.

Patients with SCA1 most often initially experience problems with gait and balance, followed later by other motor difficulties, cognitive impairment, and sometimes sensory neuropathy, dystonia, and muscle atrophy and fasciculations.

Exercise Increased Life Span

The researchers, led by John D. Fryer, Ph.D., at Baylor College of Medicine, Houston, found that a regimen of relatively light exercise 5 days per week at an early age extended the life of mice with SCA1 by up to 6 weeks but did not improve their motor performance. This exercise led to a sustained increase in the level of epidermal growth factor (EGF) in the brain stem but not in the cerebellum (Science 2011;334:690-3).

The investigators also looked at how exercise affected the function of a transcriptional repressor protein called Capicua (Cic) that interacts with the ATXN1 gene’s protein product (ataxin 1) and lies downstream of EGF signaling.

Levels of Cic in SCA1 mice declined in the brainstem but not in the cerebellum after the exercise training period. Similarly, when brainstem neuronal cultures from SCA1 mice were exposed to EGF, levels of Cic declined. This suggested that a reduction of Cic itself might improve the survival of the SCA1 mice.

Further experiments showed that genetically reducing the level of Cic by 50% in SCA1 mice significantly improved their motor coordination, learning, and memory deficits; curbed the loss of Purkinje cells at 40 weeks of age; and extended their life span.

Genetic reduction of Cic improved motor coordination, according to Dr. Fryer and his coauthors. However, exercise on its own or in the amount undertaken in the first group of SCA1 mice did not improve motor coordination, judging from the observation that it lowered Cic levels only in the brainstem rather than in the cerebellum.

The investigators suggested that the deleterious effects of mutant ataxin 1 may be moderated by lower levels of Cic because the mutant protein appeared to cause a simultaneous increase or decrease in Cic’s transcriptional repression of certain genes. Based on these results, the researchers thought that therapeutics aimed at lowering Cic levels or disrupting the interaction between Cic and mutant ataxin 1 "could potentially ameliorate the disease."

Because the effect of exercise on life span lasted long after the mice stopped exercising, they suggested that "SCA1 individuals might benefit from an exercise program early in disease course." They described the exercise regimen as being "quite gentle," so they could not rule out "the possibility that more intense or longer-duration exercise could cause a sustained EGF increase and Cic decrease in the cerebellum that could lead to motor improvements."

Dr. S. H. Subramony, codirector of the ataxia clinic in the movement disorder center at the University of Florida, Gainesville, said in an interview that the study gives greater weight for the potential use of exercise training in neurodegenerative diseases. Exercise training has not been studied, to his knowledge, in individuals with SCA1. "I think we increasingly recognize that physical activity has numerous biochemical effects, many beneficial, including changes in gene transcription."

There is evolving evidence that suggests exercise in general increases life span, "so whether there is a specific effect of exercise on SCA1 pathogenesis or a general effect is not clear to me because they do not show a SCA1-specific effect in terms of motor performance and pathology in the cerebellum, but the parallel biochemical evidence suggests that it might" said Dr. Subramony, who was not involved with the study.

It remains to be clarified whether exercise needs to start before the onset of symptoms or can be begun after or how intense it needs to be, noted Dr. Subramony, who also is director of the neuromuscular division in the department of neurology at the university.

Another Growth Factor at Work in SCA1

Another study on SCA1 mice supports the notion that mutant ataxin 1 has a toxic gain of function in repressing the transcription of certain genes. Marija Cvetanovic, Ph.D., of Northwestern University, Chicago, found that another growth factor, vascular endothelial growth factor (VEGF), also is transcriptionally repressed by mutant ataxin 1.

Dr. Cvetanovic and her associates found that the expression of the gene for VEGF, an angiogenic and neurotrophic growth factor, was downregulated in the cerebellar Purkinje neurons of SCA1 mice before they showed any behavioral or pathologic signs of the disease. Mutant ataxin 1 directly repressed the expression of VEGF mRNA in the mice. The mutation of a site on the protein known to be crucial for its toxicity stopped its ability to repress the transcription of VEGF; this demonstrated that the repression of VEGF correlates with the in vivo toxicity of the mutant protein (Nat. Med. 2011;17:1445-7).

The researchers observed that VEGF repression induced hypoxia and also limited angiogenesis in the cerebellum of SCA1 mice by significantly decreasing cerebellar microvessel density and total vessel length. Inhibition of VEGF signaling in cerebellar neuronal cultures also decreased neurite length and increased cell death.

However, the genetic overexpression of VEGF beginning during embryonic development in SCA1 mice enhanced their motor performance at 13 weeks and 6 months of age and improved their cerebellar pathology. In other SCA1 mice, continuous intracerebroventricular delivery of VEGF after the onset of disease led to similar improvements.

"Our findings suggest a role for VEGF in SCA1 pathogenesis and indicate that restoring VEGF levels may be a potentially useful treatment in patients with SCA1," the researchers concluded.

When asked to comment on this research, Dr. Subramony called the VEGF study "elegant," but noted that studies of growth factors for other diseases have had generally disappointing results in translating murine data to humans. Another concern for translating the study to humans is in getting the molecule to enough of the affected area in human brains, which is less of a problem with very small mouse brains.

In addition, the literature suggests that mutant ataxin 1 causes dysregulation of many genes, not just VEGF, so "the possibility remains that just replacing VEGF may not rescue the disease in a more comprehensive manner because we know that a number of other genetic alterations take place in these tissues because of the mutation," he said.

"From a clinical perspective, it may be easier to translate the exercise study to humans because it is easier to put patients through an exercise program than to give them a novel molecule" such as VEGF, which to Dr. Subramony’s knowledge has not been studied in a human trial for any disease.

The exercise study was supported by grants from the National Institutes of Health (NIH). Dr. Fryer performed the research for the exercise study at Baylor, but he is now at the Mayo Clinic in Jacksonville, Fla. The VEGF study was supported by grants from the NIH, the U.S. National Organization for Rare Disorders, the U.S. Brain Research Foundation, and the U.S. National Ataxia Foundation. None of the authors of that study had relevant financial disclosures. Dr. Subramony said that he serves on the speakers bureau for Athena Diagnostics and receives research funding from the National Ataxia Foundation.

Two different approaches to treating spinocerebellar ataxia type 1 – aerobic exercise or delivery of vascular endothelial growth factor – appeared to halt or slow the dysfunction of vulnerable cerebellar and brain stem cells in separate studies of a mouse model that closely mirrors the human disease.

The studies also shed light on how the poly-glutamine repeat mutation found in the AXTN1 gene of patients with spinocerebellar ataxia type 1 (SCA1) affects the transcription of particular genes that may contribute to the disease’s hallmark pathology of atrophy and loss of Purkinje neurons from the cerebellar cortex.

Patients with SCA1 most often initially experience problems with gait and balance, followed later by other motor difficulties, cognitive impairment, and sometimes sensory neuropathy, dystonia, and muscle atrophy and fasciculations.

Exercise Increased Life Span

The researchers, led by John D. Fryer, Ph.D., at Baylor College of Medicine, Houston, found that a regimen of relatively light exercise 5 days per week at an early age extended the life of mice with SCA1 by up to 6 weeks but did not improve their motor performance. This exercise led to a sustained increase in the level of epidermal growth factor (EGF) in the brain stem but not in the cerebellum (Science 2011;334:690-3).

The investigators also looked at how exercise affected the function of a transcriptional repressor protein called Capicua (Cic) that interacts with the ATXN1 gene’s protein product (ataxin 1) and lies downstream of EGF signaling.

Levels of Cic in SCA1 mice declined in the brainstem but not in the cerebellum after the exercise training period. Similarly, when brainstem neuronal cultures from SCA1 mice were exposed to EGF, levels of Cic declined. This suggested that a reduction of Cic itself might improve the survival of the SCA1 mice.

Further experiments showed that genetically reducing the level of Cic by 50% in SCA1 mice significantly improved their motor coordination, learning, and memory deficits; curbed the loss of Purkinje cells at 40 weeks of age; and extended their life span.

Genetic reduction of Cic improved motor coordination, according to Dr. Fryer and his coauthors. However, exercise on its own or in the amount undertaken in the first group of SCA1 mice did not improve motor coordination, judging from the observation that it lowered Cic levels only in the brainstem rather than in the cerebellum.

The investigators suggested that the deleterious effects of mutant ataxin 1 may be moderated by lower levels of Cic because the mutant protein appeared to cause a simultaneous increase or decrease in Cic’s transcriptional repression of certain genes. Based on these results, the researchers thought that therapeutics aimed at lowering Cic levels or disrupting the interaction between Cic and mutant ataxin 1 "could potentially ameliorate the disease."

Because the effect of exercise on life span lasted long after the mice stopped exercising, they suggested that "SCA1 individuals might benefit from an exercise program early in disease course." They described the exercise regimen as being "quite gentle," so they could not rule out "the possibility that more intense or longer-duration exercise could cause a sustained EGF increase and Cic decrease in the cerebellum that could lead to motor improvements."

Dr. S. H. Subramony, codirector of the ataxia clinic in the movement disorder center at the University of Florida, Gainesville, said in an interview that the study gives greater weight for the potential use of exercise training in neurodegenerative diseases. Exercise training has not been studied, to his knowledge, in individuals with SCA1. "I think we increasingly recognize that physical activity has numerous biochemical effects, many beneficial, including changes in gene transcription."

There is evolving evidence that suggests exercise in general increases life span, "so whether there is a specific effect of exercise on SCA1 pathogenesis or a general effect is not clear to me because they do not show a SCA1-specific effect in terms of motor performance and pathology in the cerebellum, but the parallel biochemical evidence suggests that it might" said Dr. Subramony, who was not involved with the study.

It remains to be clarified whether exercise needs to start before the onset of symptoms or can be begun after or how intense it needs to be, noted Dr. Subramony, who also is director of the neuromuscular division in the department of neurology at the university.

Another Growth Factor at Work in SCA1

Another study on SCA1 mice supports the notion that mutant ataxin 1 has a toxic gain of function in repressing the transcription of certain genes. Marija Cvetanovic, Ph.D., of Northwestern University, Chicago, found that another growth factor, vascular endothelial growth factor (VEGF), also is transcriptionally repressed by mutant ataxin 1.

Dr. Cvetanovic and her associates found that the expression of the gene for VEGF, an angiogenic and neurotrophic growth factor, was downregulated in the cerebellar Purkinje neurons of SCA1 mice before they showed any behavioral or pathologic signs of the disease. Mutant ataxin 1 directly repressed the expression of VEGF mRNA in the mice. The mutation of a site on the protein known to be crucial for its toxicity stopped its ability to repress the transcription of VEGF; this demonstrated that the repression of VEGF correlates with the in vivo toxicity of the mutant protein (Nat. Med. 2011;17:1445-7).

The researchers observed that VEGF repression induced hypoxia and also limited angiogenesis in the cerebellum of SCA1 mice by significantly decreasing cerebellar microvessel density and total vessel length. Inhibition of VEGF signaling in cerebellar neuronal cultures also decreased neurite length and increased cell death.

However, the genetic overexpression of VEGF beginning during embryonic development in SCA1 mice enhanced their motor performance at 13 weeks and 6 months of age and improved their cerebellar pathology. In other SCA1 mice, continuous intracerebroventricular delivery of VEGF after the onset of disease led to similar improvements.

"Our findings suggest a role for VEGF in SCA1 pathogenesis and indicate that restoring VEGF levels may be a potentially useful treatment in patients with SCA1," the researchers concluded.

When asked to comment on this research, Dr. Subramony called the VEGF study "elegant," but noted that studies of growth factors for other diseases have had generally disappointing results in translating murine data to humans. Another concern for translating the study to humans is in getting the molecule to enough of the affected area in human brains, which is less of a problem with very small mouse brains.

In addition, the literature suggests that mutant ataxin 1 causes dysregulation of many genes, not just VEGF, so "the possibility remains that just replacing VEGF may not rescue the disease in a more comprehensive manner because we know that a number of other genetic alterations take place in these tissues because of the mutation," he said.

"From a clinical perspective, it may be easier to translate the exercise study to humans because it is easier to put patients through an exercise program than to give them a novel molecule" such as VEGF, which to Dr. Subramony’s knowledge has not been studied in a human trial for any disease.

The exercise study was supported by grants from the National Institutes of Health (NIH). Dr. Fryer performed the research for the exercise study at Baylor, but he is now at the Mayo Clinic in Jacksonville, Fla. The VEGF study was supported by grants from the NIH, the U.S. National Organization for Rare Disorders, the U.S. Brain Research Foundation, and the U.S. National Ataxia Foundation. None of the authors of that study had relevant financial disclosures. Dr. Subramony said that he serves on the speakers bureau for Athena Diagnostics and receives research funding from the National Ataxia Foundation.

A biomarker found in the blood of patients with Huntington's disease appears to mark early stages of the disease and measure response to treatment, without confusing signs of Huntington's with those of other neurodegenerative diseases.

Yi Hu, Ph.D., of Harvard Medical School and Brigham and Women's Hospital, both in Boston, and his colleagues found the biomarker – a transcriptional modulator called H2AFY (for H2A histone family, member Y) – during a gene microarray search for messenger RNA transcripts expressed at various points in the disease process. They thought that a blood biomarker for Huntington's disease (HD) might exist, because the mutant huntingtin protein that causes the disease is expressed in nearly all tissues and “may cause detectable but clinically silent changes in gene expression and biochemistry in blood cells.”

The team found H2AFY overexpressed in the blood of HD patients relative to the controls after analyzing expression data from the genomes of 8 patients with HD and 111 control subjects, including 83 patients with other neurodegenerative diseases. The researchers found that H2AFY mRNA in blood provided high sensitivity and specificity for detecting HD in this set of patients, as well as in a second independent set (Proc. Natl. Acad. Sci. U.S.A. 2011;108:17141-6).

The investigators validated the association between elevated H2AFY mRNA levels and HD in two other independent, cross-sectional, case-control studies. In the first study, they compared H2AFY mRNA levels from 36 HD patients, 9 individuals with preclinical HD who carried the huntingtin gene mutation for HD, 50 healthy people, and 1 patient with spinocerebellar ataxia-1.

H2AFY mRNA levels were high only in the individuals with clinical or preclinical HD, which “is of critical importance for therapeutic biomarker discovery because patients with premanifest and early-stage HD are most likely to benefit from disease-modifying interventions,” the researchers said. The second case-control study of 25 HD patients and 21 age- and sex-matched control subjects demonstrated that the association between high H2AFY mRNA levels and HD remained consistent over 2-3 years.

Levels of macroH2A1 – the histone protein encoded by H2AFY – in the brains of HD patients and mouse models of HD also were elevated in comparison with those in control subjects and wild-type mice, particularly in brain areas most affected by the disease.

According to Dr. Hu and his coauthors, histone deacetylase inhibitors are a leading class of potentially disease-modifying therapeutics for HD. The researchers found that they could use macroH2A1 levels to monitor the response to treatment with the histone deacetylase inhibitor sodium phenylbutyrate (SPB) in a mouse model of HD.

To determine if a similar approach could be used with H2AFY mRNA levels in humans, the investigators analyzed frozen blood samples from HD patients participating in PHEND-HD (Safety and Tolerability Study of Phenylbutyrate in Huntington's Disease), a randomized, double-blind, phase II study. They found that longer times of patients' receiving SPB were associated with greater decreases in H2AFY mRNA levels.

Their study was funded by grants from the National Institutes of Health, the Maximillian E. & Marion O. Hoffman Foundation, the RJG Foundation, the Huntington's Disease Society of America (HDSA) Coalition for the Cure, and the New England HDSA Center for Excellence for Huntington Disease.

Two of Dr. Yu's coauthors reported serving as a consultant or scientific collaborator with companies involved in neurodegenerative disease research, as well as being coinventors listed on patent applications for diagnostics or therapeutics relating to neurodegenerative diseases.

Adviser's Viewpoint

One of the First to Vet Prevention Trial Designs?

HD is a heritable, neurodegenerative disorder of middle age that first effects muscle coordination and, in the advanced stages of the disease, cognitive ability. The HD causal mutation occurs in a gene called huntingtin (which encodes a protein product of the same name) and consists of an expanded trinucleotide repeat that results in the inclusion of a longer-than-normal polyglutamine tract in the mature protein. This leads to the development of multiple cellular changes that eventually lead to the death of a collection of susceptible neurons in the brain. Despite the identification of the causal genetic locus almost 2 decades ago, there is still no cure or disease-slowing treatment available to the HD patient.

The combination of HD's neurodegenerative nature, the standardized testing available for the causal mutation, and the high penetrance of the huntingtin mutation makes HD an excellent candidate for therapeutic prevention and disease-slowing trials.

Design of such clinical trials is underway as the neurodegenerative disease field explores ways to preemptively protect each disease's targeted neurons. These designs typically face complications regarding their power because of variability in disease course – and therefore therapeutic response – from individual to individual.

An ideal neurodegenerative disease prevention trial would include a well-demonstrated genetic risk factor, a validated biomarker panel to track therapeutic progress in affected individuals, and safe therapies that target promising molecular entities.

The work by Dr. Hu and his associates may have identified a blood-based biomarker for HD that could aid in future prevention trials. In their impressive work, the researchers demonstrate that H2AFY mRNA levels are significantly elevated and associated with disease status in HD patients, that H2AFY mRNA is significantly increased in HD even before the presence of clinically recognizable symptoms, and that the macroH2A1 protein encoded by the H2AFY gene is elevated in the brains of patients and mouse models of the disease.

Perhaps most importantly, the investigators demonstrated that blood levels of H2AFY mRNA are reduced in a randomized, double-blind, phase II clinical trial of HD patients who were treated with an emerging histone deacetylase inhibitor, SPB, that was previously shown to suppress huntingtin-induced neurodegeneration in a mouse model.

The authors discuss the limitations of their work extensively with an appropriate emphasis on independent replication in a larger sample set. Assuming that the H2AFY mRNA biomarker is independently validated, HD now tentatively meets several of the above-outlined hurdles for the initiation of well-informed neurodegenerative disease–prevention trials.

Perhaps the major question left unanswered is the efficacy of available therapeutics in combating the early stages of HD. However, if the H2AFY biomarker is eventually shown to indicate the underlying pathobiology of HD, then it is very encouraging that the histone deacetylase inhibitor appeared to shift the biomarker in the direction of the placebo group.

Neurodegenerative disease–prevention trials are clearly going to test many aspects of the standard clinical trials system, including the inclination of pharmaceutical companies to explore such trial designs and the Food and Drug Administration's willingness to acknowledge the role of such trials in the vetting of novel neurodegenerative disease–treatment approaches.

The coupling of biomarker and genetic approaches with therapeutic agents administered during the disease process when they have the greatest chance to be efficacious can be nothing but motivating for the field. The new work by Dr. Hu and his colleagues could poise HD at the front of the pack for these disease-prevention trials, and should be nothing but encouraging to individuals and families at risk for the disease.

MATTHEW J. HUENTELMAN, PH.D., is head of the neurobehavioral research unit and associate professor in the neurogenomics division of the Translational Genomics Research Institute in Phoenix. He disclosed no conflict of interest.

A biomarker found in the blood of patients with Huntington's disease appears to mark early stages of the disease and measure response to treatment, without confusing signs of Huntington's with those of other neurodegenerative diseases.

Yi Hu, Ph.D., of Harvard Medical School and Brigham and Women's Hospital, both in Boston, and his colleagues found the biomarker – a transcriptional modulator called H2AFY (for H2A histone family, member Y) – during a gene microarray search for messenger RNA transcripts expressed at various points in the disease process. They thought that a blood biomarker for Huntington's disease (HD) might exist, because the mutant huntingtin protein that causes the disease is expressed in nearly all tissues and “may cause detectable but clinically silent changes in gene expression and biochemistry in blood cells.”

The team found H2AFY overexpressed in the blood of HD patients relative to the controls after analyzing expression data from the genomes of 8 patients with HD and 111 control subjects, including 83 patients with other neurodegenerative diseases. The researchers found that H2AFY mRNA in blood provided high sensitivity and specificity for detecting HD in this set of patients, as well as in a second independent set (Proc. Natl. Acad. Sci. U.S.A. 2011;108:17141-6).

The investigators validated the association between elevated H2AFY mRNA levels and HD in two other independent, cross-sectional, case-control studies. In the first study, they compared H2AFY mRNA levels from 36 HD patients, 9 individuals with preclinical HD who carried the huntingtin gene mutation for HD, 50 healthy people, and 1 patient with spinocerebellar ataxia-1.

H2AFY mRNA levels were high only in the individuals with clinical or preclinical HD, which “is of critical importance for therapeutic biomarker discovery because patients with premanifest and early-stage HD are most likely to benefit from disease-modifying interventions,” the researchers said. The second case-control study of 25 HD patients and 21 age- and sex-matched control subjects demonstrated that the association between high H2AFY mRNA levels and HD remained consistent over 2-3 years.

Levels of macroH2A1 – the histone protein encoded by H2AFY – in the brains of HD patients and mouse models of HD also were elevated in comparison with those in control subjects and wild-type mice, particularly in brain areas most affected by the disease.

According to Dr. Hu and his coauthors, histone deacetylase inhibitors are a leading class of potentially disease-modifying therapeutics for HD. The researchers found that they could use macroH2A1 levels to monitor the response to treatment with the histone deacetylase inhibitor sodium phenylbutyrate (SPB) in a mouse model of HD.

To determine if a similar approach could be used with H2AFY mRNA levels in humans, the investigators analyzed frozen blood samples from HD patients participating in PHEND-HD (Safety and Tolerability Study of Phenylbutyrate in Huntington's Disease), a randomized, double-blind, phase II study. They found that longer times of patients' receiving SPB were associated with greater decreases in H2AFY mRNA levels.

Their study was funded by grants from the National Institutes of Health, the Maximillian E. & Marion O. Hoffman Foundation, the RJG Foundation, the Huntington's Disease Society of America (HDSA) Coalition for the Cure, and the New England HDSA Center for Excellence for Huntington Disease.

Two of Dr. Yu's coauthors reported serving as a consultant or scientific collaborator with companies involved in neurodegenerative disease research, as well as being coinventors listed on patent applications for diagnostics or therapeutics relating to neurodegenerative diseases.

Adviser's Viewpoint

One of the First to Vet Prevention Trial Designs?

HD is a heritable, neurodegenerative disorder of middle age that first effects muscle coordination and, in the advanced stages of the disease, cognitive ability. The HD causal mutation occurs in a gene called huntingtin (which encodes a protein product of the same name) and consists of an expanded trinucleotide repeat that results in the inclusion of a longer-than-normal polyglutamine tract in the mature protein. This leads to the development of multiple cellular changes that eventually lead to the death of a collection of susceptible neurons in the brain. Despite the identification of the causal genetic locus almost 2 decades ago, there is still no cure or disease-slowing treatment available to the HD patient.

The combination of HD's neurodegenerative nature, the standardized testing available for the causal mutation, and the high penetrance of the huntingtin mutation makes HD an excellent candidate for therapeutic prevention and disease-slowing trials.

Design of such clinical trials is underway as the neurodegenerative disease field explores ways to preemptively protect each disease's targeted neurons. These designs typically face complications regarding their power because of variability in disease course – and therefore therapeutic response – from individual to individual.

An ideal neurodegenerative disease prevention trial would include a well-demonstrated genetic risk factor, a validated biomarker panel to track therapeutic progress in affected individuals, and safe therapies that target promising molecular entities.

The work by Dr. Hu and his associates may have identified a blood-based biomarker for HD that could aid in future prevention trials. In their impressive work, the researchers demonstrate that H2AFY mRNA levels are significantly elevated and associated with disease status in HD patients, that H2AFY mRNA is significantly increased in HD even before the presence of clinically recognizable symptoms, and that the macroH2A1 protein encoded by the H2AFY gene is elevated in the brains of patients and mouse models of the disease.

Perhaps most importantly, the investigators demonstrated that blood levels of H2AFY mRNA are reduced in a randomized, double-blind, phase II clinical trial of HD patients who were treated with an emerging histone deacetylase inhibitor, SPB, that was previously shown to suppress huntingtin-induced neurodegeneration in a mouse model.

The authors discuss the limitations of their work extensively with an appropriate emphasis on independent replication in a larger sample set. Assuming that the H2AFY mRNA biomarker is independently validated, HD now tentatively meets several of the above-outlined hurdles for the initiation of well-informed neurodegenerative disease–prevention trials.

Perhaps the major question left unanswered is the efficacy of available therapeutics in combating the early stages of HD. However, if the H2AFY biomarker is eventually shown to indicate the underlying pathobiology of HD, then it is very encouraging that the histone deacetylase inhibitor appeared to shift the biomarker in the direction of the placebo group.

Neurodegenerative disease–prevention trials are clearly going to test many aspects of the standard clinical trials system, including the inclination of pharmaceutical companies to explore such trial designs and the Food and Drug Administration's willingness to acknowledge the role of such trials in the vetting of novel neurodegenerative disease–treatment approaches.

The coupling of biomarker and genetic approaches with therapeutic agents administered during the disease process when they have the greatest chance to be efficacious can be nothing but motivating for the field. The new work by Dr. Hu and his colleagues could poise HD at the front of the pack for these disease-prevention trials, and should be nothing but encouraging to individuals and families at risk for the disease.

MATTHEW J. HUENTELMAN, PH.D., is head of the neurobehavioral research unit and associate professor in the neurogenomics division of the Translational Genomics Research Institute in Phoenix. He disclosed no conflict of interest.

A biomarker found in the blood of patients with Huntington's disease appears to mark early stages of the disease and measure response to treatment, without confusing signs of Huntington's with those of other neurodegenerative diseases.

Yi Hu, Ph.D., of Harvard Medical School and Brigham and Women's Hospital, both in Boston, and his colleagues found the biomarker – a transcriptional modulator called H2AFY (for H2A histone family, member Y) – during a gene microarray search for messenger RNA transcripts expressed at various points in the disease process. They thought that a blood biomarker for Huntington's disease (HD) might exist, because the mutant huntingtin protein that causes the disease is expressed in nearly all tissues and “may cause detectable but clinically silent changes in gene expression and biochemistry in blood cells.”

The team found H2AFY overexpressed in the blood of HD patients relative to the controls after analyzing expression data from the genomes of 8 patients with HD and 111 control subjects, including 83 patients with other neurodegenerative diseases. The researchers found that H2AFY mRNA in blood provided high sensitivity and specificity for detecting HD in this set of patients, as well as in a second independent set (Proc. Natl. Acad. Sci. U.S.A. 2011;108:17141-6).

The investigators validated the association between elevated H2AFY mRNA levels and HD in two other independent, cross-sectional, case-control studies. In the first study, they compared H2AFY mRNA levels from 36 HD patients, 9 individuals with preclinical HD who carried the huntingtin gene mutation for HD, 50 healthy people, and 1 patient with spinocerebellar ataxia-1.

H2AFY mRNA levels were high only in the individuals with clinical or preclinical HD, which “is of critical importance for therapeutic biomarker discovery because patients with premanifest and early-stage HD are most likely to benefit from disease-modifying interventions,” the researchers said. The second case-control study of 25 HD patients and 21 age- and sex-matched control subjects demonstrated that the association between high H2AFY mRNA levels and HD remained consistent over 2-3 years.

Levels of macroH2A1 – the histone protein encoded by H2AFY – in the brains of HD patients and mouse models of HD also were elevated in comparison with those in control subjects and wild-type mice, particularly in brain areas most affected by the disease.

According to Dr. Hu and his coauthors, histone deacetylase inhibitors are a leading class of potentially disease-modifying therapeutics for HD. The researchers found that they could use macroH2A1 levels to monitor the response to treatment with the histone deacetylase inhibitor sodium phenylbutyrate (SPB) in a mouse model of HD.

To determine if a similar approach could be used with H2AFY mRNA levels in humans, the investigators analyzed frozen blood samples from HD patients participating in PHEND-HD (Safety and Tolerability Study of Phenylbutyrate in Huntington's Disease), a randomized, double-blind, phase II study. They found that longer times of patients' receiving SPB were associated with greater decreases in H2AFY mRNA levels.

Their study was funded by grants from the National Institutes of Health, the Maximillian E. & Marion O. Hoffman Foundation, the RJG Foundation, the Huntington's Disease Society of America (HDSA) Coalition for the Cure, and the New England HDSA Center for Excellence for Huntington Disease.

Two of Dr. Yu's coauthors reported serving as a consultant or scientific collaborator with companies involved in neurodegenerative disease research, as well as being coinventors listed on patent applications for diagnostics or therapeutics relating to neurodegenerative diseases.

Adviser's Viewpoint

One of the First to Vet Prevention Trial Designs?

HD is a heritable, neurodegenerative disorder of middle age that first effects muscle coordination and, in the advanced stages of the disease, cognitive ability. The HD causal mutation occurs in a gene called huntingtin (which encodes a protein product of the same name) and consists of an expanded trinucleotide repeat that results in the inclusion of a longer-than-normal polyglutamine tract in the mature protein. This leads to the development of multiple cellular changes that eventually lead to the death of a collection of susceptible neurons in the brain. Despite the identification of the causal genetic locus almost 2 decades ago, there is still no cure or disease-slowing treatment available to the HD patient.

The combination of HD's neurodegenerative nature, the standardized testing available for the causal mutation, and the high penetrance of the huntingtin mutation makes HD an excellent candidate for therapeutic prevention and disease-slowing trials.

Design of such clinical trials is underway as the neurodegenerative disease field explores ways to preemptively protect each disease's targeted neurons. These designs typically face complications regarding their power because of variability in disease course – and therefore therapeutic response – from individual to individual.

An ideal neurodegenerative disease prevention trial would include a well-demonstrated genetic risk factor, a validated biomarker panel to track therapeutic progress in affected individuals, and safe therapies that target promising molecular entities.

The work by Dr. Hu and his associates may have identified a blood-based biomarker for HD that could aid in future prevention trials. In their impressive work, the researchers demonstrate that H2AFY mRNA levels are significantly elevated and associated with disease status in HD patients, that H2AFY mRNA is significantly increased in HD even before the presence of clinically recognizable symptoms, and that the macroH2A1 protein encoded by the H2AFY gene is elevated in the brains of patients and mouse models of the disease.

Perhaps most importantly, the investigators demonstrated that blood levels of H2AFY mRNA are reduced in a randomized, double-blind, phase II clinical trial of HD patients who were treated with an emerging histone deacetylase inhibitor, SPB, that was previously shown to suppress huntingtin-induced neurodegeneration in a mouse model.

The authors discuss the limitations of their work extensively with an appropriate emphasis on independent replication in a larger sample set. Assuming that the H2AFY mRNA biomarker is independently validated, HD now tentatively meets several of the above-outlined hurdles for the initiation of well-informed neurodegenerative disease–prevention trials.

Perhaps the major question left unanswered is the efficacy of available therapeutics in combating the early stages of HD. However, if the H2AFY biomarker is eventually shown to indicate the underlying pathobiology of HD, then it is very encouraging that the histone deacetylase inhibitor appeared to shift the biomarker in the direction of the placebo group.

Neurodegenerative disease–prevention trials are clearly going to test many aspects of the standard clinical trials system, including the inclination of pharmaceutical companies to explore such trial designs and the Food and Drug Administration's willingness to acknowledge the role of such trials in the vetting of novel neurodegenerative disease–treatment approaches.

The coupling of biomarker and genetic approaches with therapeutic agents administered during the disease process when they have the greatest chance to be efficacious can be nothing but motivating for the field. The new work by Dr. Hu and his colleagues could poise HD at the front of the pack for these disease-prevention trials, and should be nothing but encouraging to individuals and families at risk for the disease.

MATTHEW J. HUENTELMAN, PH.D., is head of the neurobehavioral research unit and associate professor in the neurogenomics division of the Translational Genomics Research Institute in Phoenix. He disclosed no conflict of interest.

New evidence suggests that excessive glutamate released from glioma cells causes epileptic activity in peritumoral neurons, which may be stopped by a drug that blocks the release of glutamate from tumor cells.

Previous studies have suggested that tumor-associated seizures arise from increased levels of glutamate near areas of epileptiform activity in the peritumoral border where invading cells surround neurons, but this is the first study to establish that the activity is associated with glutamate release from the system x_c- cystine-glutamate transporter that is expressed on tumor cells, according to Susan C. Buckingham, Ph.D., and her associates at the University of Alabama at Birmingham.

The investigators detected abnormal EEG activity in 37% of immunodeficient mice 1 week after they underwent intracranial implantation of human glioma cells, but not in any mice that underwent sham implantation. This abnormal activity manifested itself as subtle changes in behavior such as freezing, facial automatisms, and tremor. Tumor-bearing cortical slices from these mice revealed a time-dependent increase in glutamate concentration (Nat. Med. 2011 Sept. 11 [doi:10.1038/nm.2453]).

Sulfasalazine (SAS), a Food and Drug Administration–approved drug that is known to inhibit system x_c-, blocked the release of glutamate from the tumor cells but not from sham slices, which suggested to the investigators “that system x_c- does not contribute substantially to glutamate release in tumor-free brain.” Electrode recordings revealed spontaneous paroxysmal discharges near tumor cells in 23% of the cortical slices, but not in sham slices. Patch-clamp recordings from neurons in these areas demonstrated increased excitability. When the researchers applied SAS to these neurons, the mean duration of epileptiform activity declined significantly. Mice with xenografted tumors that received intraperitoneal injections of SAS also showed decreased epileptic activity on EEG.

Patients with low-grade, slow-growing tumors that can become refractory to traditional antiepileptic drugs “would be most likely to benefit from SAS treatment,” the investigators noted.

Based on the approved status and tolerable side effects of SAS, the investigators are planning a trial using it as an adjuvant treatment for peritumoral epilepsy in approximately 50 patients with gliomas. They also will undergo chemical shift MRI to determine the acute effect of oral SAS on glutamate release. Although the trial is open to patients with all grades of glioma, senior author Dr. Harald Sontheimer said in an interview that his team is “primarily interested in newly diagnosed patients with low-grade gliomas who present with seizures.”

The National Institutes of Health funded the mouse study. None of the authors had relevant financial disclosures.

Adviser's Viewpoint

New Avenue for Treating Seizures

Seizures are often a presenting symptom or sometimes a contributing factor in morbidity for patients with primary brain tumors. Dr. Buckingham and her colleagues demonstrated, through a commonly used mouse model, that glutamate is released from glioblastoma cells, thereby altering the surrounding neuronal resting membrane potential. This hyperexcitable state is ultimately responsible for epileptogenesis. Tumors release glutamate via a transporter mechanism called system x_c-, which is a viable target for seizure treatment. In fact, this transporter mechanism has been downregulated through use of sulfasalazine (SAS), an FDA-approved drug for use in Crohn's disease.

In 32 of 86 mice, epileptogenic potentials were recorded. Only three experienced convulsions. The remaining mice had events that were characterized as freezing behavior, automatisms, and head tremor. Based on phenotype alone, these manifestations were not clearly epileptic. But activity seen by depth electrodes confirmed them as seizures. Once SAS was administered, the frequency of seizure activity was significantly decreased. This finding is exciting, given the prior dearth of data relating tumorigenesis and epilepsy. The subtle behavioral changes that were witnessed to correlate with epileptic activity may suggest that patients with glioblastoma are experiencing subclinical seizure activity and further morbidity that is often thought of as a direct result of tumor growth and/or sequelae of chemoradiation.

In vitro studies are needed to further assess feasibility and tolerability of SAS as an antiepileptic drug, given its short half-life and its impact on metabolism of chemotherapeutic agents. This drug has been looked at previously in patients with progressive glioblastoma in terms of activity against tumorigenesis, but not for antiepileptic activity.

ALYX B. PORTER, M.D., is an assistant professor of neurology at the Mayo Clinic in Phoenix. She specializes in neuro-oncology. She has no relevant disclosures.

Vitals

New evidence suggests that excessive glutamate released from glioma cells causes epileptic activity in peritumoral neurons, which may be stopped by a drug that blocks the release of glutamate from tumor cells.

Previous studies have suggested that tumor-associated seizures arise from increased levels of glutamate near areas of epileptiform activity in the peritumoral border where invading cells surround neurons, but this is the first study to establish that the activity is associated with glutamate release from the system x_c- cystine-glutamate transporter that is expressed on tumor cells, according to Susan C. Buckingham, Ph.D., and her associates at the University of Alabama at Birmingham.

The investigators detected abnormal EEG activity in 37% of immunodeficient mice 1 week after they underwent intracranial implantation of human glioma cells, but not in any mice that underwent sham implantation. This abnormal activity manifested itself as subtle changes in behavior such as freezing, facial automatisms, and tremor. Tumor-bearing cortical slices from these mice revealed a time-dependent increase in glutamate concentration (Nat. Med. 2011 Sept. 11 [doi:10.1038/nm.2453]).

Sulfasalazine (SAS), a Food and Drug Administration–approved drug that is known to inhibit system x_c-, blocked the release of glutamate from the tumor cells but not from sham slices, which suggested to the investigators “that system x_c- does not contribute substantially to glutamate release in tumor-free brain.” Electrode recordings revealed spontaneous paroxysmal discharges near tumor cells in 23% of the cortical slices, but not in sham slices. Patch-clamp recordings from neurons in these areas demonstrated increased excitability. When the researchers applied SAS to these neurons, the mean duration of epileptiform activity declined significantly. Mice with xenografted tumors that received intraperitoneal injections of SAS also showed decreased epileptic activity on EEG.

Patients with low-grade, slow-growing tumors that can become refractory to traditional antiepileptic drugs “would be most likely to benefit from SAS treatment,” the investigators noted.

Based on the approved status and tolerable side effects of SAS, the investigators are planning a trial using it as an adjuvant treatment for peritumoral epilepsy in approximately 50 patients with gliomas. They also will undergo chemical shift MRI to determine the acute effect of oral SAS on glutamate release. Although the trial is open to patients with all grades of glioma, senior author Dr. Harald Sontheimer said in an interview that his team is “primarily interested in newly diagnosed patients with low-grade gliomas who present with seizures.”

The National Institutes of Health funded the mouse study. None of the authors had relevant financial disclosures.

Adviser's Viewpoint

New Avenue for Treating Seizures

Seizures are often a presenting symptom or sometimes a contributing factor in morbidity for patients with primary brain tumors. Dr. Buckingham and her colleagues demonstrated, through a commonly used mouse model, that glutamate is released from glioblastoma cells, thereby altering the surrounding neuronal resting membrane potential. This hyperexcitable state is ultimately responsible for epileptogenesis. Tumors release glutamate via a transporter mechanism called system x_c-, which is a viable target for seizure treatment. In fact, this transporter mechanism has been downregulated through use of sulfasalazine (SAS), an FDA-approved drug for use in Crohn's disease.

In 32 of 86 mice, epileptogenic potentials were recorded. Only three experienced convulsions. The remaining mice had events that were characterized as freezing behavior, automatisms, and head tremor. Based on phenotype alone, these manifestations were not clearly epileptic. But activity seen by depth electrodes confirmed them as seizures. Once SAS was administered, the frequency of seizure activity was significantly decreased. This finding is exciting, given the prior dearth of data relating tumorigenesis and epilepsy. The subtle behavioral changes that were witnessed to correlate with epileptic activity may suggest that patients with glioblastoma are experiencing subclinical seizure activity and further morbidity that is often thought of as a direct result of tumor growth and/or sequelae of chemoradiation.

In vitro studies are needed to further assess feasibility and tolerability of SAS as an antiepileptic drug, given its short half-life and its impact on metabolism of chemotherapeutic agents. This drug has been looked at previously in patients with progressive glioblastoma in terms of activity against tumorigenesis, but not for antiepileptic activity.

ALYX B. PORTER, M.D., is an assistant professor of neurology at the Mayo Clinic in Phoenix. She specializes in neuro-oncology. She has no relevant disclosures.

Vitals

New evidence suggests that excessive glutamate released from glioma cells causes epileptic activity in peritumoral neurons, which may be stopped by a drug that blocks the release of glutamate from tumor cells.

Previous studies have suggested that tumor-associated seizures arise from increased levels of glutamate near areas of epileptiform activity in the peritumoral border where invading cells surround neurons, but this is the first study to establish that the activity is associated with glutamate release from the system x_c- cystine-glutamate transporter that is expressed on tumor cells, according to Susan C. Buckingham, Ph.D., and her associates at the University of Alabama at Birmingham.

The investigators detected abnormal EEG activity in 37% of immunodeficient mice 1 week after they underwent intracranial implantation of human glioma cells, but not in any mice that underwent sham implantation. This abnormal activity manifested itself as subtle changes in behavior such as freezing, facial automatisms, and tremor. Tumor-bearing cortical slices from these mice revealed a time-dependent increase in glutamate concentration (Nat. Med. 2011 Sept. 11 [doi:10.1038/nm.2453]).

Sulfasalazine (SAS), a Food and Drug Administration–approved drug that is known to inhibit system x_c-, blocked the release of glutamate from the tumor cells but not from sham slices, which suggested to the investigators “that system x_c- does not contribute substantially to glutamate release in tumor-free brain.” Electrode recordings revealed spontaneous paroxysmal discharges near tumor cells in 23% of the cortical slices, but not in sham slices. Patch-clamp recordings from neurons in these areas demonstrated increased excitability. When the researchers applied SAS to these neurons, the mean duration of epileptiform activity declined significantly. Mice with xenografted tumors that received intraperitoneal injections of SAS also showed decreased epileptic activity on EEG.

Patients with low-grade, slow-growing tumors that can become refractory to traditional antiepileptic drugs “would be most likely to benefit from SAS treatment,” the investigators noted.

Based on the approved status and tolerable side effects of SAS, the investigators are planning a trial using it as an adjuvant treatment for peritumoral epilepsy in approximately 50 patients with gliomas. They also will undergo chemical shift MRI to determine the acute effect of oral SAS on glutamate release. Although the trial is open to patients with all grades of glioma, senior author Dr. Harald Sontheimer said in an interview that his team is “primarily interested in newly diagnosed patients with low-grade gliomas who present with seizures.”

The National Institutes of Health funded the mouse study. None of the authors had relevant financial disclosures.

Adviser's Viewpoint

New Avenue for Treating Seizures

Seizures are often a presenting symptom or sometimes a contributing factor in morbidity for patients with primary brain tumors. Dr. Buckingham and her colleagues demonstrated, through a commonly used mouse model, that glutamate is released from glioblastoma cells, thereby altering the surrounding neuronal resting membrane potential. This hyperexcitable state is ultimately responsible for epileptogenesis. Tumors release glutamate via a transporter mechanism called system x_c-, which is a viable target for seizure treatment. In fact, this transporter mechanism has been downregulated through use of sulfasalazine (SAS), an FDA-approved drug for use in Crohn's disease.

In 32 of 86 mice, epileptogenic potentials were recorded. Only three experienced convulsions. The remaining mice had events that were characterized as freezing behavior, automatisms, and head tremor. Based on phenotype alone, these manifestations were not clearly epileptic. But activity seen by depth electrodes confirmed them as seizures. Once SAS was administered, the frequency of seizure activity was significantly decreased. This finding is exciting, given the prior dearth of data relating tumorigenesis and epilepsy. The subtle behavioral changes that were witnessed to correlate with epileptic activity may suggest that patients with glioblastoma are experiencing subclinical seizure activity and further morbidity that is often thought of as a direct result of tumor growth and/or sequelae of chemoradiation.

In vitro studies are needed to further assess feasibility and tolerability of SAS as an antiepileptic drug, given its short half-life and its impact on metabolism of chemotherapeutic agents. This drug has been looked at previously in patients with progressive glioblastoma in terms of activity against tumorigenesis, but not for antiepileptic activity.

ALYX B. PORTER, M.D., is an assistant professor of neurology at the Mayo Clinic in Phoenix. She specializes in neuro-oncology. She has no relevant disclosures.

Vitals

New evidence suggests that excessive glutamate released from glioma cells causes epileptic activity in peritumoral neurons, which may be stopped by a drug that blocks the release of glutamate from tumor cells.

Previous studies have suggested that tumor-associated seizures arise from increased levels of glutamate near areas of epileptiform activity in the peritumoral border where invading cells surround neurons, but this is the first study to establish that the activity is associated with glutamate release from the system x_c- cystine-glutamate transporter that is expressed on tumor cells, according to Susan C. Buckingham, Ph.D., and her associates at the University of Alabama at Birmingham.

Most patients with glioma (80%) experience at least one seizure during the course of their illness, but about one-third have recurrent seizures, known as tumor-associated epilepsy, that are often refractory to antiepileptic drugs, the investigators said.

Dr. Buckingham and her colleagues detected abnormal EEG activity in 37% of immunodeficient mice 1 week after they underwent intracranial implantation of human glioma cells, but not in any mice that underwent sham implantation. This abnormal activity manifested itself as subtle changes in behavior such as freezing, facial automatisms, and tremor. Tumor-bearing cortical slices from these mice revealed a time-dependent increase in glutamate concentration (Nat. Med. 2011 Sept. 11 [doi:10.1038/nm.2453]).

Sulfasalazine (SAS), a Food and Drug Administration-approved drug that is known to inhibit system x_c-, blocked the release of glutamate from the tumor cells but not from sham slices, which suggested to the investigators "that system x_c- does not contribute substantially to glutamate release in tumor-free brain." Electrode recordings revealed spontaneous paroxysmal discharges near tumor cells in 23% of the cortical slices, but not in sham slices. Patch-clamp recordings from neurons in these areas demonstrated increased excitability. When the researchers applied SAS to these neurons, the mean duration of epileptiform activity declined significantly. Mice with xenografted tumors that received intraperitoneal injections of SAS also showed decreased epileptic activity on EEG.

"Together with previous studies, our findings establish that system x_c- is a viable new target for seizure treatments," the authors concluded.

SAS did not inhibit tumor growth in an earlier clinical trial involving end-stage glioblastoma patients with poor neurological status, but the study did not assess its antiepileptic effects. Because "seizures often present early in disease progression, particularly among patients with low-grade, slow-growing tumors that can become refractory to traditional antiepileptic drugs," the investigators noted that such patients "would be most likely to benefit from SAS treatment" in a clinical trial.

Based on the approved status and tolerable side effects of SAS, the investigators are planning a trial using it as an adjuvant treatment for peritumoral epilepsy in approximately 50 patients with gliomas. Although the trial is open to patients with all grades of glioma, senior author Dr. Harald Sontheimer said in an interview that his team is "primarily interested in newly diagnosed patients with low-grade gliomas who present with seizures." The trial will use chemical shift MRI to determine the acute effect of oral sulfasalazine on glutamate release. A phase I trial in a several patients has already generated data showing that the treatment is feasible, Dr. Sontheimer said.

The current study was funded by grants from the National Institutes of Health. None of the authors had relevant financial disclosures.

New evidence suggests that excessive glutamate released from glioma cells causes epileptic activity in peritumoral neurons, which may be stopped by a drug that blocks the release of glutamate from tumor cells.

Previous studies have suggested that tumor-associated seizures arise from increased levels of glutamate near areas of epileptiform activity in the peritumoral border where invading cells surround neurons, but this is the first study to establish that the activity is associated with glutamate release from the system x_c- cystine-glutamate transporter that is expressed on tumor cells, according to Susan C. Buckingham, Ph.D., and her associates at the University of Alabama at Birmingham.

Most patients with glioma (80%) experience at least one seizure during the course of their illness, but about one-third have recurrent seizures, known as tumor-associated epilepsy, that are often refractory to antiepileptic drugs, the investigators said.

Dr. Buckingham and her colleagues detected abnormal EEG activity in 37% of immunodeficient mice 1 week after they underwent intracranial implantation of human glioma cells, but not in any mice that underwent sham implantation. This abnormal activity manifested itself as subtle changes in behavior such as freezing, facial automatisms, and tremor. Tumor-bearing cortical slices from these mice revealed a time-dependent increase in glutamate concentration (Nat. Med. 2011 Sept. 11 [doi:10.1038/nm.2453]).

Sulfasalazine (SAS), a Food and Drug Administration-approved drug that is known to inhibit system x_c-, blocked the release of glutamate from the tumor cells but not from sham slices, which suggested to the investigators "that system x_c- does not contribute substantially to glutamate release in tumor-free brain." Electrode recordings revealed spontaneous paroxysmal discharges near tumor cells in 23% of the cortical slices, but not in sham slices. Patch-clamp recordings from neurons in these areas demonstrated increased excitability. When the researchers applied SAS to these neurons, the mean duration of epileptiform activity declined significantly. Mice with xenografted tumors that received intraperitoneal injections of SAS also showed decreased epileptic activity on EEG.

"Together with previous studies, our findings establish that system x_c- is a viable new target for seizure treatments," the authors concluded.

SAS did not inhibit tumor growth in an earlier clinical trial involving end-stage glioblastoma patients with poor neurological status, but the study did not assess its antiepileptic effects. Because "seizures often present early in disease progression, particularly among patients with low-grade, slow-growing tumors that can become refractory to traditional antiepileptic drugs," the investigators noted that such patients "would be most likely to benefit from SAS treatment" in a clinical trial.

Based on the approved status and tolerable side effects of SAS, the investigators are planning a trial using it as an adjuvant treatment for peritumoral epilepsy in approximately 50 patients with gliomas. Although the trial is open to patients with all grades of glioma, senior author Dr. Harald Sontheimer said in an interview that his team is "primarily interested in newly diagnosed patients with low-grade gliomas who present with seizures." The trial will use chemical shift MRI to determine the acute effect of oral sulfasalazine on glutamate release. A phase I trial in a several patients has already generated data showing that the treatment is feasible, Dr. Sontheimer said.

The current study was funded by grants from the National Institutes of Health. None of the authors had relevant financial disclosures.

New evidence suggests that excessive glutamate released from glioma cells causes epileptic activity in peritumoral neurons, which may be stopped by a drug that blocks the release of glutamate from tumor cells.

Previous studies have suggested that tumor-associated seizures arise from increased levels of glutamate near areas of epileptiform activity in the peritumoral border where invading cells surround neurons, but this is the first study to establish that the activity is associated with glutamate release from the system x_c- cystine-glutamate transporter that is expressed on tumor cells, according to Susan C. Buckingham, Ph.D., and her associates at the University of Alabama at Birmingham.

Most patients with glioma (80%) experience at least one seizure during the course of their illness, but about one-third have recurrent seizures, known as tumor-associated epilepsy, that are often refractory to antiepileptic drugs, the investigators said.

Dr. Buckingham and her colleagues detected abnormal EEG activity in 37% of immunodeficient mice 1 week after they underwent intracranial implantation of human glioma cells, but not in any mice that underwent sham implantation. This abnormal activity manifested itself as subtle changes in behavior such as freezing, facial automatisms, and tremor. Tumor-bearing cortical slices from these mice revealed a time-dependent increase in glutamate concentration (Nat. Med. 2011 Sept. 11 [doi:10.1038/nm.2453]).

Sulfasalazine (SAS), a Food and Drug Administration-approved drug that is known to inhibit system x_c-, blocked the release of glutamate from the tumor cells but not from sham slices, which suggested to the investigators "that system x_c- does not contribute substantially to glutamate release in tumor-free brain." Electrode recordings revealed spontaneous paroxysmal discharges near tumor cells in 23% of the cortical slices, but not in sham slices. Patch-clamp recordings from neurons in these areas demonstrated increased excitability. When the researchers applied SAS to these neurons, the mean duration of epileptiform activity declined significantly. Mice with xenografted tumors that received intraperitoneal injections of SAS also showed decreased epileptic activity on EEG.

"Together with previous studies, our findings establish that system x_c- is a viable new target for seizure treatments," the authors concluded.

SAS did not inhibit tumor growth in an earlier clinical trial involving end-stage glioblastoma patients with poor neurological status, but the study did not assess its antiepileptic effects. Because "seizures often present early in disease progression, particularly among patients with low-grade, slow-growing tumors that can become refractory to traditional antiepileptic drugs," the investigators noted that such patients "would be most likely to benefit from SAS treatment" in a clinical trial.

Based on the approved status and tolerable side effects of SAS, the investigators are planning a trial using it as an adjuvant treatment for peritumoral epilepsy in approximately 50 patients with gliomas. Although the trial is open to patients with all grades of glioma, senior author Dr. Harald Sontheimer said in an interview that his team is "primarily interested in newly diagnosed patients with low-grade gliomas who present with seizures." The trial will use chemical shift MRI to determine the acute effect of oral sulfasalazine on glutamate release. A phase I trial in a several patients has already generated data showing that the treatment is feasible, Dr. Sontheimer said.

The current study was funded by grants from the National Institutes of Health. None of the authors had relevant financial disclosures.

Greater awareness of the potential long-term sequelae from multiple concussions has prompted nearly two-thirds of states to pass legislation that is meant to protect athletes suspected of having a concussion.

These laws are spurring wider use of concussion screening tests and educational materials to inform coaches, parents, athletes, and medical professionals of the importance of identifying players suspected of having a concussion and getting them evaluated before they can return to play. Studies also are underway or being planned to determine how the risk of concussion varies among individuals and how it is influenced by the number and severity of blows to the head.

Since the enactment of the Lystedt Law in Washington in 2009, 29 other states and the District of Columbia have passed similar laws, and an additional state has a bill that at press time awaited the governor’s signature for final passage into law, according to NFL Health & Safety. In general, the laws require that athletes suspected of having a concussion be held out of games or practice until they have been evaluated and cleared to return by a trained and licensed health care provider, whose definition varies across states.

These developments are driving a change in attitude toward how concussions are evaluated and managed at all levels of sports, both in practice and on the field. "What we’re starting to see is organizations taking a look at practice parameters, [such as] limiting the amount of contact that can happen in the practice environment," said Dr. Jeffrey S. Kutcher, director of the University of Michigan’s Neurosport Program. He noted that this year the Ivy League conference became the first to limit the amount of contact that players have during practice sessions.

Return to play is now being more widely regarded as a medical decision that must be made by qualified health care providers. In a position paper last year, the American Academy of Neurology (AAN) said that return-to-play decisions should be made by a neurologist or a physician with training in the evaluation and management of sports concussion. It also called for certified athletic trainers to be present at all sporting events and practices at which athletes are at risk of concussion.

Recognizing Concussion in Youth Athletes

But while professional sports teams and universities can provide physicians or athletic trainers to screen for and diagnose concussion, youth athletes most often won’t have those resources available. They need people trained to screen for concussion and pull them out of play until they can be evaluated by a licensed health care provider.

"[High] schools are not going to have a physician on the field," Dr. H. Hunt Batjer, professor and chair of neurological surgery at Northwestern University, Chicago, said in an interview. In the metro Chicago area, "many do not have close affiliation with a trainer. Somebody is going to have to take on that role of identifying a concussed athlete. Ideally, it would not be the coach. Ideally, it would be a health professional."

To help youth and high school coaches – as well as athletes and parents – recognize the signs of concussion and know what to do to if a player gets a head injury, the AAN is offering two free, online, 20-minute safety courses created by the University of Michigan’s Neurosport Program. Free downloadable cards that describe how to spot concussion and what to do if one occurs also are available on the academy’s website.

How to Evaluate Concussion

There are at least 16 different grading systems that attempt to measure severity of traumatic brain injury (TBI), the most recent about 10 years old, according to Dr. Michael A. Lobatz, a neurologist and the medical director at the Scripps Rehabilitation Center, Encinitas, Calif.

However, the AAN is developing a new grading system that "will probably be published by November of this year. That will be very useful and most updated based on class I evidence," noted Dr. Lobatz, who spoke at a meeting on primary care medicine sponsored by the Scripps Clinic.

©David Peeters/iStockphoto.com

Older grading systems do not properly prognosticate the severity of the concussion and duration of symptoms. They also fail to appreciate the sensitivity of children and adolescents to concussion, who are at higher risk than adults are for second-impact syndrome, and they are slower to recover than adults, Dr. Richard Ellenbogen, professor and chair of neurological surgery at the University of Washington, Seattle, said in an interview.

Rather than grade the level of concussion, "it’s more important to define and describe the symptoms and signs that they were suffering that were indicative of a concussion, so you can follow those," Dr. Ellenbogen said.

Dr. Lobatz noted that patients who have longer periods of anterograde amnesia "tend to have a more prolonged course to recovery or incomplete recovery. When you take your history, ask them what they remember, not what they were told happened or what they think happened by their own logical deduction. When you preface your question like that, you’ll get more accurate information."

Sorting out preinjury vs. postinjury factors in patients with concussion is no easy task. For example, preexisting factors "could be that they have some ADHD, poor school performance, or depression," he said. "Postinjury factors might include disruption of relationships, school, or work. You need an open mind when you see these patients, and you cannot do this [assessment] in 10 minutes."

Returning to Play Postinjury

Return to play is not advised if athletes are still experiencing symptoms of a concussion. If they return before they’re fully healed and suffer another injury, that second injury "is potentially much more severe than the first," Dr. Lobatz warned. "There may not be a loss of consciousness, but there is a much more likely possibility of swelling in the brain, and there can be as much as 50% mortality in severe cases. Furthermore, there is a much higher risk of long-term complications where patients do not return to normal. They are left with long-term deficits."

Dr. Batjer emphasized that the most important elements of return to play criteria include managing the athlete’s concussion in a quiet, nonstimulating environment; being asymptomatic at rest and during exertion; clearance from the team trainer or doctor; and clearance from an independent health care provider skilled in the treatment of concussion.

To help objectify when it’s okay to return to play, Dr. Lobatz recommended administering the ImPACT test, a computer-based assessment that provides a baseline of neurocognitive skills and takes about 30 minutes to complete. In addition, a consensus statement from the Third International Conference on Concussion in Sport provides a staged system of gradual return to physical activity (Br. J. Sports Med. 2009;43:i76-i84). It calls for no activity immediately after the injury, and progresses in a stepwise fashion to light aerobic exercise, sport-specific exercise, noncontact training, full-contact practice, and eventual return to play.

Alternative Concussion Tests

Many other alternative tests are available, Dr. Kutcher noted, including the Axon Sports Computerized Cognitive Assessment Tool, the HeadMinder Concussion Resolution Index, and CNS Vital Signs. However, he cautioned that such tests often provide a false sense of security.

"It is the nature of neurological examination that it is not very easily put into check boxes and protocols. Doing a neurologic examination is an organic process, and so while these tools are good places to start and provide a framework for evaluation, they should never be thought of as being a complete evaluation," he explained.

The new National Football League sideline concussion assessment protocol that was announced last February draws on elements of a screening tool that was recommended in the consensus statement from the Third International Conference on Concussion in Sport, the SCAT2 (Sport Concussion Assessment Tool 2), which was modified for football. It includes a focused screening neurologic examination to exclude cervical spine and intracranial bleeding, as well as assessments of orientation, immediate and delayed recall, concentration, and balance.

The protocol is designed to "create a little more homogeneity in the way players are assessed on the field" but is not meant to "ever replace the professional judgment of a team physician or trainer on the field," said Dr. Ellenbogen, who cochairs the NFL Head, Neck, and Spine Committee with Dr. Batjer.

The Future of Concussion Treatment

Future decisions on the field of play will depend in part on the conclusions of studies designed to determine what factors increase the risk of concussion and long-term neurologic deficits in different individuals. But such studies have many methodologic challenges.

"One of the problems is people are trying to connect the dots by looking retrospectively and saying ‘You played X number of years at this position and you tell me you had this many concussions,’ and trying to use that as a definition of exposure when that is fraught with all kinds of bias and ambiguity," said Dr. Kutcher, chair of the AAN’s Sports Neurology Section. "There are efforts now at different levels to try to track players prospectively. But one of the problems there is, what are you going to track as the exposure? Right now, it is the number of concussions, but that is clearly not the whole picture. You need to be tracking the number of hits.

"If we’re ever going to make decisions on whether somebody gets to play or not based on the number of hits they’ve taken, we should have a clear scientific understanding of what those hits are doing, and we don’t," Dr. Kutcher said. "There’s a general concept that the types of hits that athletes take during contact sports can’t be good for the brain. The real question is, how bad is it? The underappreciated aspect of this is how individual that answer is. If you took 100 players and gave them the same type and number of exposures over a lifetime, you’re going to get 100 different results."

Several planned studies sponsored by the NFL, the Department of Defense, and the National Institutes of Health will evaluate new football helmet designs and test accelerometers inside them to measure the frequency and force of hits in relation to the players’ neurologic status. Other studies are proposing to compare a group of age- and position-matched former NFL players with players who played at the collegiate level and control subjects who did not play sports, according to Dr. Batjer.

In another study, Dr. Kutcher said that he and investigators from the University of North Carolina at Chapel Hill and the University of California, Los Angeles, will track the longitudinal neurologic status of players of both genders in sports with and without helmets (using accelerometer-instrumented mouth guards) throughout their career and afterward against control subjects.

Doug Brunk contributed to this report.

Greater awareness of the potential long-term sequelae from multiple concussions has prompted nearly two-thirds of states to pass legislation that is meant to protect athletes suspected of having a concussion.

These laws are spurring wider use of concussion screening tests and educational materials to inform coaches, parents, athletes, and medical professionals of the importance of identifying players suspected of having a concussion and getting them evaluated before they can return to play. Studies also are underway or being planned to determine how the risk of concussion varies among individuals and how it is influenced by the number and severity of blows to the head.

Since the enactment of the Lystedt Law in Washington in 2009, 29 other states and the District of Columbia have passed similar laws, and an additional state has a bill that at press time awaited the governor’s signature for final passage into law, according to NFL Health & Safety. In general, the laws require that athletes suspected of having a concussion be held out of games or practice until they have been evaluated and cleared to return by a trained and licensed health care provider, whose definition varies across states.

These developments are driving a change in attitude toward how concussions are evaluated and managed at all levels of sports, both in practice and on the field. "What we’re starting to see is organizations taking a look at practice parameters, [such as] limiting the amount of contact that can happen in the practice environment," said Dr. Jeffrey S. Kutcher, director of the University of Michigan’s Neurosport Program. He noted that this year the Ivy League conference became the first to limit the amount of contact that players have during practice sessions.

Return to play is now being more widely regarded as a medical decision that must be made by qualified health care providers. In a position paper last year, the American Academy of Neurology (AAN) said that return-to-play decisions should be made by a neurologist or a physician with training in the evaluation and management of sports concussion. It also called for certified athletic trainers to be present at all sporting events and practices at which athletes are at risk of concussion.

Recognizing Concussion in Youth Athletes

But while professional sports teams and universities can provide physicians or athletic trainers to screen for and diagnose concussion, youth athletes most often won’t have those resources available. They need people trained to screen for concussion and pull them out of play until they can be evaluated by a licensed health care provider.

"[High] schools are not going to have a physician on the field," Dr. H. Hunt Batjer, professor and chair of neurological surgery at Northwestern University, Chicago, said in an interview. In the metro Chicago area, "many do not have close affiliation with a trainer. Somebody is going to have to take on that role of identifying a concussed athlete. Ideally, it would not be the coach. Ideally, it would be a health professional."

To help youth and high school coaches – as well as athletes and parents – recognize the signs of concussion and know what to do to if a player gets a head injury, the AAN is offering two free, online, 20-minute safety courses created by the University of Michigan’s Neurosport Program. Free downloadable cards that describe how to spot concussion and what to do if one occurs also are available on the academy’s website.

How to Evaluate Concussion

There are at least 16 different grading systems that attempt to measure severity of traumatic brain injury (TBI), the most recent about 10 years old, according to Dr. Michael A. Lobatz, a neurologist and the medical director at the Scripps Rehabilitation Center, Encinitas, Calif.

However, the AAN is developing a new grading system that "will probably be published by November of this year. That will be very useful and most updated based on class I evidence," noted Dr. Lobatz, who spoke at a meeting on primary care medicine sponsored by the Scripps Clinic.

©David Peeters/iStockphoto.com

Older grading systems do not properly prognosticate the severity of the concussion and duration of symptoms. They also fail to appreciate the sensitivity of children and adolescents to concussion, who are at higher risk than adults are for second-impact syndrome, and they are slower to recover than adults, Dr. Richard Ellenbogen, professor and chair of neurological surgery at the University of Washington, Seattle, said in an interview.

Rather than grade the level of concussion, "it’s more important to define and describe the symptoms and signs that they were suffering that were indicative of a concussion, so you can follow those," Dr. Ellenbogen said.

Dr. Lobatz noted that patients who have longer periods of anterograde amnesia "tend to have a more prolonged course to recovery or incomplete recovery. When you take your history, ask them what they remember, not what they were told happened or what they think happened by their own logical deduction. When you preface your question like that, you’ll get more accurate information."

Sorting out preinjury vs. postinjury factors in patients with concussion is no easy task. For example, preexisting factors "could be that they have some ADHD, poor school performance, or depression," he said. "Postinjury factors might include disruption of relationships, school, or work. You need an open mind when you see these patients, and you cannot do this [assessment] in 10 minutes."

Returning to Play Postinjury

Return to play is not advised if athletes are still experiencing symptoms of a concussion. If they return before they’re fully healed and suffer another injury, that second injury "is potentially much more severe than the first," Dr. Lobatz warned. "There may not be a loss of consciousness, but there is a much more likely possibility of swelling in the brain, and there can be as much as 50% mortality in severe cases. Furthermore, there is a much higher risk of long-term complications where patients do not return to normal. They are left with long-term deficits."

Dr. Batjer emphasized that the most important elements of return to play criteria include managing the athlete’s concussion in a quiet, nonstimulating environment; being asymptomatic at rest and during exertion; clearance from the team trainer or doctor; and clearance from an independent health care provider skilled in the treatment of concussion.

To help objectify when it’s okay to return to play, Dr. Lobatz recommended administering the ImPACT test, a computer-based assessment that provides a baseline of neurocognitive skills and takes about 30 minutes to complete. In addition, a consensus statement from the Third International Conference on Concussion in Sport provides a staged system of gradual return to physical activity (Br. J. Sports Med. 2009;43:i76-i84). It calls for no activity immediately after the injury, and progresses in a stepwise fashion to light aerobic exercise, sport-specific exercise, noncontact training, full-contact practice, and eventual return to play.

Alternative Concussion Tests

Many other alternative tests are available, Dr. Kutcher noted, including the Axon Sports Computerized Cognitive Assessment Tool, the HeadMinder Concussion Resolution Index, and CNS Vital Signs. However, he cautioned that such tests often provide a false sense of security.

"It is the nature of neurological examination that it is not very easily put into check boxes and protocols. Doing a neurologic examination is an organic process, and so while these tools are good places to start and provide a framework for evaluation, they should never be thought of as being a complete evaluation," he explained.

The new National Football League sideline concussion assessment protocol that was announced last February draws on elements of a screening tool that was recommended in the consensus statement from the Third International Conference on Concussion in Sport, the SCAT2 (Sport Concussion Assessment Tool 2), which was modified for football. It includes a focused screening neurologic examination to exclude cervical spine and intracranial bleeding, as well as assessments of orientation, immediate and delayed recall, concentration, and balance.

The protocol is designed to "create a little more homogeneity in the way players are assessed on the field" but is not meant to "ever replace the professional judgment of a team physician or trainer on the field," said Dr. Ellenbogen, who cochairs the NFL Head, Neck, and Spine Committee with Dr. Batjer.

The Future of Concussion Treatment

Future decisions on the field of play will depend in part on the conclusions of studies designed to determine what factors increase the risk of concussion and long-term neurologic deficits in different individuals. But such studies have many methodologic challenges.

"One of the problems is people are trying to connect the dots by looking retrospectively and saying ‘You played X number of years at this position and you tell me you had this many concussions,’ and trying to use that as a definition of exposure when that is fraught with all kinds of bias and ambiguity," said Dr. Kutcher, chair of the AAN’s Sports Neurology Section. "There are efforts now at different levels to try to track players prospectively. But one of the problems there is, what are you going to track as the exposure? Right now, it is the number of concussions, but that is clearly not the whole picture. You need to be tracking the number of hits.

"If we’re ever going to make decisions on whether somebody gets to play or not based on the number of hits they’ve taken, we should have a clear scientific understanding of what those hits are doing, and we don’t," Dr. Kutcher said. "There’s a general concept that the types of hits that athletes take during contact sports can’t be good for the brain. The real question is, how bad is it? The underappreciated aspect of this is how individual that answer is. If you took 100 players and gave them the same type and number of exposures over a lifetime, you’re going to get 100 different results."

Several planned studies sponsored by the NFL, the Department of Defense, and the National Institutes of Health will evaluate new football helmet designs and test accelerometers inside them to measure the frequency and force of hits in relation to the players’ neurologic status. Other studies are proposing to compare a group of age- and position-matched former NFL players with players who played at the collegiate level and control subjects who did not play sports, according to Dr. Batjer.

In another study, Dr. Kutcher said that he and investigators from the University of North Carolina at Chapel Hill and the University of California, Los Angeles, will track the longitudinal neurologic status of players of both genders in sports with and without helmets (using accelerometer-instrumented mouth guards) throughout their career and afterward against control subjects.

Doug Brunk contributed to this report.

Greater awareness of the potential long-term sequelae from multiple concussions has prompted nearly two-thirds of states to pass legislation that is meant to protect athletes suspected of having a concussion.

These laws are spurring wider use of concussion screening tests and educational materials to inform coaches, parents, athletes, and medical professionals of the importance of identifying players suspected of having a concussion and getting them evaluated before they can return to play. Studies also are underway or being planned to determine how the risk of concussion varies among individuals and how it is influenced by the number and severity of blows to the head.

Since the enactment of the Lystedt Law in Washington in 2009, 29 other states and the District of Columbia have passed similar laws, and an additional state has a bill that at press time awaited the governor’s signature for final passage into law, according to NFL Health & Safety. In general, the laws require that athletes suspected of having a concussion be held out of games or practice until they have been evaluated and cleared to return by a trained and licensed health care provider, whose definition varies across states.

These developments are driving a change in attitude toward how concussions are evaluated and managed at all levels of sports, both in practice and on the field. "What we’re starting to see is organizations taking a look at practice parameters, [such as] limiting the amount of contact that can happen in the practice environment," said Dr. Jeffrey S. Kutcher, director of the University of Michigan’s Neurosport Program. He noted that this year the Ivy League conference became the first to limit the amount of contact that players have during practice sessions.

Return to play is now being more widely regarded as a medical decision that must be made by qualified health care providers. In a position paper last year, the American Academy of Neurology (AAN) said that return-to-play decisions should be made by a neurologist or a physician with training in the evaluation and management of sports concussion. It also called for certified athletic trainers to be present at all sporting events and practices at which athletes are at risk of concussion.

Recognizing Concussion in Youth Athletes

But while professional sports teams and universities can provide physicians or athletic trainers to screen for and diagnose concussion, youth athletes most often won’t have those resources available. They need people trained to screen for concussion and pull them out of play until they can be evaluated by a licensed health care provider.

"[High] schools are not going to have a physician on the field," Dr. H. Hunt Batjer, professor and chair of neurological surgery at Northwestern University, Chicago, said in an interview. In the metro Chicago area, "many do not have close affiliation with a trainer. Somebody is going to have to take on that role of identifying a concussed athlete. Ideally, it would not be the coach. Ideally, it would be a health professional."

To help youth and high school coaches – as well as athletes and parents – recognize the signs of concussion and know what to do to if a player gets a head injury, the AAN is offering two free, online, 20-minute safety courses created by the University of Michigan’s Neurosport Program. Free downloadable cards that describe how to spot concussion and what to do if one occurs also are available on the academy’s website.

How to Evaluate Concussion

There are at least 16 different grading systems that attempt to measure severity of traumatic brain injury (TBI), the most recent about 10 years old, according to Dr. Michael A. Lobatz, a neurologist and the medical director at the Scripps Rehabilitation Center, Encinitas, Calif.

However, the AAN is developing a new grading system that "will probably be published by November of this year. That will be very useful and most updated based on class I evidence," noted Dr. Lobatz, who spoke at a meeting on primary care medicine sponsored by the Scripps Clinic.

©David Peeters/iStockphoto.com

Older grading systems do not properly prognosticate the severity of the concussion and duration of symptoms. They also fail to appreciate the sensitivity of children and adolescents to concussion, who are at higher risk than adults are for second-impact syndrome, and they are slower to recover than adults, Dr. Richard Ellenbogen, professor and chair of neurological surgery at the University of Washington, Seattle, said in an interview.

Rather than grade the level of concussion, "it’s more important to define and describe the symptoms and signs that they were suffering that were indicative of a concussion, so you can follow those," Dr. Ellenbogen said.

Dr. Lobatz noted that patients who have longer periods of anterograde amnesia "tend to have a more prolonged course to recovery or incomplete recovery. When you take your history, ask them what they remember, not what they were told happened or what they think happened by their own logical deduction. When you preface your question like that, you’ll get more accurate information."

Sorting out preinjury vs. postinjury factors in patients with concussion is no easy task. For example, preexisting factors "could be that they have some ADHD, poor school performance, or depression," he said. "Postinjury factors might include disruption of relationships, school, or work. You need an open mind when you see these patients, and you cannot do this [assessment] in 10 minutes."

Returning to Play Postinjury

Return to play is not advised if athletes are still experiencing symptoms of a concussion. If they return before they’re fully healed and suffer another injury, that second injury "is potentially much more severe than the first," Dr. Lobatz warned. "There may not be a loss of consciousness, but there is a much more likely possibility of swelling in the brain, and there can be as much as 50% mortality in severe cases. Furthermore, there is a much higher risk of long-term complications where patients do not return to normal. They are left with long-term deficits."

Dr. Batjer emphasized that the most important elements of return to play criteria include managing the athlete’s concussion in a quiet, nonstimulating environment; being asymptomatic at rest and during exertion; clearance from the team trainer or doctor; and clearance from an independent health care provider skilled in the treatment of concussion.

To help objectify when it’s okay to return to play, Dr. Lobatz recommended administering the ImPACT test, a computer-based assessment that provides a baseline of neurocognitive skills and takes about 30 minutes to complete. In addition, a consensus statement from the Third International Conference on Concussion in Sport provides a staged system of gradual return to physical activity (Br. J. Sports Med. 2009;43:i76-i84). It calls for no activity immediately after the injury, and progresses in a stepwise fashion to light aerobic exercise, sport-specific exercise, noncontact training, full-contact practice, and eventual return to play.

Alternative Concussion Tests

Many other alternative tests are available, Dr. Kutcher noted, including the Axon Sports Computerized Cognitive Assessment Tool, the HeadMinder Concussion Resolution Index, and CNS Vital Signs. However, he cautioned that such tests often provide a false sense of security.

"It is the nature of neurological examination that it is not very easily put into check boxes and protocols. Doing a neurologic examination is an organic process, and so while these tools are good places to start and provide a framework for evaluation, they should never be thought of as being a complete evaluation," he explained.

The new National Football League sideline concussion assessment protocol that was announced last February draws on elements of a screening tool that was recommended in the consensus statement from the Third International Conference on Concussion in Sport, the SCAT2 (Sport Concussion Assessment Tool 2), which was modified for football. It includes a focused screening neurologic examination to exclude cervical spine and intracranial bleeding, as well as assessments of orientation, immediate and delayed recall, concentration, and balance.

The protocol is designed to "create a little more homogeneity in the way players are assessed on the field" but is not meant to "ever replace the professional judgment of a team physician or trainer on the field," said Dr. Ellenbogen, who cochairs the NFL Head, Neck, and Spine Committee with Dr. Batjer.

The Future of Concussion Treatment

Future decisions on the field of play will depend in part on the conclusions of studies designed to determine what factors increase the risk of concussion and long-term neurologic deficits in different individuals. But such studies have many methodologic challenges.

"One of the problems is people are trying to connect the dots by looking retrospectively and saying ‘You played X number of years at this position and you tell me you had this many concussions,’ and trying to use that as a definition of exposure when that is fraught with all kinds of bias and ambiguity," said Dr. Kutcher, chair of the AAN’s Sports Neurology Section. "There are efforts now at different levels to try to track players prospectively. But one of the problems there is, what are you going to track as the exposure? Right now, it is the number of concussions, but that is clearly not the whole picture. You need to be tracking the number of hits.

"If we’re ever going to make decisions on whether somebody gets to play or not based on the number of hits they’ve taken, we should have a clear scientific understanding of what those hits are doing, and we don’t," Dr. Kutcher said. "There’s a general concept that the types of hits that athletes take during contact sports can’t be good for the brain. The real question is, how bad is it? The underappreciated aspect of this is how individual that answer is. If you took 100 players and gave them the same type and number of exposures over a lifetime, you’re going to get 100 different results."

Several planned studies sponsored by the NFL, the Department of Defense, and the National Institutes of Health will evaluate new football helmet designs and test accelerometers inside them to measure the frequency and force of hits in relation to the players’ neurologic status. Other studies are proposing to compare a group of age- and position-matched former NFL players with players who played at the collegiate level and control subjects who did not play sports, according to Dr. Batjer.

In another study, Dr. Kutcher said that he and investigators from the University of North Carolina at Chapel Hill and the University of California, Los Angeles, will track the longitudinal neurologic status of players of both genders in sports with and without helmets (using accelerometer-instrumented mouth guards) throughout their career and afterward against control subjects.

Doug Brunk contributed to this report.

The substantial differences among states, age groups, races, and genders in recent surveys of the prevalence of depression and other mental illnesses in adults illustrate the importance of expanding the mental health focus of surveillance and information systems to help guide national and state-level planning, according to a report released Sept. 1 by the Centers for Disease Control and Prevention.

The report describes the results of population-based surveys from selected CDC surveillance systems administered at different points during 2004-2009. The surveys indicate that southeastern states, non-Hispanic blacks, and women have the highest prevalence of depression, postpartum depression, serious psychological distress, and mentally unhealthy days per month.

However, these estimates of the prevalence of mental illness are limited by the generality of the surveys. None of the surveys, which include the state-based Behavioral Risk Factor Surveillance System (BRFSS), the Pregnancy Risk Assessment Monitoring System (PRAMS), the National Health and Nutrition Examination Survey (NHANES), and the National Health Interview Survey (NHIS), was designed solely to monitor mental illness. They have instead "added components on mental illness gradually over time as recognition of the importance of mental illness in public health has increased," wrote Dr. William C. Reeves of the CDC’s Public Health Surveillance Program Office and his colleagues (MMWR 2011;60[Suppl.]:1-29).

For instance, the BRFSS – a telephone survey of 450,000 adults in 50 states, the District of Columbia, and some territories – found a rate of depression of 8.7% in 2006 in respondents from 38 states, the District of Columbia, and territories, compared with 8.2% in 2008 in 16 states.

The number of states that conduct the BRFSS with one or two small, optional mental illness modules varies from year to year. In 2006 and 2008, depression occurred most often in Mississippi and West Virginia (13.7%) and least often in North Dakota (4.3%). Women had higher prevalences during these years (about 10%), compared with men (about 7%). Non-Hispanic blacks also had a higher prevalence of depression (11%-13%) than did non-Hispanic whites (about 8%) or Hispanics (about 10%).

Not all states collect data from the optional modules "because of financial constraints, competing state surveillance priorities, and limitations in the length of time respondents are willing to spend completing a telephone survey," the authors wrote.

National results with NHANES data indicate a prevalence of depression of 6.8% during 2005-2008, with rates of 8.4% in women, 4.9% in men, 9.7% in non-Hispanic blacks, 6.2% in non-Hispanic whites, and 7.2% among Mexican Americans.

The 22 states that conducted the PRAMS during 2004-2008 found that symptoms of postpartum depression affected 14.5% of respondents. This rate varied from a low of 10.3% among women aged 30-39 years to 23.3% among women aged 19 years or younger, and a low of 9.8% in Minnesota to a high of 21.3% in Tennessee. Non-Hispanic black women had a higher prevalence (21.5%) than did Hispanic (16.8%) and non-Hispanic white women (11.9%).

The prevalence of serious psychological distress, as defined by scores on the Kessler-6 Psychological Distress Scale, was 3.2% in 2009 in the NHIS. The same scale in the BRFSS revealed that serious psychological distress occurred in 4% in 35 states in 2007 and in 3.9% in 16 states in 2009. During those periods, the rate varied from 1.9% in Utah to 9.4% in Tennessee. The Kessler-6 definition of serious psychological distress is associated with anxiety disorders and depression but does not identify a specific mental illness.

All states and territories report the mean number of "mentally unhealthy days" per month in the BRFSS because it is a core feature of the survey. In 2009, the mean number was 3.5 days and was highest overall in the southeastern states. The mean number of days also was higher among non-Hispanic blacks (4.1) and women (4.0).

On the BRFSS, lifetime diagnoses of depression occurred in about 16% of respondents in both 2006 and 2008 despite differing numbers of participating states. Lifetime diagnoses of anxiety disorders were reported by 11.3% in 2006 and by 12.3% in 2008. The authors pointed out a general lack of data on anxiety disorders in CDC surveys and noted that "better documentation of the impact of anxiety disorders might help guide national public health policy. At the state and local levels, documenting the prevalence and impact of anxiety disorders might help ascertain the need for additional public health services for these disorders."

Lifetime diagnoses for other disorders were reported in the NHIS in 2007: 1.7 % of respondents reported a diagnosis of bipolar disorder and 0.6% reported schizophrenia.

Dr. Reeves and his associates also wrote that surveys of health care providers, such as the National Ambulatory Medical Care Survey (NAMCS), the National Hospital Ambulatory Medical Care Survey (NHAMCS), the National Hospital Discharge Survey (NHDS), and the National Nursing Home Survey (NNHS), "complement data from the population-based surveys to provide a more complete representation of the occurrence of mental illness in the United States."

These surveys indicate that most of the 47.8 million estimated ambulatory care visits for patients with primary mental health diagnoses during 2007-2008 were made most often by women (29.4 million) and most often for any depressive disorder (31%), followed by schizophrenia and other psychotic disorders (23%). Discharged patients with a primary diagnosis of a mental illness were more often aged 18-64 years (98 per 10,000 population) than 65 or older (64 per 10,000). This relationship with age was reversed among discharged patients with mental illness listed as any of the diagnoses, ranging from 231 per 10,000 among patients aged 18-44 years to 651 per 10,000 among those aged 65 years or older. In a 2004 survey, diagnoses of mental illness – most commonly dementia and Alzheimer’s disease – also were shown to increase with age among nursing home residents, from 18.7% in residents aged 65-74 years to 23.5% in those aged 85 years or older.

No information on financial disclosures of the authors was available.

The substantial differences among states, age groups, races, and genders in recent surveys of the prevalence of depression and other mental illnesses in adults illustrate the importance of expanding the mental health focus of surveillance and information systems to help guide national and state-level planning, according to a report released Sept. 1 by the Centers for Disease Control and Prevention.

The report describes the results of population-based surveys from selected CDC surveillance systems administered at different points during 2004-2009. The surveys indicate that southeastern states, non-Hispanic blacks, and women have the highest prevalence of depression, postpartum depression, serious psychological distress, and mentally unhealthy days per month.

However, these estimates of the prevalence of mental illness are limited by the generality of the surveys. None of the surveys, which include the state-based Behavioral Risk Factor Surveillance System (BRFSS), the Pregnancy Risk Assessment Monitoring System (PRAMS), the National Health and Nutrition Examination Survey (NHANES), and the National Health Interview Survey (NHIS), was designed solely to monitor mental illness. They have instead "added components on mental illness gradually over time as recognition of the importance of mental illness in public health has increased," wrote Dr. William C. Reeves of the CDC’s Public Health Surveillance Program Office and his colleagues (MMWR 2011;60[Suppl.]:1-29).

For instance, the BRFSS – a telephone survey of 450,000 adults in 50 states, the District of Columbia, and some territories – found a rate of depression of 8.7% in 2006 in respondents from 38 states, the District of Columbia, and territories, compared with 8.2% in 2008 in 16 states.

The number of states that conduct the BRFSS with one or two small, optional mental illness modules varies from year to year. In 2006 and 2008, depression occurred most often in Mississippi and West Virginia (13.7%) and least often in North Dakota (4.3%). Women had higher prevalences during these years (about 10%), compared with men (about 7%). Non-Hispanic blacks also had a higher prevalence of depression (11%-13%) than did non-Hispanic whites (about 8%) or Hispanics (about 10%).

Not all states collect data from the optional modules "because of financial constraints, competing state surveillance priorities, and limitations in the length of time respondents are willing to spend completing a telephone survey," the authors wrote.

National results with NHANES data indicate a prevalence of depression of 6.8% during 2005-2008, with rates of 8.4% in women, 4.9% in men, 9.7% in non-Hispanic blacks, 6.2% in non-Hispanic whites, and 7.2% among Mexican Americans.

The 22 states that conducted the PRAMS during 2004-2008 found that symptoms of postpartum depression affected 14.5% of respondents. This rate varied from a low of 10.3% among women aged 30-39 years to 23.3% among women aged 19 years or younger, and a low of 9.8% in Minnesota to a high of 21.3% in Tennessee. Non-Hispanic black women had a higher prevalence (21.5%) than did Hispanic (16.8%) and non-Hispanic white women (11.9%).

The prevalence of serious psychological distress, as defined by scores on the Kessler-6 Psychological Distress Scale, was 3.2% in 2009 in the NHIS. The same scale in the BRFSS revealed that serious psychological distress occurred in 4% in 35 states in 2007 and in 3.9% in 16 states in 2009. During those periods, the rate varied from 1.9% in Utah to 9.4% in Tennessee. The Kessler-6 definition of serious psychological distress is associated with anxiety disorders and depression but does not identify a specific mental illness.

All states and territories report the mean number of "mentally unhealthy days" per month in the BRFSS because it is a core feature of the survey. In 2009, the mean number was 3.5 days and was highest overall in the southeastern states. The mean number of days also was higher among non-Hispanic blacks (4.1) and women (4.0).

On the BRFSS, lifetime diagnoses of depression occurred in about 16% of respondents in both 2006 and 2008 despite differing numbers of participating states. Lifetime diagnoses of anxiety disorders were reported by 11.3% in 2006 and by 12.3% in 2008. The authors pointed out a general lack of data on anxiety disorders in CDC surveys and noted that "better documentation of the impact of anxiety disorders might help guide national public health policy. At the state and local levels, documenting the prevalence and impact of anxiety disorders might help ascertain the need for additional public health services for these disorders."

Lifetime diagnoses for other disorders were reported in the NHIS in 2007: 1.7 % of respondents reported a diagnosis of bipolar disorder and 0.6% reported schizophrenia.

Dr. Reeves and his associates also wrote that surveys of health care providers, such as the National Ambulatory Medical Care Survey (NAMCS), the National Hospital Ambulatory Medical Care Survey (NHAMCS), the National Hospital Discharge Survey (NHDS), and the National Nursing Home Survey (NNHS), "complement data from the population-based surveys to provide a more complete representation of the occurrence of mental illness in the United States."

These surveys indicate that most of the 47.8 million estimated ambulatory care visits for patients with primary mental health diagnoses during 2007-2008 were made most often by women (29.4 million) and most often for any depressive disorder (31%), followed by schizophrenia and other psychotic disorders (23%). Discharged patients with a primary diagnosis of a mental illness were more often aged 18-64 years (98 per 10,000 population) than 65 or older (64 per 10,000). This relationship with age was reversed among discharged patients with mental illness listed as any of the diagnoses, ranging from 231 per 10,000 among patients aged 18-44 years to 651 per 10,000 among those aged 65 years or older. In a 2004 survey, diagnoses of mental illness – most commonly dementia and Alzheimer’s disease – also were shown to increase with age among nursing home residents, from 18.7% in residents aged 65-74 years to 23.5% in those aged 85 years or older.

No information on financial disclosures of the authors was available.

The substantial differences among states, age groups, races, and genders in recent surveys of the prevalence of depression and other mental illnesses in adults illustrate the importance of expanding the mental health focus of surveillance and information systems to help guide national and state-level planning, according to a report released Sept. 1 by the Centers for Disease Control and Prevention.

The report describes the results of population-based surveys from selected CDC surveillance systems administered at different points during 2004-2009. The surveys indicate that southeastern states, non-Hispanic blacks, and women have the highest prevalence of depression, postpartum depression, serious psychological distress, and mentally unhealthy days per month.

However, these estimates of the prevalence of mental illness are limited by the generality of the surveys. None of the surveys, which include the state-based Behavioral Risk Factor Surveillance System (BRFSS), the Pregnancy Risk Assessment Monitoring System (PRAMS), the National Health and Nutrition Examination Survey (NHANES), and the National Health Interview Survey (NHIS), was designed solely to monitor mental illness. They have instead "added components on mental illness gradually over time as recognition of the importance of mental illness in public health has increased," wrote Dr. William C. Reeves of the CDC’s Public Health Surveillance Program Office and his colleagues (MMWR 2011;60[Suppl.]:1-29).

For instance, the BRFSS – a telephone survey of 450,000 adults in 50 states, the District of Columbia, and some territories – found a rate of depression of 8.7% in 2006 in respondents from 38 states, the District of Columbia, and territories, compared with 8.2% in 2008 in 16 states.

The number of states that conduct the BRFSS with one or two small, optional mental illness modules varies from year to year. In 2006 and 2008, depression occurred most often in Mississippi and West Virginia (13.7%) and least often in North Dakota (4.3%). Women had higher prevalences during these years (about 10%), compared with men (about 7%). Non-Hispanic blacks also had a higher prevalence of depression (11%-13%) than did non-Hispanic whites (about 8%) or Hispanics (about 10%).

Not all states collect data from the optional modules "because of financial constraints, competing state surveillance priorities, and limitations in the length of time respondents are willing to spend completing a telephone survey," the authors wrote.

National results with NHANES data indicate a prevalence of depression of 6.8% during 2005-2008, with rates of 8.4% in women, 4.9% in men, 9.7% in non-Hispanic blacks, 6.2% in non-Hispanic whites, and 7.2% among Mexican Americans.

The 22 states that conducted the PRAMS during 2004-2008 found that symptoms of postpartum depression affected 14.5% of respondents. This rate varied from a low of 10.3% among women aged 30-39 years to 23.3% among women aged 19 years or younger, and a low of 9.8% in Minnesota to a high of 21.3% in Tennessee. Non-Hispanic black women had a higher prevalence (21.5%) than did Hispanic (16.8%) and non-Hispanic white women (11.9%).

The prevalence of serious psychological distress, as defined by scores on the Kessler-6 Psychological Distress Scale, was 3.2% in 2009 in the NHIS. The same scale in the BRFSS revealed that serious psychological distress occurred in 4% in 35 states in 2007 and in 3.9% in 16 states in 2009. During those periods, the rate varied from 1.9% in Utah to 9.4% in Tennessee. The Kessler-6 definition of serious psychological distress is associated with anxiety disorders and depression but does not identify a specific mental illness.

All states and territories report the mean number of "mentally unhealthy days" per month in the BRFSS because it is a core feature of the survey. In 2009, the mean number was 3.5 days and was highest overall in the southeastern states. The mean number of days also was higher among non-Hispanic blacks (4.1) and women (4.0).

On the BRFSS, lifetime diagnoses of depression occurred in about 16% of respondents in both 2006 and 2008 despite differing numbers of participating states. Lifetime diagnoses of anxiety disorders were reported by 11.3% in 2006 and by 12.3% in 2008. The authors pointed out a general lack of data on anxiety disorders in CDC surveys and noted that "better documentation of the impact of anxiety disorders might help guide national public health policy. At the state and local levels, documenting the prevalence and impact of anxiety disorders might help ascertain the need for additional public health services for these disorders."

Lifetime diagnoses for other disorders were reported in the NHIS in 2007: 1.7 % of respondents reported a diagnosis of bipolar disorder and 0.6% reported schizophrenia.

Dr. Reeves and his associates also wrote that surveys of health care providers, such as the National Ambulatory Medical Care Survey (NAMCS), the National Hospital Ambulatory Medical Care Survey (NHAMCS), the National Hospital Discharge Survey (NHDS), and the National Nursing Home Survey (NNHS), "complement data from the population-based surveys to provide a more complete representation of the occurrence of mental illness in the United States."

These surveys indicate that most of the 47.8 million estimated ambulatory care visits for patients with primary mental health diagnoses during 2007-2008 were made most often by women (29.4 million) and most often for any depressive disorder (31%), followed by schizophrenia and other psychotic disorders (23%). Discharged patients with a primary diagnosis of a mental illness were more often aged 18-64 years (98 per 10,000 population) than 65 or older (64 per 10,000). This relationship with age was reversed among discharged patients with mental illness listed as any of the diagnoses, ranging from 231 per 10,000 among patients aged 18-44 years to 651 per 10,000 among those aged 65 years or older. In a 2004 survey, diagnoses of mental illness – most commonly dementia and Alzheimer’s disease – also were shown to increase with age among nursing home residents, from 18.7% in residents aged 65-74 years to 23.5% in those aged 85 years or older.

No information on financial disclosures of the authors was available.

Serum levels of interleukin-7 helped determine which patients with relapsing-remitting multiple sclerosis would benefit from treatment with interferon-beta in a series of experiments involving human sera and mice with experimental autoimmune encephalo-myelitis.

Patients with high IL-7 levels had a T helper cell type 1 (T_H1) form of MS that has been shown to respond better to interferon-beta therapy than does the T_H17 form of MS.

“These results not only help to clarify our understanding of a genetic risk factor associated with MS but also suggest new predictive, mechanism-based measurements for MS patient stratification,” wrote Li-Fen Lee, Ph.D., of Pfizer, and her colleagues (Sci. Transl. Med.2011;3:93ra68).

The study brings together findings from earlier reports that in totality suggested that IL-7 and its receptor, IL-7R-alpha, may be involved the pathogenesis of MS. Several genome-wide association studies have pointed to a single nucleotide polymorphism in the gene encoding IL-7R-alpha that confers increased susceptibility to MS. In another study, patients with MS had higher levels of both IL-7R and IL-7 mRNA in cerebrospinal fluid than did patients with noninflammatory neurological diseases. And other studies have shown that IL-7/IL-7R-alpha signaling is necessary for the survival of T lymphocytes in humans and animal models.

Using cells from 26 patients with relapsing-remitting MS and mice with experimental autoimmune encephalomyelitis (EAE), Dr. Lee and coauthors found that in both cases, IL-7 promotes the differentiation of naive T cells into T_H1 cells, but not T_H17 cells. Mice that were given IL-7 after EAE was established and paralysis had begun experienced worsened symptoms, whereas those that were given an antagonist IL-7R-alpha antibody had reduced disease severity.

Previous studies have suggested that interferon-beta (IFN-beta) treatment prevents EAE in mice with pathogenic T_H1 cells before symptom onset, yet it exacerbates the disease when given to mice with the T_H17 form of EAE.

The investigators examined the relationship between MS type and response to IFN-beta treatment in the 26 patients.

The level of IL-7 in serum was significantly associated with the rate of relapse. In the 2 years after treatment with IFN-beta, there were no relapses in 5 of 5 patients with an IL-7 level greater than 150 pg/mL, compared with no relapses in 7 of 21 patients with an IL-7 level less than 150 pg/mL.

“Our finding of a role for IL-7 in directing and promoting the generation of human T_H1 cells … is entirely consistent with the elevated IL-7 levels seen in patients with the IFN-beta-responsive form of MS,” the investigators wrote.

They concluded that “it is possible that serum IL-7 level may be useful for predicting clinical benefit from IFN-beta treatment in [relapsing remitting MS] patients. It is conceivable that patients with high levels of serum IL-7 might directly benefit from potential new therapies targeting either IL-7 or its receptor.”

The study was funded by grants from the National Institutes of Health and a National Multiple Sclerosis Society fellowship. Dr. Lee and eight other authors are employees of Pfizer, which has filed a patent application titled, “Antagonist Anti-IL-7 Receptor Antibodies and Methods” with three of the authors. Stanford University and two of the authors have filed a separate patent application for “Markers for Determination of Patient Responsiveness.” The remaining seven authors declared having no competing interests.

Adviser's Viewpoint

Validation, Additional Data Needed

This manuscript explores the role of IL-7 in MS and experimental autoimmune encephalomyelitis (EAE) in mice. The authors present data showing that high serum levels of IL-7, especially in association with low levels of IL-17F, predict a good clinical response to interferon-beta (IFN-beta) therapy in MS. They also show that IL-7 can induce T_H1, but not T_H17, cell differentiation in both humans and mice. They postulate a “T_H1-driven” form of MS responsive to IFN-beta and a “T_H17-driven” form of MS not responsive to IFN-beta. Use of IL-7R-alpha-blocking antibodies in EAE before or after onset of paralysis resulted in reduced severity of EAE, reductions in peripheral naive and activated T cells, and reduced lymphocyte infiltration into the central nervous system.

The authors propose that such IL-7R-alpha-blocking antibodies may be effective in treatment of MS. These results are exciting, and suggest that we may be able to predict an individual's response to treatment with IFN-beta or other MS therapies by looking at induction of specific cytokines. This would be a major advance in a field where we treat patients with a variety of disease-modifying therapies with very little knowledge of how individual responses to therapy may vary.

However, there are a few cautions to keep in mind when reviewing these results. The results are preliminary, and based on a retrospective sample of 26 patients treated with IFN-beta for at least 12 months. Two blinded neurologists classified the patients as responders or nonresponders based on historical data on the number of relapses and steroid treatments in the 2 years before initiation of therapy, compared with 2 years after starting therapy. No MRI data were reported to assess for subclinical disease activity, and neutralizing antibody status to IFN-beta was also not reported. The “high IL-7, low IL-17F” group comprised only five patients, who had an average of two relapses in the 2 years preceding treatment and no relapses in the 2 years during treatment with IFN-beta.

These results obviously need to be validated in a larger, prospectively determined cohort with appropriate MRI monitoring for subclinical MS disease activity. Past experience with MS clinical trials and our evolving knowledge of the complexity of the immune alterations in MS suggest that focusing on changes in one or two cytokines and concepts such at “T_H1-driven” and “T_H17-driven” forms of the disease are likely oversimplifications, although they may serve as useful constructs for future investigation.

JONATHAN L. CARTER, M.D., is an associate professor of neurology at the Mayo Clinic in Scottsdale, Ariz. He specializes in multiple sclerosis, optic neuritis, transverse myelitis, and neuroimmunology. He has no relevant disclosures.

Serum levels of interleukin-7 helped determine which patients with relapsing-remitting multiple sclerosis would benefit from treatment with interferon-beta in a series of experiments involving human sera and mice with experimental autoimmune encephalo-myelitis.

Patients with high IL-7 levels had a T helper cell type 1 (T_H1) form of MS that has been shown to respond better to interferon-beta therapy than does the T_H17 form of MS.

“These results not only help to clarify our understanding of a genetic risk factor associated with MS but also suggest new predictive, mechanism-based measurements for MS patient stratification,” wrote Li-Fen Lee, Ph.D., of Pfizer, and her colleagues (Sci. Transl. Med.2011;3:93ra68).

The study brings together findings from earlier reports that in totality suggested that IL-7 and its receptor, IL-7R-alpha, may be involved the pathogenesis of MS. Several genome-wide association studies have pointed to a single nucleotide polymorphism in the gene encoding IL-7R-alpha that confers increased susceptibility to MS. In another study, patients with MS had higher levels of both IL-7R and IL-7 mRNA in cerebrospinal fluid than did patients with noninflammatory neurological diseases. And other studies have shown that IL-7/IL-7R-alpha signaling is necessary for the survival of T lymphocytes in humans and animal models.

Using cells from 26 patients with relapsing-remitting MS and mice with experimental autoimmune encephalomyelitis (EAE), Dr. Lee and coauthors found that in both cases, IL-7 promotes the differentiation of naive T cells into T_H1 cells, but not T_H17 cells. Mice that were given IL-7 after EAE was established and paralysis had begun experienced worsened symptoms, whereas those that were given an antagonist IL-7R-alpha antibody had reduced disease severity.

Previous studies have suggested that interferon-beta (IFN-beta) treatment prevents EAE in mice with pathogenic T_H1 cells before symptom onset, yet it exacerbates the disease when given to mice with the T_H17 form of EAE.

The investigators examined the relationship between MS type and response to IFN-beta treatment in the 26 patients.

The level of IL-7 in serum was significantly associated with the rate of relapse. In the 2 years after treatment with IFN-beta, there were no relapses in 5 of 5 patients with an IL-7 level greater than 150 pg/mL, compared with no relapses in 7 of 21 patients with an IL-7 level less than 150 pg/mL.

“Our finding of a role for IL-7 in directing and promoting the generation of human T_H1 cells … is entirely consistent with the elevated IL-7 levels seen in patients with the IFN-beta-responsive form of MS,” the investigators wrote.

They concluded that “it is possible that serum IL-7 level may be useful for predicting clinical benefit from IFN-beta treatment in [relapsing remitting MS] patients. It is conceivable that patients with high levels of serum IL-7 might directly benefit from potential new therapies targeting either IL-7 or its receptor.”

The study was funded by grants from the National Institutes of Health and a National Multiple Sclerosis Society fellowship. Dr. Lee and eight other authors are employees of Pfizer, which has filed a patent application titled, “Antagonist Anti-IL-7 Receptor Antibodies and Methods” with three of the authors. Stanford University and two of the authors have filed a separate patent application for “Markers for Determination of Patient Responsiveness.” The remaining seven authors declared having no competing interests.

Adviser's Viewpoint

Validation, Additional Data Needed

This manuscript explores the role of IL-7 in MS and experimental autoimmune encephalomyelitis (EAE) in mice. The authors present data showing that high serum levels of IL-7, especially in association with low levels of IL-17F, predict a good clinical response to interferon-beta (IFN-beta) therapy in MS. They also show that IL-7 can induce T_H1, but not T_H17, cell differentiation in both humans and mice. They postulate a “T_H1-driven” form of MS responsive to IFN-beta and a “T_H17-driven” form of MS not responsive to IFN-beta. Use of IL-7R-alpha-blocking antibodies in EAE before or after onset of paralysis resulted in reduced severity of EAE, reductions in peripheral naive and activated T cells, and reduced lymphocyte infiltration into the central nervous system.

The authors propose that such IL-7R-alpha-blocking antibodies may be effective in treatment of MS. These results are exciting, and suggest that we may be able to predict an individual's response to treatment with IFN-beta or other MS therapies by looking at induction of specific cytokines. This would be a major advance in a field where we treat patients with a variety of disease-modifying therapies with very little knowledge of how individual responses to therapy may vary.

However, there are a few cautions to keep in mind when reviewing these results. The results are preliminary, and based on a retrospective sample of 26 patients treated with IFN-beta for at least 12 months. Two blinded neurologists classified the patients as responders or nonresponders based on historical data on the number of relapses and steroid treatments in the 2 years before initiation of therapy, compared with 2 years after starting therapy. No MRI data were reported to assess for subclinical disease activity, and neutralizing antibody status to IFN-beta was also not reported. The “high IL-7, low IL-17F” group comprised only five patients, who had an average of two relapses in the 2 years preceding treatment and no relapses in the 2 years during treatment with IFN-beta.

These results obviously need to be validated in a larger, prospectively determined cohort with appropriate MRI monitoring for subclinical MS disease activity. Past experience with MS clinical trials and our evolving knowledge of the complexity of the immune alterations in MS suggest that focusing on changes in one or two cytokines and concepts such at “T_H1-driven” and “T_H17-driven” forms of the disease are likely oversimplifications, although they may serve as useful constructs for future investigation.

JONATHAN L. CARTER, M.D., is an associate professor of neurology at the Mayo Clinic in Scottsdale, Ariz. He specializes in multiple sclerosis, optic neuritis, transverse myelitis, and neuroimmunology. He has no relevant disclosures.

Serum levels of interleukin-7 helped determine which patients with relapsing-remitting multiple sclerosis would benefit from treatment with interferon-beta in a series of experiments involving human sera and mice with experimental autoimmune encephalo-myelitis.

Patients with high IL-7 levels had a T helper cell type 1 (T_H1) form of MS that has been shown to respond better to interferon-beta therapy than does the T_H17 form of MS.

“These results not only help to clarify our understanding of a genetic risk factor associated with MS but also suggest new predictive, mechanism-based measurements for MS patient stratification,” wrote Li-Fen Lee, Ph.D., of Pfizer, and her colleagues (Sci. Transl. Med.2011;3:93ra68).

The study brings together findings from earlier reports that in totality suggested that IL-7 and its receptor, IL-7R-alpha, may be involved the pathogenesis of MS. Several genome-wide association studies have pointed to a single nucleotide polymorphism in the gene encoding IL-7R-alpha that confers increased susceptibility to MS. In another study, patients with MS had higher levels of both IL-7R and IL-7 mRNA in cerebrospinal fluid than did patients with noninflammatory neurological diseases. And other studies have shown that IL-7/IL-7R-alpha signaling is necessary for the survival of T lymphocytes in humans and animal models.

Using cells from 26 patients with relapsing-remitting MS and mice with experimental autoimmune encephalomyelitis (EAE), Dr. Lee and coauthors found that in both cases, IL-7 promotes the differentiation of naive T cells into T_H1 cells, but not T_H17 cells. Mice that were given IL-7 after EAE was established and paralysis had begun experienced worsened symptoms, whereas those that were given an antagonist IL-7R-alpha antibody had reduced disease severity.

Previous studies have suggested that interferon-beta (IFN-beta) treatment prevents EAE in mice with pathogenic T_H1 cells before symptom onset, yet it exacerbates the disease when given to mice with the T_H17 form of EAE.

The investigators examined the relationship between MS type and response to IFN-beta treatment in the 26 patients.

The level of IL-7 in serum was significantly associated with the rate of relapse. In the 2 years after treatment with IFN-beta, there were no relapses in 5 of 5 patients with an IL-7 level greater than 150 pg/mL, compared with no relapses in 7 of 21 patients with an IL-7 level less than 150 pg/mL.

“Our finding of a role for IL-7 in directing and promoting the generation of human T_H1 cells … is entirely consistent with the elevated IL-7 levels seen in patients with the IFN-beta-responsive form of MS,” the investigators wrote.

They concluded that “it is possible that serum IL-7 level may be useful for predicting clinical benefit from IFN-beta treatment in [relapsing remitting MS] patients. It is conceivable that patients with high levels of serum IL-7 might directly benefit from potential new therapies targeting either IL-7 or its receptor.”

The study was funded by grants from the National Institutes of Health and a National Multiple Sclerosis Society fellowship. Dr. Lee and eight other authors are employees of Pfizer, which has filed a patent application titled, “Antagonist Anti-IL-7 Receptor Antibodies and Methods” with three of the authors. Stanford University and two of the authors have filed a separate patent application for “Markers for Determination of Patient Responsiveness.” The remaining seven authors declared having no competing interests.

Adviser's Viewpoint

Validation, Additional Data Needed

This manuscript explores the role of IL-7 in MS and experimental autoimmune encephalomyelitis (EAE) in mice. The authors present data showing that high serum levels of IL-7, especially in association with low levels of IL-17F, predict a good clinical response to interferon-beta (IFN-beta) therapy in MS. They also show that IL-7 can induce T_H1, but not T_H17, cell differentiation in both humans and mice. They postulate a “T_H1-driven” form of MS responsive to IFN-beta and a “T_H17-driven” form of MS not responsive to IFN-beta. Use of IL-7R-alpha-blocking antibodies in EAE before or after onset of paralysis resulted in reduced severity of EAE, reductions in peripheral naive and activated T cells, and reduced lymphocyte infiltration into the central nervous system.

The authors propose that such IL-7R-alpha-blocking antibodies may be effective in treatment of MS. These results are exciting, and suggest that we may be able to predict an individual's response to treatment with IFN-beta or other MS therapies by looking at induction of specific cytokines. This would be a major advance in a field where we treat patients with a variety of disease-modifying therapies with very little knowledge of how individual responses to therapy may vary.

However, there are a few cautions to keep in mind when reviewing these results. The results are preliminary, and based on a retrospective sample of 26 patients treated with IFN-beta for at least 12 months. Two blinded neurologists classified the patients as responders or nonresponders based on historical data on the number of relapses and steroid treatments in the 2 years before initiation of therapy, compared with 2 years after starting therapy. No MRI data were reported to assess for subclinical disease activity, and neutralizing antibody status to IFN-beta was also not reported. The “high IL-7, low IL-17F” group comprised only five patients, who had an average of two relapses in the 2 years preceding treatment and no relapses in the 2 years during treatment with IFN-beta.

These results obviously need to be validated in a larger, prospectively determined cohort with appropriate MRI monitoring for subclinical MS disease activity. Past experience with MS clinical trials and our evolving knowledge of the complexity of the immune alterations in MS suggest that focusing on changes in one or two cytokines and concepts such at “T_H1-driven” and “T_H17-driven” forms of the disease are likely oversimplifications, although they may serve as useful constructs for future investigation.

JONATHAN L. CARTER, M.D., is an associate professor of neurology at the Mayo Clinic in Scottsdale, Ariz. He specializes in multiple sclerosis, optic neuritis, transverse myelitis, and neuroimmunology. He has no relevant disclosures.