Neuromuscular Disorders

NEW ORLEANS – It is a good idea to cast a wide net when asking patients with facioscapulohumeral muscular dystrophy about their symptoms because many problems go unrecognized, and some are at least partially treatable, according to a survey of 328 patients in the National Registry of Myotonic Dystrophy and FSHD Patients and Family Members.

For example, patients said not being able to play sports with their children, family, and friends was important. "Dancing is important in this population, too. I would never have guessed it, but it is," said lead investigator Dr. Chad Heatwole, an assistant professor of neurology at the University of Rochester (N.Y.).

For some, not being able to ski or play golf was more important than was difficulty walking.

It might take some creativity to help with such problems, but emotional problems – mostly depression and anxiety – were reported by about 75% of patients, and are readily treated with counseling and medication. These problems "are highly prevalent and an issue we didn’t expect," Dr. Heatwole said at the annual meeting of the American Academy of Neurology.

Usually all we ask is, "How strong are you? Can you go up the stairs?" he said. "These aren’t very amenable to therapy. But pain, fatigue, depression, anxiety, and the different types of emotional problems – you wouldn’t think to ask about these – they’re important but not that addressed."

The roots of the survey were extensive interviews of 20 patients with FSHD (facioscapulohumeral muscular dystrophy) that revealed 250 symptoms and 14 symptom categories of likely importance to the FSHD community. The 328 surveyed patients with FSHD from 46 states had a mean age of 55 years (range, 23-86 years). About half had a job.

More than 90% reported a variety of symptoms and limitations:

• An inability to do previous activities.

• Physical, emotional, or cognitive fatigue.

• Back, chest, or abdominal weakness.

• Mobility or walking limitations.

• Shoulder and arm problems.

• Disease-related changes in body image to the point that patients didn’t like to go swimming because of it.

Shoulder weakness, leg fatigue, decreased range of motion, and inability to exercise were common, as were difficulty lifting objects and reaching overhead items.

Patients said their lives were at least moderately affected by such problems, as well as by difficulty with stairs, inability to run, difficulty thinking, pain, decreased satisfaction in social situations, decreased performance in social situations, and inability to do specific activities. Emotional and communication issues, as well as hand or finger difficulties, also significantly affected patients’ lives. Fatigue and impaired social performance affected women more than men.

Ninety-four percent of patients said they were aware that their disease was getting worse; about 94% also said they feared the progression. About 14% had had their symptoms mistaken for drunkenness, and 64% for another disease; 37% said they try to hide their condition from friends, and 35% reported they have a hard time getting information about FSHD. "We need to do better providing information," Dr. Heatwole said.

Overall, patients were less likely to get further in school if they had difficulty thinking and communicating, or if they had emotional or hand-use problems. Patients with mobility, hand-use, or eating problems were less likely to be employed.

The findings have been turned into a quality of life assessment tool for upcoming FSHD trials, he said.

Dr. Heatwole said that he had no disclosures.

NEW ORLEANS – It is a good idea to cast a wide net when asking patients with facioscapulohumeral muscular dystrophy about their symptoms because many problems go unrecognized, and some are at least partially treatable, according to a survey of 328 patients in the National Registry of Myotonic Dystrophy and FSHD Patients and Family Members.

For example, patients said not being able to play sports with their children, family, and friends was important. "Dancing is important in this population, too. I would never have guessed it, but it is," said lead investigator Dr. Chad Heatwole, an assistant professor of neurology at the University of Rochester (N.Y.).

For some, not being able to ski or play golf was more important than was difficulty walking.

It might take some creativity to help with such problems, but emotional problems – mostly depression and anxiety – were reported by about 75% of patients, and are readily treated with counseling and medication. These problems "are highly prevalent and an issue we didn’t expect," Dr. Heatwole said at the annual meeting of the American Academy of Neurology.

Usually all we ask is, "How strong are you? Can you go up the stairs?" he said. "These aren’t very amenable to therapy. But pain, fatigue, depression, anxiety, and the different types of emotional problems – you wouldn’t think to ask about these – they’re important but not that addressed."

The roots of the survey were extensive interviews of 20 patients with FSHD (facioscapulohumeral muscular dystrophy) that revealed 250 symptoms and 14 symptom categories of likely importance to the FSHD community. The 328 surveyed patients with FSHD from 46 states had a mean age of 55 years (range, 23-86 years). About half had a job.

More than 90% reported a variety of symptoms and limitations:

• An inability to do previous activities.

• Physical, emotional, or cognitive fatigue.

• Back, chest, or abdominal weakness.

• Mobility or walking limitations.

• Shoulder and arm problems.

• Disease-related changes in body image to the point that patients didn’t like to go swimming because of it.

Shoulder weakness, leg fatigue, decreased range of motion, and inability to exercise were common, as were difficulty lifting objects and reaching overhead items.

Patients said their lives were at least moderately affected by such problems, as well as by difficulty with stairs, inability to run, difficulty thinking, pain, decreased satisfaction in social situations, decreased performance in social situations, and inability to do specific activities. Emotional and communication issues, as well as hand or finger difficulties, also significantly affected patients’ lives. Fatigue and impaired social performance affected women more than men.

Ninety-four percent of patients said they were aware that their disease was getting worse; about 94% also said they feared the progression. About 14% had had their symptoms mistaken for drunkenness, and 64% for another disease; 37% said they try to hide their condition from friends, and 35% reported they have a hard time getting information about FSHD. "We need to do better providing information," Dr. Heatwole said.

Overall, patients were less likely to get further in school if they had difficulty thinking and communicating, or if they had emotional or hand-use problems. Patients with mobility, hand-use, or eating problems were less likely to be employed.

The findings have been turned into a quality of life assessment tool for upcoming FSHD trials, he said.

Dr. Heatwole said that he had no disclosures.

NEW ORLEANS – It is a good idea to cast a wide net when asking patients with facioscapulohumeral muscular dystrophy about their symptoms because many problems go unrecognized, and some are at least partially treatable, according to a survey of 328 patients in the National Registry of Myotonic Dystrophy and FSHD Patients and Family Members.

For example, patients said not being able to play sports with their children, family, and friends was important. "Dancing is important in this population, too. I would never have guessed it, but it is," said lead investigator Dr. Chad Heatwole, an assistant professor of neurology at the University of Rochester (N.Y.).

For some, not being able to ski or play golf was more important than was difficulty walking.

It might take some creativity to help with such problems, but emotional problems – mostly depression and anxiety – were reported by about 75% of patients, and are readily treated with counseling and medication. These problems "are highly prevalent and an issue we didn’t expect," Dr. Heatwole said at the annual meeting of the American Academy of Neurology.

Usually all we ask is, "How strong are you? Can you go up the stairs?" he said. "These aren’t very amenable to therapy. But pain, fatigue, depression, anxiety, and the different types of emotional problems – you wouldn’t think to ask about these – they’re important but not that addressed."

The roots of the survey were extensive interviews of 20 patients with FSHD (facioscapulohumeral muscular dystrophy) that revealed 250 symptoms and 14 symptom categories of likely importance to the FSHD community. The 328 surveyed patients with FSHD from 46 states had a mean age of 55 years (range, 23-86 years). About half had a job.

More than 90% reported a variety of symptoms and limitations:

• An inability to do previous activities.

• Physical, emotional, or cognitive fatigue.

• Back, chest, or abdominal weakness.

• Mobility or walking limitations.

• Shoulder and arm problems.

• Disease-related changes in body image to the point that patients didn’t like to go swimming because of it.

Shoulder weakness, leg fatigue, decreased range of motion, and inability to exercise were common, as were difficulty lifting objects and reaching overhead items.

Patients said their lives were at least moderately affected by such problems, as well as by difficulty with stairs, inability to run, difficulty thinking, pain, decreased satisfaction in social situations, decreased performance in social situations, and inability to do specific activities. Emotional and communication issues, as well as hand or finger difficulties, also significantly affected patients’ lives. Fatigue and impaired social performance affected women more than men.

Ninety-four percent of patients said they were aware that their disease was getting worse; about 94% also said they feared the progression. About 14% had had their symptoms mistaken for drunkenness, and 64% for another disease; 37% said they try to hide their condition from friends, and 35% reported they have a hard time getting information about FSHD. "We need to do better providing information," Dr. Heatwole said.

Overall, patients were less likely to get further in school if they had difficulty thinking and communicating, or if they had emotional or hand-use problems. Patients with mobility, hand-use, or eating problems were less likely to be employed.

The findings have been turned into a quality of life assessment tool for upcoming FSHD trials, he said.

Dr. Heatwole said that he had no disclosures.

In recent months, the discovery of the C9ORF72 mutation has added fresh insight into the causes of frontotemporal dementia and amyotrophic lateral sclerosis. Now, a series of new studies describes the frequency of the mutation and how the mutation reveals itself clinically in a spectrum of phenotypes in patients with either disease.

The series of studies found that the mutation most often is associated with behavioral variant frontotemporal dementia (FTD), and occurred in 2%-5% of patients with sporadic FTD and 15%-48% of patients with familial FTD. For amyotrophic lateral sclerosis (ALS) patients, the mutation occurred in 4%-7% of sporadic cases and 22%-43% of familial cases. Another 20%-40% of patients who show symptoms of both diseases had the mutation; the rate reached almost 50% among these patients with a family history of ALS or FTD. Some studies reported finding the mutation in 0%-28% of patients who present with the progressive nonfluent aphasia variant of FTD.

The eventual clinical impact of identifying the C9ORF72 mutation is the availability of a population of at-risk carriers of the mutation to aid research into the preclinical phase of disease, said Dr. Kevin Talbot, professor of motor neuron biology at the University of Oxford, England. "Rather than work in the phase of established disease, which may be intractable to disease-modifying therapy, this provides a new departure to ‘fill in’ a phase in the natural history of ALS which has hitherto not been amenable to study." Dr. Talbot was a coauthor on a study that screened 4,448 patients with ALS and 1,425 patients with FTD for the mutation (Lancet Neurol. 2012 March 9 [doi:10.1016/S1474-4422(12)70043-1]).

The discovery of the mutation and the subsequent characterization among patients who have FTD, ALS, both FTD and ALS, or primary progressive aphasia are just the first steps of many before treatments can be based on the new knowledge, said Dr. Paul Schulz of the department of neurology at the University of Texas, Houston, where his lab examines the mechanisms underlying normal cognition and neurodegenerative disorders.

To illustrate his point, Dr. Schulz cited how the genes for myotonic dystrophy and Huntington’s disease were discovered in 1992 and 1994, respectively, but researchers still know little about them. "We don’t know what they do, how the mutations cause problems, and how to replace them."

Preliminary findings underpinning the discovery of C9ORF72 were made in 2006 when investigators discovered that either FTD and ALS or a combination of both diseases were linked to a region on chromosome 9p21 in members of some families with the diseases. The big step came in September 2011 when two research groups independently identified the precise nature of the long-sought-after mutation (Neuron 2011;72:245-56; 257-68). It proved to be a GGGGCC hexanucleotide repeat in the noncoding region of the C9ORF72 gene.

Originally, no mutation had been found even after repeated sequencing of the investigational region on chromosome 9p21, but eventually, the two research groups examined the pattern of inheritance and noticed that only the good gene appeared to be inherited rather than one gene from each parent.

"After various experiments, it was realized that the abnormal gene was invisible to gene sequencing because the hexanucleotide bound to itself," related Dr. Schulz. "As a result, it was impenetrable by normal PCR [polymerase chain reaction] amplification. Now that this mechanism of mutation is known, I’m sure gene hunters are looking for others that are also ‘silent.’ "

Mutation Screening in FTD and ALS

In the Lancet Neurology study of 4,448 ALS patients and 1,425 FTD patients from the United States, Europe, and Australia, researchers found the C9ORF79 mutation in 7% of sporadic ALS in white patients and 4.1% of black patients. It was present in 6% of white patients with sporadic FTD. The results of those with familial FTD or ALS were more surprising, with the expansion present in 38% of all patients with familial ALS and 25% in white patients with familial FTD.

A series of four papers published in Brain by groups from the Netherlands; Manchester, England; London, England; and the Mayo Clinic in Rochester, Minn., and Jacksonville, Fla., reported the results of screening large cohorts of patients with FTD totaling nearly 1,200 cases. Overall, 7%-12% of the cohorts were found to have the mutation (Brain 2012;135:693-708; 723-35; 736-50; 765-83).

Another two papers and the same Mayo Clinic paper reported on the frequency of the mutation in patients with ALS. In 563 ALS patients from northern England, including 63 with a family history of ALS, the C9ORF72 expansion was found in 11%, but it occurred more often among patients with familial disease (43%) than with sporadic (7%) disease (Brain 2012;135:751-64).

Among patients with familial ALS, the mutation occurred in 38% of 141 Italian cases (including 57% in 21 Sardinian cases) and in 22% of 41 German cases (Brain 2012;135:784-93).

Mayo Clinic researchers detected the mutation in 7% of 229 ALS patients and in 24% of 34 patients with familial ALS, parkinsonism, or dementia. Only 4% of sporadic ALS cases had the mutation. Among patients with a clinical phenotype of FTD and ALS, the prevalence of the mutation was 22%, but it approached 50% among those with a positive family history (Brain 2012;135:765-83).

Another study that will be reported April 25 at the annual meeting of the American Academy of Neurology focused on 1,488 patients (1,082 with FTD, 328 with ALS, and 78 with both) in the European Early-Onset Dementia consortium. In patients with a family history of dementia or ALS, the relative contribution of C9ORF72 was 10% in the FTD patients, 42% in the ALS patients, and 48% in the FTD-ALS patients.

"All of these statistics mean that this hexameric repeat is fairly common amongst those with familial FTD or ALS, or especially FTD with ALS," according to Dr. Schulz. But familial FTD was present in only 40% of those with FTD, and familial ALS was present in only 5% of ALS patients, he noted.

"This means that most sporadic FTD, ALS, or FTD-ALS patients are not accounted for. In sporadic FTD, which is more common than familial FTD, then the rate of C9ORF72 mutations appears to be between 2% and 5%," Dr. Schulz said.

Effect of Other FTD/ALS Mutations

The new C9ORF72 expansion joins two other mutations found in patients with FTD and/or ALS, namely those affecting the genes for microtubulin-associated protein tau (MAPT) and progranulin (GRN). In a commentary on the studies featured in Brain, Dr. John Hodges of Neuroscience Research Australia and the University of New South Wales in Sydney, NSW, Australia, noted that the results of the London-based group (Brain 2012;135:736-50) provide some insight into how likely it is that a patient would have a C9ORF72 mutation and whether this likelihood could be predicted based upon family history and clinical features.

The researchers found that the prevalences of the three mutations were roughly equal in their sample. They also found – based on their Goldman scoring method for quantifying family history – that 88% of patients with a score of 1 (representing an autosomal dominant family history of FTD or ALS) had a mutation in one of those three genes.

However, the Mayo Clinic samples suggest that the C9ORF72 mutation is the most common FTD mutation, present in one-third of people with a family history.

Links Between FTD and ALS

The C9ORF72 mutation may also provide some insight on the links between FTD and ALS. In all cohorts, the prevalence of C9ORF72 was highest in those with FTD/ALS at 20%-40%, and approached 50% among FTD/ALS cases with a positive family history. Dr. Brad Dickerson, director of the frontotemporal dementia unit and laboratory of neuroimaging at Massachusetts General Hospital in Boston, Mass., said that linking FTD and ALS through this gene was especially important because it would likely lead to research that sheds light on what causes cells in different parts of the brain to be vulnerable in both of these diseases.

"This once again underscores the value that studying one neurodegenerative disease can have for other neurodegenerative disease," he said. "In the case of this gene, advances in understanding its role in FTD will have direct implications for understanding its role in ALS, and vice versa."

Dr. Marsel Mesulam, director of the cognitive neurology and Alzheimer’s disease center at Northwestern University in Chicago, said that "exactly how the hopes raised by the C9ORF72 finding will be realized is currently unclear, since we do not yet fully understand the function of C9ORF72." He added that the discovery also generates new puzzles. "Why does the same type of mutation cause ALS in some patients, behavioral FTD in others, and PPA [primary progressive aphasia] in still others?"

Behavioral Variant FTD Most Common

The behavioral variant of FTD was the most common clinical phenotype associated with the C9ORF72 expansion, and was often accompanied by features of ALS as the disease progressed.

Some studies showed that patients with the C9ORF72 mutation also presented with progressive nonfluent aphasia, Dr. Hodges noted in his commentary. Major psychiatric symptoms also were very common, but more details are needed, he wrote. "It appears, therefore, that the majority of patients have the behavioral variant of FTD, although a pattern of progressive [nonfluent aphasia] should not mitigate against screening for the mutation in patients with a strong family history or concurrent features of ALS."

Who Should Undergo Screening?

Given that some patients had the C9ORF72 mutation even without a strong family history, "the most important immediate clinical implication is that we will likely begin screening patients for this mutation once a standard laboratory test for this gene becomes available," Dr. Dickerson said.

In a commentary, Rosa Rademakers, Ph.D., of the Mayo Clinic in Jacksonville, Fla., argued that the use of a clinical screening algorithm to decide whether to test for the C9ORF72 mutation in a patient with a family history of ALS or FTD – or when a patient is behaviorally impaired – may not work, because detailed information about family history is often unavailable. Instead, it should be considered in all patients, particularly because 6%-7% of whites with sporadic disease in the Lancet Neurology paper had the mutation, and the clinical phenotype associated with the C9ORF72 expansion extends beyond FTD and ALS. At the moment, however, caution is advised on testing because "our present understanding of the disease penetrance and range of clinical phenotypes associated with this mutation is poor and the smallest repeat size needed for pathogenicity is unknown," Dr. Rademakers wrote.

The sources interviewed for this article did not have any relevant financial disclosures. Dr. Rademakers disclosed that she has a patent pending on the discovery of the hexanucleotide repeat expansion in the C9ORF72 gene.

In recent months, the discovery of the C9ORF72 mutation has added fresh insight into the causes of frontotemporal dementia and amyotrophic lateral sclerosis. Now, a series of new studies describes the frequency of the mutation and how the mutation reveals itself clinically in a spectrum of phenotypes in patients with either disease.

The series of studies found that the mutation most often is associated with behavioral variant frontotemporal dementia (FTD), and occurred in 2%-5% of patients with sporadic FTD and 15%-48% of patients with familial FTD. For amyotrophic lateral sclerosis (ALS) patients, the mutation occurred in 4%-7% of sporadic cases and 22%-43% of familial cases. Another 20%-40% of patients who show symptoms of both diseases had the mutation; the rate reached almost 50% among these patients with a family history of ALS or FTD. Some studies reported finding the mutation in 0%-28% of patients who present with the progressive nonfluent aphasia variant of FTD.

The eventual clinical impact of identifying the C9ORF72 mutation is the availability of a population of at-risk carriers of the mutation to aid research into the preclinical phase of disease, said Dr. Kevin Talbot, professor of motor neuron biology at the University of Oxford, England. "Rather than work in the phase of established disease, which may be intractable to disease-modifying therapy, this provides a new departure to ‘fill in’ a phase in the natural history of ALS which has hitherto not been amenable to study." Dr. Talbot was a coauthor on a study that screened 4,448 patients with ALS and 1,425 patients with FTD for the mutation (Lancet Neurol. 2012 March 9 [doi:10.1016/S1474-4422(12)70043-1]).

The discovery of the mutation and the subsequent characterization among patients who have FTD, ALS, both FTD and ALS, or primary progressive aphasia are just the first steps of many before treatments can be based on the new knowledge, said Dr. Paul Schulz of the department of neurology at the University of Texas, Houston, where his lab examines the mechanisms underlying normal cognition and neurodegenerative disorders.

To illustrate his point, Dr. Schulz cited how the genes for myotonic dystrophy and Huntington’s disease were discovered in 1992 and 1994, respectively, but researchers still know little about them. "We don’t know what they do, how the mutations cause problems, and how to replace them."

Preliminary findings underpinning the discovery of C9ORF72 were made in 2006 when investigators discovered that either FTD and ALS or a combination of both diseases were linked to a region on chromosome 9p21 in members of some families with the diseases. The big step came in September 2011 when two research groups independently identified the precise nature of the long-sought-after mutation (Neuron 2011;72:245-56; 257-68). It proved to be a GGGGCC hexanucleotide repeat in the noncoding region of the C9ORF72 gene.

Originally, no mutation had been found even after repeated sequencing of the investigational region on chromosome 9p21, but eventually, the two research groups examined the pattern of inheritance and noticed that only the good gene appeared to be inherited rather than one gene from each parent.

"After various experiments, it was realized that the abnormal gene was invisible to gene sequencing because the hexanucleotide bound to itself," related Dr. Schulz. "As a result, it was impenetrable by normal PCR [polymerase chain reaction] amplification. Now that this mechanism of mutation is known, I’m sure gene hunters are looking for others that are also ‘silent.’ "

Mutation Screening in FTD and ALS

In the Lancet Neurology study of 4,448 ALS patients and 1,425 FTD patients from the United States, Europe, and Australia, researchers found the C9ORF79 mutation in 7% of sporadic ALS in white patients and 4.1% of black patients. It was present in 6% of white patients with sporadic FTD. The results of those with familial FTD or ALS were more surprising, with the expansion present in 38% of all patients with familial ALS and 25% in white patients with familial FTD.

A series of four papers published in Brain by groups from the Netherlands; Manchester, England; London, England; and the Mayo Clinic in Rochester, Minn., and Jacksonville, Fla., reported the results of screening large cohorts of patients with FTD totaling nearly 1,200 cases. Overall, 7%-12% of the cohorts were found to have the mutation (Brain 2012;135:693-708; 723-35; 736-50; 765-83).

Another two papers and the same Mayo Clinic paper reported on the frequency of the mutation in patients with ALS. In 563 ALS patients from northern England, including 63 with a family history of ALS, the C9ORF72 expansion was found in 11%, but it occurred more often among patients with familial disease (43%) than with sporadic (7%) disease (Brain 2012;135:751-64).

Among patients with familial ALS, the mutation occurred in 38% of 141 Italian cases (including 57% in 21 Sardinian cases) and in 22% of 41 German cases (Brain 2012;135:784-93).

Mayo Clinic researchers detected the mutation in 7% of 229 ALS patients and in 24% of 34 patients with familial ALS, parkinsonism, or dementia. Only 4% of sporadic ALS cases had the mutation. Among patients with a clinical phenotype of FTD and ALS, the prevalence of the mutation was 22%, but it approached 50% among those with a positive family history (Brain 2012;135:765-83).

Another study that will be reported April 25 at the annual meeting of the American Academy of Neurology focused on 1,488 patients (1,082 with FTD, 328 with ALS, and 78 with both) in the European Early-Onset Dementia consortium. In patients with a family history of dementia or ALS, the relative contribution of C9ORF72 was 10% in the FTD patients, 42% in the ALS patients, and 48% in the FTD-ALS patients.

"All of these statistics mean that this hexameric repeat is fairly common amongst those with familial FTD or ALS, or especially FTD with ALS," according to Dr. Schulz. But familial FTD was present in only 40% of those with FTD, and familial ALS was present in only 5% of ALS patients, he noted.

"This means that most sporadic FTD, ALS, or FTD-ALS patients are not accounted for. In sporadic FTD, which is more common than familial FTD, then the rate of C9ORF72 mutations appears to be between 2% and 5%," Dr. Schulz said.

Effect of Other FTD/ALS Mutations

The new C9ORF72 expansion joins two other mutations found in patients with FTD and/or ALS, namely those affecting the genes for microtubulin-associated protein tau (MAPT) and progranulin (GRN). In a commentary on the studies featured in Brain, Dr. John Hodges of Neuroscience Research Australia and the University of New South Wales in Sydney, NSW, Australia, noted that the results of the London-based group (Brain 2012;135:736-50) provide some insight into how likely it is that a patient would have a C9ORF72 mutation and whether this likelihood could be predicted based upon family history and clinical features.

The researchers found that the prevalences of the three mutations were roughly equal in their sample. They also found – based on their Goldman scoring method for quantifying family history – that 88% of patients with a score of 1 (representing an autosomal dominant family history of FTD or ALS) had a mutation in one of those three genes.

However, the Mayo Clinic samples suggest that the C9ORF72 mutation is the most common FTD mutation, present in one-third of people with a family history.

Links Between FTD and ALS

The C9ORF72 mutation may also provide some insight on the links between FTD and ALS. In all cohorts, the prevalence of C9ORF72 was highest in those with FTD/ALS at 20%-40%, and approached 50% among FTD/ALS cases with a positive family history. Dr. Brad Dickerson, director of the frontotemporal dementia unit and laboratory of neuroimaging at Massachusetts General Hospital in Boston, Mass., said that linking FTD and ALS through this gene was especially important because it would likely lead to research that sheds light on what causes cells in different parts of the brain to be vulnerable in both of these diseases.

"This once again underscores the value that studying one neurodegenerative disease can have for other neurodegenerative disease," he said. "In the case of this gene, advances in understanding its role in FTD will have direct implications for understanding its role in ALS, and vice versa."

Dr. Marsel Mesulam, director of the cognitive neurology and Alzheimer’s disease center at Northwestern University in Chicago, said that "exactly how the hopes raised by the C9ORF72 finding will be realized is currently unclear, since we do not yet fully understand the function of C9ORF72." He added that the discovery also generates new puzzles. "Why does the same type of mutation cause ALS in some patients, behavioral FTD in others, and PPA [primary progressive aphasia] in still others?"

Behavioral Variant FTD Most Common

The behavioral variant of FTD was the most common clinical phenotype associated with the C9ORF72 expansion, and was often accompanied by features of ALS as the disease progressed.

Some studies showed that patients with the C9ORF72 mutation also presented with progressive nonfluent aphasia, Dr. Hodges noted in his commentary. Major psychiatric symptoms also were very common, but more details are needed, he wrote. "It appears, therefore, that the majority of patients have the behavioral variant of FTD, although a pattern of progressive [nonfluent aphasia] should not mitigate against screening for the mutation in patients with a strong family history or concurrent features of ALS."

Who Should Undergo Screening?

Given that some patients had the C9ORF72 mutation even without a strong family history, "the most important immediate clinical implication is that we will likely begin screening patients for this mutation once a standard laboratory test for this gene becomes available," Dr. Dickerson said.

In a commentary, Rosa Rademakers, Ph.D., of the Mayo Clinic in Jacksonville, Fla., argued that the use of a clinical screening algorithm to decide whether to test for the C9ORF72 mutation in a patient with a family history of ALS or FTD – or when a patient is behaviorally impaired – may not work, because detailed information about family history is often unavailable. Instead, it should be considered in all patients, particularly because 6%-7% of whites with sporadic disease in the Lancet Neurology paper had the mutation, and the clinical phenotype associated with the C9ORF72 expansion extends beyond FTD and ALS. At the moment, however, caution is advised on testing because "our present understanding of the disease penetrance and range of clinical phenotypes associated with this mutation is poor and the smallest repeat size needed for pathogenicity is unknown," Dr. Rademakers wrote.

The sources interviewed for this article did not have any relevant financial disclosures. Dr. Rademakers disclosed that she has a patent pending on the discovery of the hexanucleotide repeat expansion in the C9ORF72 gene.

In recent months, the discovery of the C9ORF72 mutation has added fresh insight into the causes of frontotemporal dementia and amyotrophic lateral sclerosis. Now, a series of new studies describes the frequency of the mutation and how the mutation reveals itself clinically in a spectrum of phenotypes in patients with either disease.

The series of studies found that the mutation most often is associated with behavioral variant frontotemporal dementia (FTD), and occurred in 2%-5% of patients with sporadic FTD and 15%-48% of patients with familial FTD. For amyotrophic lateral sclerosis (ALS) patients, the mutation occurred in 4%-7% of sporadic cases and 22%-43% of familial cases. Another 20%-40% of patients who show symptoms of both diseases had the mutation; the rate reached almost 50% among these patients with a family history of ALS or FTD. Some studies reported finding the mutation in 0%-28% of patients who present with the progressive nonfluent aphasia variant of FTD.

The eventual clinical impact of identifying the C9ORF72 mutation is the availability of a population of at-risk carriers of the mutation to aid research into the preclinical phase of disease, said Dr. Kevin Talbot, professor of motor neuron biology at the University of Oxford, England. "Rather than work in the phase of established disease, which may be intractable to disease-modifying therapy, this provides a new departure to ‘fill in’ a phase in the natural history of ALS which has hitherto not been amenable to study." Dr. Talbot was a coauthor on a study that screened 4,448 patients with ALS and 1,425 patients with FTD for the mutation (Lancet Neurol. 2012 March 9 [doi:10.1016/S1474-4422(12)70043-1]).

The discovery of the mutation and the subsequent characterization among patients who have FTD, ALS, both FTD and ALS, or primary progressive aphasia are just the first steps of many before treatments can be based on the new knowledge, said Dr. Paul Schulz of the department of neurology at the University of Texas, Houston, where his lab examines the mechanisms underlying normal cognition and neurodegenerative disorders.

To illustrate his point, Dr. Schulz cited how the genes for myotonic dystrophy and Huntington’s disease were discovered in 1992 and 1994, respectively, but researchers still know little about them. "We don’t know what they do, how the mutations cause problems, and how to replace them."

Preliminary findings underpinning the discovery of C9ORF72 were made in 2006 when investigators discovered that either FTD and ALS or a combination of both diseases were linked to a region on chromosome 9p21 in members of some families with the diseases. The big step came in September 2011 when two research groups independently identified the precise nature of the long-sought-after mutation (Neuron 2011;72:245-56; 257-68). It proved to be a GGGGCC hexanucleotide repeat in the noncoding region of the C9ORF72 gene.

Originally, no mutation had been found even after repeated sequencing of the investigational region on chromosome 9p21, but eventually, the two research groups examined the pattern of inheritance and noticed that only the good gene appeared to be inherited rather than one gene from each parent.

"After various experiments, it was realized that the abnormal gene was invisible to gene sequencing because the hexanucleotide bound to itself," related Dr. Schulz. "As a result, it was impenetrable by normal PCR [polymerase chain reaction] amplification. Now that this mechanism of mutation is known, I’m sure gene hunters are looking for others that are also ‘silent.’ "

Mutation Screening in FTD and ALS

In the Lancet Neurology study of 4,448 ALS patients and 1,425 FTD patients from the United States, Europe, and Australia, researchers found the C9ORF79 mutation in 7% of sporadic ALS in white patients and 4.1% of black patients. It was present in 6% of white patients with sporadic FTD. The results of those with familial FTD or ALS were more surprising, with the expansion present in 38% of all patients with familial ALS and 25% in white patients with familial FTD.

A series of four papers published in Brain by groups from the Netherlands; Manchester, England; London, England; and the Mayo Clinic in Rochester, Minn., and Jacksonville, Fla., reported the results of screening large cohorts of patients with FTD totaling nearly 1,200 cases. Overall, 7%-12% of the cohorts were found to have the mutation (Brain 2012;135:693-708; 723-35; 736-50; 765-83).

Another two papers and the same Mayo Clinic paper reported on the frequency of the mutation in patients with ALS. In 563 ALS patients from northern England, including 63 with a family history of ALS, the C9ORF72 expansion was found in 11%, but it occurred more often among patients with familial disease (43%) than with sporadic (7%) disease (Brain 2012;135:751-64).

Among patients with familial ALS, the mutation occurred in 38% of 141 Italian cases (including 57% in 21 Sardinian cases) and in 22% of 41 German cases (Brain 2012;135:784-93).

Mayo Clinic researchers detected the mutation in 7% of 229 ALS patients and in 24% of 34 patients with familial ALS, parkinsonism, or dementia. Only 4% of sporadic ALS cases had the mutation. Among patients with a clinical phenotype of FTD and ALS, the prevalence of the mutation was 22%, but it approached 50% among those with a positive family history (Brain 2012;135:765-83).

Another study that will be reported April 25 at the annual meeting of the American Academy of Neurology focused on 1,488 patients (1,082 with FTD, 328 with ALS, and 78 with both) in the European Early-Onset Dementia consortium. In patients with a family history of dementia or ALS, the relative contribution of C9ORF72 was 10% in the FTD patients, 42% in the ALS patients, and 48% in the FTD-ALS patients.

"All of these statistics mean that this hexameric repeat is fairly common amongst those with familial FTD or ALS, or especially FTD with ALS," according to Dr. Schulz. But familial FTD was present in only 40% of those with FTD, and familial ALS was present in only 5% of ALS patients, he noted.

"This means that most sporadic FTD, ALS, or FTD-ALS patients are not accounted for. In sporadic FTD, which is more common than familial FTD, then the rate of C9ORF72 mutations appears to be between 2% and 5%," Dr. Schulz said.

Effect of Other FTD/ALS Mutations

The new C9ORF72 expansion joins two other mutations found in patients with FTD and/or ALS, namely those affecting the genes for microtubulin-associated protein tau (MAPT) and progranulin (GRN). In a commentary on the studies featured in Brain, Dr. John Hodges of Neuroscience Research Australia and the University of New South Wales in Sydney, NSW, Australia, noted that the results of the London-based group (Brain 2012;135:736-50) provide some insight into how likely it is that a patient would have a C9ORF72 mutation and whether this likelihood could be predicted based upon family history and clinical features.

The researchers found that the prevalences of the three mutations were roughly equal in their sample. They also found – based on their Goldman scoring method for quantifying family history – that 88% of patients with a score of 1 (representing an autosomal dominant family history of FTD or ALS) had a mutation in one of those three genes.

However, the Mayo Clinic samples suggest that the C9ORF72 mutation is the most common FTD mutation, present in one-third of people with a family history.

Links Between FTD and ALS

The C9ORF72 mutation may also provide some insight on the links between FTD and ALS. In all cohorts, the prevalence of C9ORF72 was highest in those with FTD/ALS at 20%-40%, and approached 50% among FTD/ALS cases with a positive family history. Dr. Brad Dickerson, director of the frontotemporal dementia unit and laboratory of neuroimaging at Massachusetts General Hospital in Boston, Mass., said that linking FTD and ALS through this gene was especially important because it would likely lead to research that sheds light on what causes cells in different parts of the brain to be vulnerable in both of these diseases.

"This once again underscores the value that studying one neurodegenerative disease can have for other neurodegenerative disease," he said. "In the case of this gene, advances in understanding its role in FTD will have direct implications for understanding its role in ALS, and vice versa."

Dr. Marsel Mesulam, director of the cognitive neurology and Alzheimer’s disease center at Northwestern University in Chicago, said that "exactly how the hopes raised by the C9ORF72 finding will be realized is currently unclear, since we do not yet fully understand the function of C9ORF72." He added that the discovery also generates new puzzles. "Why does the same type of mutation cause ALS in some patients, behavioral FTD in others, and PPA [primary progressive aphasia] in still others?"

Behavioral Variant FTD Most Common

The behavioral variant of FTD was the most common clinical phenotype associated with the C9ORF72 expansion, and was often accompanied by features of ALS as the disease progressed.

Some studies showed that patients with the C9ORF72 mutation also presented with progressive nonfluent aphasia, Dr. Hodges noted in his commentary. Major psychiatric symptoms also were very common, but more details are needed, he wrote. "It appears, therefore, that the majority of patients have the behavioral variant of FTD, although a pattern of progressive [nonfluent aphasia] should not mitigate against screening for the mutation in patients with a strong family history or concurrent features of ALS."

Who Should Undergo Screening?

Given that some patients had the C9ORF72 mutation even without a strong family history, "the most important immediate clinical implication is that we will likely begin screening patients for this mutation once a standard laboratory test for this gene becomes available," Dr. Dickerson said.

In a commentary, Rosa Rademakers, Ph.D., of the Mayo Clinic in Jacksonville, Fla., argued that the use of a clinical screening algorithm to decide whether to test for the C9ORF72 mutation in a patient with a family history of ALS or FTD – or when a patient is behaviorally impaired – may not work, because detailed information about family history is often unavailable. Instead, it should be considered in all patients, particularly because 6%-7% of whites with sporadic disease in the Lancet Neurology paper had the mutation, and the clinical phenotype associated with the C9ORF72 expansion extends beyond FTD and ALS. At the moment, however, caution is advised on testing because "our present understanding of the disease penetrance and range of clinical phenotypes associated with this mutation is poor and the smallest repeat size needed for pathogenicity is unknown," Dr. Rademakers wrote.

The sources interviewed for this article did not have any relevant financial disclosures. Dr. Rademakers disclosed that she has a patent pending on the discovery of the hexanucleotide repeat expansion in the C9ORF72 gene.

A strategy of implanting permanent cardiac pacing markedly improved survival for patients with myotonic dystrophy type 1 who presented with surface electrocardiogram manifestations of cardiac conduction abnormalities, compared with a noninvasive strategy of regular surveillance, according to a retrospective cohort study published March 28 in JAMA.

The likelihood of dying during a median 7.4 years of follow-up was nearly 40% lower among patients who underwent electrophysiological testing and, potentially, prophylactic pacing, than among those who did not undergo electrophysiological testing or pacing. The difference between the two groups was largely attributed to a decrease in sudden death in those who received a pacemaker or implantable cardioverter-defibrillator (ICD), said Dr. Karim Wahbi of the departments of cardiology and neurology at Cochin Hospital and the Myology Institute at Pitié-Salpêtrière Hospital, both in Paris, and his associates.

The study findings suggest that conduction system disease "is a major cause of sudden death that appears to be preventable" in this patient population, they noted.

Myotonic dystrophy type 1, also known as Steinert disease, is the most common inherited neuromuscular disease in adults and is characterized by muscle weakness, myotonia, multiple endocrine disorders, respiratory insufficiency, and cardiac abnormalities. As many as one-third of patients succumb to sudden death.

Both the American College of Cardiology and the American Heart Association recommend permanent pacing in patients with myotonic dystrophy type 1 when complete atrioventricular block or advanced high-degree atrioventricular block are detected, or prophylactically when first-degree atrioventricular or fascicular block are detected on ECG. However, whether this invasive approach actually prevents sudden death has never been assessed in a clinical study until now, Dr. Wahbi and his colleagues said.

Of 914 consecutive adults in the DM1 Heart Registry at the Myology Institute who were admitted during 2000-2009 for management of myotonic dystrophy type 1, 486 had ECGs showing minor conduction defects.

Of these subjects, 341 were managed invasively on the advice of their cardiologists. Electrophysiological testing in these patients found an HV interval greater than 70 ms in 164 patients and sustained ventricular tachyarrhythmias that were induced by programmed ventricular stimulation in 70 patients. The patients with an HV interval greater than 70 ms underwent placement of a pacemaker (150) or received an ICD (14). The remaining patients in the invasive-strategy group did not undergo a device implantation.

The remaining 145 subjects were managed noninvasively on the advice of their cardiologists. They had no electrophysiological study and no implantation of pacing devices, but were followed yearly by a neurologist and a cardiologist, both of whom specialized in muscular diseases.

Overall, 49 patients received antiarrhythmic drugs, including amiodarone and beta-blockers.

During a median follow-up of 7.4 years (range, 0-9.9 years), 80 patients died (50 in the invasive-strategy group and 30 in the noninvasive group), giving a 9-year overall survival of 74.4%. Survival at 9 years was 76.7% in the invasive strategy group and 69.2% in the noninvasive group.

After the data were adjusted to account for patient age, sex, history of supraventricular tachyarrhythmia, left ventricular ejection fraction, PR interval, QRS duration, and heart rate, the invasive strategy group had a hazard ratio of 0.61 for dying when compared with the noninvasive-strategy group (JAMA 2012;307:1292-301).

This difference was attributable mostly to the lower rate of sudden death in the invasive-strategy group (10 sudden deaths: 8 pacemaker recipients, 1 ICD recipient, and 1 patient without a pacing device), compared with those in the noninvasive strategy group (16 sudden deaths). "The 9-year cumulative incidence of sudden death was 4.5% in the invasive-strategy group and 18.0% in the noninvasive-strategy group," they added.

There were no significant differences between the two study groups in deaths due to respiratory failure or to other causes.

"While other studies are needed to confirm these findings, consideration of [the invasive] strategy may be prudent in this population, [who are] at higher than average risk for sudden death," Dr. Wahbi and his associates wrote.

This study was funded by the Association Française Contre les Myopathies. Dr. Wahbi reported no financial conflicts of interest, and two of his coauthors reported ties to Boston Scientific, Sorin Group France, Biotronik France, and Genzyme.

A strategy of implanting permanent cardiac pacing markedly improved survival for patients with myotonic dystrophy type 1 who presented with surface electrocardiogram manifestations of cardiac conduction abnormalities, compared with a noninvasive strategy of regular surveillance, according to a retrospective cohort study published March 28 in JAMA.

The likelihood of dying during a median 7.4 years of follow-up was nearly 40% lower among patients who underwent electrophysiological testing and, potentially, prophylactic pacing, than among those who did not undergo electrophysiological testing or pacing. The difference between the two groups was largely attributed to a decrease in sudden death in those who received a pacemaker or implantable cardioverter-defibrillator (ICD), said Dr. Karim Wahbi of the departments of cardiology and neurology at Cochin Hospital and the Myology Institute at Pitié-Salpêtrière Hospital, both in Paris, and his associates.

The study findings suggest that conduction system disease "is a major cause of sudden death that appears to be preventable" in this patient population, they noted.

Myotonic dystrophy type 1, also known as Steinert disease, is the most common inherited neuromuscular disease in adults and is characterized by muscle weakness, myotonia, multiple endocrine disorders, respiratory insufficiency, and cardiac abnormalities. As many as one-third of patients succumb to sudden death.

Both the American College of Cardiology and the American Heart Association recommend permanent pacing in patients with myotonic dystrophy type 1 when complete atrioventricular block or advanced high-degree atrioventricular block are detected, or prophylactically when first-degree atrioventricular or fascicular block are detected on ECG. However, whether this invasive approach actually prevents sudden death has never been assessed in a clinical study until now, Dr. Wahbi and his colleagues said.

Of 914 consecutive adults in the DM1 Heart Registry at the Myology Institute who were admitted during 2000-2009 for management of myotonic dystrophy type 1, 486 had ECGs showing minor conduction defects.

Of these subjects, 341 were managed invasively on the advice of their cardiologists. Electrophysiological testing in these patients found an HV interval greater than 70 ms in 164 patients and sustained ventricular tachyarrhythmias that were induced by programmed ventricular stimulation in 70 patients. The patients with an HV interval greater than 70 ms underwent placement of a pacemaker (150) or received an ICD (14). The remaining patients in the invasive-strategy group did not undergo a device implantation.

The remaining 145 subjects were managed noninvasively on the advice of their cardiologists. They had no electrophysiological study and no implantation of pacing devices, but were followed yearly by a neurologist and a cardiologist, both of whom specialized in muscular diseases.

Overall, 49 patients received antiarrhythmic drugs, including amiodarone and beta-blockers.

During a median follow-up of 7.4 years (range, 0-9.9 years), 80 patients died (50 in the invasive-strategy group and 30 in the noninvasive group), giving a 9-year overall survival of 74.4%. Survival at 9 years was 76.7% in the invasive strategy group and 69.2% in the noninvasive group.

After the data were adjusted to account for patient age, sex, history of supraventricular tachyarrhythmia, left ventricular ejection fraction, PR interval, QRS duration, and heart rate, the invasive strategy group had a hazard ratio of 0.61 for dying when compared with the noninvasive-strategy group (JAMA 2012;307:1292-301).

This difference was attributable mostly to the lower rate of sudden death in the invasive-strategy group (10 sudden deaths: 8 pacemaker recipients, 1 ICD recipient, and 1 patient without a pacing device), compared with those in the noninvasive strategy group (16 sudden deaths). "The 9-year cumulative incidence of sudden death was 4.5% in the invasive-strategy group and 18.0% in the noninvasive-strategy group," they added.

There were no significant differences between the two study groups in deaths due to respiratory failure or to other causes.

"While other studies are needed to confirm these findings, consideration of [the invasive] strategy may be prudent in this population, [who are] at higher than average risk for sudden death," Dr. Wahbi and his associates wrote.

This study was funded by the Association Française Contre les Myopathies. Dr. Wahbi reported no financial conflicts of interest, and two of his coauthors reported ties to Boston Scientific, Sorin Group France, Biotronik France, and Genzyme.

A strategy of implanting permanent cardiac pacing markedly improved survival for patients with myotonic dystrophy type 1 who presented with surface electrocardiogram manifestations of cardiac conduction abnormalities, compared with a noninvasive strategy of regular surveillance, according to a retrospective cohort study published March 28 in JAMA.

The likelihood of dying during a median 7.4 years of follow-up was nearly 40% lower among patients who underwent electrophysiological testing and, potentially, prophylactic pacing, than among those who did not undergo electrophysiological testing or pacing. The difference between the two groups was largely attributed to a decrease in sudden death in those who received a pacemaker or implantable cardioverter-defibrillator (ICD), said Dr. Karim Wahbi of the departments of cardiology and neurology at Cochin Hospital and the Myology Institute at Pitié-Salpêtrière Hospital, both in Paris, and his associates.

The study findings suggest that conduction system disease "is a major cause of sudden death that appears to be preventable" in this patient population, they noted.

Myotonic dystrophy type 1, also known as Steinert disease, is the most common inherited neuromuscular disease in adults and is characterized by muscle weakness, myotonia, multiple endocrine disorders, respiratory insufficiency, and cardiac abnormalities. As many as one-third of patients succumb to sudden death.

Both the American College of Cardiology and the American Heart Association recommend permanent pacing in patients with myotonic dystrophy type 1 when complete atrioventricular block or advanced high-degree atrioventricular block are detected, or prophylactically when first-degree atrioventricular or fascicular block are detected on ECG. However, whether this invasive approach actually prevents sudden death has never been assessed in a clinical study until now, Dr. Wahbi and his colleagues said.

Of 914 consecutive adults in the DM1 Heart Registry at the Myology Institute who were admitted during 2000-2009 for management of myotonic dystrophy type 1, 486 had ECGs showing minor conduction defects.

Of these subjects, 341 were managed invasively on the advice of their cardiologists. Electrophysiological testing in these patients found an HV interval greater than 70 ms in 164 patients and sustained ventricular tachyarrhythmias that were induced by programmed ventricular stimulation in 70 patients. The patients with an HV interval greater than 70 ms underwent placement of a pacemaker (150) or received an ICD (14). The remaining patients in the invasive-strategy group did not undergo a device implantation.

The remaining 145 subjects were managed noninvasively on the advice of their cardiologists. They had no electrophysiological study and no implantation of pacing devices, but were followed yearly by a neurologist and a cardiologist, both of whom specialized in muscular diseases.

Overall, 49 patients received antiarrhythmic drugs, including amiodarone and beta-blockers.

During a median follow-up of 7.4 years (range, 0-9.9 years), 80 patients died (50 in the invasive-strategy group and 30 in the noninvasive group), giving a 9-year overall survival of 74.4%. Survival at 9 years was 76.7% in the invasive strategy group and 69.2% in the noninvasive group.

After the data were adjusted to account for patient age, sex, history of supraventricular tachyarrhythmia, left ventricular ejection fraction, PR interval, QRS duration, and heart rate, the invasive strategy group had a hazard ratio of 0.61 for dying when compared with the noninvasive-strategy group (JAMA 2012;307:1292-301).

This difference was attributable mostly to the lower rate of sudden death in the invasive-strategy group (10 sudden deaths: 8 pacemaker recipients, 1 ICD recipient, and 1 patient without a pacing device), compared with those in the noninvasive strategy group (16 sudden deaths). "The 9-year cumulative incidence of sudden death was 4.5% in the invasive-strategy group and 18.0% in the noninvasive-strategy group," they added.

There were no significant differences between the two study groups in deaths due to respiratory failure or to other causes.

"While other studies are needed to confirm these findings, consideration of [the invasive] strategy may be prudent in this population, [who are] at higher than average risk for sudden death," Dr. Wahbi and his associates wrote.

This study was funded by the Association Française Contre les Myopathies. Dr. Wahbi reported no financial conflicts of interest, and two of his coauthors reported ties to Boston Scientific, Sorin Group France, Biotronik France, and Genzyme.

The devastating nature of neurogenic orthostatic hypotension, coupled with the lack of good treatment options, tipped a Food and Drug Administration panel vote in favor of approval for droxidopa for the orphan condition Feb. 23.

Seven of 13 members of the Cardiovascular and Renal Drugs Advisory Committee supported approval for treatment of symptomatic NOH in patients with primary autonomic failure (Parkinson’s disease, multiple system atrophy, and pure autonomic failure), dopamine beta-hydroxylase deficiency, and nondiabetic autonomic neuropathy.

Panelists in the majority said droxidopa (Northera), a prodrug of norepinephrine, appears effective in at least some patients who experience devastating and debilitating symptoms that limit their ability to stand, walk, and function.

"I voted ‘yes’ for my patients with a horrible disease that really there isn’t any effective therapy right now," said temporary voting member Dr. Jeffrey Cohen, of Dartmouth Hitchcock Medical Center, the lone neurologist on the committee. The adverse events potentially associated with the drug are "none the worse of what we presently have, at least as I can see."

However, the vote in favor of approval was far from a wholehearted endorsement. Four panel members dissented, citing the need for another randomized trial with longer-term efficacy and safety data before approval. One panel member who abstained and one panel member who did not vote also generally took negative views of the drug.

Given the advisory committee’s mixed verdict, coupled with the FDA review team’s own negative evaluation of the drug’s risk/benefit profile and criticisms of the patient-reported outcomes instrument used in the pivotal trials, droxidopa would appear to face a high hurdle to approval by its March 28 user fee deadline.

NOH is an orphan indication with few good therapeutic alternatives. The only drug approved for the indication is midodrine (Shire’s ProAmatine and generics), for which confirmatory trials have failed to verify clinical benefit. Shire and the Center for Drug Evaluation and Research recently reached an agreement pursuant to which midodrine will remain on the market while Shire conducts another study.

Midodrine carries a "black box" warning about supine hypertension; other drugs used off-label in treating NOH also are associated with serious safety concerns.

In briefing documents and at the advisory committee meeting, clinical reviewer Dr. Melanie Blank recommended against approving droxidopa at this time due to the lack of evidence of a durable treatment effect and questions about the drug’s long-term safety. The New Drug Application was supported by only one trial, Study 301, that met its primary efficacy end point based upon improvement in the composite Orthostatic Hypotension Questionnaire (OHQ), which comprises two subscales that rate the presence and severity of symptoms and their impact on daily activities that require standing or walking.

However, the randomized, double-blind portion of Study 301 lasted only 1 week. Two other studies, 302 and 303, failed to achieve their primary end points and had randomized, double-blind periods that lasted only 2 weeks.

This short duration of the studies’ randomized, double-blind phases created questions about the duration of benefit in a chronic condition and made it difficult to characterize the agent’s long-term safety, Dr. Blank said. Safety issues of concern included 19 deaths in phase III studies, hypertensive events, worsening of underlying neurological disease, and reports of neuroleptic malignant syndrome from Japan, where the drug has been available since 1989.

The committee also heard from Study Endpoints and Labeling Development clinical reviewer Dr. Elektra Papadopoulos, who said the OHQ instrument was not well validated and did not adequately measure NOH symptoms or the impact of those symptoms, although the component measuring dizziness/lightheadedness could be enough to support a labeling claim.

Most committee members believed that Studies 302 and 303 could not serve as confirmatory evidence of efficacy. Nevertheless, those voting in favor of approval believed that Study 301 showed that droxidopa can be effective for some patients. They also found persuasive the testimony of more than a half dozen NOH patients and caregivers during the open public portion of the meeting. The patients and their family members testified to dramatic quality-of-life improvements with droxidopa use.

"In the end, this is an effective agent for a very difficult disease," said committee chairman Dr. Michael Lincoff, of the Cleveland Clinic, adding that the drug’s risks are not unpredictable and are related to the known effects of norepinephrine.

"It appears there is a subset of patients that have marked improvement," said committee member Dr. Judith Hochman, of New York University. "The degree of impairment in terms of quality of life of these patients is severe, and quality of life is an extremely important outcome. I think the uncertainty regarding the safety profile can be dealt with in terms of labeling and also in terms of postmarketing studies."

However, committee members who did not support approval said they were troubled by the lack of evidence on durability of effect and the limited safety data.

Committee member Dr. Darren McGuire, of the University of Texas Southwestern Medical Center, said he was encouraged by the data but did not think they were "sufficiently persuasive for a single trial to bring approval, even factoring in the orphan nature of the disease.

"These are vulnerable patients and they have lots of disability, and they present clinical challenges that we all struggle with when we treat them. That vulnerability makes us want to rush new drugs to market," but care must be taken that "the drugs we’re rushing to market are going to do more good than harm." Dr. McGuire suggested that the sponsor, Chelsea Therapeutics International, conduct another randomized trial lasting 3 to 6 months.

"I think I can forgive almost an entire absence of safety data if I’m very convinced of the efficacy data," said committee member Dr. Mori Krantz, of Denver Health Medical Center, who abstained. "But I just felt with the 1-week duration for a chronic condition ... I was contorting myself and doing a backbend. I think this drug has promise, but at this point I was just uncomfortable without further data."

This coverage is provided courtesy of "The Pink Sheet." Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

The devastating nature of neurogenic orthostatic hypotension, coupled with the lack of good treatment options, tipped a Food and Drug Administration panel vote in favor of approval for droxidopa for the orphan condition Feb. 23.

Seven of 13 members of the Cardiovascular and Renal Drugs Advisory Committee supported approval for treatment of symptomatic NOH in patients with primary autonomic failure (Parkinson’s disease, multiple system atrophy, and pure autonomic failure), dopamine beta-hydroxylase deficiency, and nondiabetic autonomic neuropathy.

Panelists in the majority said droxidopa (Northera), a prodrug of norepinephrine, appears effective in at least some patients who experience devastating and debilitating symptoms that limit their ability to stand, walk, and function.

"I voted ‘yes’ for my patients with a horrible disease that really there isn’t any effective therapy right now," said temporary voting member Dr. Jeffrey Cohen, of Dartmouth Hitchcock Medical Center, the lone neurologist on the committee. The adverse events potentially associated with the drug are "none the worse of what we presently have, at least as I can see."

However, the vote in favor of approval was far from a wholehearted endorsement. Four panel members dissented, citing the need for another randomized trial with longer-term efficacy and safety data before approval. One panel member who abstained and one panel member who did not vote also generally took negative views of the drug.

Given the advisory committee’s mixed verdict, coupled with the FDA review team’s own negative evaluation of the drug’s risk/benefit profile and criticisms of the patient-reported outcomes instrument used in the pivotal trials, droxidopa would appear to face a high hurdle to approval by its March 28 user fee deadline.

NOH is an orphan indication with few good therapeutic alternatives. The only drug approved for the indication is midodrine (Shire’s ProAmatine and generics), for which confirmatory trials have failed to verify clinical benefit. Shire and the Center for Drug Evaluation and Research recently reached an agreement pursuant to which midodrine will remain on the market while Shire conducts another study.

Midodrine carries a "black box" warning about supine hypertension; other drugs used off-label in treating NOH also are associated with serious safety concerns.

In briefing documents and at the advisory committee meeting, clinical reviewer Dr. Melanie Blank recommended against approving droxidopa at this time due to the lack of evidence of a durable treatment effect and questions about the drug’s long-term safety. The New Drug Application was supported by only one trial, Study 301, that met its primary efficacy end point based upon improvement in the composite Orthostatic Hypotension Questionnaire (OHQ), which comprises two subscales that rate the presence and severity of symptoms and their impact on daily activities that require standing or walking.

However, the randomized, double-blind portion of Study 301 lasted only 1 week. Two other studies, 302 and 303, failed to achieve their primary end points and had randomized, double-blind periods that lasted only 2 weeks.

This short duration of the studies’ randomized, double-blind phases created questions about the duration of benefit in a chronic condition and made it difficult to characterize the agent’s long-term safety, Dr. Blank said. Safety issues of concern included 19 deaths in phase III studies, hypertensive events, worsening of underlying neurological disease, and reports of neuroleptic malignant syndrome from Japan, where the drug has been available since 1989.

The committee also heard from Study Endpoints and Labeling Development clinical reviewer Dr. Elektra Papadopoulos, who said the OHQ instrument was not well validated and did not adequately measure NOH symptoms or the impact of those symptoms, although the component measuring dizziness/lightheadedness could be enough to support a labeling claim.

Most committee members believed that Studies 302 and 303 could not serve as confirmatory evidence of efficacy. Nevertheless, those voting in favor of approval believed that Study 301 showed that droxidopa can be effective for some patients. They also found persuasive the testimony of more than a half dozen NOH patients and caregivers during the open public portion of the meeting. The patients and their family members testified to dramatic quality-of-life improvements with droxidopa use.

"In the end, this is an effective agent for a very difficult disease," said committee chairman Dr. Michael Lincoff, of the Cleveland Clinic, adding that the drug’s risks are not unpredictable and are related to the known effects of norepinephrine.

"It appears there is a subset of patients that have marked improvement," said committee member Dr. Judith Hochman, of New York University. "The degree of impairment in terms of quality of life of these patients is severe, and quality of life is an extremely important outcome. I think the uncertainty regarding the safety profile can be dealt with in terms of labeling and also in terms of postmarketing studies."

However, committee members who did not support approval said they were troubled by the lack of evidence on durability of effect and the limited safety data.

Committee member Dr. Darren McGuire, of the University of Texas Southwestern Medical Center, said he was encouraged by the data but did not think they were "sufficiently persuasive for a single trial to bring approval, even factoring in the orphan nature of the disease.

"These are vulnerable patients and they have lots of disability, and they present clinical challenges that we all struggle with when we treat them. That vulnerability makes us want to rush new drugs to market," but care must be taken that "the drugs we’re rushing to market are going to do more good than harm." Dr. McGuire suggested that the sponsor, Chelsea Therapeutics International, conduct another randomized trial lasting 3 to 6 months.

"I think I can forgive almost an entire absence of safety data if I’m very convinced of the efficacy data," said committee member Dr. Mori Krantz, of Denver Health Medical Center, who abstained. "But I just felt with the 1-week duration for a chronic condition ... I was contorting myself and doing a backbend. I think this drug has promise, but at this point I was just uncomfortable without further data."

This coverage is provided courtesy of "The Pink Sheet." Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

The devastating nature of neurogenic orthostatic hypotension, coupled with the lack of good treatment options, tipped a Food and Drug Administration panel vote in favor of approval for droxidopa for the orphan condition Feb. 23.

Seven of 13 members of the Cardiovascular and Renal Drugs Advisory Committee supported approval for treatment of symptomatic NOH in patients with primary autonomic failure (Parkinson’s disease, multiple system atrophy, and pure autonomic failure), dopamine beta-hydroxylase deficiency, and nondiabetic autonomic neuropathy.

Panelists in the majority said droxidopa (Northera), a prodrug of norepinephrine, appears effective in at least some patients who experience devastating and debilitating symptoms that limit their ability to stand, walk, and function.

"I voted ‘yes’ for my patients with a horrible disease that really there isn’t any effective therapy right now," said temporary voting member Dr. Jeffrey Cohen, of Dartmouth Hitchcock Medical Center, the lone neurologist on the committee. The adverse events potentially associated with the drug are "none the worse of what we presently have, at least as I can see."

However, the vote in favor of approval was far from a wholehearted endorsement. Four panel members dissented, citing the need for another randomized trial with longer-term efficacy and safety data before approval. One panel member who abstained and one panel member who did not vote also generally took negative views of the drug.

Given the advisory committee’s mixed verdict, coupled with the FDA review team’s own negative evaluation of the drug’s risk/benefit profile and criticisms of the patient-reported outcomes instrument used in the pivotal trials, droxidopa would appear to face a high hurdle to approval by its March 28 user fee deadline.

NOH is an orphan indication with few good therapeutic alternatives. The only drug approved for the indication is midodrine (Shire’s ProAmatine and generics), for which confirmatory trials have failed to verify clinical benefit. Shire and the Center for Drug Evaluation and Research recently reached an agreement pursuant to which midodrine will remain on the market while Shire conducts another study.

Midodrine carries a "black box" warning about supine hypertension; other drugs used off-label in treating NOH also are associated with serious safety concerns.

In briefing documents and at the advisory committee meeting, clinical reviewer Dr. Melanie Blank recommended against approving droxidopa at this time due to the lack of evidence of a durable treatment effect and questions about the drug’s long-term safety. The New Drug Application was supported by only one trial, Study 301, that met its primary efficacy end point based upon improvement in the composite Orthostatic Hypotension Questionnaire (OHQ), which comprises two subscales that rate the presence and severity of symptoms and their impact on daily activities that require standing or walking.

However, the randomized, double-blind portion of Study 301 lasted only 1 week. Two other studies, 302 and 303, failed to achieve their primary end points and had randomized, double-blind periods that lasted only 2 weeks.

This short duration of the studies’ randomized, double-blind phases created questions about the duration of benefit in a chronic condition and made it difficult to characterize the agent’s long-term safety, Dr. Blank said. Safety issues of concern included 19 deaths in phase III studies, hypertensive events, worsening of underlying neurological disease, and reports of neuroleptic malignant syndrome from Japan, where the drug has been available since 1989.

The committee also heard from Study Endpoints and Labeling Development clinical reviewer Dr. Elektra Papadopoulos, who said the OHQ instrument was not well validated and did not adequately measure NOH symptoms or the impact of those symptoms, although the component measuring dizziness/lightheadedness could be enough to support a labeling claim.

Most committee members believed that Studies 302 and 303 could not serve as confirmatory evidence of efficacy. Nevertheless, those voting in favor of approval believed that Study 301 showed that droxidopa can be effective for some patients. They also found persuasive the testimony of more than a half dozen NOH patients and caregivers during the open public portion of the meeting. The patients and their family members testified to dramatic quality-of-life improvements with droxidopa use.

"In the end, this is an effective agent for a very difficult disease," said committee chairman Dr. Michael Lincoff, of the Cleveland Clinic, adding that the drug’s risks are not unpredictable and are related to the known effects of norepinephrine.

"It appears there is a subset of patients that have marked improvement," said committee member Dr. Judith Hochman, of New York University. "The degree of impairment in terms of quality of life of these patients is severe, and quality of life is an extremely important outcome. I think the uncertainty regarding the safety profile can be dealt with in terms of labeling and also in terms of postmarketing studies."

However, committee members who did not support approval said they were troubled by the lack of evidence on durability of effect and the limited safety data.

Committee member Dr. Darren McGuire, of the University of Texas Southwestern Medical Center, said he was encouraged by the data but did not think they were "sufficiently persuasive for a single trial to bring approval, even factoring in the orphan nature of the disease.

"These are vulnerable patients and they have lots of disability, and they present clinical challenges that we all struggle with when we treat them. That vulnerability makes us want to rush new drugs to market," but care must be taken that "the drugs we’re rushing to market are going to do more good than harm." Dr. McGuire suggested that the sponsor, Chelsea Therapeutics International, conduct another randomized trial lasting 3 to 6 months.

"I think I can forgive almost an entire absence of safety data if I’m very convinced of the efficacy data," said committee member Dr. Mori Krantz, of Denver Health Medical Center, who abstained. "But I just felt with the 1-week duration for a chronic condition ... I was contorting myself and doing a backbend. I think this drug has promise, but at this point I was just uncomfortable without further data."

This coverage is provided courtesy of "The Pink Sheet." Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

A 2-year weight-lifting program improved physical symptoms of Parkinson’s disease – including tremor – and seemed to slow their progression.

The progressive resistance routine, which alternated between increasing strength and speed in weight-lifting, was significantly more effective than was an often-recommended program of strengthening, flexibility, and balance, according to Daniel Corcos, Ph.D., lead author of the comparative study. By the end of the study period, patients who were lifting weights maintained a significant level of improvement, but scores of the other group had fallen back to their baseline levels.

Photo courtesy kali9/iStockphoto.com

While weight lifting obviously benefits a patient by muscular strengthening, there seems to be a neuronal component as well, Dr. Corcos said in an interview.

"There is no question that part of the changes are related to what goes on in the brain. Every time you make a muscle contract, you involve the motor cortex and basal ganglia," he said. This repetitive experience appears to alter cortical excitability, improving the connection between brain and muscles, which deteriorates in Parkinson’s, said Dr. Corcos, a kinesiologist and professor of neurologic sciences at the University of Illinois, Chicago.

The investigation randomized 48 people with Parkinson’s disease to the progressive resistance program or to Fitness Counts, a program created by the National Parkinson’s Disease Foundation. Fitness Counts is performed without weights and includes 12 stretching exercises, 7 strengthening exercises, and a set of balancing exercises.

Patients in the weight-training program exercised upper and lower body muscle groups with ever-increasing weight. The initial step determined the heaviest weight a patient could tolerate. Resistance was set at 30%-40% of that maximum weight for the upper body exercises and 50%-60-% of the maximum for the lower body exercises. Weight was increased by at least 5% as soon as the exercise became easier. Every 8 weeks, the program alternated between strength training alone and the combination of strength and speed training, with emphasis on how quickly each repetition could be performed with good form.

The researchers expected each patient to complete 208 sessions by 24 months – usually 2 sessions each week. If they missed a two sessions in a row, the exercise study coordinator contacted the patient. The primary outcome was change on the Unified Parkinson’s Disease Rating Scale III (UPDRS-III) score off medication from baseline to the end of the study.

The patients’ mean age at study entry was 59 years. Most (38) completed the entire 2-year program.

Both the strength training and overall fitness programs had significantly reduced the UPDRS-III score at 6 months (by 6.42 and 5.38 points, respectively). But by the end of 2 years, the weight training group had maintained its improvement (7.3 points), while the fitness group’s score had dropped back to its baseline levels.

The study shows that patients with Parkinson’s can adhere to a sustained exercise regimen and reap valuable benefits from it, Dr. Corcos said. The average Parkinson’s patient experiences about a 30% decrease in normal activity, which provokes muscle deterioration even apart from disease progression. "Think about it. If you, a healthy person, stopped doing anything and laid up in bed for a year, you would still end up in a sorry state," Dr. Corcos said.

Depression probably contributes to reduced activity along with muscular problems. "Depression is part of Parkinson’s and although not every patient has it, it can be quite disabling. As it becomes harder and harder to move, people lose the motivation [to exercise]."

Patients also tend to put exercise at the bottom of their personal "to do" list, just as many healthy people do.

"As the medications lose effectiveness, patients have fewer periods during which they can get things done," Dr. Corcos said. "When it’s working well, they have so many things to do that they just don’t find the time for exercise. I hope this objective evidence may motivate patients to realize that exercise should be a top priority."

His is not the only study expanding the knowledge base in this area.

Fuzhong Li, Ph.D., of the Oregon Research Institute, Eugene, and his colleagues recently published the results of a randomized trial that explored the effect of a modified tai chi program on physical function in Parkinson’s patients. The study randomized 195 patients to tai chi, resistance training, or stretching for 24 weeks. The tai chi group experienced a significantly greater improvement in the UPDRS-III score than did the stretching group (but not the resistance training group), as well as significantly fewer falls than either of the other groups. They retained these benefits at 3 months after the intervention (N. Engl. J. Med. 2012;366:511-9).

Dr. Corcos is scheduled to present the full results of his study in late April at the annual meeting of the America Academy of Neurology.

The National Institutes of Health funded the study. Dr. Corcos had no financial disclosures.

A 2-year weight-lifting program improved physical symptoms of Parkinson’s disease – including tremor – and seemed to slow their progression.

The progressive resistance routine, which alternated between increasing strength and speed in weight-lifting, was significantly more effective than was an often-recommended program of strengthening, flexibility, and balance, according to Daniel Corcos, Ph.D., lead author of the comparative study. By the end of the study period, patients who were lifting weights maintained a significant level of improvement, but scores of the other group had fallen back to their baseline levels.

Photo courtesy kali9/iStockphoto.com

While weight lifting obviously benefits a patient by muscular strengthening, there seems to be a neuronal component as well, Dr. Corcos said in an interview.

"There is no question that part of the changes are related to what goes on in the brain. Every time you make a muscle contract, you involve the motor cortex and basal ganglia," he said. This repetitive experience appears to alter cortical excitability, improving the connection between brain and muscles, which deteriorates in Parkinson’s, said Dr. Corcos, a kinesiologist and professor of neurologic sciences at the University of Illinois, Chicago.

The investigation randomized 48 people with Parkinson’s disease to the progressive resistance program or to Fitness Counts, a program created by the National Parkinson’s Disease Foundation. Fitness Counts is performed without weights and includes 12 stretching exercises, 7 strengthening exercises, and a set of balancing exercises.

Patients in the weight-training program exercised upper and lower body muscle groups with ever-increasing weight. The initial step determined the heaviest weight a patient could tolerate. Resistance was set at 30%-40% of that maximum weight for the upper body exercises and 50%-60-% of the maximum for the lower body exercises. Weight was increased by at least 5% as soon as the exercise became easier. Every 8 weeks, the program alternated between strength training alone and the combination of strength and speed training, with emphasis on how quickly each repetition could be performed with good form.

The researchers expected each patient to complete 208 sessions by 24 months – usually 2 sessions each week. If they missed a two sessions in a row, the exercise study coordinator contacted the patient. The primary outcome was change on the Unified Parkinson’s Disease Rating Scale III (UPDRS-III) score off medication from baseline to the end of the study.

The patients’ mean age at study entry was 59 years. Most (38) completed the entire 2-year program.

Both the strength training and overall fitness programs had significantly reduced the UPDRS-III score at 6 months (by 6.42 and 5.38 points, respectively). But by the end of 2 years, the weight training group had maintained its improvement (7.3 points), while the fitness group’s score had dropped back to its baseline levels.

The study shows that patients with Parkinson’s can adhere to a sustained exercise regimen and reap valuable benefits from it, Dr. Corcos said. The average Parkinson’s patient experiences about a 30% decrease in normal activity, which provokes muscle deterioration even apart from disease progression. "Think about it. If you, a healthy person, stopped doing anything and laid up in bed for a year, you would still end up in a sorry state," Dr. Corcos said.

Depression probably contributes to reduced activity along with muscular problems. "Depression is part of Parkinson’s and although not every patient has it, it can be quite disabling. As it becomes harder and harder to move, people lose the motivation [to exercise]."

Patients also tend to put exercise at the bottom of their personal "to do" list, just as many healthy people do.

"As the medications lose effectiveness, patients have fewer periods during which they can get things done," Dr. Corcos said. "When it’s working well, they have so many things to do that they just don’t find the time for exercise. I hope this objective evidence may motivate patients to realize that exercise should be a top priority."

His is not the only study expanding the knowledge base in this area.

Fuzhong Li, Ph.D., of the Oregon Research Institute, Eugene, and his colleagues recently published the results of a randomized trial that explored the effect of a modified tai chi program on physical function in Parkinson’s patients. The study randomized 195 patients to tai chi, resistance training, or stretching for 24 weeks. The tai chi group experienced a significantly greater improvement in the UPDRS-III score than did the stretching group (but not the resistance training group), as well as significantly fewer falls than either of the other groups. They retained these benefits at 3 months after the intervention (N. Engl. J. Med. 2012;366:511-9).

Dr. Corcos is scheduled to present the full results of his study in late April at the annual meeting of the America Academy of Neurology.

The National Institutes of Health funded the study. Dr. Corcos had no financial disclosures.

A 2-year weight-lifting program improved physical symptoms of Parkinson’s disease – including tremor – and seemed to slow their progression.

The progressive resistance routine, which alternated between increasing strength and speed in weight-lifting, was significantly more effective than was an often-recommended program of strengthening, flexibility, and balance, according to Daniel Corcos, Ph.D., lead author of the comparative study. By the end of the study period, patients who were lifting weights maintained a significant level of improvement, but scores of the other group had fallen back to their baseline levels.

Photo courtesy kali9/iStockphoto.com

While weight lifting obviously benefits a patient by muscular strengthening, there seems to be a neuronal component as well, Dr. Corcos said in an interview.

"There is no question that part of the changes are related to what goes on in the brain. Every time you make a muscle contract, you involve the motor cortex and basal ganglia," he said. This repetitive experience appears to alter cortical excitability, improving the connection between brain and muscles, which deteriorates in Parkinson’s, said Dr. Corcos, a kinesiologist and professor of neurologic sciences at the University of Illinois, Chicago.

The investigation randomized 48 people with Parkinson’s disease to the progressive resistance program or to Fitness Counts, a program created by the National Parkinson’s Disease Foundation. Fitness Counts is performed without weights and includes 12 stretching exercises, 7 strengthening exercises, and a set of balancing exercises.

Patients in the weight-training program exercised upper and lower body muscle groups with ever-increasing weight. The initial step determined the heaviest weight a patient could tolerate. Resistance was set at 30%-40% of that maximum weight for the upper body exercises and 50%-60-% of the maximum for the lower body exercises. Weight was increased by at least 5% as soon as the exercise became easier. Every 8 weeks, the program alternated between strength training alone and the combination of strength and speed training, with emphasis on how quickly each repetition could be performed with good form.

The researchers expected each patient to complete 208 sessions by 24 months – usually 2 sessions each week. If they missed a two sessions in a row, the exercise study coordinator contacted the patient. The primary outcome was change on the Unified Parkinson’s Disease Rating Scale III (UPDRS-III) score off medication from baseline to the end of the study.

The patients’ mean age at study entry was 59 years. Most (38) completed the entire 2-year program.

Both the strength training and overall fitness programs had significantly reduced the UPDRS-III score at 6 months (by 6.42 and 5.38 points, respectively). But by the end of 2 years, the weight training group had maintained its improvement (7.3 points), while the fitness group’s score had dropped back to its baseline levels.

The study shows that patients with Parkinson’s can adhere to a sustained exercise regimen and reap valuable benefits from it, Dr. Corcos said. The average Parkinson’s patient experiences about a 30% decrease in normal activity, which provokes muscle deterioration even apart from disease progression. "Think about it. If you, a healthy person, stopped doing anything and laid up in bed for a year, you would still end up in a sorry state," Dr. Corcos said.

Depression probably contributes to reduced activity along with muscular problems. "Depression is part of Parkinson’s and although not every patient has it, it can be quite disabling. As it becomes harder and harder to move, people lose the motivation [to exercise]."

Patients also tend to put exercise at the bottom of their personal "to do" list, just as many healthy people do.

"As the medications lose effectiveness, patients have fewer periods during which they can get things done," Dr. Corcos said. "When it’s working well, they have so many things to do that they just don’t find the time for exercise. I hope this objective evidence may motivate patients to realize that exercise should be a top priority."

His is not the only study expanding the knowledge base in this area.

Fuzhong Li, Ph.D., of the Oregon Research Institute, Eugene, and his colleagues recently published the results of a randomized trial that explored the effect of a modified tai chi program on physical function in Parkinson’s patients. The study randomized 195 patients to tai chi, resistance training, or stretching for 24 weeks. The tai chi group experienced a significantly greater improvement in the UPDRS-III score than did the stretching group (but not the resistance training group), as well as significantly fewer falls than either of the other groups. They retained these benefits at 3 months after the intervention (N. Engl. J. Med. 2012;366:511-9).

Dr. Corcos is scheduled to present the full results of his study in late April at the annual meeting of the America Academy of Neurology.

The National Institutes of Health funded the study. Dr. Corcos had no financial disclosures.

MIAM BEACH – Botulinum toxin injections provided good, long-term symptom control for many patients with oromandibular dystonia in a retrospective analysis of a series of patients treated at a single center.

Oromandibular dystonia (OMD) is involuntary, repetitive, or twisting spasms of the muscles around the mouth and lower face. Affected people experience jaw opening, jaw closing, lateral jaw deviation, or a combination of these forms.

"Long-term management of OMD with botulinum toxin has minimal morbidity and is useful for all clinical forms," Dr. Catherine F. Sinclair said at the Triological Society’s Combined Sections meeting. With no cure for the condition and oral medication that only improves symptoms for about one-third of patients, botulinum toxin is considered a treatment option, she added.

Along with colleagues Dr. Lowell E. Gurey and Dr. Andrew Blitzer, Dr. Sinclair reported on a series of 59 patients treated with onabotulinumtoxinA (Botox) for OMD since 1995. They assessed the long-term management of the patients and also sought to develop a treatment algorithm for OMD and compare the current series with an original cohort of 20 OMD patients treated by Dr. Blitzer in the 1980s (Ann. Otol. Rhinol. Laryngol. 1989;98:93-7).

In the current series, 10 patients required only one treatment session, another 10 had two sessions, and 39 returned more than twice for subsequent injections of onabotulinumtoxinA. Functional response determined the need and timing of subsequent injections. For example, patients with less than a 50% improvement on a 1 to 100 function rating scale were re-injected less than a month following their initial treatment. The overall median time between treatments was 3 months.

An advantage of onabotulinumtoxinA injections, compared with oral medications, is a greater ability to tailor the treatment. "Injections can be titrated by dose and site to address the predominant muscle systems involved," Dr. Sinclair said at the meeting, which was jointly sponsored by The Triological Society and the American College of Surgeons.

Initial injection dosage ranged from 2.4 U to 5.0 U onabotulinumtoxinA. "Regardless of clinical type, if a patient experiences no response or less than 50% functional improvement, they should be re-injected with either the same dose as the initial injection or with a dose increase of 5 U to 10 U botulinum toxin," said Dr. Sinclair, an otolaryngology fellow at St. Luke’s–Roosevelt Hospital in New York. Also consider treatment of additional muscles, she added.

OMD subtype dictated the specific muscles injected. The masseter and/or temporalis muscles were most often injected for the jaw closing subtype, for example. The internal pterygoid was most often injected for the jaw opening and lateral deviation types of OMD. All injections were percutaneous except for external pterygoid injections, where were done intra-orally, Dr. Sinclair said.

One major caveat is to avoid significant post-injection dysphagia. For this reason, Dr. Sinclair said, anterior digastric muscle injections are performed superficially to avoid diffusion into the underlying floor of the mouth and tongue base musculature. In the study patients, automated machine guidance coupled with visual inspection of areas of maximum muscular hypertrophy determined initial needle placement. Optimal placement was confirmed with voluntary movement.

Not surprisingly, large muscles such at the masseter and temporalis typically receive higher toxin dose and a higher median number of injections. For example, these two muscles are typically injected at five sites, compared with three each for the pterygoid or digastric muscles, Dr. Sinclair said.

The injections appear to be relatively safe in this population. There were no complications reported post-injection by any patient in the current series, Dr. Sinclair said.

The mean age among the 59 patients was 57 years, and 72% were women. The mean follow-up time was 4.3 years.

"Of note, significantly more patients with jaw opening form of OMD were treated in the more recent data set," Dr. Sinclair said. "In line with this, there was an increase in lateral pterygoid and anterior digastric injections," compared with the older series. Despite the increase in jaw opening dystonia in more recent years, the majority of patients (65%) still presented with the jaw closing form.

Dr. Sinclair reported having no relevant financial disclosures.

MIAM BEACH – Botulinum toxin injections provided good, long-term symptom control for many patients with oromandibular dystonia in a retrospective analysis of a series of patients treated at a single center.

Oromandibular dystonia (OMD) is involuntary, repetitive, or twisting spasms of the muscles around the mouth and lower face. Affected people experience jaw opening, jaw closing, lateral jaw deviation, or a combination of these forms.

"Long-term management of OMD with botulinum toxin has minimal morbidity and is useful for all clinical forms," Dr. Catherine F. Sinclair said at the Triological Society’s Combined Sections meeting. With no cure for the condition and oral medication that only improves symptoms for about one-third of patients, botulinum toxin is considered a treatment option, she added.

Along with colleagues Dr. Lowell E. Gurey and Dr. Andrew Blitzer, Dr. Sinclair reported on a series of 59 patients treated with onabotulinumtoxinA (Botox) for OMD since 1995. They assessed the long-term management of the patients and also sought to develop a treatment algorithm for OMD and compare the current series with an original cohort of 20 OMD patients treated by Dr. Blitzer in the 1980s (Ann. Otol. Rhinol. Laryngol. 1989;98:93-7).

In the current series, 10 patients required only one treatment session, another 10 had two sessions, and 39 returned more than twice for subsequent injections of onabotulinumtoxinA. Functional response determined the need and timing of subsequent injections. For example, patients with less than a 50% improvement on a 1 to 100 function rating scale were re-injected less than a month following their initial treatment. The overall median time between treatments was 3 months.

An advantage of onabotulinumtoxinA injections, compared with oral medications, is a greater ability to tailor the treatment. "Injections can be titrated by dose and site to address the predominant muscle systems involved," Dr. Sinclair said at the meeting, which was jointly sponsored by The Triological Society and the American College of Surgeons.

Initial injection dosage ranged from 2.4 U to 5.0 U onabotulinumtoxinA. "Regardless of clinical type, if a patient experiences no response or less than 50% functional improvement, they should be re-injected with either the same dose as the initial injection or with a dose increase of 5 U to 10 U botulinum toxin," said Dr. Sinclair, an otolaryngology fellow at St. Luke’s–Roosevelt Hospital in New York. Also consider treatment of additional muscles, she added.

OMD subtype dictated the specific muscles injected. The masseter and/or temporalis muscles were most often injected for the jaw closing subtype, for example. The internal pterygoid was most often injected for the jaw opening and lateral deviation types of OMD. All injections were percutaneous except for external pterygoid injections, where were done intra-orally, Dr. Sinclair said.

One major caveat is to avoid significant post-injection dysphagia. For this reason, Dr. Sinclair said, anterior digastric muscle injections are performed superficially to avoid diffusion into the underlying floor of the mouth and tongue base musculature. In the study patients, automated machine guidance coupled with visual inspection of areas of maximum muscular hypertrophy determined initial needle placement. Optimal placement was confirmed with voluntary movement.

Not surprisingly, large muscles such at the masseter and temporalis typically receive higher toxin dose and a higher median number of injections. For example, these two muscles are typically injected at five sites, compared with three each for the pterygoid or digastric muscles, Dr. Sinclair said.

The injections appear to be relatively safe in this population. There were no complications reported post-injection by any patient in the current series, Dr. Sinclair said.

The mean age among the 59 patients was 57 years, and 72% were women. The mean follow-up time was 4.3 years.

"Of note, significantly more patients with jaw opening form of OMD were treated in the more recent data set," Dr. Sinclair said. "In line with this, there was an increase in lateral pterygoid and anterior digastric injections," compared with the older series. Despite the increase in jaw opening dystonia in more recent years, the majority of patients (65%) still presented with the jaw closing form.

Dr. Sinclair reported having no relevant financial disclosures.

MIAM BEACH – Botulinum toxin injections provided good, long-term symptom control for many patients with oromandibular dystonia in a retrospective analysis of a series of patients treated at a single center.

Oromandibular dystonia (OMD) is involuntary, repetitive, or twisting spasms of the muscles around the mouth and lower face. Affected people experience jaw opening, jaw closing, lateral jaw deviation, or a combination of these forms.

"Long-term management of OMD with botulinum toxin has minimal morbidity and is useful for all clinical forms," Dr. Catherine F. Sinclair said at the Triological Society’s Combined Sections meeting. With no cure for the condition and oral medication that only improves symptoms for about one-third of patients, botulinum toxin is considered a treatment option, she added.

Along with colleagues Dr. Lowell E. Gurey and Dr. Andrew Blitzer, Dr. Sinclair reported on a series of 59 patients treated with onabotulinumtoxinA (Botox) for OMD since 1995. They assessed the long-term management of the patients and also sought to develop a treatment algorithm for OMD and compare the current series with an original cohort of 20 OMD patients treated by Dr. Blitzer in the 1980s (Ann. Otol. Rhinol. Laryngol. 1989;98:93-7).

In the current series, 10 patients required only one treatment session, another 10 had two sessions, and 39 returned more than twice for subsequent injections of onabotulinumtoxinA. Functional response determined the need and timing of subsequent injections. For example, patients with less than a 50% improvement on a 1 to 100 function rating scale were re-injected less than a month following their initial treatment. The overall median time between treatments was 3 months.

An advantage of onabotulinumtoxinA injections, compared with oral medications, is a greater ability to tailor the treatment. "Injections can be titrated by dose and site to address the predominant muscle systems involved," Dr. Sinclair said at the meeting, which was jointly sponsored by The Triological Society and the American College of Surgeons.

Initial injection dosage ranged from 2.4 U to 5.0 U onabotulinumtoxinA. "Regardless of clinical type, if a patient experiences no response or less than 50% functional improvement, they should be re-injected with either the same dose as the initial injection or with a dose increase of 5 U to 10 U botulinum toxin," said Dr. Sinclair, an otolaryngology fellow at St. Luke’s–Roosevelt Hospital in New York. Also consider treatment of additional muscles, she added.

OMD subtype dictated the specific muscles injected. The masseter and/or temporalis muscles were most often injected for the jaw closing subtype, for example. The internal pterygoid was most often injected for the jaw opening and lateral deviation types of OMD. All injections were percutaneous except for external pterygoid injections, where were done intra-orally, Dr. Sinclair said.

One major caveat is to avoid significant post-injection dysphagia. For this reason, Dr. Sinclair said, anterior digastric muscle injections are performed superficially to avoid diffusion into the underlying floor of the mouth and tongue base musculature. In the study patients, automated machine guidance coupled with visual inspection of areas of maximum muscular hypertrophy determined initial needle placement. Optimal placement was confirmed with voluntary movement.

Not surprisingly, large muscles such at the masseter and temporalis typically receive higher toxin dose and a higher median number of injections. For example, these two muscles are typically injected at five sites, compared with three each for the pterygoid or digastric muscles, Dr. Sinclair said.

The injections appear to be relatively safe in this population. There were no complications reported post-injection by any patient in the current series, Dr. Sinclair said.

The mean age among the 59 patients was 57 years, and 72% were women. The mean follow-up time was 4.3 years.

"Of note, significantly more patients with jaw opening form of OMD were treated in the more recent data set," Dr. Sinclair said. "In line with this, there was an increase in lateral pterygoid and anterior digastric injections," compared with the older series. Despite the increase in jaw opening dystonia in more recent years, the majority of patients (65%) still presented with the jaw closing form.

Dr. Sinclair reported having no relevant financial disclosures.

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.

Further evidence is reported indicating that magnesium sulfate administered before preterm birth may reduce the risk of cerebral palsy in offspring.

SAN FRANCISCO—The use of magnesium sulfate significantly reduced neonatal brain injury associated with maternal inflammation or maternal infection, according to research presented at the 31st Annual Meeting of the Society for Maternal-Fetal Medicine.

“We knew there were indications from other studies that magnesium sulfate might protect a preterm fetus from cerebral palsy, but we wanted to demonstrate direct and conclusive protective effect on the offspring brain in cases of maternal inflammation,” said study coauthor Ron Beloosesky, MD, of the Rambam Medical Center in Haifa, Israel. “We wanted to learn more about the protective effects of magnesium sulfate in cases where maternal inflammation causes preterm birth, so we used the very sensitive diffusion-tensor imaging, MRI, to study how magnesium sulfate works.”

Dr. Beloosesky and colleagues studied pregnant Sprague-Dawley rats at 18 days gestation that received i.p. lipopolysaccharide (LPS) (500 µg/kg) or saline at baseline. Dams were randomized to treatment with s.c. saline or magnesium sulfate (270 mg/kg loading followed by 27 mg/kg q20 min) for two hours prior to and following the i.p. LPS or saline. Pups were delivered spontaneously (e21) and allowed to mature until postnatal day 25. Female offspring (four to eight per group) were examined under isoflurane anesthesia with use of MRI and analyzed using voxel-based analysis after spatial normalization. T2 relaxation time was used to assess for white matter injury and diffusion-tensor imaging for fractional anisotropy comparison.

The results showed that offspring of LPS-treated dams exhibited significantly increased T2 levels, and reduced fractional anisotropy levels in white and gray matter (eg, corpus callosum, thalamus, hippocampus), consistent with diffuse cerebral injury. In contrast, offspring of magnesium sulfate–treated LPS dams demonstrated similar T2 and fractional anisotropy levels as controls in both white and gray matter.

The researchers concluded that magnesium sulfate treatment significantly reduced evidence of neonatal brain injury associated with maternal LPS. The findings suggest that maternal magnesium sulfate therapy may be most effective in human preterm deliveries associated with maternal/fetal inflammation.

“The next step,” said Dr. Beloosesky, “is to do more studies to understand exactly how the magnesium sulfate works and protects the fetal brain.”

Further evidence is reported indicating that magnesium sulfate administered before preterm birth may reduce the risk of cerebral palsy in offspring.

SAN FRANCISCO—The use of magnesium sulfate significantly reduced neonatal brain injury associated with maternal inflammation or maternal infection, according to research presented at the 31st Annual Meeting of the Society for Maternal-Fetal Medicine.

“We knew there were indications from other studies that magnesium sulfate might protect a preterm fetus from cerebral palsy, but we wanted to demonstrate direct and conclusive protective effect on the offspring brain in cases of maternal inflammation,” said study coauthor Ron Beloosesky, MD, of the Rambam Medical Center in Haifa, Israel. “We wanted to learn more about the protective effects of magnesium sulfate in cases where maternal inflammation causes preterm birth, so we used the very sensitive diffusion-tensor imaging, MRI, to study how magnesium sulfate works.”

Dr. Beloosesky and colleagues studied pregnant Sprague-Dawley rats at 18 days gestation that received i.p. lipopolysaccharide (LPS) (500 µg/kg) or saline at baseline. Dams were randomized to treatment with s.c. saline or magnesium sulfate (270 mg/kg loading followed by 27 mg/kg q20 min) for two hours prior to and following the i.p. LPS or saline. Pups were delivered spontaneously (e21) and allowed to mature until postnatal day 25. Female offspring (four to eight per group) were examined under isoflurane anesthesia with use of MRI and analyzed using voxel-based analysis after spatial normalization. T2 relaxation time was used to assess for white matter injury and diffusion-tensor imaging for fractional anisotropy comparison.

The results showed that offspring of LPS-treated dams exhibited significantly increased T2 levels, and reduced fractional anisotropy levels in white and gray matter (eg, corpus callosum, thalamus, hippocampus), consistent with diffuse cerebral injury. In contrast, offspring of magnesium sulfate–treated LPS dams demonstrated similar T2 and fractional anisotropy levels as controls in both white and gray matter.

The researchers concluded that magnesium sulfate treatment significantly reduced evidence of neonatal brain injury associated with maternal LPS. The findings suggest that maternal magnesium sulfate therapy may be most effective in human preterm deliveries associated with maternal/fetal inflammation.

“The next step,” said Dr. Beloosesky, “is to do more studies to understand exactly how the magnesium sulfate works and protects the fetal brain.”

Further evidence is reported indicating that magnesium sulfate administered before preterm birth may reduce the risk of cerebral palsy in offspring.

SAN FRANCISCO—The use of magnesium sulfate significantly reduced neonatal brain injury associated with maternal inflammation or maternal infection, according to research presented at the 31st Annual Meeting of the Society for Maternal-Fetal Medicine.

“We knew there were indications from other studies that magnesium sulfate might protect a preterm fetus from cerebral palsy, but we wanted to demonstrate direct and conclusive protective effect on the offspring brain in cases of maternal inflammation,” said study coauthor Ron Beloosesky, MD, of the Rambam Medical Center in Haifa, Israel. “We wanted to learn more about the protective effects of magnesium sulfate in cases where maternal inflammation causes preterm birth, so we used the very sensitive diffusion-tensor imaging, MRI, to study how magnesium sulfate works.”

Dr. Beloosesky and colleagues studied pregnant Sprague-Dawley rats at 18 days gestation that received i.p. lipopolysaccharide (LPS) (500 µg/kg) or saline at baseline. Dams were randomized to treatment with s.c. saline or magnesium sulfate (270 mg/kg loading followed by 27 mg/kg q20 min) for two hours prior to and following the i.p. LPS or saline. Pups were delivered spontaneously (e21) and allowed to mature until postnatal day 25. Female offspring (four to eight per group) were examined under isoflurane anesthesia with use of MRI and analyzed using voxel-based analysis after spatial normalization. T2 relaxation time was used to assess for white matter injury and diffusion-tensor imaging for fractional anisotropy comparison.

The results showed that offspring of LPS-treated dams exhibited significantly increased T2 levels, and reduced fractional anisotropy levels in white and gray matter (eg, corpus callosum, thalamus, hippocampus), consistent with diffuse cerebral injury. In contrast, offspring of magnesium sulfate–treated LPS dams demonstrated similar T2 and fractional anisotropy levels as controls in both white and gray matter.

The researchers concluded that magnesium sulfate treatment significantly reduced evidence of neonatal brain injury associated with maternal LPS. The findings suggest that maternal magnesium sulfate therapy may be most effective in human preterm deliveries associated with maternal/fetal inflammation.

“The next step,” said Dr. Beloosesky, “is to do more studies to understand exactly how the magnesium sulfate works and protects the fetal brain.”

Vulnerability to Sleep Loss Varies by Individual
Researchers studying the effects of sleep restriction on brain function have found that some individuals are more vulnerable to sleep deprivation than others, and that the ability to recover from chronic sleep restriction also varies.

Through a series of nine studies, David Dinges, PhD, Professor and Chief of the Division of Sleep and Chronobiology in the Department of Psychiatry at the University of Pennsylvania School of Medicine in Philadelphia, and colleagues sought to identify changes in brain function as a result of chronic sleep deprivation, as well as differences in individuals’ sleep need, vulnerability to sleep restrictions, and ease of recovery after sleep deprivation.

The studies involved more than 500 healthy adults, including men, women, whites, and minorities. The average age of participants was 30 (range, 21 to 50). Each study included 40 to 150 participants, who lived in the laboratory 24 hours a day for two to three weeks.

The researchers found that there were large individual differences among healthy persons in response to chronic sleep restriction. Some people were severely affected and showed a dramatic decline in alertness from continued deprivation. Others were not as severely affected, and a subset showed no cognitive deficits from the sleep restriction.

“Our findings indicate that there are likely people who are resistant to the effects of sleep restriction and those who are very vulnerable,” said Dr. Dinges. “Even though they all obtain the same amount of sleep normally in their lives, and even though they are getting the same restriction in the laboratory, they are having markedly different neurobehavioral responses to the reduction of sleep.”

The researchers found that all subjects who slept seven to eight hours a night functioned normally, but with each day of sleep restriction, differences between the groups started to emerge. As sleep was reduced, cognitive functioning was impaired, with the rate of change determined by membership in one of the three groups. Changes began to occur when participants slept fewer than seven hours each night and became much more dramatic when sleep time was reduced to four hours per night.

Through psychomotor vigilance testing, a test of sustained attention that is used to detect sleepiness, the investigators identified the effects of sleep restriction on each participant. Using this test as a marker, they found that attention was profoundly affected by inadequate sleep. For most people, attention destabilizes early in the sleep restriction and was more affected by restriction than any other cognitive area. However, not everyone showed these effects.

“This is not a simple story, because each person’s sleep needs and response to sleep restriction are unique,” Dr. Dinges said. “The bottom line is that it is important not to restrict your sleep, and that if you do it night after night, most people will begin to see the effects in behavior and brain function. Furthermore, it’s important to oversleep when possible in order to recover from any sleep deficit to the extent possible.”

High-Fat Diet During Pregnancy Causes Brain Inflammation in Offspring
A pregnant mother’s high-fat diet can have profound and lasting effects on the brain of her offspring, according to evidence from an animal study. Researchers believe that high-fat diets activate immune cells in the brain, causing inflammation, a process that may lead to neurodegenerative conditions such as multiple sclerosis and Alzheimer’s disease.

“Obesity is generally thought of as a condition that happens to the body but doesn’t impact the brain,” said Staci Bilbo, PhD, Assistant Professor of Psychology and Neuroscience at Duke University in Durham, North Carolina. “But our research found that changes in the brain of offspring are linked to what a mother eats during pregnancy.”

Previous research has shown a link between obesity and inflammation in the body, but little is known about whether obesity might affect inflammation in the brain or if obesity in a pregnant mother can affect brain functions in her offspring. Dr. Bilbo and her team investigated how immune cells in the brain of a pup respond to or are activated by a high-fat content in its mother’s diet during pregnancy.

“When the brain’s immune system is out of balance, it becomes inflamed,” said Dr. Bilbo. “Inflammation is good in the short term, because it can aid in healing and alert us to tissue damage, but in the long run, constant inflammation can be damaging to neurons and brain function.”

The researchers fed female breeding rats one of three diets—a 60% saturated high-fat diet, a 60% trans high-fat diet, or a 10% low-fat control diet for four weeks prior to mating and throughout pregnancy and lactation. After weaning (day 21), all pups were fed the low-fat diet, so they were never on a high-fat diet themselves.

To examine the pups’ response to the mothers’ diets, brain samples and peripheral tissue (fat, blood, and liver) were collected at one day after birth, at weaning (20 days after birth), and in early adulthood (days 60 to 90). The investigators tested immune system functioning in the liver and in the brain, as well as behavioral measures of anxiety and the ability to learn and remember a maze.

Inflammatory response was tested in the pups after weaning (day 20) and in adulthood (days 60 to 90) by comparing immune response four hours after injections of dead bacteria. This procedure activates the immune system without causing an infection that would have a negative impact on an animal’s health.

The researchers observed clear evidence of brain inflammation in the pups born to mothers on high-fat diets. From birth through adulthood, there was evidence of low-level inflammation in brain samples from high-fat groups, including activation of microglia (immune cells) in the hippocampus of the brain. Inflammation also was present outside the brain as evidenced by increased C-reactive protein in the liver.

Most striking was the difference in response to immune challenge. Adult animals whose mothers had been on high-fat diets had a greatly exaggerated inflammatory response in these same areas, compared with low-fat control animals.

“It was absolutely one of the largest responses we have ever seen,” said Dr. Bilbo. In response to anxiety and cognition tests, adult animals whose mothers were given the high-fat diets were considerably more anxious than adult animals from the low-fat group. However, no negative impact was noted on cognition as a consequence of mothers’ high-fat diets.

“Dietary fats are critical to a healthy pregnancy, so we were unsure if the placenta would serve as a protector from the negative effects of the fats, but it seems this is not the case,” said Dr. Bilbo. “The mothers’ diet during pregnancy determines a lifelong neuroinflammatory condition for the fetus that cannot be reversed with low-fat diet alone.”

Dr. Bilbo emphasized that while these findings are noteworthy, this is the first look at the effects of mothers’ obesity on the fetal brain. More research is needed on the composition of the diet before drawing inferences for humans.

The next step in Dr. Bilbo’s research will be to look at the success of reversing the impact of the mothers’ diet of brain inflammation through interventions that target the fetal immune response.

Eating Disorders Linked With Disrupted Rewards Process in the Brain
New findings on eating disorders, including obesity and anorexia nervosa, demonstrate the influence the brain has on appetite and weight control.

Obesity and anorexia, often considered metabolic in nature, appear to also reflect brain functions involving reward and inhibition. Past studies have shown that individual differences may predispose a person to undereat or overeat. These behaviors are influenced by the pleasure derived from eating and drinking, sensory properties of food and a person’s prior experiences, current internal state, expectations, beliefs, and genes.

Multiple studies examined several of these factors and the brain activity associated with them. They revealed a complex, integrated system in which signals from the body interact with brain circuitry to control eating behavior. Desensitization to these signals may lead to pathologic eating. As in other addictions, the dopamine reward system is critically involved. The similarities hold implications for potential treatment and prevention of obesity, according to Nora D. Volkow, MD, Director of the National Institute on Drug Abuse in Bethesda, Maryland.

“The brain is a complicated, integrated system whose responses are linked to changes in the body, as well as predisposing factors associated with a person’s experiences with food,” said Dr. Volkow. “When the brain senses the need for food, the reward system is activated. But the more a person overeats, the more insensitive to food rewards they may become, potentially causing a need to increase stimuli, which in this case is more food intake.”

Examining the brain’s response to certain foods, Dana M. Small, PhD, of the John B. Pierce Laboratory and Yale University in New Haven, Connecticut, found an inverse relationship between a person’s BMI and the brain’s response to a milkshake. Obese persons experienced much less activation of reward centers as they ate the food. The study determined that the response of the caudate to a milkshake was a better predictor of future weight gain than many traditional measures.

Cary R. Savage, PhD, of the University of Kansas Medical Center in Kansas City, conducted a study of food motivation using fMRI. He and his colleagues found that individuals who were obese differed from healthy-weight participants in the way that the brain responded to anticipated food or monetary rewards and punishments. Obese individuals showed greater brain sensitivity to anticipated rewards and less sensitivity to anticipated negative consequences than did healthy-weight individuals.

Other researchers made presentations on the topic as well. To better understand the brain functions of individuals with anorexia nervosa and bulimia nervosa, Walter H. Kaye, MD, and colleagues at the University of California, San Diego, used fMRI to examine the brain’s response to the taste of sucrose and an artificial sweetener and the brain’s response to pictures of palatable foods, compared with color-matched neutral objects. Their findings suggest that individuals who undereat or overeat have an altered sensitivity when consuming sucrose.

Julie L. Fudge, MD, of the University of Rochester Medical Center, followed the “taste pathway” in humans to better understand how information received by various areas of the brain is involved in eating behaviors. Her findings suggest a way that emotional associations with food can converge with taste and instinctive sensations to influence eating behavior.

Disturbances in appetite and weight regulation affect a significant proportion of the US population, and obesity is considered a national epidemic. One in every three adults and one of six children are obese, a condition that arises from chronic imbalances between energy intake and expenditure.

“The studies in this panel represent a growing body of research linking the brain and the wiring in the brain to overeating and obesity,” Dr. Volkow commented. “We really need to do much more work to better understand integration with processes that regulate food intake and reward processing in the brain. This research opens the doors to a much greater understanding of obesity.”

Omega-3 Supplements Show Promise in Alleviating Depression
A new analysis of the effects of omega-3 essential fatty acids offers the hope of enhanced treatment options for patients with depression. Two critical omega-3 essential fatty acids available from certain food or nutritional supplements but not manufactured by the body—eicosapentaenoic acid (EPA) and docosahexaenoic (DHA)—may play a role in optimal brain functioning and have antidepressant benefits that have not been fully recognized.

In a meta-analysis of 15 randomized, double-blind, placebo-controlled studies, researchers from the University of Illinois at Chicago, led by John M. Davis, MD, found that patients taking omega-3 with either EPA or a combination of EPA and DHA experienced clear antidepressant benefits. However, across studies, patients taking the pure DHA form of omega-3 showed no antidepressant effect.

“Our analysis clarifies the precise type of omega-3 fatty acid that is effective for people with depression and explains why previous findings have been contradictory,” said Dr. Davis. “The EPA predominant formulation is necessary for the therapeutic action to occur. The DHA predominant formulation does not have antidepressant efficacy.”

Although the investigators noted that omega-3 produces beneficial effects in patients with depression, EPA does not improve mood in persons who are not depressed. In several studies, people without depression experienced no difference in mood as a result of omega-3 consumption.

In another study, Dr. Davis and his team found that women with inadequate omega-3 intake were more likely to experience depression during and after pregnancy than were women with adequate omega-3 in their diets.

“The findings are unambiguous,” said Dr. Davis. “Omega-3 fatty acids have antidepressant properties, and this effect is ready to be tested in a large study to establish the dose range and to pave the way for FDA approval. In the meantime, omega-3 fatty acids containing EPA could be useful to augment effects of antidepressant medications.”

However, the researchers cautioned that patients should always talk with their physician before taking omega-3 fatty acids to alleviate symptoms of depression.

Dr. Davis and colleagues are now examining the link between soy intake and depression, and they expect those findings to be published next year. He noted that soy products contain omega-6 fatty acids, which compete with omega-3 fatty acids.

Vulnerability to Sleep Loss Varies by Individual
Researchers studying the effects of sleep restriction on brain function have found that some individuals are more vulnerable to sleep deprivation than others, and that the ability to recover from chronic sleep restriction also varies.

Through a series of nine studies, David Dinges, PhD, Professor and Chief of the Division of Sleep and Chronobiology in the Department of Psychiatry at the University of Pennsylvania School of Medicine in Philadelphia, and colleagues sought to identify changes in brain function as a result of chronic sleep deprivation, as well as differences in individuals’ sleep need, vulnerability to sleep restrictions, and ease of recovery after sleep deprivation.

The studies involved more than 500 healthy adults, including men, women, whites, and minorities. The average age of participants was 30 (range, 21 to 50). Each study included 40 to 150 participants, who lived in the laboratory 24 hours a day for two to three weeks.

The researchers found that there were large individual differences among healthy persons in response to chronic sleep restriction. Some people were severely affected and showed a dramatic decline in alertness from continued deprivation. Others were not as severely affected, and a subset showed no cognitive deficits from the sleep restriction.

“Our findings indicate that there are likely people who are resistant to the effects of sleep restriction and those who are very vulnerable,” said Dr. Dinges. “Even though they all obtain the same amount of sleep normally in their lives, and even though they are getting the same restriction in the laboratory, they are having markedly different neurobehavioral responses to the reduction of sleep.”

The researchers found that all subjects who slept seven to eight hours a night functioned normally, but with each day of sleep restriction, differences between the groups started to emerge. As sleep was reduced, cognitive functioning was impaired, with the rate of change determined by membership in one of the three groups. Changes began to occur when participants slept fewer than seven hours each night and became much more dramatic when sleep time was reduced to four hours per night.

Through psychomotor vigilance testing, a test of sustained attention that is used to detect sleepiness, the investigators identified the effects of sleep restriction on each participant. Using this test as a marker, they found that attention was profoundly affected by inadequate sleep. For most people, attention destabilizes early in the sleep restriction and was more affected by restriction than any other cognitive area. However, not everyone showed these effects.

“This is not a simple story, because each person’s sleep needs and response to sleep restriction are unique,” Dr. Dinges said. “The bottom line is that it is important not to restrict your sleep, and that if you do it night after night, most people will begin to see the effects in behavior and brain function. Furthermore, it’s important to oversleep when possible in order to recover from any sleep deficit to the extent possible.”

High-Fat Diet During Pregnancy Causes Brain Inflammation in Offspring
A pregnant mother’s high-fat diet can have profound and lasting effects on the brain of her offspring, according to evidence from an animal study. Researchers believe that high-fat diets activate immune cells in the brain, causing inflammation, a process that may lead to neurodegenerative conditions such as multiple sclerosis and Alzheimer’s disease.

“Obesity is generally thought of as a condition that happens to the body but doesn’t impact the brain,” said Staci Bilbo, PhD, Assistant Professor of Psychology and Neuroscience at Duke University in Durham, North Carolina. “But our research found that changes in the brain of offspring are linked to what a mother eats during pregnancy.”

Previous research has shown a link between obesity and inflammation in the body, but little is known about whether obesity might affect inflammation in the brain or if obesity in a pregnant mother can affect brain functions in her offspring. Dr. Bilbo and her team investigated how immune cells in the brain of a pup respond to or are activated by a high-fat content in its mother’s diet during pregnancy.

“When the brain’s immune system is out of balance, it becomes inflamed,” said Dr. Bilbo. “Inflammation is good in the short term, because it can aid in healing and alert us to tissue damage, but in the long run, constant inflammation can be damaging to neurons and brain function.”

The researchers fed female breeding rats one of three diets—a 60% saturated high-fat diet, a 60% trans high-fat diet, or a 10% low-fat control diet for four weeks prior to mating and throughout pregnancy and lactation. After weaning (day 21), all pups were fed the low-fat diet, so they were never on a high-fat diet themselves.

To examine the pups’ response to the mothers’ diets, brain samples and peripheral tissue (fat, blood, and liver) were collected at one day after birth, at weaning (20 days after birth), and in early adulthood (days 60 to 90). The investigators tested immune system functioning in the liver and in the brain, as well as behavioral measures of anxiety and the ability to learn and remember a maze.

Inflammatory response was tested in the pups after weaning (day 20) and in adulthood (days 60 to 90) by comparing immune response four hours after injections of dead bacteria. This procedure activates the immune system without causing an infection that would have a negative impact on an animal’s health.

The researchers observed clear evidence of brain inflammation in the pups born to mothers on high-fat diets. From birth through adulthood, there was evidence of low-level inflammation in brain samples from high-fat groups, including activation of microglia (immune cells) in the hippocampus of the brain. Inflammation also was present outside the brain as evidenced by increased C-reactive protein in the liver.

Most striking was the difference in response to immune challenge. Adult animals whose mothers had been on high-fat diets had a greatly exaggerated inflammatory response in these same areas, compared with low-fat control animals.

“It was absolutely one of the largest responses we have ever seen,” said Dr. Bilbo. In response to anxiety and cognition tests, adult animals whose mothers were given the high-fat diets were considerably more anxious than adult animals from the low-fat group. However, no negative impact was noted on cognition as a consequence of mothers’ high-fat diets.

“Dietary fats are critical to a healthy pregnancy, so we were unsure if the placenta would serve as a protector from the negative effects of the fats, but it seems this is not the case,” said Dr. Bilbo. “The mothers’ diet during pregnancy determines a lifelong neuroinflammatory condition for the fetus that cannot be reversed with low-fat diet alone.”

Dr. Bilbo emphasized that while these findings are noteworthy, this is the first look at the effects of mothers’ obesity on the fetal brain. More research is needed on the composition of the diet before drawing inferences for humans.

The next step in Dr. Bilbo’s research will be to look at the success of reversing the impact of the mothers’ diet of brain inflammation through interventions that target the fetal immune response.

Eating Disorders Linked With Disrupted Rewards Process in the Brain
New findings on eating disorders, including obesity and anorexia nervosa, demonstrate the influence the brain has on appetite and weight control.

Obesity and anorexia, often considered metabolic in nature, appear to also reflect brain functions involving reward and inhibition. Past studies have shown that individual differences may predispose a person to undereat or overeat. These behaviors are influenced by the pleasure derived from eating and drinking, sensory properties of food and a person’s prior experiences, current internal state, expectations, beliefs, and genes.

Multiple studies examined several of these factors and the brain activity associated with them. They revealed a complex, integrated system in which signals from the body interact with brain circuitry to control eating behavior. Desensitization to these signals may lead to pathologic eating. As in other addictions, the dopamine reward system is critically involved. The similarities hold implications for potential treatment and prevention of obesity, according to Nora D. Volkow, MD, Director of the National Institute on Drug Abuse in Bethesda, Maryland.

“The brain is a complicated, integrated system whose responses are linked to changes in the body, as well as predisposing factors associated with a person’s experiences with food,” said Dr. Volkow. “When the brain senses the need for food, the reward system is activated. But the more a person overeats, the more insensitive to food rewards they may become, potentially causing a need to increase stimuli, which in this case is more food intake.”

Examining the brain’s response to certain foods, Dana M. Small, PhD, of the John B. Pierce Laboratory and Yale University in New Haven, Connecticut, found an inverse relationship between a person’s BMI and the brain’s response to a milkshake. Obese persons experienced much less activation of reward centers as they ate the food. The study determined that the response of the caudate to a milkshake was a better predictor of future weight gain than many traditional measures.

Cary R. Savage, PhD, of the University of Kansas Medical Center in Kansas City, conducted a study of food motivation using fMRI. He and his colleagues found that individuals who were obese differed from healthy-weight participants in the way that the brain responded to anticipated food or monetary rewards and punishments. Obese individuals showed greater brain sensitivity to anticipated rewards and less sensitivity to anticipated negative consequences than did healthy-weight individuals.

Other researchers made presentations on the topic as well. To better understand the brain functions of individuals with anorexia nervosa and bulimia nervosa, Walter H. Kaye, MD, and colleagues at the University of California, San Diego, used fMRI to examine the brain’s response to the taste of sucrose and an artificial sweetener and the brain’s response to pictures of palatable foods, compared with color-matched neutral objects. Their findings suggest that individuals who undereat or overeat have an altered sensitivity when consuming sucrose.

Julie L. Fudge, MD, of the University of Rochester Medical Center, followed the “taste pathway” in humans to better understand how information received by various areas of the brain is involved in eating behaviors. Her findings suggest a way that emotional associations with food can converge with taste and instinctive sensations to influence eating behavior.

Disturbances in appetite and weight regulation affect a significant proportion of the US population, and obesity is considered a national epidemic. One in every three adults and one of six children are obese, a condition that arises from chronic imbalances between energy intake and expenditure.

“The studies in this panel represent a growing body of research linking the brain and the wiring in the brain to overeating and obesity,” Dr. Volkow commented. “We really need to do much more work to better understand integration with processes that regulate food intake and reward processing in the brain. This research opens the doors to a much greater understanding of obesity.”

Omega-3 Supplements Show Promise in Alleviating Depression
A new analysis of the effects of omega-3 essential fatty acids offers the hope of enhanced treatment options for patients with depression. Two critical omega-3 essential fatty acids available from certain food or nutritional supplements but not manufactured by the body—eicosapentaenoic acid (EPA) and docosahexaenoic (DHA)—may play a role in optimal brain functioning and have antidepressant benefits that have not been fully recognized.

In a meta-analysis of 15 randomized, double-blind, placebo-controlled studies, researchers from the University of Illinois at Chicago, led by John M. Davis, MD, found that patients taking omega-3 with either EPA or a combination of EPA and DHA experienced clear antidepressant benefits. However, across studies, patients taking the pure DHA form of omega-3 showed no antidepressant effect.

“Our analysis clarifies the precise type of omega-3 fatty acid that is effective for people with depression and explains why previous findings have been contradictory,” said Dr. Davis. “The EPA predominant formulation is necessary for the therapeutic action to occur. The DHA predominant formulation does not have antidepressant efficacy.”

Although the investigators noted that omega-3 produces beneficial effects in patients with depression, EPA does not improve mood in persons who are not depressed. In several studies, people without depression experienced no difference in mood as a result of omega-3 consumption.

In another study, Dr. Davis and his team found that women with inadequate omega-3 intake were more likely to experience depression during and after pregnancy than were women with adequate omega-3 in their diets.

“The findings are unambiguous,” said Dr. Davis. “Omega-3 fatty acids have antidepressant properties, and this effect is ready to be tested in a large study to establish the dose range and to pave the way for FDA approval. In the meantime, omega-3 fatty acids containing EPA could be useful to augment effects of antidepressant medications.”

However, the researchers cautioned that patients should always talk with their physician before taking omega-3 fatty acids to alleviate symptoms of depression.

Dr. Davis and colleagues are now examining the link between soy intake and depression, and they expect those findings to be published next year. He noted that soy products contain omega-6 fatty acids, which compete with omega-3 fatty acids.

Vulnerability to Sleep Loss Varies by Individual
Researchers studying the effects of sleep restriction on brain function have found that some individuals are more vulnerable to sleep deprivation than others, and that the ability to recover from chronic sleep restriction also varies.

Through a series of nine studies, David Dinges, PhD, Professor and Chief of the Division of Sleep and Chronobiology in the Department of Psychiatry at the University of Pennsylvania School of Medicine in Philadelphia, and colleagues sought to identify changes in brain function as a result of chronic sleep deprivation, as well as differences in individuals’ sleep need, vulnerability to sleep restrictions, and ease of recovery after sleep deprivation.

The studies involved more than 500 healthy adults, including men, women, whites, and minorities. The average age of participants was 30 (range, 21 to 50). Each study included 40 to 150 participants, who lived in the laboratory 24 hours a day for two to three weeks.

The researchers found that there were large individual differences among healthy persons in response to chronic sleep restriction. Some people were severely affected and showed a dramatic decline in alertness from continued deprivation. Others were not as severely affected, and a subset showed no cognitive deficits from the sleep restriction.

“Our findings indicate that there are likely people who are resistant to the effects of sleep restriction and those who are very vulnerable,” said Dr. Dinges. “Even though they all obtain the same amount of sleep normally in their lives, and even though they are getting the same restriction in the laboratory, they are having markedly different neurobehavioral responses to the reduction of sleep.”

The researchers found that all subjects who slept seven to eight hours a night functioned normally, but with each day of sleep restriction, differences between the groups started to emerge. As sleep was reduced, cognitive functioning was impaired, with the rate of change determined by membership in one of the three groups. Changes began to occur when participants slept fewer than seven hours each night and became much more dramatic when sleep time was reduced to four hours per night.

Through psychomotor vigilance testing, a test of sustained attention that is used to detect sleepiness, the investigators identified the effects of sleep restriction on each participant. Using this test as a marker, they found that attention was profoundly affected by inadequate sleep. For most people, attention destabilizes early in the sleep restriction and was more affected by restriction than any other cognitive area. However, not everyone showed these effects.

“This is not a simple story, because each person’s sleep needs and response to sleep restriction are unique,” Dr. Dinges said. “The bottom line is that it is important not to restrict your sleep, and that if you do it night after night, most people will begin to see the effects in behavior and brain function. Furthermore, it’s important to oversleep when possible in order to recover from any sleep deficit to the extent possible.”

High-Fat Diet During Pregnancy Causes Brain Inflammation in Offspring
A pregnant mother’s high-fat diet can have profound and lasting effects on the brain of her offspring, according to evidence from an animal study. Researchers believe that high-fat diets activate immune cells in the brain, causing inflammation, a process that may lead to neurodegenerative conditions such as multiple sclerosis and Alzheimer’s disease.

“Obesity is generally thought of as a condition that happens to the body but doesn’t impact the brain,” said Staci Bilbo, PhD, Assistant Professor of Psychology and Neuroscience at Duke University in Durham, North Carolina. “But our research found that changes in the brain of offspring are linked to what a mother eats during pregnancy.”

Previous research has shown a link between obesity and inflammation in the body, but little is known about whether obesity might affect inflammation in the brain or if obesity in a pregnant mother can affect brain functions in her offspring. Dr. Bilbo and her team investigated how immune cells in the brain of a pup respond to or are activated by a high-fat content in its mother’s diet during pregnancy.

“When the brain’s immune system is out of balance, it becomes inflamed,” said Dr. Bilbo. “Inflammation is good in the short term, because it can aid in healing and alert us to tissue damage, but in the long run, constant inflammation can be damaging to neurons and brain function.”

The researchers fed female breeding rats one of three diets—a 60% saturated high-fat diet, a 60% trans high-fat diet, or a 10% low-fat control diet for four weeks prior to mating and throughout pregnancy and lactation. After weaning (day 21), all pups were fed the low-fat diet, so they were never on a high-fat diet themselves.

To examine the pups’ response to the mothers’ diets, brain samples and peripheral tissue (fat, blood, and liver) were collected at one day after birth, at weaning (20 days after birth), and in early adulthood (days 60 to 90). The investigators tested immune system functioning in the liver and in the brain, as well as behavioral measures of anxiety and the ability to learn and remember a maze.

Inflammatory response was tested in the pups after weaning (day 20) and in adulthood (days 60 to 90) by comparing immune response four hours after injections of dead bacteria. This procedure activates the immune system without causing an infection that would have a negative impact on an animal’s health.

The researchers observed clear evidence of brain inflammation in the pups born to mothers on high-fat diets. From birth through adulthood, there was evidence of low-level inflammation in brain samples from high-fat groups, including activation of microglia (immune cells) in the hippocampus of the brain. Inflammation also was present outside the brain as evidenced by increased C-reactive protein in the liver.

Most striking was the difference in response to immune challenge. Adult animals whose mothers had been on high-fat diets had a greatly exaggerated inflammatory response in these same areas, compared with low-fat control animals.

“It was absolutely one of the largest responses we have ever seen,” said Dr. Bilbo. In response to anxiety and cognition tests, adult animals whose mothers were given the high-fat diets were considerably more anxious than adult animals from the low-fat group. However, no negative impact was noted on cognition as a consequence of mothers’ high-fat diets.

“Dietary fats are critical to a healthy pregnancy, so we were unsure if the placenta would serve as a protector from the negative effects of the fats, but it seems this is not the case,” said Dr. Bilbo. “The mothers’ diet during pregnancy determines a lifelong neuroinflammatory condition for the fetus that cannot be reversed with low-fat diet alone.”

Dr. Bilbo emphasized that while these findings are noteworthy, this is the first look at the effects of mothers’ obesity on the fetal brain. More research is needed on the composition of the diet before drawing inferences for humans.

The next step in Dr. Bilbo’s research will be to look at the success of reversing the impact of the mothers’ diet of brain inflammation through interventions that target the fetal immune response.

Eating Disorders Linked With Disrupted Rewards Process in the Brain
New findings on eating disorders, including obesity and anorexia nervosa, demonstrate the influence the brain has on appetite and weight control.

Obesity and anorexia, often considered metabolic in nature, appear to also reflect brain functions involving reward and inhibition. Past studies have shown that individual differences may predispose a person to undereat or overeat. These behaviors are influenced by the pleasure derived from eating and drinking, sensory properties of food and a person’s prior experiences, current internal state, expectations, beliefs, and genes.

Multiple studies examined several of these factors and the brain activity associated with them. They revealed a complex, integrated system in which signals from the body interact with brain circuitry to control eating behavior. Desensitization to these signals may lead to pathologic eating. As in other addictions, the dopamine reward system is critically involved. The similarities hold implications for potential treatment and prevention of obesity, according to Nora D. Volkow, MD, Director of the National Institute on Drug Abuse in Bethesda, Maryland.

“The brain is a complicated, integrated system whose responses are linked to changes in the body, as well as predisposing factors associated with a person’s experiences with food,” said Dr. Volkow. “When the brain senses the need for food, the reward system is activated. But the more a person overeats, the more insensitive to food rewards they may become, potentially causing a need to increase stimuli, which in this case is more food intake.”

Examining the brain’s response to certain foods, Dana M. Small, PhD, of the John B. Pierce Laboratory and Yale University in New Haven, Connecticut, found an inverse relationship between a person’s BMI and the brain’s response to a milkshake. Obese persons experienced much less activation of reward centers as they ate the food. The study determined that the response of the caudate to a milkshake was a better predictor of future weight gain than many traditional measures.

Cary R. Savage, PhD, of the University of Kansas Medical Center in Kansas City, conducted a study of food motivation using fMRI. He and his colleagues found that individuals who were obese differed from healthy-weight participants in the way that the brain responded to anticipated food or monetary rewards and punishments. Obese individuals showed greater brain sensitivity to anticipated rewards and less sensitivity to anticipated negative consequences than did healthy-weight individuals.

Other researchers made presentations on the topic as well. To better understand the brain functions of individuals with anorexia nervosa and bulimia nervosa, Walter H. Kaye, MD, and colleagues at the University of California, San Diego, used fMRI to examine the brain’s response to the taste of sucrose and an artificial sweetener and the brain’s response to pictures of palatable foods, compared with color-matched neutral objects. Their findings suggest that individuals who undereat or overeat have an altered sensitivity when consuming sucrose.

Julie L. Fudge, MD, of the University of Rochester Medical Center, followed the “taste pathway” in humans to better understand how information received by various areas of the brain is involved in eating behaviors. Her findings suggest a way that emotional associations with food can converge with taste and instinctive sensations to influence eating behavior.

Disturbances in appetite and weight regulation affect a significant proportion of the US population, and obesity is considered a national epidemic. One in every three adults and one of six children are obese, a condition that arises from chronic imbalances between energy intake and expenditure.

“The studies in this panel represent a growing body of research linking the brain and the wiring in the brain to overeating and obesity,” Dr. Volkow commented. “We really need to do much more work to better understand integration with processes that regulate food intake and reward processing in the brain. This research opens the doors to a much greater understanding of obesity.”

Omega-3 Supplements Show Promise in Alleviating Depression
A new analysis of the effects of omega-3 essential fatty acids offers the hope of enhanced treatment options for patients with depression. Two critical omega-3 essential fatty acids available from certain food or nutritional supplements but not manufactured by the body—eicosapentaenoic acid (EPA) and docosahexaenoic (DHA)—may play a role in optimal brain functioning and have antidepressant benefits that have not been fully recognized.

In a meta-analysis of 15 randomized, double-blind, placebo-controlled studies, researchers from the University of Illinois at Chicago, led by John M. Davis, MD, found that patients taking omega-3 with either EPA or a combination of EPA and DHA experienced clear antidepressant benefits. However, across studies, patients taking the pure DHA form of omega-3 showed no antidepressant effect.

“Our analysis clarifies the precise type of omega-3 fatty acid that is effective for people with depression and explains why previous findings have been contradictory,” said Dr. Davis. “The EPA predominant formulation is necessary for the therapeutic action to occur. The DHA predominant formulation does not have antidepressant efficacy.”

Although the investigators noted that omega-3 produces beneficial effects in patients with depression, EPA does not improve mood in persons who are not depressed. In several studies, people without depression experienced no difference in mood as a result of omega-3 consumption.

In another study, Dr. Davis and his team found that women with inadequate omega-3 intake were more likely to experience depression during and after pregnancy than were women with adequate omega-3 in their diets.

“The findings are unambiguous,” said Dr. Davis. “Omega-3 fatty acids have antidepressant properties, and this effect is ready to be tested in a large study to establish the dose range and to pave the way for FDA approval. In the meantime, omega-3 fatty acids containing EPA could be useful to augment effects of antidepressant medications.”

However, the researchers cautioned that patients should always talk with their physician before taking omega-3 fatty acids to alleviate symptoms of depression.

Dr. Davis and colleagues are now examining the link between soy intake and depression, and they expect those findings to be published next year. He noted that soy products contain omega-6 fatty acids, which compete with omega-3 fatty acids.