Michele G. Sullivan

Major Finding: Intranasally delivered insulin boosted cognition and brain activity in patients with mild cognitive impairment and early Alzheimer's disease.

Data Source: A placebo-controlled trial that randomized 104 patients to placebo or to 20 IU or 40 IU of intranasal insulin every day for 4 months.

Disclosures: The study was sponsored by the National Institute on Aging and the Department of Veterans Affairs. Dr. Craft said she had no financial disclosures.

Intranasal insulin boosted cognitive function and even brain activity in patients with mild cognitive impairment and early Alzheimer's disease in a 4-month, randomized, placebo-controlled trial.

The study, presented at the meeting, holds tantalizing hints of an Alzheimer's therapy that could be relatively inexpensive and easy to administer, but more research on a much larger scale is necessary before this science could move into the clinic.

Dr. Suzanne Craft of the University of Washington, Seattle, said growing evidence suggests that insulin may play a key role in cognition and that patients with Alzheimer's disease have significantly disrupted brain-insulin interactions.

“Insulin plays a number of important roles in the brain, and many are functions of great relevance to Alzheimer's disease,” she said in an interview.

Insulin normally crosses the blood-brain barrier to bind with receptors in the hippocampus, frontal cortex, and other regions involved in cognition. “It also enhances memory, we believe through mediating glucose metabolism in the hippocampus, as well as by mediating levels of neurotransmitters, including acetylcholine,” she said.

Insulin also improves blood flow to the brain and works to prevent beta-amyloid from aggregating on neurons. “It appears to help the beta-amyloid move from inside the brain cells to the interstitial space, where it can be cleared,” she said. “It also increases the availability of a specific enzyme that breaks down amyloid.”

In an extension of her previous work, Dr. Craft randomized 104 patients with mild cognitive impairment (MCI) or early Alzheimer's disease to placebo or to 20 or 40 IU daily of intranasal insulin. The compound is sprayed into the nose, where insulin bypasses the blood-brain barrier and travels directly into the brain along the perivascular channels around the olfactory and trigeminal nerves, allowing the drug to bind to brain receptors within 15–30 minutes of administration.

The patients' average age was 73 years. Their mean combined score on three baseline Mini-Mental State Examination tests was about 82. All patients took the Alzheimer's Disease Assessment Scale cognitive test for MCI (ADAS-cog/MCI), the Dementia Severity Rating Scale (DSRS), and the Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) measures.

The 20-IU group experienced a significantly improved delayed story recall compared with the placebo group. The 20-IU group also showed significantly improved functional status on the DSRS. These improvements persisted for 2 months after insulin was ceased.

On the ADCS-ADL, placebo patients declined significantly more than 20-IU patients; 40-IU patients had no change in their score. On the ADAS-cog/MCI test, placebo patients scored significantly worse than both intervention groups, and the 40-IU group scored significantly better than did the 20-IU group.

Dr. Craft said that “it's hard to say for certain in a 4-month study that this would translate into clinical improvement, but on the ADAS-cog, we saw a 25% difference between the highest-dose insulin group and the placebo group. And we also saw improvements in a caregiver-rated functional scale. So I would say that these findings do suggest clinical improvement.”

The fact that the improvements were maintained throughout the study and even after treatment stopped suggests that insulin has a cumulative effect in improving brain function, she added.

In a subgroup of 40 patients who underwent fluorodeoxyglucose PET scanning at baseline and during follow-up, those taking placebo showed a slowing of the cerebral metabolic rate for glucose utilization. This slowing was not seen in either the 20-IU or 40-IU subjects—a finding that Dr. Craft suggested may show slowing of disease progression.

“This is a new and very encouraging finding,” she said.

Major Finding: Intranasally delivered insulin boosted cognition and brain activity in patients with mild cognitive impairment and early Alzheimer's disease.

Data Source: A placebo-controlled trial that randomized 104 patients to placebo or to 20 IU or 40 IU of intranasal insulin every day for 4 months.

Disclosures: The study was sponsored by the National Institute on Aging and the Department of Veterans Affairs. Dr. Craft said she had no financial disclosures.

Intranasal insulin boosted cognitive function and even brain activity in patients with mild cognitive impairment and early Alzheimer's disease in a 4-month, randomized, placebo-controlled trial.

The study, presented at the meeting, holds tantalizing hints of an Alzheimer's therapy that could be relatively inexpensive and easy to administer, but more research on a much larger scale is necessary before this science could move into the clinic.

Dr. Suzanne Craft of the University of Washington, Seattle, said growing evidence suggests that insulin may play a key role in cognition and that patients with Alzheimer's disease have significantly disrupted brain-insulin interactions.

“Insulin plays a number of important roles in the brain, and many are functions of great relevance to Alzheimer's disease,” she said in an interview.

Insulin normally crosses the blood-brain barrier to bind with receptors in the hippocampus, frontal cortex, and other regions involved in cognition. “It also enhances memory, we believe through mediating glucose metabolism in the hippocampus, as well as by mediating levels of neurotransmitters, including acetylcholine,” she said.

Insulin also improves blood flow to the brain and works to prevent beta-amyloid from aggregating on neurons. “It appears to help the beta-amyloid move from inside the brain cells to the interstitial space, where it can be cleared,” she said. “It also increases the availability of a specific enzyme that breaks down amyloid.”

In an extension of her previous work, Dr. Craft randomized 104 patients with mild cognitive impairment (MCI) or early Alzheimer's disease to placebo or to 20 or 40 IU daily of intranasal insulin. The compound is sprayed into the nose, where insulin bypasses the blood-brain barrier and travels directly into the brain along the perivascular channels around the olfactory and trigeminal nerves, allowing the drug to bind to brain receptors within 15–30 minutes of administration.

The patients' average age was 73 years. Their mean combined score on three baseline Mini-Mental State Examination tests was about 82. All patients took the Alzheimer's Disease Assessment Scale cognitive test for MCI (ADAS-cog/MCI), the Dementia Severity Rating Scale (DSRS), and the Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) measures.

The 20-IU group experienced a significantly improved delayed story recall compared with the placebo group. The 20-IU group also showed significantly improved functional status on the DSRS. These improvements persisted for 2 months after insulin was ceased.

On the ADCS-ADL, placebo patients declined significantly more than 20-IU patients; 40-IU patients had no change in their score. On the ADAS-cog/MCI test, placebo patients scored significantly worse than both intervention groups, and the 40-IU group scored significantly better than did the 20-IU group.

Dr. Craft said that “it's hard to say for certain in a 4-month study that this would translate into clinical improvement, but on the ADAS-cog, we saw a 25% difference between the highest-dose insulin group and the placebo group. And we also saw improvements in a caregiver-rated functional scale. So I would say that these findings do suggest clinical improvement.”

The fact that the improvements were maintained throughout the study and even after treatment stopped suggests that insulin has a cumulative effect in improving brain function, she added.

In a subgroup of 40 patients who underwent fluorodeoxyglucose PET scanning at baseline and during follow-up, those taking placebo showed a slowing of the cerebral metabolic rate for glucose utilization. This slowing was not seen in either the 20-IU or 40-IU subjects—a finding that Dr. Craft suggested may show slowing of disease progression.

“This is a new and very encouraging finding,” she said.

Major Finding: Intranasally delivered insulin boosted cognition and brain activity in patients with mild cognitive impairment and early Alzheimer's disease.

Data Source: A placebo-controlled trial that randomized 104 patients to placebo or to 20 IU or 40 IU of intranasal insulin every day for 4 months.

Disclosures: The study was sponsored by the National Institute on Aging and the Department of Veterans Affairs. Dr. Craft said she had no financial disclosures.

Intranasal insulin boosted cognitive function and even brain activity in patients with mild cognitive impairment and early Alzheimer's disease in a 4-month, randomized, placebo-controlled trial.

The study, presented at the meeting, holds tantalizing hints of an Alzheimer's therapy that could be relatively inexpensive and easy to administer, but more research on a much larger scale is necessary before this science could move into the clinic.

Dr. Suzanne Craft of the University of Washington, Seattle, said growing evidence suggests that insulin may play a key role in cognition and that patients with Alzheimer's disease have significantly disrupted brain-insulin interactions.

“Insulin plays a number of important roles in the brain, and many are functions of great relevance to Alzheimer's disease,” she said in an interview.

Insulin normally crosses the blood-brain barrier to bind with receptors in the hippocampus, frontal cortex, and other regions involved in cognition. “It also enhances memory, we believe through mediating glucose metabolism in the hippocampus, as well as by mediating levels of neurotransmitters, including acetylcholine,” she said.

Insulin also improves blood flow to the brain and works to prevent beta-amyloid from aggregating on neurons. “It appears to help the beta-amyloid move from inside the brain cells to the interstitial space, where it can be cleared,” she said. “It also increases the availability of a specific enzyme that breaks down amyloid.”

In an extension of her previous work, Dr. Craft randomized 104 patients with mild cognitive impairment (MCI) or early Alzheimer's disease to placebo or to 20 or 40 IU daily of intranasal insulin. The compound is sprayed into the nose, where insulin bypasses the blood-brain barrier and travels directly into the brain along the perivascular channels around the olfactory and trigeminal nerves, allowing the drug to bind to brain receptors within 15–30 minutes of administration.

The patients' average age was 73 years. Their mean combined score on three baseline Mini-Mental State Examination tests was about 82. All patients took the Alzheimer's Disease Assessment Scale cognitive test for MCI (ADAS-cog/MCI), the Dementia Severity Rating Scale (DSRS), and the Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) measures.

The 20-IU group experienced a significantly improved delayed story recall compared with the placebo group. The 20-IU group also showed significantly improved functional status on the DSRS. These improvements persisted for 2 months after insulin was ceased.

On the ADCS-ADL, placebo patients declined significantly more than 20-IU patients; 40-IU patients had no change in their score. On the ADAS-cog/MCI test, placebo patients scored significantly worse than both intervention groups, and the 40-IU group scored significantly better than did the 20-IU group.

Dr. Craft said that “it's hard to say for certain in a 4-month study that this would translate into clinical improvement, but on the ADAS-cog, we saw a 25% difference between the highest-dose insulin group and the placebo group. And we also saw improvements in a caregiver-rated functional scale. So I would say that these findings do suggest clinical improvement.”

The fact that the improvements were maintained throughout the study and even after treatment stopped suggests that insulin has a cumulative effect in improving brain function, she added.

In a subgroup of 40 patients who underwent fluorodeoxyglucose PET scanning at baseline and during follow-up, those taking placebo showed a slowing of the cerebral metabolic rate for glucose utilization. This slowing was not seen in either the 20-IU or 40-IU subjects—a finding that Dr. Craft suggested may show slowing of disease progression.

“This is a new and very encouraging finding,” she said.

Major Finding: A diagnosis of type 1 or 2 diabetes appears to significantly increase the risk of incident depression, especially in younger men.

Data Source: An analysis of a population database containing more than 75,000 people who developed diabetes.

Disclosures: The study was sponsored by the Steno Diabetes Center, which is an independent academic institution owned by Novo Nordisk A/S and the Novo Nordisk Foundation. Dr. Rasmussen is an employee of the center.

ORLANDO — Patients with newly diagnosed diabetes also might be at an increased risk of depression, a large Danish registry study has determined.

Men seemed particularly at risk, Dr. Jeppe Nørgaard Rasmussen said. “Men with diabetes were 50% more likely than men without diabetes to develop incident depression,” said Dr. Rasmussen of the Steno Diabetes Center in Gentofte, Denmark, and the University of Copenhagen.

The relative risk for women, although lower, was still significantly higher than the risk of depression among women without diabetes (relative risk, 1.25).

Dr. Rasmussen analyzed a national Danish health care registry that included information on all citizens of Denmark aged 30–100 years and free from diabetes and depression at baseline (3.8 million). The study period covered 2000–2006.

The primary outcome was development of depression (defined as at least one health care claim for prescription antidepressant medication, or a first hospitalization for depression).

Of the 3.8 million person cohort, 75,101 developed diabetes, with 1,955 classified as type 1 and 73,146 as type 2. Incident depression developed in 44,441 who were admitted to the hospital for depression and in 567,358 who had antidepressant medication claims.

A diagnosis of type 2 diabetes was associated with a significantly increased risk of depression in both men and women, particularly in those aged 30–39 years.

After adjustment for age, socioeconomic status, and education, the relative risk of hospital admission for depression for men with diabetes was 1.73; for women, it was 1.21.

The relative risk for antidepressant medication for men with diabetes was 1.46; for women, it was 1.20.

The risk was similarly increased in patients of both sexes aged 40–49 years.

For men, the risk of hospital admission was 1.43 and for antidepressant drugs, 1.36.

For women, the relative risk for admission was 1.53 and for medications, 1.36. The risk decreased with increasing age.

In an age/sex analysis, the diagnosis of type 1 diabetes for men aged 30–39 years resulted in a relative risk of 2.76 for hospital admission for depression and 1.57 for antidepressant medication. For women of the same age, the risk for admission was 1.57 and for medication, 1.69. The risks became equaled for patients aged 40–49 years.

For men, the risk of hospital admission was 2.98 and for antidepressant drugs, 2.23. For women the same age, the relative risk for admission was 3.86 and for medications, 1.90.

Because the two disorders seem to have a bidirectional association, it's difficult to draw any conclusions about the causal nature of their relationship, Dr. Rasmussen said.

The diabetes-depression link was significant in men and women, particularly those aged 30–39 years.

Source DR. RASMUSSEN

Major Finding: A diagnosis of type 1 or 2 diabetes appears to significantly increase the risk of incident depression, especially in younger men.

Data Source: An analysis of a population database containing more than 75,000 people who developed diabetes.

Disclosures: The study was sponsored by the Steno Diabetes Center, which is an independent academic institution owned by Novo Nordisk A/S and the Novo Nordisk Foundation. Dr. Rasmussen is an employee of the center.

ORLANDO — Patients with newly diagnosed diabetes also might be at an increased risk of depression, a large Danish registry study has determined.

Men seemed particularly at risk, Dr. Jeppe Nørgaard Rasmussen said. “Men with diabetes were 50% more likely than men without diabetes to develop incident depression,” said Dr. Rasmussen of the Steno Diabetes Center in Gentofte, Denmark, and the University of Copenhagen.

The relative risk for women, although lower, was still significantly higher than the risk of depression among women without diabetes (relative risk, 1.25).

Dr. Rasmussen analyzed a national Danish health care registry that included information on all citizens of Denmark aged 30–100 years and free from diabetes and depression at baseline (3.8 million). The study period covered 2000–2006.

The primary outcome was development of depression (defined as at least one health care claim for prescription antidepressant medication, or a first hospitalization for depression).

Of the 3.8 million person cohort, 75,101 developed diabetes, with 1,955 classified as type 1 and 73,146 as type 2. Incident depression developed in 44,441 who were admitted to the hospital for depression and in 567,358 who had antidepressant medication claims.

A diagnosis of type 2 diabetes was associated with a significantly increased risk of depression in both men and women, particularly in those aged 30–39 years.

After adjustment for age, socioeconomic status, and education, the relative risk of hospital admission for depression for men with diabetes was 1.73; for women, it was 1.21.

The relative risk for antidepressant medication for men with diabetes was 1.46; for women, it was 1.20.

The risk was similarly increased in patients of both sexes aged 40–49 years.

For men, the risk of hospital admission was 1.43 and for antidepressant drugs, 1.36.

For women, the relative risk for admission was 1.53 and for medications, 1.36. The risk decreased with increasing age.

In an age/sex analysis, the diagnosis of type 1 diabetes for men aged 30–39 years resulted in a relative risk of 2.76 for hospital admission for depression and 1.57 for antidepressant medication. For women of the same age, the risk for admission was 1.57 and for medication, 1.69. The risks became equaled for patients aged 40–49 years.

For men, the risk of hospital admission was 2.98 and for antidepressant drugs, 2.23. For women the same age, the relative risk for admission was 3.86 and for medications, 1.90.

Because the two disorders seem to have a bidirectional association, it's difficult to draw any conclusions about the causal nature of their relationship, Dr. Rasmussen said.

The diabetes-depression link was significant in men and women, particularly those aged 30–39 years.

Source DR. RASMUSSEN

Major Finding: A diagnosis of type 1 or 2 diabetes appears to significantly increase the risk of incident depression, especially in younger men.

Data Source: An analysis of a population database containing more than 75,000 people who developed diabetes.

Disclosures: The study was sponsored by the Steno Diabetes Center, which is an independent academic institution owned by Novo Nordisk A/S and the Novo Nordisk Foundation. Dr. Rasmussen is an employee of the center.

ORLANDO — Patients with newly diagnosed diabetes also might be at an increased risk of depression, a large Danish registry study has determined.

Men seemed particularly at risk, Dr. Jeppe Nørgaard Rasmussen said. “Men with diabetes were 50% more likely than men without diabetes to develop incident depression,” said Dr. Rasmussen of the Steno Diabetes Center in Gentofte, Denmark, and the University of Copenhagen.

The relative risk for women, although lower, was still significantly higher than the risk of depression among women without diabetes (relative risk, 1.25).

Dr. Rasmussen analyzed a national Danish health care registry that included information on all citizens of Denmark aged 30–100 years and free from diabetes and depression at baseline (3.8 million). The study period covered 2000–2006.

The primary outcome was development of depression (defined as at least one health care claim for prescription antidepressant medication, or a first hospitalization for depression).

Of the 3.8 million person cohort, 75,101 developed diabetes, with 1,955 classified as type 1 and 73,146 as type 2. Incident depression developed in 44,441 who were admitted to the hospital for depression and in 567,358 who had antidepressant medication claims.

A diagnosis of type 2 diabetes was associated with a significantly increased risk of depression in both men and women, particularly in those aged 30–39 years.

After adjustment for age, socioeconomic status, and education, the relative risk of hospital admission for depression for men with diabetes was 1.73; for women, it was 1.21.

The relative risk for antidepressant medication for men with diabetes was 1.46; for women, it was 1.20.

The risk was similarly increased in patients of both sexes aged 40–49 years.

For men, the risk of hospital admission was 1.43 and for antidepressant drugs, 1.36.

For women, the relative risk for admission was 1.53 and for medications, 1.36. The risk decreased with increasing age.

In an age/sex analysis, the diagnosis of type 1 diabetes for men aged 30–39 years resulted in a relative risk of 2.76 for hospital admission for depression and 1.57 for antidepressant medication. For women of the same age, the risk for admission was 1.57 and for medication, 1.69. The risks became equaled for patients aged 40–49 years.

For men, the risk of hospital admission was 2.98 and for antidepressant drugs, 2.23. For women the same age, the relative risk for admission was 3.86 and for medications, 1.90.

Because the two disorders seem to have a bidirectional association, it's difficult to draw any conclusions about the causal nature of their relationship, Dr. Rasmussen said.

The diabetes-depression link was significant in men and women, particularly those aged 30–39 years.

Source DR. RASMUSSEN

Major Finding: Particular variants of the TOMM40 gene are associated with declines in regional gray matter volume and in verbal learning and memory that may presage Alzheimer's disease.

Data Source: Two prospective studies of healthy volunteers with TOMM40 genotyping, one involving MR imaging of 117 participants and another involving verbal learning and memory testing in 337 participants.

Disclosures: Both studies were funded by the National Institute on Aging. Neither investigator had any potential financial conflict.

People who have a newly discovered gene variant that increases the risk of Alzheimer's disease appear to experience subtle changes in both cognition and brain structure years before even the earliest signs of Alzheimer's appear.

The gene, TOMM40, was associated with small but measurable declines in verbal learning and memory, and with decreases in gray matter volume, particularly in the posterior cingulate and precuneus—both areas that are highly involved with memory retrieval.

“Brain changes in these regions are particularly interesting because they are also associated with a high amyloid burden in people with Alzheimer's,” Sterling Johnson, Ph.D., said in an interview. “Many studies have shown that these areas are active when you are recalling the recent past. So seeing changes there fits very nicely with a major symptom of Alzheimer's: recent memory loss.”

Dr. Johnson and Dr. Mark Sager, both of the University of Wisconsin, Madison, said the work may open an important door on the ability to risk-stratify patients for early treatment, potentially identifying them before they experience significant brain damage from the disease. “Right now we're spending billions of dollars on trying to find a disease-modifying therapy, but we don't really know who we would give that to,” Dr. Johnson said. In the same way that those with high cholesterol benefit most from statins, patients with a demonstrated risk of Alzheimer's would be the best candidates for any drug therapy, he noted.

TOMM40 has variable lengths that are defined by how many thymidine bases are contained in a specific section of the gene. The very long form (30 or more thymidine bases) is associated with an earlier onset of Alzheimer's disease, whereas the very short length (20 or fewer) is associated with a later onset. Some people have a long form (20-30 bases) that confers intermediate risk for Alzheimer's disease.

In 2009, researchers at Duke University, Durham, N.C., first showed that among patients who developed Alzheimer's after 60 years of age and were homozygous or heterozygous for the apolipoprotein E e3 (APOE-3) allele, those with two copies of the long TOMM40 developed the disease an average of 7 years earlier than did those with shorter TOMM40 lengths (Pharmacogenomics J. 2009 Dec. 22 [doi:10.1038/tpj.2009.69]).

Dr. Johnson's study consisted of 117 healthy volunteers (mean age, 57 years) who were known to be homozygous for the APOE-3 allele. APOE-3 homozygotes are thought to have a neutral risk for Alzheimer's disease. He then tested the subjects to determine what variant of TOMM40 they had.

In Dr. Johnson's study group, 38 patients were homozygous for the very short length TOMM40; 44 had one short and one long or very long allele; and 35 were homozygous for the very long form of TOMM40. All of the volunteers underwent brain scanning with voxel-based morphometry to assess gray matter volume in different brain regions.

The subjects with two copies of the very long TOMM40 allele had significantly less gray matter in both the ventral posterior cingulate and the precuneus than did those with two short alleles. These are both regions that show early deterioration in late-onset Alzheimer's disease. “This is very important, because we are finding brain changes in people who are quite young,” Dr. Johnson said. “The brain differences between the groups were very similar to, but less severe than, what is observed in full-blown Alzheimer's. It may be that the TOMM40 gene will be a useful measure of Alzheimer's risk in middle age, but additional research with longitudinal follow-up is necessary.”

Dr. Sager examined the gene's potential effect on memory in a cohort of 337 adults (mean age, 54) who were genotyped for APOE and TOMM40. Of these, 128 were homozygous for the short form of TOMM40, indicating a lower risk. The long or very long forms were seen in 219 subjects. In the low-risk group, 57% had a family history of Alzheimer's, compared with 77% of the high-risk group—a significant difference.

All subjects took the Auditory-Verbal Learning Test, which involves five trials of learning two 15-word sets. The mean scores for both groups were within the normal range, but the mean was significantly lower in the group with longer forms of TOMM40.

He stressed that none of the subjects in either the brain volume study or the memory study had any observable memory difficulties in their everyday life. “But these findings of gray matter loss and cognitive changes in these relatively young people are very important,” and suggest that “we may have the ability to find people at risk of Alzheimer's very early on in the disease process, far in advance of any significant cognitive problems.”

Patients with short TOMM40 had greater gray matter volume that did those with two very long versions.

Source Courtesy Dr. Sterling Johnson

Major Finding: Particular variants of the TOMM40 gene are associated with declines in regional gray matter volume and in verbal learning and memory that may presage Alzheimer's disease.

Data Source: Two prospective studies of healthy volunteers with TOMM40 genotyping, one involving MR imaging of 117 participants and another involving verbal learning and memory testing in 337 participants.

Disclosures: Both studies were funded by the National Institute on Aging. Neither investigator had any potential financial conflict.

People who have a newly discovered gene variant that increases the risk of Alzheimer's disease appear to experience subtle changes in both cognition and brain structure years before even the earliest signs of Alzheimer's appear.

The gene, TOMM40, was associated with small but measurable declines in verbal learning and memory, and with decreases in gray matter volume, particularly in the posterior cingulate and precuneus—both areas that are highly involved with memory retrieval.

“Brain changes in these regions are particularly interesting because they are also associated with a high amyloid burden in people with Alzheimer's,” Sterling Johnson, Ph.D., said in an interview. “Many studies have shown that these areas are active when you are recalling the recent past. So seeing changes there fits very nicely with a major symptom of Alzheimer's: recent memory loss.”

Dr. Johnson and Dr. Mark Sager, both of the University of Wisconsin, Madison, said the work may open an important door on the ability to risk-stratify patients for early treatment, potentially identifying them before they experience significant brain damage from the disease. “Right now we're spending billions of dollars on trying to find a disease-modifying therapy, but we don't really know who we would give that to,” Dr. Johnson said. In the same way that those with high cholesterol benefit most from statins, patients with a demonstrated risk of Alzheimer's would be the best candidates for any drug therapy, he noted.

TOMM40 has variable lengths that are defined by how many thymidine bases are contained in a specific section of the gene. The very long form (30 or more thymidine bases) is associated with an earlier onset of Alzheimer's disease, whereas the very short length (20 or fewer) is associated with a later onset. Some people have a long form (20-30 bases) that confers intermediate risk for Alzheimer's disease.

In 2009, researchers at Duke University, Durham, N.C., first showed that among patients who developed Alzheimer's after 60 years of age and were homozygous or heterozygous for the apolipoprotein E e3 (APOE-3) allele, those with two copies of the long TOMM40 developed the disease an average of 7 years earlier than did those with shorter TOMM40 lengths (Pharmacogenomics J. 2009 Dec. 22 [doi:10.1038/tpj.2009.69]).

Dr. Johnson's study consisted of 117 healthy volunteers (mean age, 57 years) who were known to be homozygous for the APOE-3 allele. APOE-3 homozygotes are thought to have a neutral risk for Alzheimer's disease. He then tested the subjects to determine what variant of TOMM40 they had.

In Dr. Johnson's study group, 38 patients were homozygous for the very short length TOMM40; 44 had one short and one long or very long allele; and 35 were homozygous for the very long form of TOMM40. All of the volunteers underwent brain scanning with voxel-based morphometry to assess gray matter volume in different brain regions.

The subjects with two copies of the very long TOMM40 allele had significantly less gray matter in both the ventral posterior cingulate and the precuneus than did those with two short alleles. These are both regions that show early deterioration in late-onset Alzheimer's disease. “This is very important, because we are finding brain changes in people who are quite young,” Dr. Johnson said. “The brain differences between the groups were very similar to, but less severe than, what is observed in full-blown Alzheimer's. It may be that the TOMM40 gene will be a useful measure of Alzheimer's risk in middle age, but additional research with longitudinal follow-up is necessary.”

Dr. Sager examined the gene's potential effect on memory in a cohort of 337 adults (mean age, 54) who were genotyped for APOE and TOMM40. Of these, 128 were homozygous for the short form of TOMM40, indicating a lower risk. The long or very long forms were seen in 219 subjects. In the low-risk group, 57% had a family history of Alzheimer's, compared with 77% of the high-risk group—a significant difference.

All subjects took the Auditory-Verbal Learning Test, which involves five trials of learning two 15-word sets. The mean scores for both groups were within the normal range, but the mean was significantly lower in the group with longer forms of TOMM40.

He stressed that none of the subjects in either the brain volume study or the memory study had any observable memory difficulties in their everyday life. “But these findings of gray matter loss and cognitive changes in these relatively young people are very important,” and suggest that “we may have the ability to find people at risk of Alzheimer's very early on in the disease process, far in advance of any significant cognitive problems.”

Patients with short TOMM40 had greater gray matter volume that did those with two very long versions.

Source Courtesy Dr. Sterling Johnson

Major Finding: Particular variants of the TOMM40 gene are associated with declines in regional gray matter volume and in verbal learning and memory that may presage Alzheimer's disease.

Data Source: Two prospective studies of healthy volunteers with TOMM40 genotyping, one involving MR imaging of 117 participants and another involving verbal learning and memory testing in 337 participants.

Disclosures: Both studies were funded by the National Institute on Aging. Neither investigator had any potential financial conflict.

People who have a newly discovered gene variant that increases the risk of Alzheimer's disease appear to experience subtle changes in both cognition and brain structure years before even the earliest signs of Alzheimer's appear.

The gene, TOMM40, was associated with small but measurable declines in verbal learning and memory, and with decreases in gray matter volume, particularly in the posterior cingulate and precuneus—both areas that are highly involved with memory retrieval.

“Brain changes in these regions are particularly interesting because they are also associated with a high amyloid burden in people with Alzheimer's,” Sterling Johnson, Ph.D., said in an interview. “Many studies have shown that these areas are active when you are recalling the recent past. So seeing changes there fits very nicely with a major symptom of Alzheimer's: recent memory loss.”

Dr. Johnson and Dr. Mark Sager, both of the University of Wisconsin, Madison, said the work may open an important door on the ability to risk-stratify patients for early treatment, potentially identifying them before they experience significant brain damage from the disease. “Right now we're spending billions of dollars on trying to find a disease-modifying therapy, but we don't really know who we would give that to,” Dr. Johnson said. In the same way that those with high cholesterol benefit most from statins, patients with a demonstrated risk of Alzheimer's would be the best candidates for any drug therapy, he noted.

TOMM40 has variable lengths that are defined by how many thymidine bases are contained in a specific section of the gene. The very long form (30 or more thymidine bases) is associated with an earlier onset of Alzheimer's disease, whereas the very short length (20 or fewer) is associated with a later onset. Some people have a long form (20-30 bases) that confers intermediate risk for Alzheimer's disease.

In 2009, researchers at Duke University, Durham, N.C., first showed that among patients who developed Alzheimer's after 60 years of age and were homozygous or heterozygous for the apolipoprotein E e3 (APOE-3) allele, those with two copies of the long TOMM40 developed the disease an average of 7 years earlier than did those with shorter TOMM40 lengths (Pharmacogenomics J. 2009 Dec. 22 [doi:10.1038/tpj.2009.69]).

Dr. Johnson's study consisted of 117 healthy volunteers (mean age, 57 years) who were known to be homozygous for the APOE-3 allele. APOE-3 homozygotes are thought to have a neutral risk for Alzheimer's disease. He then tested the subjects to determine what variant of TOMM40 they had.

In Dr. Johnson's study group, 38 patients were homozygous for the very short length TOMM40; 44 had one short and one long or very long allele; and 35 were homozygous for the very long form of TOMM40. All of the volunteers underwent brain scanning with voxel-based morphometry to assess gray matter volume in different brain regions.

The subjects with two copies of the very long TOMM40 allele had significantly less gray matter in both the ventral posterior cingulate and the precuneus than did those with two short alleles. These are both regions that show early deterioration in late-onset Alzheimer's disease. “This is very important, because we are finding brain changes in people who are quite young,” Dr. Johnson said. “The brain differences between the groups were very similar to, but less severe than, what is observed in full-blown Alzheimer's. It may be that the TOMM40 gene will be a useful measure of Alzheimer's risk in middle age, but additional research with longitudinal follow-up is necessary.”

Dr. Sager examined the gene's potential effect on memory in a cohort of 337 adults (mean age, 54) who were genotyped for APOE and TOMM40. Of these, 128 were homozygous for the short form of TOMM40, indicating a lower risk. The long or very long forms were seen in 219 subjects. In the low-risk group, 57% had a family history of Alzheimer's, compared with 77% of the high-risk group—a significant difference.

All subjects took the Auditory-Verbal Learning Test, which involves five trials of learning two 15-word sets. The mean scores for both groups were within the normal range, but the mean was significantly lower in the group with longer forms of TOMM40.

He stressed that none of the subjects in either the brain volume study or the memory study had any observable memory difficulties in their everyday life. “But these findings of gray matter loss and cognitive changes in these relatively young people are very important,” and suggest that “we may have the ability to find people at risk of Alzheimer's very early on in the disease process, far in advance of any significant cognitive problems.”

Patients with short TOMM40 had greater gray matter volume that did those with two very long versions.

Source Courtesy Dr. Sterling Johnson

An interactive telephone- and Web-based service now lets Alzheimer's patients, caregivers, and their physicians connect more easily with ongoing clinical trials.

The service—Alzheimer's Association TrialMatch—has the potential to greatly enrich the research into more effective treatment options and the ultimate goal of an Alzheimer's cure, William Thies, Ph.D., chief medical officer of the Alzheimer's Association, said at a press briefing. “Alzheimer's disease is clearly the No. 1 health challenge of the 21st century, and research is the only way to solve this problem,” Dr. Thies said at the meeting in Honolulu. “TrialMatch provides a first-of-its-kind service in Alzheimer's by delivering a user-friendly and individualized guide to clinical trials.”

Approximately 150 clinical studies for Alzheimer's and dementia are ongoing, but not enough patients volunteer for them, Dr. Reisa Sperling said in an interview. “At the rate we have people signing up now, it takes 12-18 months just to complete enrollment,” said Dr. Sperling, director of clinical research at the memory disorders unit of Brigham and Women's Hospital, Boston.

Currently, there are 10 drugs in large-scale clinical trials and another 20 in preclinical studies. Even when patients do volunteer for trials, screening eliminates many candidates, she said. “For every patient we enroll, we typically need to screen three or four. TrialMatch will collect detailed information in a confidential way, online, and that will speed up the matching process considerably.”

Interested parties can visit the TrialMatch Web site (www.alz.org/TrialMatch

The studies included on TrialMatch include large, industry-sponsored drug trials, natural history and imaging studies, federally funded trials, and smaller, investigator-initiated studies. All of them are important, Dr. Sperling noted.

Alzheimer's disease threatens to overwhelm the national health care scene in the next 50 years, when there could be 1 million new cases diagnosed each year in the United States alone. “I'd like to take a page from the success some of my oncology colleagues have seen,” Dr. Sperling said. “For example, as soon as 80% of children with certain pediatric tumors began enrolling in research, there were huge leaps forward in finding treatment. Finding answers is directly proportional to research.”

Entering a clinical trial also is an important way for both physicians and patients to claim some power in a situation that can make them feel quite helpless, she added. “I hope this can change the landscape of thinking about what patients and doctors can do to be proactive about this disease. Instead of hiding from it, let's agree to fight it tooth and nail.”

Dr. Eric Tangalos, codirector of education for the Mayo Clinic's Alzheimer's Disease Research Center in Rochester, Minn., agreed. “TrialMatch is a wonderful innovation,” he said in an interview. “As a primary care physician, I want my patients and families to run toward a diagnosis rather than away from it. Moreover, people who volunteer for research studies tend to do better than people who do not volunteer. There is not only the direct benefit of being engaged but [also] a social and societal advantage that plays out positively for the volunteer.”

Disclosures: TrialMatch is funded by the Alzheimer's Association. Dr. Sperling and Dr. Tangalos had no relevant disclosures.

An interactive telephone- and Web-based service now lets Alzheimer's patients, caregivers, and their physicians connect more easily with ongoing clinical trials.

The service—Alzheimer's Association TrialMatch—has the potential to greatly enrich the research into more effective treatment options and the ultimate goal of an Alzheimer's cure, William Thies, Ph.D., chief medical officer of the Alzheimer's Association, said at a press briefing. “Alzheimer's disease is clearly the No. 1 health challenge of the 21st century, and research is the only way to solve this problem,” Dr. Thies said at the meeting in Honolulu. “TrialMatch provides a first-of-its-kind service in Alzheimer's by delivering a user-friendly and individualized guide to clinical trials.”

Approximately 150 clinical studies for Alzheimer's and dementia are ongoing, but not enough patients volunteer for them, Dr. Reisa Sperling said in an interview. “At the rate we have people signing up now, it takes 12-18 months just to complete enrollment,” said Dr. Sperling, director of clinical research at the memory disorders unit of Brigham and Women's Hospital, Boston.

Currently, there are 10 drugs in large-scale clinical trials and another 20 in preclinical studies. Even when patients do volunteer for trials, screening eliminates many candidates, she said. “For every patient we enroll, we typically need to screen three or four. TrialMatch will collect detailed information in a confidential way, online, and that will speed up the matching process considerably.”

Interested parties can visit the TrialMatch Web site (www.alz.org/TrialMatch

The studies included on TrialMatch include large, industry-sponsored drug trials, natural history and imaging studies, federally funded trials, and smaller, investigator-initiated studies. All of them are important, Dr. Sperling noted.

Alzheimer's disease threatens to overwhelm the national health care scene in the next 50 years, when there could be 1 million new cases diagnosed each year in the United States alone. “I'd like to take a page from the success some of my oncology colleagues have seen,” Dr. Sperling said. “For example, as soon as 80% of children with certain pediatric tumors began enrolling in research, there were huge leaps forward in finding treatment. Finding answers is directly proportional to research.”

Entering a clinical trial also is an important way for both physicians and patients to claim some power in a situation that can make them feel quite helpless, she added. “I hope this can change the landscape of thinking about what patients and doctors can do to be proactive about this disease. Instead of hiding from it, let's agree to fight it tooth and nail.”

Dr. Eric Tangalos, codirector of education for the Mayo Clinic's Alzheimer's Disease Research Center in Rochester, Minn., agreed. “TrialMatch is a wonderful innovation,” he said in an interview. “As a primary care physician, I want my patients and families to run toward a diagnosis rather than away from it. Moreover, people who volunteer for research studies tend to do better than people who do not volunteer. There is not only the direct benefit of being engaged but [also] a social and societal advantage that plays out positively for the volunteer.”

Disclosures: TrialMatch is funded by the Alzheimer's Association. Dr. Sperling and Dr. Tangalos had no relevant disclosures.

An interactive telephone- and Web-based service now lets Alzheimer's patients, caregivers, and their physicians connect more easily with ongoing clinical trials.

The service—Alzheimer's Association TrialMatch—has the potential to greatly enrich the research into more effective treatment options and the ultimate goal of an Alzheimer's cure, William Thies, Ph.D., chief medical officer of the Alzheimer's Association, said at a press briefing. “Alzheimer's disease is clearly the No. 1 health challenge of the 21st century, and research is the only way to solve this problem,” Dr. Thies said at the meeting in Honolulu. “TrialMatch provides a first-of-its-kind service in Alzheimer's by delivering a user-friendly and individualized guide to clinical trials.”

Approximately 150 clinical studies for Alzheimer's and dementia are ongoing, but not enough patients volunteer for them, Dr. Reisa Sperling said in an interview. “At the rate we have people signing up now, it takes 12-18 months just to complete enrollment,” said Dr. Sperling, director of clinical research at the memory disorders unit of Brigham and Women's Hospital, Boston.

Currently, there are 10 drugs in large-scale clinical trials and another 20 in preclinical studies. Even when patients do volunteer for trials, screening eliminates many candidates, she said. “For every patient we enroll, we typically need to screen three or four. TrialMatch will collect detailed information in a confidential way, online, and that will speed up the matching process considerably.”

Interested parties can visit the TrialMatch Web site (www.alz.org/TrialMatch

The studies included on TrialMatch include large, industry-sponsored drug trials, natural history and imaging studies, federally funded trials, and smaller, investigator-initiated studies. All of them are important, Dr. Sperling noted.

Alzheimer's disease threatens to overwhelm the national health care scene in the next 50 years, when there could be 1 million new cases diagnosed each year in the United States alone. “I'd like to take a page from the success some of my oncology colleagues have seen,” Dr. Sperling said. “For example, as soon as 80% of children with certain pediatric tumors began enrolling in research, there were huge leaps forward in finding treatment. Finding answers is directly proportional to research.”

Entering a clinical trial also is an important way for both physicians and patients to claim some power in a situation that can make them feel quite helpless, she added. “I hope this can change the landscape of thinking about what patients and doctors can do to be proactive about this disease. Instead of hiding from it, let's agree to fight it tooth and nail.”

Dr. Eric Tangalos, codirector of education for the Mayo Clinic's Alzheimer's Disease Research Center in Rochester, Minn., agreed. “TrialMatch is a wonderful innovation,” he said in an interview. “As a primary care physician, I want my patients and families to run toward a diagnosis rather than away from it. Moreover, people who volunteer for research studies tend to do better than people who do not volunteer. There is not only the direct benefit of being engaged but [also] a social and societal advantage that plays out positively for the volunteer.”

Disclosures: TrialMatch is funded by the Alzheimer's Association. Dr. Sperling and Dr. Tangalos had no relevant disclosures.

Updated diagnostic criteria for Alzheimer's disease will allow physicians to identify patients in the earliest possible stages of the disease, capitalizing on the treatments now available and enriching therapeutic research.

Unveiled at the meeting, the proposed criteria are the first updates to Alzheimer's diagnosis in 25 years, Dr. Ronald Peterson said in an interview.

“Our current criteria were established in 1984,” said Dr. Peterson, director of the Mayo Clinic Alzheimer Disease Research Center, Rochester, Minn. “They functioned well for 25 years, but they were completely syndromic. The field has moved on. There has been an explosion of information, including neuroimaging and biomarkers, which allows us to recognize a milder state of clinical impairment and is informing us about the underlying pathology. These need to be included in our diagnostic workups.”

The new criteria form the basis of a more flexible diagnostic tool—one that can be annually revisited and updated as new data demand, he said.

The National Institute on Aging and the Alzheimer's Association agreed last year to examine how to better incorporate new knowledge into the existing diagnostic criteria. The agencies created work groups to explore this idea in three stages of the disease process—preclinical, mild cognitive impairment, and Alzheimer's dementia.

Dr. Reisa Sperling, director of clinical research at the Memory Disorders Unit, Brigham and Women's Hospital, Boston, headed the preclinical group. “For me, this is the most exciting area, because it's the newest,” she said in an interview. “We have never tried to set criteria to diagnose Alzheimer's before there is significant clinical impairment.”

And yet, she said, this period may be the most crucial, for two reasons. First, because the earlier existing treatments are employed, the more effective they are. Second, because identifying a prodromal stage of Alzheimer's will, eventually, be key to developing new therapies.

Alzheimer's has never been viewed as a disease with an identifiable, but asymptomatic, prodromal state. “Our best chance at treating the disease and changing its course will be to treat before any symptoms appear, or when there are only very mild symptoms,” Dr. Sperling said.

The preclinical group identified three diagnostic criteria for the earliest stage of Alzheimer's:

▸ Asymptomatic amyloidosis, defined by evidence of abnormal levels of amyloid in the spinal fluid or on a brain scan, but no cognitive or functional symptoms.

▸ Amyloidosis plus one other marker of disease, which could be brain atrophy on imaging, functional abnormalities on positron emission tomography (PET), or abnormal levels of phosphorylated tau in spinal fluid.

▸ Amyloidosis plus a biomarker and slight cognitive symptoms. “This may be the most important stage, because there is good evidence that people experience cognitive changes years before they progress to mild cognitive impairment,” Dr. Sperling said. “Right now, we can't differentiate normal aging from the very beginning of Alzheimer's. But the combination of these biomarkers and memory trouble will allow us to predict who is on the Alzheimer's trajectory.”

Research may especially benefit from this identification, because drugs to slow or halt disease progression will be most effective in patients with the least neuronal damage, she added.

Dr. Peterson is a member of the work group that examined diagnostic criteria for mild cognitive impairment (MCI). That group also identified three criteria:

▸ The already-established clinical syndrome of MCI in which patients are aware of their memory problem and have a measurable deficit, but other cognitive and functional skills are preserved.

▸ In addition to MCI, there is some evidence of change in brain topography—either hippocampal atrophy or hypometabolic brain regions.

▸ In addition to MCI and topographical brain changes, a confirmed measure of amyloid abnormality, including reduced amyloid-beta₄₂ in cerebrospinal fluid (indicating its accumulation in the brain) or positive amyloid brain imaging.

“This represents the progression in a perfect world,” Dr. Peterson said. “But the devil is in the details. What if you have the clinical syndrome but your biomarkers go in the opposite direction, or you have an incomplete set? That is where research is going to fill in the gaps in our knowledge.”

Dr. John Morris, director of the Alzheimer's Disease Research Center at Washington University, St. Louis, is a member of the dementia working group. Because diagnostic algorithms for dementia were already in place—albeit 25 years old—his group made modifications to the existing criteria.

“With the addition of biomarkers to support the clinical suspicion of dementia, we have been able to strengthen those criteria substantially, giving physicians the ability to be much more confident in their diagnoses,” Dr. Morris said.

Previously, the only way to obtain a definitive Alzheimer's disease diagnosis was through brain autopsy; the presence of amyloid plaques and neurofibrillary tangles has been the key diagnostic feature. “With these strengthened criteria, we can now diagnose it in a living person.”

Documented and measurable memory deficits in the presence of at least one biomarker now correlates to the diagnosis of “probable Alzheimer's.” In addition to memory deficits, the presence of several biomarkers—structural brain changes, functional brain changes, positive amyloid imaging, spinal fluid abnormalities, or genetic markers—can strengthen the diagnosis of probable disease.

The presence of a genetic marker in this mix, especially the apolipoprotein E e4 allele, equates to a definitive diagnosis.

The work groups are now seeking feedback on the criteria. Comments can be submitted to the Alzheimer's Association Web site (www.alz.org/research/diagnostic_criteria

“By the time symptoms appear, there has already been substantial neuronal loss in critical brain areas, and it's been impossible to arrest the disease once this damage has occurred,” Dr. Morris said. “It makes great sense to intervene earlier—even before MCI—to see if we can treat with the hope of preventing disease progression.

The project was funded by the National Institute on Aging and the Alzheimer's Association. None of the physicians reported any potential financial conflicts.

The criteria may help diagnose AD before there is significant impairment, Dr. Reisa Sperling said.

Source Courtesy Alzheimer's Association/Lucy Pemoni

My Take

The Criteria Mark Our Progress

The proposal to update Alzheimer's disease diagnostic criteria will incorporate the progress made these last 20 years in our understanding of the disease. We already have a number of promising approaches to the disease that include both drug and non-drug interventions and much has been done to understand the basic biology and pathology of disease progression. Even though we have no cure and currently cannot prevent Alzheimer's disease, I prefer my patients to run toward a diagnosis rather than away from it, so I expect that these criteria will help.

With each advance in medicine, more sensitive and specific tests (i.e. biomarkers) are validated and used to diagnose and treat a wide assortment of conditions. This is now the case with Alzheimer's disease. It is the inclusion of these biomarkers in the updated diagnostic criteria that will help us arrive at a diagnosis sooner and to allow us to study a variety of drug and non-drug interventions in an attempt to modify disease progression.

Clinicians use a variety of tools to assess the patient. We use laboratory tests including blood, urine and cerebrospinal fluid, imaging studies, pathologic findings, and interpretation of the history and physical to arrive at our conclusions. The more sensitive and specific the test, the more sure we are that the diagnosis is correct. Alzheimer's disease is coming of age and if new tests move us forward, then we need to incorporate these tools into our plan of care.

Our understanding of amyloid and its toxic role in Alzheimer's disease has led to its inclusion as one of the biomarker criteria. The sophistication of our imaging studies has placed positron emission tomography (PET), targeted radiolabeling, and other imaging modalities into the equation as well. The genetic work that has been done including apolipoprotein E and tau now let us use this information as well in formulating a diagnosis.

As we wait for additional treatments to become available, the new criteria should not be burdensome to the clinician. Those interested in earlier interventions will need to understand these criteria and their application in establishing a diagnosis. We will need to judge if these biomarkers lead us down the right path to be worth the effort in case finding. If the criteria provide us with a more efficient route to therapy, the better we are at addressing the patient and family needs sooner rather than later.

ERIC G. TANGALOS, M.D., is co-director of education at the Mayo Clinic Alzheimer's Disease Research Center. He is also professor of medicine at the Mayo Clinic College of Medicine in Rochester, Minn. Dr. Tangalos is a consultant to Novartis and is on the data safety board for Eli Lilly; his wife owns stock in Johnson& Johnson, all of which have Alzheimer's disease products.

Updated diagnostic criteria for Alzheimer's disease will allow physicians to identify patients in the earliest possible stages of the disease, capitalizing on the treatments now available and enriching therapeutic research.

Unveiled at the meeting, the proposed criteria are the first updates to Alzheimer's diagnosis in 25 years, Dr. Ronald Peterson said in an interview.

“Our current criteria were established in 1984,” said Dr. Peterson, director of the Mayo Clinic Alzheimer Disease Research Center, Rochester, Minn. “They functioned well for 25 years, but they were completely syndromic. The field has moved on. There has been an explosion of information, including neuroimaging and biomarkers, which allows us to recognize a milder state of clinical impairment and is informing us about the underlying pathology. These need to be included in our diagnostic workups.”

The new criteria form the basis of a more flexible diagnostic tool—one that can be annually revisited and updated as new data demand, he said.

The National Institute on Aging and the Alzheimer's Association agreed last year to examine how to better incorporate new knowledge into the existing diagnostic criteria. The agencies created work groups to explore this idea in three stages of the disease process—preclinical, mild cognitive impairment, and Alzheimer's dementia.

Dr. Reisa Sperling, director of clinical research at the Memory Disorders Unit, Brigham and Women's Hospital, Boston, headed the preclinical group. “For me, this is the most exciting area, because it's the newest,” she said in an interview. “We have never tried to set criteria to diagnose Alzheimer's before there is significant clinical impairment.”

And yet, she said, this period may be the most crucial, for two reasons. First, because the earlier existing treatments are employed, the more effective they are. Second, because identifying a prodromal stage of Alzheimer's will, eventually, be key to developing new therapies.

Alzheimer's has never been viewed as a disease with an identifiable, but asymptomatic, prodromal state. “Our best chance at treating the disease and changing its course will be to treat before any symptoms appear, or when there are only very mild symptoms,” Dr. Sperling said.

The preclinical group identified three diagnostic criteria for the earliest stage of Alzheimer's:

▸ Asymptomatic amyloidosis, defined by evidence of abnormal levels of amyloid in the spinal fluid or on a brain scan, but no cognitive or functional symptoms.

▸ Amyloidosis plus one other marker of disease, which could be brain atrophy on imaging, functional abnormalities on positron emission tomography (PET), or abnormal levels of phosphorylated tau in spinal fluid.

▸ Amyloidosis plus a biomarker and slight cognitive symptoms. “This may be the most important stage, because there is good evidence that people experience cognitive changes years before they progress to mild cognitive impairment,” Dr. Sperling said. “Right now, we can't differentiate normal aging from the very beginning of Alzheimer's. But the combination of these biomarkers and memory trouble will allow us to predict who is on the Alzheimer's trajectory.”

Research may especially benefit from this identification, because drugs to slow or halt disease progression will be most effective in patients with the least neuronal damage, she added.

Dr. Peterson is a member of the work group that examined diagnostic criteria for mild cognitive impairment (MCI). That group also identified three criteria:

▸ The already-established clinical syndrome of MCI in which patients are aware of their memory problem and have a measurable deficit, but other cognitive and functional skills are preserved.

▸ In addition to MCI, there is some evidence of change in brain topography—either hippocampal atrophy or hypometabolic brain regions.

▸ In addition to MCI and topographical brain changes, a confirmed measure of amyloid abnormality, including reduced amyloid-beta₄₂ in cerebrospinal fluid (indicating its accumulation in the brain) or positive amyloid brain imaging.

“This represents the progression in a perfect world,” Dr. Peterson said. “But the devil is in the details. What if you have the clinical syndrome but your biomarkers go in the opposite direction, or you have an incomplete set? That is where research is going to fill in the gaps in our knowledge.”

Dr. John Morris, director of the Alzheimer's Disease Research Center at Washington University, St. Louis, is a member of the dementia working group. Because diagnostic algorithms for dementia were already in place—albeit 25 years old—his group made modifications to the existing criteria.

“With the addition of biomarkers to support the clinical suspicion of dementia, we have been able to strengthen those criteria substantially, giving physicians the ability to be much more confident in their diagnoses,” Dr. Morris said.

Previously, the only way to obtain a definitive Alzheimer's disease diagnosis was through brain autopsy; the presence of amyloid plaques and neurofibrillary tangles has been the key diagnostic feature. “With these strengthened criteria, we can now diagnose it in a living person.”

Documented and measurable memory deficits in the presence of at least one biomarker now correlates to the diagnosis of “probable Alzheimer's.” In addition to memory deficits, the presence of several biomarkers—structural brain changes, functional brain changes, positive amyloid imaging, spinal fluid abnormalities, or genetic markers—can strengthen the diagnosis of probable disease.

The presence of a genetic marker in this mix, especially the apolipoprotein E e4 allele, equates to a definitive diagnosis.

The work groups are now seeking feedback on the criteria. Comments can be submitted to the Alzheimer's Association Web site (www.alz.org/research/diagnostic_criteria

“By the time symptoms appear, there has already been substantial neuronal loss in critical brain areas, and it's been impossible to arrest the disease once this damage has occurred,” Dr. Morris said. “It makes great sense to intervene earlier—even before MCI—to see if we can treat with the hope of preventing disease progression.

The project was funded by the National Institute on Aging and the Alzheimer's Association. None of the physicians reported any potential financial conflicts.

The criteria may help diagnose AD before there is significant impairment, Dr. Reisa Sperling said.

Source Courtesy Alzheimer's Association/Lucy Pemoni

My Take

The Criteria Mark Our Progress

The proposal to update Alzheimer's disease diagnostic criteria will incorporate the progress made these last 20 years in our understanding of the disease. We already have a number of promising approaches to the disease that include both drug and non-drug interventions and much has been done to understand the basic biology and pathology of disease progression. Even though we have no cure and currently cannot prevent Alzheimer's disease, I prefer my patients to run toward a diagnosis rather than away from it, so I expect that these criteria will help.

With each advance in medicine, more sensitive and specific tests (i.e. biomarkers) are validated and used to diagnose and treat a wide assortment of conditions. This is now the case with Alzheimer's disease. It is the inclusion of these biomarkers in the updated diagnostic criteria that will help us arrive at a diagnosis sooner and to allow us to study a variety of drug and non-drug interventions in an attempt to modify disease progression.

Clinicians use a variety of tools to assess the patient. We use laboratory tests including blood, urine and cerebrospinal fluid, imaging studies, pathologic findings, and interpretation of the history and physical to arrive at our conclusions. The more sensitive and specific the test, the more sure we are that the diagnosis is correct. Alzheimer's disease is coming of age and if new tests move us forward, then we need to incorporate these tools into our plan of care.

Our understanding of amyloid and its toxic role in Alzheimer's disease has led to its inclusion as one of the biomarker criteria. The sophistication of our imaging studies has placed positron emission tomography (PET), targeted radiolabeling, and other imaging modalities into the equation as well. The genetic work that has been done including apolipoprotein E and tau now let us use this information as well in formulating a diagnosis.

As we wait for additional treatments to become available, the new criteria should not be burdensome to the clinician. Those interested in earlier interventions will need to understand these criteria and their application in establishing a diagnosis. We will need to judge if these biomarkers lead us down the right path to be worth the effort in case finding. If the criteria provide us with a more efficient route to therapy, the better we are at addressing the patient and family needs sooner rather than later.

ERIC G. TANGALOS, M.D., is co-director of education at the Mayo Clinic Alzheimer's Disease Research Center. He is also professor of medicine at the Mayo Clinic College of Medicine in Rochester, Minn. Dr. Tangalos is a consultant to Novartis and is on the data safety board for Eli Lilly; his wife owns stock in Johnson& Johnson, all of which have Alzheimer's disease products.

Updated diagnostic criteria for Alzheimer's disease will allow physicians to identify patients in the earliest possible stages of the disease, capitalizing on the treatments now available and enriching therapeutic research.

Unveiled at the meeting, the proposed criteria are the first updates to Alzheimer's diagnosis in 25 years, Dr. Ronald Peterson said in an interview.

“Our current criteria were established in 1984,” said Dr. Peterson, director of the Mayo Clinic Alzheimer Disease Research Center, Rochester, Minn. “They functioned well for 25 years, but they were completely syndromic. The field has moved on. There has been an explosion of information, including neuroimaging and biomarkers, which allows us to recognize a milder state of clinical impairment and is informing us about the underlying pathology. These need to be included in our diagnostic workups.”

The new criteria form the basis of a more flexible diagnostic tool—one that can be annually revisited and updated as new data demand, he said.

The National Institute on Aging and the Alzheimer's Association agreed last year to examine how to better incorporate new knowledge into the existing diagnostic criteria. The agencies created work groups to explore this idea in three stages of the disease process—preclinical, mild cognitive impairment, and Alzheimer's dementia.

Dr. Reisa Sperling, director of clinical research at the Memory Disorders Unit, Brigham and Women's Hospital, Boston, headed the preclinical group. “For me, this is the most exciting area, because it's the newest,” she said in an interview. “We have never tried to set criteria to diagnose Alzheimer's before there is significant clinical impairment.”

And yet, she said, this period may be the most crucial, for two reasons. First, because the earlier existing treatments are employed, the more effective they are. Second, because identifying a prodromal stage of Alzheimer's will, eventually, be key to developing new therapies.

Alzheimer's has never been viewed as a disease with an identifiable, but asymptomatic, prodromal state. “Our best chance at treating the disease and changing its course will be to treat before any symptoms appear, or when there are only very mild symptoms,” Dr. Sperling said.

The preclinical group identified three diagnostic criteria for the earliest stage of Alzheimer's:

▸ Asymptomatic amyloidosis, defined by evidence of abnormal levels of amyloid in the spinal fluid or on a brain scan, but no cognitive or functional symptoms.

▸ Amyloidosis plus one other marker of disease, which could be brain atrophy on imaging, functional abnormalities on positron emission tomography (PET), or abnormal levels of phosphorylated tau in spinal fluid.

▸ Amyloidosis plus a biomarker and slight cognitive symptoms. “This may be the most important stage, because there is good evidence that people experience cognitive changes years before they progress to mild cognitive impairment,” Dr. Sperling said. “Right now, we can't differentiate normal aging from the very beginning of Alzheimer's. But the combination of these biomarkers and memory trouble will allow us to predict who is on the Alzheimer's trajectory.”

Research may especially benefit from this identification, because drugs to slow or halt disease progression will be most effective in patients with the least neuronal damage, she added.

Dr. Peterson is a member of the work group that examined diagnostic criteria for mild cognitive impairment (MCI). That group also identified three criteria:

▸ The already-established clinical syndrome of MCI in which patients are aware of their memory problem and have a measurable deficit, but other cognitive and functional skills are preserved.

▸ In addition to MCI, there is some evidence of change in brain topography—either hippocampal atrophy or hypometabolic brain regions.

▸ In addition to MCI and topographical brain changes, a confirmed measure of amyloid abnormality, including reduced amyloid-beta₄₂ in cerebrospinal fluid (indicating its accumulation in the brain) or positive amyloid brain imaging.

“This represents the progression in a perfect world,” Dr. Peterson said. “But the devil is in the details. What if you have the clinical syndrome but your biomarkers go in the opposite direction, or you have an incomplete set? That is where research is going to fill in the gaps in our knowledge.”

Dr. John Morris, director of the Alzheimer's Disease Research Center at Washington University, St. Louis, is a member of the dementia working group. Because diagnostic algorithms for dementia were already in place—albeit 25 years old—his group made modifications to the existing criteria.

“With the addition of biomarkers to support the clinical suspicion of dementia, we have been able to strengthen those criteria substantially, giving physicians the ability to be much more confident in their diagnoses,” Dr. Morris said.

Previously, the only way to obtain a definitive Alzheimer's disease diagnosis was through brain autopsy; the presence of amyloid plaques and neurofibrillary tangles has been the key diagnostic feature. “With these strengthened criteria, we can now diagnose it in a living person.”

Documented and measurable memory deficits in the presence of at least one biomarker now correlates to the diagnosis of “probable Alzheimer's.” In addition to memory deficits, the presence of several biomarkers—structural brain changes, functional brain changes, positive amyloid imaging, spinal fluid abnormalities, or genetic markers—can strengthen the diagnosis of probable disease.

The presence of a genetic marker in this mix, especially the apolipoprotein E e4 allele, equates to a definitive diagnosis.

The work groups are now seeking feedback on the criteria. Comments can be submitted to the Alzheimer's Association Web site (www.alz.org/research/diagnostic_criteria

“By the time symptoms appear, there has already been substantial neuronal loss in critical brain areas, and it's been impossible to arrest the disease once this damage has occurred,” Dr. Morris said. “It makes great sense to intervene earlier—even before MCI—to see if we can treat with the hope of preventing disease progression.

The project was funded by the National Institute on Aging and the Alzheimer's Association. None of the physicians reported any potential financial conflicts.

The criteria may help diagnose AD before there is significant impairment, Dr. Reisa Sperling said.

Source Courtesy Alzheimer's Association/Lucy Pemoni

My Take

The Criteria Mark Our Progress

The proposal to update Alzheimer's disease diagnostic criteria will incorporate the progress made these last 20 years in our understanding of the disease. We already have a number of promising approaches to the disease that include both drug and non-drug interventions and much has been done to understand the basic biology and pathology of disease progression. Even though we have no cure and currently cannot prevent Alzheimer's disease, I prefer my patients to run toward a diagnosis rather than away from it, so I expect that these criteria will help.

With each advance in medicine, more sensitive and specific tests (i.e. biomarkers) are validated and used to diagnose and treat a wide assortment of conditions. This is now the case with Alzheimer's disease. It is the inclusion of these biomarkers in the updated diagnostic criteria that will help us arrive at a diagnosis sooner and to allow us to study a variety of drug and non-drug interventions in an attempt to modify disease progression.

Clinicians use a variety of tools to assess the patient. We use laboratory tests including blood, urine and cerebrospinal fluid, imaging studies, pathologic findings, and interpretation of the history and physical to arrive at our conclusions. The more sensitive and specific the test, the more sure we are that the diagnosis is correct. Alzheimer's disease is coming of age and if new tests move us forward, then we need to incorporate these tools into our plan of care.

Our understanding of amyloid and its toxic role in Alzheimer's disease has led to its inclusion as one of the biomarker criteria. The sophistication of our imaging studies has placed positron emission tomography (PET), targeted radiolabeling, and other imaging modalities into the equation as well. The genetic work that has been done including apolipoprotein E and tau now let us use this information as well in formulating a diagnosis.

As we wait for additional treatments to become available, the new criteria should not be burdensome to the clinician. Those interested in earlier interventions will need to understand these criteria and their application in establishing a diagnosis. We will need to judge if these biomarkers lead us down the right path to be worth the effort in case finding. If the criteria provide us with a more efficient route to therapy, the better we are at addressing the patient and family needs sooner rather than later.

ERIC G. TANGALOS, M.D., is co-director of education at the Mayo Clinic Alzheimer's Disease Research Center. He is also professor of medicine at the Mayo Clinic College of Medicine in Rochester, Minn. Dr. Tangalos is a consultant to Novartis and is on the data safety board for Eli Lilly; his wife owns stock in Johnson& Johnson, all of which have Alzheimer's disease products.

Major Finding: Most of the children seen (53%) had public insurance, 43% had private insurance, and the rest were uninsured.

Data Source: A survey of 467 parents utilizing a pediatric ED.

Disclosures: None was reported.

PHILADELPHIA — The ongoing economic recession is driving demographic change in the pediatric emergency department, with some parents substituting emergency physicians for pediatricians, a small cross-sectional study has concluded.

“The seed for this study came from anecdotes from our emergency department registrars, who noted that many of our patients were coming to the pediatric ED because they had lost their health insurance, or could not pay their copay at the pediatrician's office,” Dr. Mark Cicero said. “We thought that parental job loss might be associated with avoidance of the pediatrician's office and low-acuity presentation at the ED.”

Dr. Cicero, of Yale University, New Haven, and his colleagues examined the associations between parental job loss, health insurance loss, annual household income, and the acuity of visits in a large pediatric emergency department. The study enrolled parents who visited the ED over a 2-month period in 2009. Parents were asked questions about their job and insurance status, as well as their anxiety about paying for health care and household expenses.

The survey was completed by 467 parents. The mean age of children being seen was 7 years. Race and ethnicity were nearly evenly split between black (28%), Hispanic (28%), and white (36%) families; other ethnicities made up the remainder of the respondents. Most of the children seen (53%) had public insurance, 43% had private insurance, and the rest were uninsured. A total of 9% of the parents reported that their health insurance had been discontinued in the past 6 months.

The prevalence of parental job loss in the prior 6 months was 22%—more than twice the national unemployment rate in the same period. Job loss was significantly associated with nonwhite ethnicity and an annual household income of less than $45,000.

Very low acuity visits were significantly associated with a low household income and having no insurance or public insurance. Parents with a low household income were also four times as likely as those with higher incomes to have lost their child's health insurance, twice as likely to report concern about paying for the ED visit, and eight times as likely to have been unable to pay for a child's medication in the past 6 months.

Compared with employed parents, unemployed parents were six times as likely to have lost their child's health insurance, and twice as likely to report avoiding the pediatrician's office because of cost.

“In interpreting what's going on with our patients' families, it seems that parents in our pediatric emergency department may be more impacted by the recession than the general population,” Dr. Cicero said.

Major Finding: Most of the children seen (53%) had public insurance, 43% had private insurance, and the rest were uninsured.

Data Source: A survey of 467 parents utilizing a pediatric ED.

Disclosures: None was reported.

PHILADELPHIA — The ongoing economic recession is driving demographic change in the pediatric emergency department, with some parents substituting emergency physicians for pediatricians, a small cross-sectional study has concluded.

“The seed for this study came from anecdotes from our emergency department registrars, who noted that many of our patients were coming to the pediatric ED because they had lost their health insurance, or could not pay their copay at the pediatrician's office,” Dr. Mark Cicero said. “We thought that parental job loss might be associated with avoidance of the pediatrician's office and low-acuity presentation at the ED.”

Dr. Cicero, of Yale University, New Haven, and his colleagues examined the associations between parental job loss, health insurance loss, annual household income, and the acuity of visits in a large pediatric emergency department. The study enrolled parents who visited the ED over a 2-month period in 2009. Parents were asked questions about their job and insurance status, as well as their anxiety about paying for health care and household expenses.

The survey was completed by 467 parents. The mean age of children being seen was 7 years. Race and ethnicity were nearly evenly split between black (28%), Hispanic (28%), and white (36%) families; other ethnicities made up the remainder of the respondents. Most of the children seen (53%) had public insurance, 43% had private insurance, and the rest were uninsured. A total of 9% of the parents reported that their health insurance had been discontinued in the past 6 months.

The prevalence of parental job loss in the prior 6 months was 22%—more than twice the national unemployment rate in the same period. Job loss was significantly associated with nonwhite ethnicity and an annual household income of less than $45,000.

Very low acuity visits were significantly associated with a low household income and having no insurance or public insurance. Parents with a low household income were also four times as likely as those with higher incomes to have lost their child's health insurance, twice as likely to report concern about paying for the ED visit, and eight times as likely to have been unable to pay for a child's medication in the past 6 months.

Compared with employed parents, unemployed parents were six times as likely to have lost their child's health insurance, and twice as likely to report avoiding the pediatrician's office because of cost.

“In interpreting what's going on with our patients' families, it seems that parents in our pediatric emergency department may be more impacted by the recession than the general population,” Dr. Cicero said.

Major Finding: Most of the children seen (53%) had public insurance, 43% had private insurance, and the rest were uninsured.

Data Source: A survey of 467 parents utilizing a pediatric ED.

Disclosures: None was reported.

PHILADELPHIA — The ongoing economic recession is driving demographic change in the pediatric emergency department, with some parents substituting emergency physicians for pediatricians, a small cross-sectional study has concluded.

“The seed for this study came from anecdotes from our emergency department registrars, who noted that many of our patients were coming to the pediatric ED because they had lost their health insurance, or could not pay their copay at the pediatrician's office,” Dr. Mark Cicero said. “We thought that parental job loss might be associated with avoidance of the pediatrician's office and low-acuity presentation at the ED.”

Dr. Cicero, of Yale University, New Haven, and his colleagues examined the associations between parental job loss, health insurance loss, annual household income, and the acuity of visits in a large pediatric emergency department. The study enrolled parents who visited the ED over a 2-month period in 2009. Parents were asked questions about their job and insurance status, as well as their anxiety about paying for health care and household expenses.

The survey was completed by 467 parents. The mean age of children being seen was 7 years. Race and ethnicity were nearly evenly split between black (28%), Hispanic (28%), and white (36%) families; other ethnicities made up the remainder of the respondents. Most of the children seen (53%) had public insurance, 43% had private insurance, and the rest were uninsured. A total of 9% of the parents reported that their health insurance had been discontinued in the past 6 months.

The prevalence of parental job loss in the prior 6 months was 22%—more than twice the national unemployment rate in the same period. Job loss was significantly associated with nonwhite ethnicity and an annual household income of less than $45,000.

Very low acuity visits were significantly associated with a low household income and having no insurance or public insurance. Parents with a low household income were also four times as likely as those with higher incomes to have lost their child's health insurance, twice as likely to report concern about paying for the ED visit, and eight times as likely to have been unable to pay for a child's medication in the past 6 months.

Compared with employed parents, unemployed parents were six times as likely to have lost their child's health insurance, and twice as likely to report avoiding the pediatrician's office because of cost.

“In interpreting what's going on with our patients' families, it seems that parents in our pediatric emergency department may be more impacted by the recession than the general population,” Dr. Cicero said.

Major Finding: Of the estimated 12,000 Florida children infected with hepatitis C, 14% have been diagnosed and 1% have been treated.

Data Source: The third NHANES and the Florida Merlin database.

Disclosures: The Robert Wood Johnson Foundation and the National Institutes of Health funded the study. Dr. Delgado-Borrego said she had no relevant financial disclosures.

NEW ORLEANS — Only a small fraction of Florida children with hepatitis C—about 14%—have been identified, and the situation may be even worse in other parts of the United States, a study has shown.

The projection is based on data from the third National Health and Nutrition Examination Survey (NHANES), which indicate that hepatitis C affects 0.2%–0.4% of the pediatric population.

Extrapolating that number to the Florida population, the state should have 12,155 cases of pediatric hepatitis C, said Dr. Aymin Delgado-Borrego.

Yet the state's database, which is called Merlin, contained 1,755 pediatric cases—just 14% of the expected number.

In contrast, the Merlin database has recorded more than 46% of the state's projected number of adult cases.

Further analysis suggested that 150 children—1.2% of the expected number of those infected—are being treated for their infection.

“Most children never have symptoms, or have nonspecific symptoms that don't help in the recognition of the infection,” said Dr. Delgado-Borrego, a pediatric gastroenterologist at the University of Miami.

Pediatric hepatitis C needs to be on the screening radar, especially for at-risk children whose mothers are infected.

Cases need to be referred to a specialist as soon as they're identified, she emphasized.

“Early identification of pediatric hepatitis C infection would likely help us cure the infection in more than 50% of children who currently have it,” she said.

This would limit the spread of disease and “would save children from liver damage as well as possible liver failure, cancer, and even death,” according to the pediatric gastroenterologist.

Dr. Delgado-Borrego and her colleagues examined the incidence of pediatric hepatitis C infection in Florida because its database, Merlin, registered every reported case of hepatitis C in the state from 2000 to 2008.

“Our preliminary analysis of national data shows that this percentage may be even much lower for the nation as a whole,” she said.

Although the investigators have not completed their analysis, the data they have gathered so far indicate that only 5% of children in the entire country who have hepatitis C have been identified.

“We have a few states yet that we need to look at, so this number has not been confirmed,” she said.

“But we estimate that among those who have been identified with hepatitis C, the percentage of those getting medical care is also unacceptably low,” Dr. Delgado-Borrego noted.

Major Finding: Of the estimated 12,000 Florida children infected with hepatitis C, 14% have been diagnosed and 1% have been treated.

Data Source: The third NHANES and the Florida Merlin database.

Disclosures: The Robert Wood Johnson Foundation and the National Institutes of Health funded the study. Dr. Delgado-Borrego said she had no relevant financial disclosures.

NEW ORLEANS — Only a small fraction of Florida children with hepatitis C—about 14%—have been identified, and the situation may be even worse in other parts of the United States, a study has shown.

The projection is based on data from the third National Health and Nutrition Examination Survey (NHANES), which indicate that hepatitis C affects 0.2%–0.4% of the pediatric population.

Extrapolating that number to the Florida population, the state should have 12,155 cases of pediatric hepatitis C, said Dr. Aymin Delgado-Borrego.

Yet the state's database, which is called Merlin, contained 1,755 pediatric cases—just 14% of the expected number.

In contrast, the Merlin database has recorded more than 46% of the state's projected number of adult cases.

Further analysis suggested that 150 children—1.2% of the expected number of those infected—are being treated for their infection.

“Most children never have symptoms, or have nonspecific symptoms that don't help in the recognition of the infection,” said Dr. Delgado-Borrego, a pediatric gastroenterologist at the University of Miami.

Pediatric hepatitis C needs to be on the screening radar, especially for at-risk children whose mothers are infected.

Cases need to be referred to a specialist as soon as they're identified, she emphasized.

“Early identification of pediatric hepatitis C infection would likely help us cure the infection in more than 50% of children who currently have it,” she said.

This would limit the spread of disease and “would save children from liver damage as well as possible liver failure, cancer, and even death,” according to the pediatric gastroenterologist.

Dr. Delgado-Borrego and her colleagues examined the incidence of pediatric hepatitis C infection in Florida because its database, Merlin, registered every reported case of hepatitis C in the state from 2000 to 2008.

“Our preliminary analysis of national data shows that this percentage may be even much lower for the nation as a whole,” she said.

Although the investigators have not completed their analysis, the data they have gathered so far indicate that only 5% of children in the entire country who have hepatitis C have been identified.

“We have a few states yet that we need to look at, so this number has not been confirmed,” she said.

“But we estimate that among those who have been identified with hepatitis C, the percentage of those getting medical care is also unacceptably low,” Dr. Delgado-Borrego noted.

Major Finding: Of the estimated 12,000 Florida children infected with hepatitis C, 14% have been diagnosed and 1% have been treated.

Data Source: The third NHANES and the Florida Merlin database.

Disclosures: The Robert Wood Johnson Foundation and the National Institutes of Health funded the study. Dr. Delgado-Borrego said she had no relevant financial disclosures.

NEW ORLEANS — Only a small fraction of Florida children with hepatitis C—about 14%—have been identified, and the situation may be even worse in other parts of the United States, a study has shown.

The projection is based on data from the third National Health and Nutrition Examination Survey (NHANES), which indicate that hepatitis C affects 0.2%–0.4% of the pediatric population.

Extrapolating that number to the Florida population, the state should have 12,155 cases of pediatric hepatitis C, said Dr. Aymin Delgado-Borrego.

Yet the state's database, which is called Merlin, contained 1,755 pediatric cases—just 14% of the expected number.

In contrast, the Merlin database has recorded more than 46% of the state's projected number of adult cases.

Further analysis suggested that 150 children—1.2% of the expected number of those infected—are being treated for their infection.

“Most children never have symptoms, or have nonspecific symptoms that don't help in the recognition of the infection,” said Dr. Delgado-Borrego, a pediatric gastroenterologist at the University of Miami.

Pediatric hepatitis C needs to be on the screening radar, especially for at-risk children whose mothers are infected.

Cases need to be referred to a specialist as soon as they're identified, she emphasized.

“Early identification of pediatric hepatitis C infection would likely help us cure the infection in more than 50% of children who currently have it,” she said.

This would limit the spread of disease and “would save children from liver damage as well as possible liver failure, cancer, and even death,” according to the pediatric gastroenterologist.

Dr. Delgado-Borrego and her colleagues examined the incidence of pediatric hepatitis C infection in Florida because its database, Merlin, registered every reported case of hepatitis C in the state from 2000 to 2008.

“Our preliminary analysis of national data shows that this percentage may be even much lower for the nation as a whole,” she said.

Although the investigators have not completed their analysis, the data they have gathered so far indicate that only 5% of children in the entire country who have hepatitis C have been identified.

“We have a few states yet that we need to look at, so this number has not been confirmed,” she said.

“But we estimate that among those who have been identified with hepatitis C, the percentage of those getting medical care is also unacceptably low,” Dr. Delgado-Borrego noted.

Major Finding: Among 52 elderly patients taking 12 or more drugs, 51 had drug combinations that could be dangerous.

Data Source: A retrospective chart study.

Disclosures: Dr. Ilan said he had no relevant disclosures for this study.

CANCÚN, MEXICO — Potentially dangerous drug interactions are almost unavoidable in elderly patients who regularly take 12 or more medications, a chart review study suggests.

Alpha and beta receptor blockers, statins, warfarin, and proton pump inhibitors are some of the drugs most commonly involved in these interactions, which can cause problems ranging from orthostatic hypotension to potentiated blood thinning, and even death, Dr. Heinrich Ilan said at the World Conference of Family Physicians.

“Elderly patients are at an increased risk of drug interactions because they have multiple caregivers, including family doctors, specialists—with or without gatekeeping by primary care—private consultants, and what I call 'physicians in the family'” —trusted family members who offer medical advice with or without the benefit of a medical degree, said Dr. Ilan of the Rav Kook Primary Care Clinic in Kiryat Motzkin, Haifa, Israel. “The huge polypharmacy burden in geriatric care is a direct pathway to harm for these fragile patients.”

Dr. Ilan and his associates investigated drug interactions in a group of 1,124 patients aged 75 years or older. Of those, they identified 52 patients who took at least 12 different medications over a 3-month period; these could have been prescription drugs, over-the-counter preparations, or herbal preparations.

The team used the Lexi-Comp online database to determine unsafe drug combinations. The software identifies three types of possible interactions:

▸ C: A combination that requires monitoring, and of which the physician should be aware and weigh the risks and benefits.

▸ D: A combination that carries a high probability of a serious interaction; the physician should avoid the combination if possible, or consider lowering the dosages. If used, drug levels should be monitored.

▸ X: Potentially fatal interaction that should be avoided at all cost.

Only a single patient had no interactions, Dr. Ilan said.

Two patients had type X combinations. One patient was taking escitalopram and the monoamine oxidase inhibitor selegiline. This combination can cause serotonin syndrome; possible symptoms include hyperthermia, rigidity, myoclonus, autonomic instability with rapid vital sign fluctuation, and extreme agitation progressing to delirium or coma.

The second X-type combination was found in a patient taking clarithromycin and salbutamol (known as albuterol in the United States). Possible reactions to this combination include prolongation of the QT interval and ventricular arrhythmias.

Fifty-seven D-type combinations involving 37 drugs were identified. The most commonly observed included 14 combinations of a beta-blocker and an alpha-1 receptor blocker, which can cause orthostatic hypotension and falls; and 5 combinations of a beta-blocker and alpha-2 receptor blocker, which can cause rebound hypertension if the drugs are suddenly stopped. There also were five cases of warfarin combined with levothyroxine and five cases of warfarin combined with amiodarone. Both of these combinations can potentiate the effects of warfarin, Dr. Ilan explained.

Other type D combinations included five cases of patients taking simvastatin along with a calcium channel blocker, which increases the risk of rhabdomyolysis. There were 23 other different type D combinations.

Nineteen patients were free of D-type combinations. Eighteen patients had one type D combination, 11 patients had two type D combinations, 1 patient each had three, four, and five type D combinations.

There were 328 C-type combinations involving 144 drugs. Thirty-four of those involved a statin and a proton pump inhibitor, which can lead to an increased risk of rhabdomyolysis. “The most common offenders in type C reactions were doxazosin, oxazepam, and statins,” Dr. Ilan said.

Most patients had multiple type C combinations, Dr. Ilan said. Two patients each had 12, while some patients had as many as 18.

In an interview, he suggested avoiding unnecessary polypharmacy may contribute to longevity. “From my clinical impression, it seems that '10th decade' patients—the late survivors—consume less medications, compared to their fellow 9th- and 8th-decade elderly. Therefore, it seems they are the fittest and the healthier, just to survive the very late elderly years, or that their relative lack of multidrug consumption offers some kind of [survival] advantage.”

“The huge polypharmacy burden in geriatric care is a direct pathway to harm,” said Dr. Heinrich Ilan.

Source ©Andrzej Tokarski/Fotolia.com

Major Finding: Among 52 elderly patients taking 12 or more drugs, 51 had drug combinations that could be dangerous.

Data Source: A retrospective chart study.

Disclosures: Dr. Ilan said he had no relevant disclosures for this study.

CANCÚN, MEXICO — Potentially dangerous drug interactions are almost unavoidable in elderly patients who regularly take 12 or more medications, a chart review study suggests.

Alpha and beta receptor blockers, statins, warfarin, and proton pump inhibitors are some of the drugs most commonly involved in these interactions, which can cause problems ranging from orthostatic hypotension to potentiated blood thinning, and even death, Dr. Heinrich Ilan said at the World Conference of Family Physicians.

“Elderly patients are at an increased risk of drug interactions because they have multiple caregivers, including family doctors, specialists—with or without gatekeeping by primary care—private consultants, and what I call 'physicians in the family'” —trusted family members who offer medical advice with or without the benefit of a medical degree, said Dr. Ilan of the Rav Kook Primary Care Clinic in Kiryat Motzkin, Haifa, Israel. “The huge polypharmacy burden in geriatric care is a direct pathway to harm for these fragile patients.”

Dr. Ilan and his associates investigated drug interactions in a group of 1,124 patients aged 75 years or older. Of those, they identified 52 patients who took at least 12 different medications over a 3-month period; these could have been prescription drugs, over-the-counter preparations, or herbal preparations.

The team used the Lexi-Comp online database to determine unsafe drug combinations. The software identifies three types of possible interactions:

▸ C: A combination that requires monitoring, and of which the physician should be aware and weigh the risks and benefits.

▸ D: A combination that carries a high probability of a serious interaction; the physician should avoid the combination if possible, or consider lowering the dosages. If used, drug levels should be monitored.

▸ X: Potentially fatal interaction that should be avoided at all cost.

Only a single patient had no interactions, Dr. Ilan said.

Two patients had type X combinations. One patient was taking escitalopram and the monoamine oxidase inhibitor selegiline. This combination can cause serotonin syndrome; possible symptoms include hyperthermia, rigidity, myoclonus, autonomic instability with rapid vital sign fluctuation, and extreme agitation progressing to delirium or coma.

The second X-type combination was found in a patient taking clarithromycin and salbutamol (known as albuterol in the United States). Possible reactions to this combination include prolongation of the QT interval and ventricular arrhythmias.

Fifty-seven D-type combinations involving 37 drugs were identified. The most commonly observed included 14 combinations of a beta-blocker and an alpha-1 receptor blocker, which can cause orthostatic hypotension and falls; and 5 combinations of a beta-blocker and alpha-2 receptor blocker, which can cause rebound hypertension if the drugs are suddenly stopped. There also were five cases of warfarin combined with levothyroxine and five cases of warfarin combined with amiodarone. Both of these combinations can potentiate the effects of warfarin, Dr. Ilan explained.

Other type D combinations included five cases of patients taking simvastatin along with a calcium channel blocker, which increases the risk of rhabdomyolysis. There were 23 other different type D combinations.

Nineteen patients were free of D-type combinations. Eighteen patients had one type D combination, 11 patients had two type D combinations, 1 patient each had three, four, and five type D combinations.

There were 328 C-type combinations involving 144 drugs. Thirty-four of those involved a statin and a proton pump inhibitor, which can lead to an increased risk of rhabdomyolysis. “The most common offenders in type C reactions were doxazosin, oxazepam, and statins,” Dr. Ilan said.

Most patients had multiple type C combinations, Dr. Ilan said. Two patients each had 12, while some patients had as many as 18.

In an interview, he suggested avoiding unnecessary polypharmacy may contribute to longevity. “From my clinical impression, it seems that '10th decade' patients—the late survivors—consume less medications, compared to their fellow 9th- and 8th-decade elderly. Therefore, it seems they are the fittest and the healthier, just to survive the very late elderly years, or that their relative lack of multidrug consumption offers some kind of [survival] advantage.”

“The huge polypharmacy burden in geriatric care is a direct pathway to harm,” said Dr. Heinrich Ilan.

Source ©Andrzej Tokarski/Fotolia.com

Major Finding: Among 52 elderly patients taking 12 or more drugs, 51 had drug combinations that could be dangerous.

Data Source: A retrospective chart study.

Disclosures: Dr. Ilan said he had no relevant disclosures for this study.

CANCÚN, MEXICO — Potentially dangerous drug interactions are almost unavoidable in elderly patients who regularly take 12 or more medications, a chart review study suggests.

Alpha and beta receptor blockers, statins, warfarin, and proton pump inhibitors are some of the drugs most commonly involved in these interactions, which can cause problems ranging from orthostatic hypotension to potentiated blood thinning, and even death, Dr. Heinrich Ilan said at the World Conference of Family Physicians.

“Elderly patients are at an increased risk of drug interactions because they have multiple caregivers, including family doctors, specialists—with or without gatekeeping by primary care—private consultants, and what I call 'physicians in the family'” —trusted family members who offer medical advice with or without the benefit of a medical degree, said Dr. Ilan of the Rav Kook Primary Care Clinic in Kiryat Motzkin, Haifa, Israel. “The huge polypharmacy burden in geriatric care is a direct pathway to harm for these fragile patients.”

Dr. Ilan and his associates investigated drug interactions in a group of 1,124 patients aged 75 years or older. Of those, they identified 52 patients who took at least 12 different medications over a 3-month period; these could have been prescription drugs, over-the-counter preparations, or herbal preparations.

The team used the Lexi-Comp online database to determine unsafe drug combinations. The software identifies three types of possible interactions:

▸ C: A combination that requires monitoring, and of which the physician should be aware and weigh the risks and benefits.

▸ D: A combination that carries a high probability of a serious interaction; the physician should avoid the combination if possible, or consider lowering the dosages. If used, drug levels should be monitored.

▸ X: Potentially fatal interaction that should be avoided at all cost.

Only a single patient had no interactions, Dr. Ilan said.

Two patients had type X combinations. One patient was taking escitalopram and the monoamine oxidase inhibitor selegiline. This combination can cause serotonin syndrome; possible symptoms include hyperthermia, rigidity, myoclonus, autonomic instability with rapid vital sign fluctuation, and extreme agitation progressing to delirium or coma.

The second X-type combination was found in a patient taking clarithromycin and salbutamol (known as albuterol in the United States). Possible reactions to this combination include prolongation of the QT interval and ventricular arrhythmias.

Fifty-seven D-type combinations involving 37 drugs were identified. The most commonly observed included 14 combinations of a beta-blocker and an alpha-1 receptor blocker, which can cause orthostatic hypotension and falls; and 5 combinations of a beta-blocker and alpha-2 receptor blocker, which can cause rebound hypertension if the drugs are suddenly stopped. There also were five cases of warfarin combined with levothyroxine and five cases of warfarin combined with amiodarone. Both of these combinations can potentiate the effects of warfarin, Dr. Ilan explained.

Other type D combinations included five cases of patients taking simvastatin along with a calcium channel blocker, which increases the risk of rhabdomyolysis. There were 23 other different type D combinations.

Nineteen patients were free of D-type combinations. Eighteen patients had one type D combination, 11 patients had two type D combinations, 1 patient each had three, four, and five type D combinations.

There were 328 C-type combinations involving 144 drugs. Thirty-four of those involved a statin and a proton pump inhibitor, which can lead to an increased risk of rhabdomyolysis. “The most common offenders in type C reactions were doxazosin, oxazepam, and statins,” Dr. Ilan said.

Most patients had multiple type C combinations, Dr. Ilan said. Two patients each had 12, while some patients had as many as 18.

In an interview, he suggested avoiding unnecessary polypharmacy may contribute to longevity. “From my clinical impression, it seems that '10th decade' patients—the late survivors—consume less medications, compared to their fellow 9th- and 8th-decade elderly. Therefore, it seems they are the fittest and the healthier, just to survive the very late elderly years, or that their relative lack of multidrug consumption offers some kind of [survival] advantage.”

“The huge polypharmacy burden in geriatric care is a direct pathway to harm,” said Dr. Heinrich Ilan.

Source ©Andrzej Tokarski/Fotolia.com

CANCÚN, MEXICO — Osteoarthritis flares were reduced by 42% in patients who took 200 mg of celecoxib every day, compared with those who took the medication only when they experienced a disease flare, judging from randomized, placebo-controlled trial findings.

Osteoarthritis patients who took the drug daily were no more likely than intermittent users to experience either new-onset hypertension or an aggravation of existing hypertension, Dr. George Sands reported.”

“Over the 22-week treatment period, continuous daily celecoxib was more effective in terms of fewer osteoarthritis flares, less pain, and less stiffness than intermittent celecoxib, with no difference in overall adverse effects or in hypertension,” said Dr. Sands, senior medical director at Pfizer Inc., which sponsored the study.

The study group comprised 875 patients with hip or knee osteoarthritis. All patients had to be taking a daily NSAID to control their disease. The study consisted of three phases: In phase I, patients stopped their NSAID until they had a flare at their index joint. In phase II, patients with flares received open-label celecoxib until the flare resolved. Phase III consisted of the 22-week randomized, placebo-controlled study. Patients had two study medications, one for daily use and one for use during a flare. Half of the patients (440) received celecoxib every day and a placebo during the flare. The rest of the group (435) received daily placebo and celecoxib during the flare. Treatment continued for 22 weeks.

“Only patients who had resolved flares could be entered into the trial,” Dr Sands said. “This is different from the usual arthritis studies, where they stop their NSAID, get worse, and are treated. In this study, patients were randomized after a successful treatment of a flare.”

The patients' mean age was 58 years; 30% were 65 or older. Their mean weight was 83 kg. Most (80%) had knee osteoarthritis; the hip was the affected joint in the remaining 20%. The baseline WOMAC (Western Ontario and McMaster Universities) Osteoarthritis Index score was 25 in both groups. Hypertension was present in 45%. Most of the continuous-use patients (80%) and 74% of the intermittent-use patients completed the trial.

The primary end point was the number of flares occurring during the randomized portion of the study. The median time to first flare was significantly longer in the continuous-use group than in the intermittent-use group (16 days vs. 8 days, respectively). “This is not surprising, since in this part of the study, before anyone had a flare, you were testing celecoxib against placebo,” noted Dr. Sands.

By the end of the 22-week treatment period, continuous users had a mean of 0.54 flares per month, significantly fewer than the mean 0.93 flares experienced by the intermittent users. “This translates into 42% fewer flares per month, which is equivalent to about two fewer flares per month,” Dr. Sands said.

At the end of the treatment period, WOMAC scores were significantly better in the continuous-use group than in the intermittent-use group. The change in total WOMAC score was 1.6 in the continuous users vs. 4.99 in the intermittent users. The WOMAC subscore change for pain was also significantly better in the continuous users than the intermittent users (0.37 vs. 1.88), as was the change in the stiffness subscore (0.12 vs. 0.4).

At the final visit, 23% of the continuous-use group and 11% of the intermittent-use group had been flare free—a significant difference in favor of continuous treatment. At that time, 16% of the continuous-use patients and 9% of the intermittent-use patients reported their overall symptoms to be “very good.”

Adverse events were similar between both groups, occurring in 57% of the continuous users and 59% of the intermittent users. Headache was the most frequent complaint (15% continuous vs. 16% intermittent), followed by back pain (5% vs. 7%).

Disclosures: Dr. Sands is senior medical director at Pfizer Inc., which makes celecoxib and sponsored the study.

CANCÚN, MEXICO — Osteoarthritis flares were reduced by 42% in patients who took 200 mg of celecoxib every day, compared with those who took the medication only when they experienced a disease flare, judging from randomized, placebo-controlled trial findings.

Osteoarthritis patients who took the drug daily were no more likely than intermittent users to experience either new-onset hypertension or an aggravation of existing hypertension, Dr. George Sands reported.”

“Over the 22-week treatment period, continuous daily celecoxib was more effective in terms of fewer osteoarthritis flares, less pain, and less stiffness than intermittent celecoxib, with no difference in overall adverse effects or in hypertension,” said Dr. Sands, senior medical director at Pfizer Inc., which sponsored the study.

The study group comprised 875 patients with hip or knee osteoarthritis. All patients had to be taking a daily NSAID to control their disease. The study consisted of three phases: In phase I, patients stopped their NSAID until they had a flare at their index joint. In phase II, patients with flares received open-label celecoxib until the flare resolved. Phase III consisted of the 22-week randomized, placebo-controlled study. Patients had two study medications, one for daily use and one for use during a flare. Half of the patients (440) received celecoxib every day and a placebo during the flare. The rest of the group (435) received daily placebo and celecoxib during the flare. Treatment continued for 22 weeks.

“Only patients who had resolved flares could be entered into the trial,” Dr Sands said. “This is different from the usual arthritis studies, where they stop their NSAID, get worse, and are treated. In this study, patients were randomized after a successful treatment of a flare.”

The patients' mean age was 58 years; 30% were 65 or older. Their mean weight was 83 kg. Most (80%) had knee osteoarthritis; the hip was the affected joint in the remaining 20%. The baseline WOMAC (Western Ontario and McMaster Universities) Osteoarthritis Index score was 25 in both groups. Hypertension was present in 45%. Most of the continuous-use patients (80%) and 74% of the intermittent-use patients completed the trial.

The primary end point was the number of flares occurring during the randomized portion of the study. The median time to first flare was significantly longer in the continuous-use group than in the intermittent-use group (16 days vs. 8 days, respectively). “This is not surprising, since in this part of the study, before anyone had a flare, you were testing celecoxib against placebo,” noted Dr. Sands.

By the end of the 22-week treatment period, continuous users had a mean of 0.54 flares per month, significantly fewer than the mean 0.93 flares experienced by the intermittent users. “This translates into 42% fewer flares per month, which is equivalent to about two fewer flares per month,” Dr. Sands said.

At the end of the treatment period, WOMAC scores were significantly better in the continuous-use group than in the intermittent-use group. The change in total WOMAC score was 1.6 in the continuous users vs. 4.99 in the intermittent users. The WOMAC subscore change for pain was also significantly better in the continuous users than the intermittent users (0.37 vs. 1.88), as was the change in the stiffness subscore (0.12 vs. 0.4).

At the final visit, 23% of the continuous-use group and 11% of the intermittent-use group had been flare free—a significant difference in favor of continuous treatment. At that time, 16% of the continuous-use patients and 9% of the intermittent-use patients reported their overall symptoms to be “very good.”

Adverse events were similar between both groups, occurring in 57% of the continuous users and 59% of the intermittent users. Headache was the most frequent complaint (15% continuous vs. 16% intermittent), followed by back pain (5% vs. 7%).

Disclosures: Dr. Sands is senior medical director at Pfizer Inc., which makes celecoxib and sponsored the study.

CANCÚN, MEXICO — Osteoarthritis flares were reduced by 42% in patients who took 200 mg of celecoxib every day, compared with those who took the medication only when they experienced a disease flare, judging from randomized, placebo-controlled trial findings.

Osteoarthritis patients who took the drug daily were no more likely than intermittent users to experience either new-onset hypertension or an aggravation of existing hypertension, Dr. George Sands reported.”

“Over the 22-week treatment period, continuous daily celecoxib was more effective in terms of fewer osteoarthritis flares, less pain, and less stiffness than intermittent celecoxib, with no difference in overall adverse effects or in hypertension,” said Dr. Sands, senior medical director at Pfizer Inc., which sponsored the study.

The study group comprised 875 patients with hip or knee osteoarthritis. All patients had to be taking a daily NSAID to control their disease. The study consisted of three phases: In phase I, patients stopped their NSAID until they had a flare at their index joint. In phase II, patients with flares received open-label celecoxib until the flare resolved. Phase III consisted of the 22-week randomized, placebo-controlled study. Patients had two study medications, one for daily use and one for use during a flare. Half of the patients (440) received celecoxib every day and a placebo during the flare. The rest of the group (435) received daily placebo and celecoxib during the flare. Treatment continued for 22 weeks.

“Only patients who had resolved flares could be entered into the trial,” Dr Sands said. “This is different from the usual arthritis studies, where they stop their NSAID, get worse, and are treated. In this study, patients were randomized after a successful treatment of a flare.”

The patients' mean age was 58 years; 30% were 65 or older. Their mean weight was 83 kg. Most (80%) had knee osteoarthritis; the hip was the affected joint in the remaining 20%. The baseline WOMAC (Western Ontario and McMaster Universities) Osteoarthritis Index score was 25 in both groups. Hypertension was present in 45%. Most of the continuous-use patients (80%) and 74% of the intermittent-use patients completed the trial.

The primary end point was the number of flares occurring during the randomized portion of the study. The median time to first flare was significantly longer in the continuous-use group than in the intermittent-use group (16 days vs. 8 days, respectively). “This is not surprising, since in this part of the study, before anyone had a flare, you were testing celecoxib against placebo,” noted Dr. Sands.

By the end of the 22-week treatment period, continuous users had a mean of 0.54 flares per month, significantly fewer than the mean 0.93 flares experienced by the intermittent users. “This translates into 42% fewer flares per month, which is equivalent to about two fewer flares per month,” Dr. Sands said.

At the end of the treatment period, WOMAC scores were significantly better in the continuous-use group than in the intermittent-use group. The change in total WOMAC score was 1.6 in the continuous users vs. 4.99 in the intermittent users. The WOMAC subscore change for pain was also significantly better in the continuous users than the intermittent users (0.37 vs. 1.88), as was the change in the stiffness subscore (0.12 vs. 0.4).

At the final visit, 23% of the continuous-use group and 11% of the intermittent-use group had been flare free—a significant difference in favor of continuous treatment. At that time, 16% of the continuous-use patients and 9% of the intermittent-use patients reported their overall symptoms to be “very good.”

Adverse events were similar between both groups, occurring in 57% of the continuous users and 59% of the intermittent users. Headache was the most frequent complaint (15% continuous vs. 16% intermittent), followed by back pain (5% vs. 7%).

Disclosures: Dr. Sands is senior medical director at Pfizer Inc., which makes celecoxib and sponsored the study.

Major Finding: Non–plaque forming fragments of the amyloid beta protein, once thought to be non-neurotoxic, may be more dangerous to the brain than the full-length, plaque-forming amyloid.

Data Source: A series of in vitro studies.

Disclosures: The work was funded by the National Institute of Aging, National Cancer Institute and Alzheimer's Association. None of the authors declared a potential financial conflict.

Small fragments of the beta amyloid peptide, previously thought to be nontoxic to the brain, may actually be part of the root cause of Alzheimer's disease, new research findings suggest.

These small beta amyloid (Abeta) fragments group together to create pores that let toxic calcium enter neurons, causing neurodegeneration and cell death, Ratnesh Lal, Ph.D., and his colleagues reported in the Proceedings of the National Academy of Sciences of the United States of America (Proc. Natl. Acad. Sci. U.S.A. 2010 [doi/10.1073/pnas.0914251107

The findings may offer some insight into the limitations of Alzheimer's drugs targeted to reduce the full-length beta amyloid peptides, Abeta_1-40/42, which form the brain plaques seen in Alzheimer's and are the supposed cause of the disease.

While these drugs do decrease the amount of Abeta_1-40/42, they also increase the amount of the shorter peptides, which may negate any benefit of the drugs and compound the natural progression of Alzheimer's disease, Dr. Lal said in an interview.

“Any positive effect of these drugs may be masked by the negative effect,” of increasing the number of the pore-forming shorter Abeta peptides, said Dr. Lal, professor of Bioengineering and Mechanical Engineering at the University of California, San Diego.

The findings by Dr. Lal and his colleagues, Ruth Nussinov, Ph.D., and Dr. Bruce Kagan, could revolutionize Alzheimer's drug research, said Dr. Richard J. Caselli, professor of neurology at the Mayo Clinic Arizona, Scottsdale. The idea that nonamyloidogenic fragments are themselves neurotoxic preserves a central role for amyloid in Alzheimer's pathophysiology but alters the specifics in ways that could impact future therapeutic development efforts, he said in an interview.

“The amyloid hypothesis has never accounted for the failure of amyloid-clearing immunotherapy to retard the progression of dementia, or for any of the other treatment failures based on the Abeta_1-40/42 model. This may be a reason why. It is potentially so important in my opinion, that it warrants replication as soon as possible in other labs, and if replicated, should serve as a paradigmmodifying piece of work in our understanding of amyloid's role in Alzheimer's pathogenesis.”

Dr. Lal and his colleagues examined the effect of two short fragments of the Abeta peptide: Abeta_9–42 and Abeta_17–42. They found that both fragments can form mobile ion channels on neuronal cell membranes. When the fragments were added to a culture of mouse fibroblasts that were bathed in a calcium solution, the cells readily took up the calcium. Adding zinc to the mixture, however, blocked the influx of calcium, showing that the pore channel can be inactivated.

When the same procedure was performed on human cortical neurons, the investigators observed an association between the dose of Abeta peptide fragments and how long it took for neurodegeneration to become apparent. The fragments formed pores that allowed calcium to enter the cell. At the smallest dose of the two fragments, it took 24 hours for neurodegeneration to become apparent. It was only detectable with atomic force microscopy. At higher doses, the neurodegeneration was visible with light microscopy by 24 hours. At the highest dose, there was a dramatic reduction in neuronal processes within 15 minutes. Cells showed disrupted, leaking membranes and a decreased number of neurites. Again, cells pretreated with zinc seemed to be protected from damage, even at the highest dosage of the fragments.

The model refines the amyloid hypothesis, Dr. Lal said, suggesting that neurodegeneration may be the result of the smaller Abeta fragments of the larger plaque-forming peptides. “You can put those smaller proteins right on top of neurons in culture and replicate all the damages induced by the full-length amyloid proteins,” he said.

“What we are showing is that the smallest nonamyloid-forming peptides might actually be the most important part of the Abeta hypothesis.”

The next research step, he said, will be to identify which of the 10-12 amino acids that comprise each ion pore control its behavior. “What we are doing is to try and change each one of the proteins to see how it affects the behavior of the pore,” he said. “If you can find the one that closes the pore that would be a target for a small molecule drug.”

Because the research was performed completely in vitro, it's too soon to know how–or even whether–the ion pores would affect Alzheimer's disease progression, said Mark A. Smith, Ph.D., an Alzheimer's disease researcher at Case Western University, Cleveland.

Neurodegeneration may be the result of the smaller Abeta pieces of the larger plaque-forming peptides.

Source DR. LAL

Major Finding: Non–plaque forming fragments of the amyloid beta protein, once thought to be non-neurotoxic, may be more dangerous to the brain than the full-length, plaque-forming amyloid.

Data Source: A series of in vitro studies.

Disclosures: The work was funded by the National Institute of Aging, National Cancer Institute and Alzheimer's Association. None of the authors declared a potential financial conflict.

Small fragments of the beta amyloid peptide, previously thought to be nontoxic to the brain, may actually be part of the root cause of Alzheimer's disease, new research findings suggest.

These small beta amyloid (Abeta) fragments group together to create pores that let toxic calcium enter neurons, causing neurodegeneration and cell death, Ratnesh Lal, Ph.D., and his colleagues reported in the Proceedings of the National Academy of Sciences of the United States of America (Proc. Natl. Acad. Sci. U.S.A. 2010 [doi/10.1073/pnas.0914251107

The findings may offer some insight into the limitations of Alzheimer's drugs targeted to reduce the full-length beta amyloid peptides, Abeta_1-40/42, which form the brain plaques seen in Alzheimer's and are the supposed cause of the disease.

While these drugs do decrease the amount of Abeta_1-40/42, they also increase the amount of the shorter peptides, which may negate any benefit of the drugs and compound the natural progression of Alzheimer's disease, Dr. Lal said in an interview.

“Any positive effect of these drugs may be masked by the negative effect,” of increasing the number of the pore-forming shorter Abeta peptides, said Dr. Lal, professor of Bioengineering and Mechanical Engineering at the University of California, San Diego.

The findings by Dr. Lal and his colleagues, Ruth Nussinov, Ph.D., and Dr. Bruce Kagan, could revolutionize Alzheimer's drug research, said Dr. Richard J. Caselli, professor of neurology at the Mayo Clinic Arizona, Scottsdale. The idea that nonamyloidogenic fragments are themselves neurotoxic preserves a central role for amyloid in Alzheimer's pathophysiology but alters the specifics in ways that could impact future therapeutic development efforts, he said in an interview.

“The amyloid hypothesis has never accounted for the failure of amyloid-clearing immunotherapy to retard the progression of dementia, or for any of the other treatment failures based on the Abeta_1-40/42 model. This may be a reason why. It is potentially so important in my opinion, that it warrants replication as soon as possible in other labs, and if replicated, should serve as a paradigmmodifying piece of work in our understanding of amyloid's role in Alzheimer's pathogenesis.”

Dr. Lal and his colleagues examined the effect of two short fragments of the Abeta peptide: Abeta_9–42 and Abeta_17–42. They found that both fragments can form mobile ion channels on neuronal cell membranes. When the fragments were added to a culture of mouse fibroblasts that were bathed in a calcium solution, the cells readily took up the calcium. Adding zinc to the mixture, however, blocked the influx of calcium, showing that the pore channel can be inactivated.

When the same procedure was performed on human cortical neurons, the investigators observed an association between the dose of Abeta peptide fragments and how long it took for neurodegeneration to become apparent. The fragments formed pores that allowed calcium to enter the cell. At the smallest dose of the two fragments, it took 24 hours for neurodegeneration to become apparent. It was only detectable with atomic force microscopy. At higher doses, the neurodegeneration was visible with light microscopy by 24 hours. At the highest dose, there was a dramatic reduction in neuronal processes within 15 minutes. Cells showed disrupted, leaking membranes and a decreased number of neurites. Again, cells pretreated with zinc seemed to be protected from damage, even at the highest dosage of the fragments.

The model refines the amyloid hypothesis, Dr. Lal said, suggesting that neurodegeneration may be the result of the smaller Abeta fragments of the larger plaque-forming peptides. “You can put those smaller proteins right on top of neurons in culture and replicate all the damages induced by the full-length amyloid proteins,” he said.

“What we are showing is that the smallest nonamyloid-forming peptides might actually be the most important part of the Abeta hypothesis.”

The next research step, he said, will be to identify which of the 10-12 amino acids that comprise each ion pore control its behavior. “What we are doing is to try and change each one of the proteins to see how it affects the behavior of the pore,” he said. “If you can find the one that closes the pore that would be a target for a small molecule drug.”

Because the research was performed completely in vitro, it's too soon to know how–or even whether–the ion pores would affect Alzheimer's disease progression, said Mark A. Smith, Ph.D., an Alzheimer's disease researcher at Case Western University, Cleveland.

Neurodegeneration may be the result of the smaller Abeta pieces of the larger plaque-forming peptides.

Source DR. LAL

Major Finding: Non–plaque forming fragments of the amyloid beta protein, once thought to be non-neurotoxic, may be more dangerous to the brain than the full-length, plaque-forming amyloid.

Data Source: A series of in vitro studies.

Disclosures: The work was funded by the National Institute of Aging, National Cancer Institute and Alzheimer's Association. None of the authors declared a potential financial conflict.

Small fragments of the beta amyloid peptide, previously thought to be nontoxic to the brain, may actually be part of the root cause of Alzheimer's disease, new research findings suggest.

These small beta amyloid (Abeta) fragments group together to create pores that let toxic calcium enter neurons, causing neurodegeneration and cell death, Ratnesh Lal, Ph.D., and his colleagues reported in the Proceedings of the National Academy of Sciences of the United States of America (Proc. Natl. Acad. Sci. U.S.A. 2010 [doi/10.1073/pnas.0914251107

The findings may offer some insight into the limitations of Alzheimer's drugs targeted to reduce the full-length beta amyloid peptides, Abeta_1-40/42, which form the brain plaques seen in Alzheimer's and are the supposed cause of the disease.

While these drugs do decrease the amount of Abeta_1-40/42, they also increase the amount of the shorter peptides, which may negate any benefit of the drugs and compound the natural progression of Alzheimer's disease, Dr. Lal said in an interview.

“Any positive effect of these drugs may be masked by the negative effect,” of increasing the number of the pore-forming shorter Abeta peptides, said Dr. Lal, professor of Bioengineering and Mechanical Engineering at the University of California, San Diego.

The findings by Dr. Lal and his colleagues, Ruth Nussinov, Ph.D., and Dr. Bruce Kagan, could revolutionize Alzheimer's drug research, said Dr. Richard J. Caselli, professor of neurology at the Mayo Clinic Arizona, Scottsdale. The idea that nonamyloidogenic fragments are themselves neurotoxic preserves a central role for amyloid in Alzheimer's pathophysiology but alters the specifics in ways that could impact future therapeutic development efforts, he said in an interview.

“The amyloid hypothesis has never accounted for the failure of amyloid-clearing immunotherapy to retard the progression of dementia, or for any of the other treatment failures based on the Abeta_1-40/42 model. This may be a reason why. It is potentially so important in my opinion, that it warrants replication as soon as possible in other labs, and if replicated, should serve as a paradigmmodifying piece of work in our understanding of amyloid's role in Alzheimer's pathogenesis.”

Dr. Lal and his colleagues examined the effect of two short fragments of the Abeta peptide: Abeta_9–42 and Abeta_17–42. They found that both fragments can form mobile ion channels on neuronal cell membranes. When the fragments were added to a culture of mouse fibroblasts that were bathed in a calcium solution, the cells readily took up the calcium. Adding zinc to the mixture, however, blocked the influx of calcium, showing that the pore channel can be inactivated.

When the same procedure was performed on human cortical neurons, the investigators observed an association between the dose of Abeta peptide fragments and how long it took for neurodegeneration to become apparent. The fragments formed pores that allowed calcium to enter the cell. At the smallest dose of the two fragments, it took 24 hours for neurodegeneration to become apparent. It was only detectable with atomic force microscopy. At higher doses, the neurodegeneration was visible with light microscopy by 24 hours. At the highest dose, there was a dramatic reduction in neuronal processes within 15 minutes. Cells showed disrupted, leaking membranes and a decreased number of neurites. Again, cells pretreated with zinc seemed to be protected from damage, even at the highest dosage of the fragments.

The model refines the amyloid hypothesis, Dr. Lal said, suggesting that neurodegeneration may be the result of the smaller Abeta fragments of the larger plaque-forming peptides. “You can put those smaller proteins right on top of neurons in culture and replicate all the damages induced by the full-length amyloid proteins,” he said.

“What we are showing is that the smallest nonamyloid-forming peptides might actually be the most important part of the Abeta hypothesis.”

The next research step, he said, will be to identify which of the 10-12 amino acids that comprise each ion pore control its behavior. “What we are doing is to try and change each one of the proteins to see how it affects the behavior of the pore,” he said. “If you can find the one that closes the pore that would be a target for a small molecule drug.”

Because the research was performed completely in vitro, it's too soon to know how–or even whether–the ion pores would affect Alzheimer's disease progression, said Mark A. Smith, Ph.D., an Alzheimer's disease researcher at Case Western University, Cleveland.

Neurodegeneration may be the result of the smaller Abeta pieces of the larger plaque-forming peptides.

Source DR. LAL