Michele G. Sullivan

While pandemic flu will probably be widespread throughout the country this fall and winter, the vast majority of people who contract pandemic influenza A (H1N1) will recover without testing and without any special treatment.

“On the other hand, if someone has an underlying condition or severe illness, it's really important that they get treated promptly,” Dr. Thomas R. Frieden, director of the Centers for Disease Control and Prevention, said in a teleconference.

The message may be “complicated,” he said, “but getting it right is not only going to be important for helping people stay healthy, it's [also] going to be very important for making sure that our hospitals and our emergency departments are available to the community and to the people who really need treatment.”

Individuals who are at high risk for severe illness from pandemic influenza A (H1N1), such as those who are pregnant or who have chronic conditions, should be given antiviral treatment as soon as possible, even before confirmatory laboratory results are available, according to updated recommendations, said Dr. Anne Schuchat of the CDC.

Physicians should warn high-risk patients to actively seek treatment for flulike symptoms.

“If you have an underlying condition such as diabetes, pregnancy, heart disease, or lung disease, it's important to be seen promptly if you get a fever” so that antiviral treatment can be initiated within the first 48 hours of illness. “This can make a big difference in hastening your recovery, the difference between becoming seriously ill or recovering well,” Dr. Frieden said.

Another red flag would be a recurrence of fever after a seeming recovery, he added. Ten of 36 children who died of H1N1 infection also had invasive bacterial infections, probably picked up while they were recovering at home (MMWR 2009;58:941-7).

“An important message for doctors is that if someone has the flu, they get better, and then they get worse again with a high fever, that is a clue that maybe they should be treated with antibiotics,” Dr. Frieden said.

The updated guidance recommends treatment with antivirals for hospitalized patients with confirmed, probable, or suspected pandemic flu, and for individuals who are at increased risk for flu-related complications.

The CDC recommends either oseltamivir (Tamiflu) or zanamivir (Relenza) for antiviral treatment of the pandemic flu.

Most people won't know whether their flulike symptoms are seasonal flu or pandemic flu, so the guidance encourages health care providers to use their judgment when treating high-risk patients.

Dr. Schuchat suggested that clinicians consider writing antiviral prescriptions in advance for patients in high-risk groups. This would allow an individual who develops flulike symptoms to call his or her physician, discuss the symptoms, and determine whether to fill the prescription. Antivirals are most effective when begun within 48 hours of symptom onset, Dr. Schuchat said.

While prompt treatment is important for very ill and high-risk patients, Dr. Schuchat emphasized that the CDC promotes “smart use of antivirals” to minimize the development of resistant strains, and added that most children and adults who become ill with the H1N1 virus will not need treatment with antivirals.

At press time, 13 cases of pandemic H1N1 flu that were resistant to oseltamivir had been reported, according to data from a media briefing by Tamiflu manufacturer Roche.

Heidi Splete contributed to this report.

While pandemic flu will probably be widespread throughout the country this fall and winter, the vast majority of people who contract pandemic influenza A (H1N1) will recover without testing and without any special treatment.

“On the other hand, if someone has an underlying condition or severe illness, it's really important that they get treated promptly,” Dr. Thomas R. Frieden, director of the Centers for Disease Control and Prevention, said in a teleconference.

The message may be “complicated,” he said, “but getting it right is not only going to be important for helping people stay healthy, it's [also] going to be very important for making sure that our hospitals and our emergency departments are available to the community and to the people who really need treatment.”

Individuals who are at high risk for severe illness from pandemic influenza A (H1N1), such as those who are pregnant or who have chronic conditions, should be given antiviral treatment as soon as possible, even before confirmatory laboratory results are available, according to updated recommendations, said Dr. Anne Schuchat of the CDC.

Physicians should warn high-risk patients to actively seek treatment for flulike symptoms.

“If you have an underlying condition such as diabetes, pregnancy, heart disease, or lung disease, it's important to be seen promptly if you get a fever” so that antiviral treatment can be initiated within the first 48 hours of illness. “This can make a big difference in hastening your recovery, the difference between becoming seriously ill or recovering well,” Dr. Frieden said.

Another red flag would be a recurrence of fever after a seeming recovery, he added. Ten of 36 children who died of H1N1 infection also had invasive bacterial infections, probably picked up while they were recovering at home (MMWR 2009;58:941-7).

“An important message for doctors is that if someone has the flu, they get better, and then they get worse again with a high fever, that is a clue that maybe they should be treated with antibiotics,” Dr. Frieden said.

The updated guidance recommends treatment with antivirals for hospitalized patients with confirmed, probable, or suspected pandemic flu, and for individuals who are at increased risk for flu-related complications.

The CDC recommends either oseltamivir (Tamiflu) or zanamivir (Relenza) for antiviral treatment of the pandemic flu.

Most people won't know whether their flulike symptoms are seasonal flu or pandemic flu, so the guidance encourages health care providers to use their judgment when treating high-risk patients.

Dr. Schuchat suggested that clinicians consider writing antiviral prescriptions in advance for patients in high-risk groups. This would allow an individual who develops flulike symptoms to call his or her physician, discuss the symptoms, and determine whether to fill the prescription. Antivirals are most effective when begun within 48 hours of symptom onset, Dr. Schuchat said.

While prompt treatment is important for very ill and high-risk patients, Dr. Schuchat emphasized that the CDC promotes “smart use of antivirals” to minimize the development of resistant strains, and added that most children and adults who become ill with the H1N1 virus will not need treatment with antivirals.

At press time, 13 cases of pandemic H1N1 flu that were resistant to oseltamivir had been reported, according to data from a media briefing by Tamiflu manufacturer Roche.

Heidi Splete contributed to this report.

While pandemic flu will probably be widespread throughout the country this fall and winter, the vast majority of people who contract pandemic influenza A (H1N1) will recover without testing and without any special treatment.

“On the other hand, if someone has an underlying condition or severe illness, it's really important that they get treated promptly,” Dr. Thomas R. Frieden, director of the Centers for Disease Control and Prevention, said in a teleconference.

The message may be “complicated,” he said, “but getting it right is not only going to be important for helping people stay healthy, it's [also] going to be very important for making sure that our hospitals and our emergency departments are available to the community and to the people who really need treatment.”

Individuals who are at high risk for severe illness from pandemic influenza A (H1N1), such as those who are pregnant or who have chronic conditions, should be given antiviral treatment as soon as possible, even before confirmatory laboratory results are available, according to updated recommendations, said Dr. Anne Schuchat of the CDC.

Physicians should warn high-risk patients to actively seek treatment for flulike symptoms.

“If you have an underlying condition such as diabetes, pregnancy, heart disease, or lung disease, it's important to be seen promptly if you get a fever” so that antiviral treatment can be initiated within the first 48 hours of illness. “This can make a big difference in hastening your recovery, the difference between becoming seriously ill or recovering well,” Dr. Frieden said.

Another red flag would be a recurrence of fever after a seeming recovery, he added. Ten of 36 children who died of H1N1 infection also had invasive bacterial infections, probably picked up while they were recovering at home (MMWR 2009;58:941-7).

“An important message for doctors is that if someone has the flu, they get better, and then they get worse again with a high fever, that is a clue that maybe they should be treated with antibiotics,” Dr. Frieden said.

The updated guidance recommends treatment with antivirals for hospitalized patients with confirmed, probable, or suspected pandemic flu, and for individuals who are at increased risk for flu-related complications.

The CDC recommends either oseltamivir (Tamiflu) or zanamivir (Relenza) for antiviral treatment of the pandemic flu.

Most people won't know whether their flulike symptoms are seasonal flu or pandemic flu, so the guidance encourages health care providers to use their judgment when treating high-risk patients.

Dr. Schuchat suggested that clinicians consider writing antiviral prescriptions in advance for patients in high-risk groups. This would allow an individual who develops flulike symptoms to call his or her physician, discuss the symptoms, and determine whether to fill the prescription. Antivirals are most effective when begun within 48 hours of symptom onset, Dr. Schuchat said.

While prompt treatment is important for very ill and high-risk patients, Dr. Schuchat emphasized that the CDC promotes “smart use of antivirals” to minimize the development of resistant strains, and added that most children and adults who become ill with the H1N1 virus will not need treatment with antivirals.

At press time, 13 cases of pandemic H1N1 flu that were resistant to oseltamivir had been reported, according to data from a media briefing by Tamiflu manufacturer Roche.

Heidi Splete contributed to this report.

Fewer than half of health care workers were willing to accept prepandemic influenza vaccinations to either the H5N1 or the pandemic H1N1 viruses, despite a jump in the World Health Organization alert level, according to a survey study conducted in Hong Kong.

Even when the WHO alert level for H1N1 increased to 5—indicating confirmed human-human spread—only 48% of those surveyed said they intended to take the vaccine. The most common barriers to vaccination were worries about side effects and doubts about effectiveness, lead authors Josette Chor and Dr. Paul Chan wrote in BMJ online (BMJ 2009; doi:10.1136/bmj.b3391

The findings are of great concern, since vaccination of health care workers provides several key benefits during a disease outbreak, wrote Ms. Chor and Dr. Chan of the Chinese University of Hong Kong, and their associates.

Ms. Chor and her coauthors conducted two surveys in 31 Hong Kong hospitals. The first survey, conducted from January to March, asked physicians, nurses, and other health professionals employed at the facilities if they would take a prepandemic H5N1 vaccine. At that time, the WHO alert level for H5N1 was 3, indicating sporadic disease in humans but no evidence of human-human transmission strong enough to generate a community outbreak.

The second survey was conducted in May, after the WHO influenza alert level for H1N1 had been raised to phase 5. This survey asked about the willingness to accept both of the vaccines.

A total of 2,255 health care workers responded to the surveys. Nurses accounted for 71% of the respondents and physicians for 19%.

Overall, only 28% of respondents to the first survey said they would accept an H5N1 vaccine. That percentage increased, though not significantly so, to 35% for the second survey.

More respondents (48%) said they would accept an H1N1 vaccine. Most of those who said they would accept H5N1 vaccination said they would also accept H1N1 vaccination (91%). But only 24% of those who would decline the H5N1 vaccine said they would accept the H1N1 vaccine.

The most common reasons for vaccine acceptance were a wish to be protected and the following of government advice. The most common reasons for declining vaccination were worry about side effects and doubts about vaccine efficacy.

The investigators declared that they had no conflicts.

Fewer than half of health care workers were willing to accept prepandemic influenza vaccinations to either the H5N1 or the pandemic H1N1 viruses, despite a jump in the World Health Organization alert level, according to a survey study conducted in Hong Kong.

Even when the WHO alert level for H1N1 increased to 5—indicating confirmed human-human spread—only 48% of those surveyed said they intended to take the vaccine. The most common barriers to vaccination were worries about side effects and doubts about effectiveness, lead authors Josette Chor and Dr. Paul Chan wrote in BMJ online (BMJ 2009; doi:10.1136/bmj.b3391

The findings are of great concern, since vaccination of health care workers provides several key benefits during a disease outbreak, wrote Ms. Chor and Dr. Chan of the Chinese University of Hong Kong, and their associates.

Ms. Chor and her coauthors conducted two surveys in 31 Hong Kong hospitals. The first survey, conducted from January to March, asked physicians, nurses, and other health professionals employed at the facilities if they would take a prepandemic H5N1 vaccine. At that time, the WHO alert level for H5N1 was 3, indicating sporadic disease in humans but no evidence of human-human transmission strong enough to generate a community outbreak.

The second survey was conducted in May, after the WHO influenza alert level for H1N1 had been raised to phase 5. This survey asked about the willingness to accept both of the vaccines.

A total of 2,255 health care workers responded to the surveys. Nurses accounted for 71% of the respondents and physicians for 19%.

Overall, only 28% of respondents to the first survey said they would accept an H5N1 vaccine. That percentage increased, though not significantly so, to 35% for the second survey.

More respondents (48%) said they would accept an H1N1 vaccine. Most of those who said they would accept H5N1 vaccination said they would also accept H1N1 vaccination (91%). But only 24% of those who would decline the H5N1 vaccine said they would accept the H1N1 vaccine.

The most common reasons for vaccine acceptance were a wish to be protected and the following of government advice. The most common reasons for declining vaccination were worry about side effects and doubts about vaccine efficacy.

The investigators declared that they had no conflicts.

Fewer than half of health care workers were willing to accept prepandemic influenza vaccinations to either the H5N1 or the pandemic H1N1 viruses, despite a jump in the World Health Organization alert level, according to a survey study conducted in Hong Kong.

Even when the WHO alert level for H1N1 increased to 5—indicating confirmed human-human spread—only 48% of those surveyed said they intended to take the vaccine. The most common barriers to vaccination were worries about side effects and doubts about effectiveness, lead authors Josette Chor and Dr. Paul Chan wrote in BMJ online (BMJ 2009; doi:10.1136/bmj.b3391

The findings are of great concern, since vaccination of health care workers provides several key benefits during a disease outbreak, wrote Ms. Chor and Dr. Chan of the Chinese University of Hong Kong, and their associates.

Ms. Chor and her coauthors conducted two surveys in 31 Hong Kong hospitals. The first survey, conducted from January to March, asked physicians, nurses, and other health professionals employed at the facilities if they would take a prepandemic H5N1 vaccine. At that time, the WHO alert level for H5N1 was 3, indicating sporadic disease in humans but no evidence of human-human transmission strong enough to generate a community outbreak.

The second survey was conducted in May, after the WHO influenza alert level for H1N1 had been raised to phase 5. This survey asked about the willingness to accept both of the vaccines.

A total of 2,255 health care workers responded to the surveys. Nurses accounted for 71% of the respondents and physicians for 19%.

Overall, only 28% of respondents to the first survey said they would accept an H5N1 vaccine. That percentage increased, though not significantly so, to 35% for the second survey.

More respondents (48%) said they would accept an H1N1 vaccine. Most of those who said they would accept H5N1 vaccination said they would also accept H1N1 vaccination (91%). But only 24% of those who would decline the H5N1 vaccine said they would accept the H1N1 vaccine.

The most common reasons for vaccine acceptance were a wish to be protected and the following of government advice. The most common reasons for declining vaccination were worry about side effects and doubts about vaccine efficacy.

The investigators declared that they had no conflicts.

A biosciences company in Canada has developed a genetic assay for in-office use to identify oseltamivir-resistant pandemic influenza A(H1N1).

The test results, available in 2 working days, could be used to help guide patient treatment decisions, said Yvan P. Côté, Ph.D., vice president of Warnex Medical Laboratories Inc., Montreal. Although physicians shouldn't wait on test results to initiate treatment, the short turnaround time would give quick notice on any need to switch drugs due to resistance, he said in an interview.

The test uses genetic sequencing to detect the H275Y mutation of the neuraminidase gene, which has been shown to cause resistance to oseltamivir. Dr. Cote said that Warnex could supply testing kits to physicians, who would then send the sample to the Montreal lab for processing.

The prevalence of oseltamivir-resistant mutations is unclear, Dr. Cote said. “We are doing some research on that, but have no data to share. What we do believe is that there is a potential for increased resistance as [oseltamivir] is used more frequently.”

Isolated incidents of resistance have been seen in Denmark, Japan, Hong Kong, and Canada. Four cases have been detected so far in the United States, according to the Centers for Disease Control and Prevention. All tested viruses retain their sensitivity to the other neuraminidase inhibitor, zanamivir, although the pandemic H1N1 strain is universally resistant to the adamantane antiviral medications, amantadine and rimantadine.

A biosciences company in Canada has developed a genetic assay for in-office use to identify oseltamivir-resistant pandemic influenza A(H1N1).

The test results, available in 2 working days, could be used to help guide patient treatment decisions, said Yvan P. Côté, Ph.D., vice president of Warnex Medical Laboratories Inc., Montreal. Although physicians shouldn't wait on test results to initiate treatment, the short turnaround time would give quick notice on any need to switch drugs due to resistance, he said in an interview.

The test uses genetic sequencing to detect the H275Y mutation of the neuraminidase gene, which has been shown to cause resistance to oseltamivir. Dr. Cote said that Warnex could supply testing kits to physicians, who would then send the sample to the Montreal lab for processing.

The prevalence of oseltamivir-resistant mutations is unclear, Dr. Cote said. “We are doing some research on that, but have no data to share. What we do believe is that there is a potential for increased resistance as [oseltamivir] is used more frequently.”

Isolated incidents of resistance have been seen in Denmark, Japan, Hong Kong, and Canada. Four cases have been detected so far in the United States, according to the Centers for Disease Control and Prevention. All tested viruses retain their sensitivity to the other neuraminidase inhibitor, zanamivir, although the pandemic H1N1 strain is universally resistant to the adamantane antiviral medications, amantadine and rimantadine.

A biosciences company in Canada has developed a genetic assay for in-office use to identify oseltamivir-resistant pandemic influenza A(H1N1).

The test results, available in 2 working days, could be used to help guide patient treatment decisions, said Yvan P. Côté, Ph.D., vice president of Warnex Medical Laboratories Inc., Montreal. Although physicians shouldn't wait on test results to initiate treatment, the short turnaround time would give quick notice on any need to switch drugs due to resistance, he said in an interview.

The test uses genetic sequencing to detect the H275Y mutation of the neuraminidase gene, which has been shown to cause resistance to oseltamivir. Dr. Cote said that Warnex could supply testing kits to physicians, who would then send the sample to the Montreal lab for processing.

The prevalence of oseltamivir-resistant mutations is unclear, Dr. Cote said. “We are doing some research on that, but have no data to share. What we do believe is that there is a potential for increased resistance as [oseltamivir] is used more frequently.”

Isolated incidents of resistance have been seen in Denmark, Japan, Hong Kong, and Canada. Four cases have been detected so far in the United States, according to the Centers for Disease Control and Prevention. All tested viruses retain their sensitivity to the other neuraminidase inhibitor, zanamivir, although the pandemic H1N1 strain is universally resistant to the adamantane antiviral medications, amantadine and rimantadine.

VIENNA — Good linguistic ability in early life seems to stave off the dementia of Alzheimer's disease, even when neuritic plaques and tangles are present in the brain.

The finding supports the theory that adequate cognitive reserve can delay or prevent cognitive decline in the elderly, Suzanne Tyas, Ph.D., said at the International Conference on Alzheimer's Disease.

“Linguistic ability may be one of these early-life characteristics that reflects reserve capacity that can help us resist the clinical expression of Alzheimer's,” said Dr. Tyas, an epidemiologist at the University of Waterloo (Ont.). “We also found that these early-life factors interact with late-life factors, such as brain atrophy,” to further inhibit Alzheimer's symptoms.

Dr. Tyas and her colleagues used the ongoing Nun Study as the basis of their analysis. The study examines aging and Alzheimer's disease in a cohort of 678 women who are members of the School Sisters of Notre Dame. All of the women have agreed to undergo an annual physical and cognitive assessment, and to donate their brains for study after death.

The sisters provide a unique population for studying factors that might affect cognitive decline, Dr. Tyas said. “It's a great study to look at early-life factors because these women had a relatively constant adult lifestyle between early-life cognitive factors and late-life dementia.”

Dr. Tyas based her analysis on 180 deceased women who had handwritten autobiographies that they wrote around age 22, when they were postulants for their religious community. Of these women, 56 had brains that met the neuropathologic criteria for Alzheimer's disease. However, only 29 of those 56 had dementia at the time of death.

A linguist rated the autobiographies' linguistic complexity on two scales: idea density and grammatical complexity. Idea density referred to the number of ideas in each utterance; grammatical complexity referred to sentence structure. Each characteristic was scored in quartiles, with quartile 1 being the lowest complexity.

Among those in the lowest quartile of idea density, only 7% were nondemented, while 44% of those in the highest quartile remained nondemented. The findings were similar when examining grammatical complexity. Among those in the lowest quartile, 11% remained nondemented in the presence of neuropathologic Alzheimer's, compared with 33% of those in the highest quartile.

The investigators also looked at the interaction of linguistic ability and symptomatic Alzheimer's in the presence of brain atrophy.

Among those with atrophy and low grammatical complexity, 100% had dementia, Dr. Tyas said in an interview. “In comparison, only 45% of those with moderate to high grammatical complexity were demented. This difference was highly significant,” with a P value of less than .002. “The pattern was the same for idea density, although the difference was smaller. The percentage with dementia was 91% of those with low idea density and 52% of those with moderate to high idea density.”

The investigators then conducted a logistic regression analysis that compared the lowest quartile to the three higher quartiles. The model controlled for education, ApoE4 status, and age at death.

The model found that those in the top three quartiles of idea density were seven times more likely to have asymptomatic Alzheimer's at the time of their death than those in the lowest quartile. Those in the top three quartiles of grammatical complexity were eight times more likely to have asymptomatic Alzheimer's than those in the lowest quartile.

“While understanding the brain pathology of Alzheimer's is important, understanding the factors that affect the clinical expression of that pathology is just as critical,” Dr. Tyas said. “Having AD pathology without the signs of dementia substantially reduces the impact of the disease on patients, their families, and society, even though we are not stopping the development of the disease.”

VIENNA — Good linguistic ability in early life seems to stave off the dementia of Alzheimer's disease, even when neuritic plaques and tangles are present in the brain.

The finding supports the theory that adequate cognitive reserve can delay or prevent cognitive decline in the elderly, Suzanne Tyas, Ph.D., said at the International Conference on Alzheimer's Disease.

“Linguistic ability may be one of these early-life characteristics that reflects reserve capacity that can help us resist the clinical expression of Alzheimer's,” said Dr. Tyas, an epidemiologist at the University of Waterloo (Ont.). “We also found that these early-life factors interact with late-life factors, such as brain atrophy,” to further inhibit Alzheimer's symptoms.

Dr. Tyas and her colleagues used the ongoing Nun Study as the basis of their analysis. The study examines aging and Alzheimer's disease in a cohort of 678 women who are members of the School Sisters of Notre Dame. All of the women have agreed to undergo an annual physical and cognitive assessment, and to donate their brains for study after death.

The sisters provide a unique population for studying factors that might affect cognitive decline, Dr. Tyas said. “It's a great study to look at early-life factors because these women had a relatively constant adult lifestyle between early-life cognitive factors and late-life dementia.”

Dr. Tyas based her analysis on 180 deceased women who had handwritten autobiographies that they wrote around age 22, when they were postulants for their religious community. Of these women, 56 had brains that met the neuropathologic criteria for Alzheimer's disease. However, only 29 of those 56 had dementia at the time of death.

A linguist rated the autobiographies' linguistic complexity on two scales: idea density and grammatical complexity. Idea density referred to the number of ideas in each utterance; grammatical complexity referred to sentence structure. Each characteristic was scored in quartiles, with quartile 1 being the lowest complexity.

Among those in the lowest quartile of idea density, only 7% were nondemented, while 44% of those in the highest quartile remained nondemented. The findings were similar when examining grammatical complexity. Among those in the lowest quartile, 11% remained nondemented in the presence of neuropathologic Alzheimer's, compared with 33% of those in the highest quartile.

The investigators also looked at the interaction of linguistic ability and symptomatic Alzheimer's in the presence of brain atrophy.

Among those with atrophy and low grammatical complexity, 100% had dementia, Dr. Tyas said in an interview. “In comparison, only 45% of those with moderate to high grammatical complexity were demented. This difference was highly significant,” with a P value of less than .002. “The pattern was the same for idea density, although the difference was smaller. The percentage with dementia was 91% of those with low idea density and 52% of those with moderate to high idea density.”

The investigators then conducted a logistic regression analysis that compared the lowest quartile to the three higher quartiles. The model controlled for education, ApoE4 status, and age at death.

The model found that those in the top three quartiles of idea density were seven times more likely to have asymptomatic Alzheimer's at the time of their death than those in the lowest quartile. Those in the top three quartiles of grammatical complexity were eight times more likely to have asymptomatic Alzheimer's than those in the lowest quartile.

“While understanding the brain pathology of Alzheimer's is important, understanding the factors that affect the clinical expression of that pathology is just as critical,” Dr. Tyas said. “Having AD pathology without the signs of dementia substantially reduces the impact of the disease on patients, their families, and society, even though we are not stopping the development of the disease.”

VIENNA — Good linguistic ability in early life seems to stave off the dementia of Alzheimer's disease, even when neuritic plaques and tangles are present in the brain.

The finding supports the theory that adequate cognitive reserve can delay or prevent cognitive decline in the elderly, Suzanne Tyas, Ph.D., said at the International Conference on Alzheimer's Disease.

“Linguistic ability may be one of these early-life characteristics that reflects reserve capacity that can help us resist the clinical expression of Alzheimer's,” said Dr. Tyas, an epidemiologist at the University of Waterloo (Ont.). “We also found that these early-life factors interact with late-life factors, such as brain atrophy,” to further inhibit Alzheimer's symptoms.

Dr. Tyas and her colleagues used the ongoing Nun Study as the basis of their analysis. The study examines aging and Alzheimer's disease in a cohort of 678 women who are members of the School Sisters of Notre Dame. All of the women have agreed to undergo an annual physical and cognitive assessment, and to donate their brains for study after death.

The sisters provide a unique population for studying factors that might affect cognitive decline, Dr. Tyas said. “It's a great study to look at early-life factors because these women had a relatively constant adult lifestyle between early-life cognitive factors and late-life dementia.”

Dr. Tyas based her analysis on 180 deceased women who had handwritten autobiographies that they wrote around age 22, when they were postulants for their religious community. Of these women, 56 had brains that met the neuropathologic criteria for Alzheimer's disease. However, only 29 of those 56 had dementia at the time of death.

A linguist rated the autobiographies' linguistic complexity on two scales: idea density and grammatical complexity. Idea density referred to the number of ideas in each utterance; grammatical complexity referred to sentence structure. Each characteristic was scored in quartiles, with quartile 1 being the lowest complexity.

Among those in the lowest quartile of idea density, only 7% were nondemented, while 44% of those in the highest quartile remained nondemented. The findings were similar when examining grammatical complexity. Among those in the lowest quartile, 11% remained nondemented in the presence of neuropathologic Alzheimer's, compared with 33% of those in the highest quartile.

The investigators also looked at the interaction of linguistic ability and symptomatic Alzheimer's in the presence of brain atrophy.

Among those with atrophy and low grammatical complexity, 100% had dementia, Dr. Tyas said in an interview. “In comparison, only 45% of those with moderate to high grammatical complexity were demented. This difference was highly significant,” with a P value of less than .002. “The pattern was the same for idea density, although the difference was smaller. The percentage with dementia was 91% of those with low idea density and 52% of those with moderate to high idea density.”

The investigators then conducted a logistic regression analysis that compared the lowest quartile to the three higher quartiles. The model controlled for education, ApoE4 status, and age at death.

The model found that those in the top three quartiles of idea density were seven times more likely to have asymptomatic Alzheimer's at the time of their death than those in the lowest quartile. Those in the top three quartiles of grammatical complexity were eight times more likely to have asymptomatic Alzheimer's than those in the lowest quartile.

“While understanding the brain pathology of Alzheimer's is important, understanding the factors that affect the clinical expression of that pathology is just as critical,” Dr. Tyas said. “Having AD pathology without the signs of dementia substantially reduces the impact of the disease on patients, their families, and society, even though we are not stopping the development of the disease.”

VIENNA — Markers of metabolic dysfunction are associated with changes in brain volume and cognition, suggesting that these prediabetic conditions accelerate brain aging, according to researchers who undertook a study of more than 2,000 subjects.

Subjects with these markers—hyperinsulinemia, hyperglycemia, and insulin resistance—had decreased total cerebral volume equivalent to 6 years' worth of structural brain aging, Dr. Zaldy S. Tan said at the International Conference on Alzheimer's Disease.

“These changes were seen even among nondiabetics,” said Dr. Tan, suggesting that metabolic dysregulation might affect the brain long before diabetes becomes clinically apparent.

Dr. Tan, of Harvard Medical School, Boston, and his colleagues based the study on data extracted from the Framingham Heart Study Offspring Cohort. This group consists of 5,124 men and women who are the children of the original Framingham cohort. They have undergone up to eight examinations since their cohort was established in 1975; exams are conducted every 4-6 years.

Dr. Tan and his colleagues focused on 2,518 participants who had attended the seventh examination cycle, were free of stroke and clinical dementia, and had undergone volumetric brain MRI and cognitive testing. Their mean age was 63 years; 269 had diabetes.

The researchers correlated MRI and cognitive measures with diabetes, fasting glucose levels, hemoglobin A_1c, fasting insulin, and homeostatic model assessment–estimated insulin resistance (HOMA-IR). The models controlled for age, sex, education, stroke risk factors, ApoE4 status, and homocysteine, C-reactive protein, and interleukin-6 levels.

No correlates were found between metabolic dysfunction and hippocampal volume, but total cerebral brain volume was inversely correlated with diabetes, HbA_1c, fasting insulin level, and insulin resistance. “These changes were equivalent to 6 years of structural brain aging, and persisted even among those without diabetes,” Dr. Tan said.

He also found an inverse correlation between executive function and diabetes, fasting glucose, HbA_1c, fasting insulin level, and insulin resistance, in patients with and without diabetes.

Visual memory was inversely related to fasting insulin and insulin resistance, but there were no significant relationships between measures of metabolic dysfunction and verbal memory.

Two proposed mechanisms account for the association of diabetes and structural brain volume. Diabetes is a known vascular risk factor and might induce cerebrovascular brain injury, and eventual structural and cognitive brain aging. But even before diabetes arises, altered insulin levels in the brain also might exert a negative effect.

The conference was sponsored by the Alzheimer's Association.

VIENNA — Markers of metabolic dysfunction are associated with changes in brain volume and cognition, suggesting that these prediabetic conditions accelerate brain aging, according to researchers who undertook a study of more than 2,000 subjects.

Subjects with these markers—hyperinsulinemia, hyperglycemia, and insulin resistance—had decreased total cerebral volume equivalent to 6 years' worth of structural brain aging, Dr. Zaldy S. Tan said at the International Conference on Alzheimer's Disease.

“These changes were seen even among nondiabetics,” said Dr. Tan, suggesting that metabolic dysregulation might affect the brain long before diabetes becomes clinically apparent.

Dr. Tan, of Harvard Medical School, Boston, and his colleagues based the study on data extracted from the Framingham Heart Study Offspring Cohort. This group consists of 5,124 men and women who are the children of the original Framingham cohort. They have undergone up to eight examinations since their cohort was established in 1975; exams are conducted every 4-6 years.

Dr. Tan and his colleagues focused on 2,518 participants who had attended the seventh examination cycle, were free of stroke and clinical dementia, and had undergone volumetric brain MRI and cognitive testing. Their mean age was 63 years; 269 had diabetes.

The researchers correlated MRI and cognitive measures with diabetes, fasting glucose levels, hemoglobin A_1c, fasting insulin, and homeostatic model assessment–estimated insulin resistance (HOMA-IR). The models controlled for age, sex, education, stroke risk factors, ApoE4 status, and homocysteine, C-reactive protein, and interleukin-6 levels.

No correlates were found between metabolic dysfunction and hippocampal volume, but total cerebral brain volume was inversely correlated with diabetes, HbA_1c, fasting insulin level, and insulin resistance. “These changes were equivalent to 6 years of structural brain aging, and persisted even among those without diabetes,” Dr. Tan said.

He also found an inverse correlation between executive function and diabetes, fasting glucose, HbA_1c, fasting insulin level, and insulin resistance, in patients with and without diabetes.

Visual memory was inversely related to fasting insulin and insulin resistance, but there were no significant relationships between measures of metabolic dysfunction and verbal memory.

Two proposed mechanisms account for the association of diabetes and structural brain volume. Diabetes is a known vascular risk factor and might induce cerebrovascular brain injury, and eventual structural and cognitive brain aging. But even before diabetes arises, altered insulin levels in the brain also might exert a negative effect.

The conference was sponsored by the Alzheimer's Association.

VIENNA — Markers of metabolic dysfunction are associated with changes in brain volume and cognition, suggesting that these prediabetic conditions accelerate brain aging, according to researchers who undertook a study of more than 2,000 subjects.

Subjects with these markers—hyperinsulinemia, hyperglycemia, and insulin resistance—had decreased total cerebral volume equivalent to 6 years' worth of structural brain aging, Dr. Zaldy S. Tan said at the International Conference on Alzheimer's Disease.

“These changes were seen even among nondiabetics,” said Dr. Tan, suggesting that metabolic dysregulation might affect the brain long before diabetes becomes clinically apparent.

Dr. Tan, of Harvard Medical School, Boston, and his colleagues based the study on data extracted from the Framingham Heart Study Offspring Cohort. This group consists of 5,124 men and women who are the children of the original Framingham cohort. They have undergone up to eight examinations since their cohort was established in 1975; exams are conducted every 4-6 years.

Dr. Tan and his colleagues focused on 2,518 participants who had attended the seventh examination cycle, were free of stroke and clinical dementia, and had undergone volumetric brain MRI and cognitive testing. Their mean age was 63 years; 269 had diabetes.

The researchers correlated MRI and cognitive measures with diabetes, fasting glucose levels, hemoglobin A_1c, fasting insulin, and homeostatic model assessment–estimated insulin resistance (HOMA-IR). The models controlled for age, sex, education, stroke risk factors, ApoE4 status, and homocysteine, C-reactive protein, and interleukin-6 levels.

No correlates were found between metabolic dysfunction and hippocampal volume, but total cerebral brain volume was inversely correlated with diabetes, HbA_1c, fasting insulin level, and insulin resistance. “These changes were equivalent to 6 years of structural brain aging, and persisted even among those without diabetes,” Dr. Tan said.

He also found an inverse correlation between executive function and diabetes, fasting glucose, HbA_1c, fasting insulin level, and insulin resistance, in patients with and without diabetes.

Visual memory was inversely related to fasting insulin and insulin resistance, but there were no significant relationships between measures of metabolic dysfunction and verbal memory.

Two proposed mechanisms account for the association of diabetes and structural brain volume. Diabetes is a known vascular risk factor and might induce cerebrovascular brain injury, and eventual structural and cognitive brain aging. But even before diabetes arises, altered insulin levels in the brain also might exert a negative effect.

The conference was sponsored by the Alzheimer's Association.

VIENNA — The rising tides of Alzheimer's disease and obesity could join in the next 40 years to create a flood of dementia associated with type 2 diabetes.

The outlook may be dire, researchers said at the International Conference on Alzheimer's Disease. If the trends in child and adolescent obesity continue unabated, by 2040 one-third of the 81 million expected Alzheimer's cases worldwide may be a direct result of obesity-driven diabetes, Mary Haan, Ph.D., said at the meeting.

“We need to identify the contributions to this increase in dementia and figure out how to decrease this burden,” Dr. Haan said. “In the setting of diabetes and Alzheimer's, this means we need to think about intervening earlier in the process and treating across the life span. Our focus should be prevention, which is probably more effective when begun at younger ages.”

Dr. Haan is the primary investigator on the Sacramento Area Latino Study on Aging (SALSA), a prospective cohort study that has been ongoing since 1997. SALSA consists entirely of Mexican Americans, whose high rates of type 2 diabetes, metabolic syndrome, and hypertension create an ideal population in which to study the impact of these disorders on cognition.

At the meeting, Dr. Haan of the University of California, San Francisco, presented 9 years of follow-up data on this group of 1,789 men and women (mean baseline age 72 years). At study entrance, 33% of the group had type 2 diabetes and 40% had a body mass index of more than 25 kg/m

Over 9 years, 158 incident cases of dementia or nondementia cognitive impairment developed. After controlling for age, gender, girth, diabetes treatment, fasting insulin, and C-reactive protein, Dr. Haan said the presence of diabetes at baseline more than doubled the risk of dementia or cognitive impairment. “This translates into a population attributable risk of 19%,” she said. “Nineteen percent of all these dementia cases were the direct result of type 2 diabetes.”

When carried forward in accordance with projected increases in obesity, the 19% figure means that by 2040, 24 million cases of dementia could be directly tied to type 2 diabetes, she said. However, “there are no randomized controlled trials that support the notion that we should be treating [cognitive impairment] with an antidiabetic drug,” she said. Instead, the most effective method is probably to prevent obesity and insulin resistance—the two factors that most strongly influence the development of diabetes.

Suzanne Craft, Ph.D., agreed. “The concern is this current epidemic of diabetes associated with insulin resistance, in conjunction with a rapidly aging population, foreshadows an epidemic of Alzheimer's.” And although it makes sense to investigate the impact that diabetes treatment might have on cognition, an incredibly effective intervention already exists.

“Exercise is the most potent insulin-sensitizing agent we have,” said Dr. Craft, a geriatrician and Alzheimer's researcher at the Veterans Administration Puget Sound Health Care System, Seattle. “A single bout of aerobic exercise improves insulin sensitivity for 24 hours. It's much more potent than any medication. Caloric restriction also lowers hyperinsulinemia and improves insulin sensitivity.”

A large body of work now suggests that insulin resistance increases the risk of Alzheimer's by multiple mechanisms, Dr. Craft said. Far from being active only in the periphery, insulin readily crosses the blood-brain barrier and binds to receptors located throughout the brain. Once in the brain, insulin interacts with amyloid beta in several ways, increasing its intracellular clearance through insulin degrading enzyme and apparently even protecting neurons from the protein's toxic effects.

“This has been known for some time, but recent research has shown that amyloid beta may have its own independent effects on insulin signaling,” Dr. Craft said. A series of experiments by William L. Klein, Ph.D., concluded that soluble oligomers of amyloid beta can remove insulin receptors from the dendritic plasma membranes of hippocampal neurons. The study concluded that insulin receptor signaling downregulated the oligomeric binding sites. The addition of rosiglitazone potentiated this effect, suggesting that insulin-sensitizing agents may have some role in cognitive protection (Proc. Natl. Acad. Sci. U.S.A. 2009;106:1971-6).

“Insulin appears to mitigate many of the negative effects of amyloid and regulates its clearance, while beta amyloid appears to reduce insulin signaling. So high levels of insulin in the brain can induce a brain insulin-resistance by removing the insulin receptors from the nerve cell membranes,” Dr. Craft said.

She recently investigated insulin's effect on memory in a group of 33 patients with Alzheimer's or mild cognitive impairment and 59 elderly controls. The patients received placebo or five escalating doses of intranasal insulin, which travels directly into the central nervous system along the olfactory and trigeminal vasculature. Cognition was tested 15 minutes after each treatment. “We saw a 50% improvement in memory compared to baseline with the highest dose,” Dr. Craft said (J. Alz. Dis. 2008;13:323-31).

Insulin also affects vascular function in the brain. “It's very well known that insulin resistance is accompanied by peripheral vascular dysfunction, but the understanding that this may also manifest in the brain is very new and potentially important.”

In insulin resistance, there is a down-regulation of the phosphoinositide-3 (PI3) kinase pathway, which mediates vascular relaxation. But the mitogen-activated protein (MAP) kinase pathway, which mediates vasoconstriction, is driven by high levels of insulin and does not downregulate with insulin resistance. “You get a reduction in vasodilation and hyperactivation of vasoconstriction,” Dr. Craft said. “This imbalance is thought to underlie many of the vascular dysfunctions associated with insulin resistance.”

She saw this in a recent study of 196 brains (71 with dementia). The brains were divided into four groups: normal, diabetic without dementia, diabetic with dementia, and dementia without diabetes (Arch. Neuro. 2009;66:315-22).

“We saw a surprising pattern when we looked at plaques and tangles: The brains of the patients with dementia but no diabetes had a high load, as anticipated, but the brains of diabetic patients with dementia had a plaque load that was similar to the normal controls.”

The patients with both dementia and diabetes did, however, show high levels of microvascular lesions, which were absent in the other groups. “The volume of the lesions is small, so they are almost certainly not directly responsible for the cognitive impairment, but this finding may point to some broader based vascular dysfunction,” Dr. Craft said.

Memory loss in Alzheimer's may be tied to loss of insulin receptors (red).

Source Courtesy Fernanda G. De Felice and William L. Klein, Ph.D. (appeared in Proc. Natl. Acad. Sci. U.S.A. 2009;106:1971-6)

VIENNA — The rising tides of Alzheimer's disease and obesity could join in the next 40 years to create a flood of dementia associated with type 2 diabetes.

The outlook may be dire, researchers said at the International Conference on Alzheimer's Disease. If the trends in child and adolescent obesity continue unabated, by 2040 one-third of the 81 million expected Alzheimer's cases worldwide may be a direct result of obesity-driven diabetes, Mary Haan, Ph.D., said at the meeting.

“We need to identify the contributions to this increase in dementia and figure out how to decrease this burden,” Dr. Haan said. “In the setting of diabetes and Alzheimer's, this means we need to think about intervening earlier in the process and treating across the life span. Our focus should be prevention, which is probably more effective when begun at younger ages.”

Dr. Haan is the primary investigator on the Sacramento Area Latino Study on Aging (SALSA), a prospective cohort study that has been ongoing since 1997. SALSA consists entirely of Mexican Americans, whose high rates of type 2 diabetes, metabolic syndrome, and hypertension create an ideal population in which to study the impact of these disorders on cognition.

At the meeting, Dr. Haan of the University of California, San Francisco, presented 9 years of follow-up data on this group of 1,789 men and women (mean baseline age 72 years). At study entrance, 33% of the group had type 2 diabetes and 40% had a body mass index of more than 25 kg/m

Over 9 years, 158 incident cases of dementia or nondementia cognitive impairment developed. After controlling for age, gender, girth, diabetes treatment, fasting insulin, and C-reactive protein, Dr. Haan said the presence of diabetes at baseline more than doubled the risk of dementia or cognitive impairment. “This translates into a population attributable risk of 19%,” she said. “Nineteen percent of all these dementia cases were the direct result of type 2 diabetes.”

When carried forward in accordance with projected increases in obesity, the 19% figure means that by 2040, 24 million cases of dementia could be directly tied to type 2 diabetes, she said. However, “there are no randomized controlled trials that support the notion that we should be treating [cognitive impairment] with an antidiabetic drug,” she said. Instead, the most effective method is probably to prevent obesity and insulin resistance—the two factors that most strongly influence the development of diabetes.

Suzanne Craft, Ph.D., agreed. “The concern is this current epidemic of diabetes associated with insulin resistance, in conjunction with a rapidly aging population, foreshadows an epidemic of Alzheimer's.” And although it makes sense to investigate the impact that diabetes treatment might have on cognition, an incredibly effective intervention already exists.

“Exercise is the most potent insulin-sensitizing agent we have,” said Dr. Craft, a geriatrician and Alzheimer's researcher at the Veterans Administration Puget Sound Health Care System, Seattle. “A single bout of aerobic exercise improves insulin sensitivity for 24 hours. It's much more potent than any medication. Caloric restriction also lowers hyperinsulinemia and improves insulin sensitivity.”

A large body of work now suggests that insulin resistance increases the risk of Alzheimer's by multiple mechanisms, Dr. Craft said. Far from being active only in the periphery, insulin readily crosses the blood-brain barrier and binds to receptors located throughout the brain. Once in the brain, insulin interacts with amyloid beta in several ways, increasing its intracellular clearance through insulin degrading enzyme and apparently even protecting neurons from the protein's toxic effects.

“This has been known for some time, but recent research has shown that amyloid beta may have its own independent effects on insulin signaling,” Dr. Craft said. A series of experiments by William L. Klein, Ph.D., concluded that soluble oligomers of amyloid beta can remove insulin receptors from the dendritic plasma membranes of hippocampal neurons. The study concluded that insulin receptor signaling downregulated the oligomeric binding sites. The addition of rosiglitazone potentiated this effect, suggesting that insulin-sensitizing agents may have some role in cognitive protection (Proc. Natl. Acad. Sci. U.S.A. 2009;106:1971-6).

“Insulin appears to mitigate many of the negative effects of amyloid and regulates its clearance, while beta amyloid appears to reduce insulin signaling. So high levels of insulin in the brain can induce a brain insulin-resistance by removing the insulin receptors from the nerve cell membranes,” Dr. Craft said.

She recently investigated insulin's effect on memory in a group of 33 patients with Alzheimer's or mild cognitive impairment and 59 elderly controls. The patients received placebo or five escalating doses of intranasal insulin, which travels directly into the central nervous system along the olfactory and trigeminal vasculature. Cognition was tested 15 minutes after each treatment. “We saw a 50% improvement in memory compared to baseline with the highest dose,” Dr. Craft said (J. Alz. Dis. 2008;13:323-31).

Insulin also affects vascular function in the brain. “It's very well known that insulin resistance is accompanied by peripheral vascular dysfunction, but the understanding that this may also manifest in the brain is very new and potentially important.”

In insulin resistance, there is a down-regulation of the phosphoinositide-3 (PI3) kinase pathway, which mediates vascular relaxation. But the mitogen-activated protein (MAP) kinase pathway, which mediates vasoconstriction, is driven by high levels of insulin and does not downregulate with insulin resistance. “You get a reduction in vasodilation and hyperactivation of vasoconstriction,” Dr. Craft said. “This imbalance is thought to underlie many of the vascular dysfunctions associated with insulin resistance.”

She saw this in a recent study of 196 brains (71 with dementia). The brains were divided into four groups: normal, diabetic without dementia, diabetic with dementia, and dementia without diabetes (Arch. Neuro. 2009;66:315-22).

“We saw a surprising pattern when we looked at plaques and tangles: The brains of the patients with dementia but no diabetes had a high load, as anticipated, but the brains of diabetic patients with dementia had a plaque load that was similar to the normal controls.”

The patients with both dementia and diabetes did, however, show high levels of microvascular lesions, which were absent in the other groups. “The volume of the lesions is small, so they are almost certainly not directly responsible for the cognitive impairment, but this finding may point to some broader based vascular dysfunction,” Dr. Craft said.

Memory loss in Alzheimer's may be tied to loss of insulin receptors (red).

Source Courtesy Fernanda G. De Felice and William L. Klein, Ph.D. (appeared in Proc. Natl. Acad. Sci. U.S.A. 2009;106:1971-6)

VIENNA — The rising tides of Alzheimer's disease and obesity could join in the next 40 years to create a flood of dementia associated with type 2 diabetes.

The outlook may be dire, researchers said at the International Conference on Alzheimer's Disease. If the trends in child and adolescent obesity continue unabated, by 2040 one-third of the 81 million expected Alzheimer's cases worldwide may be a direct result of obesity-driven diabetes, Mary Haan, Ph.D., said at the meeting.

“We need to identify the contributions to this increase in dementia and figure out how to decrease this burden,” Dr. Haan said. “In the setting of diabetes and Alzheimer's, this means we need to think about intervening earlier in the process and treating across the life span. Our focus should be prevention, which is probably more effective when begun at younger ages.”

Dr. Haan is the primary investigator on the Sacramento Area Latino Study on Aging (SALSA), a prospective cohort study that has been ongoing since 1997. SALSA consists entirely of Mexican Americans, whose high rates of type 2 diabetes, metabolic syndrome, and hypertension create an ideal population in which to study the impact of these disorders on cognition.

At the meeting, Dr. Haan of the University of California, San Francisco, presented 9 years of follow-up data on this group of 1,789 men and women (mean baseline age 72 years). At study entrance, 33% of the group had type 2 diabetes and 40% had a body mass index of more than 25 kg/m

Over 9 years, 158 incident cases of dementia or nondementia cognitive impairment developed. After controlling for age, gender, girth, diabetes treatment, fasting insulin, and C-reactive protein, Dr. Haan said the presence of diabetes at baseline more than doubled the risk of dementia or cognitive impairment. “This translates into a population attributable risk of 19%,” she said. “Nineteen percent of all these dementia cases were the direct result of type 2 diabetes.”

When carried forward in accordance with projected increases in obesity, the 19% figure means that by 2040, 24 million cases of dementia could be directly tied to type 2 diabetes, she said. However, “there are no randomized controlled trials that support the notion that we should be treating [cognitive impairment] with an antidiabetic drug,” she said. Instead, the most effective method is probably to prevent obesity and insulin resistance—the two factors that most strongly influence the development of diabetes.

Suzanne Craft, Ph.D., agreed. “The concern is this current epidemic of diabetes associated with insulin resistance, in conjunction with a rapidly aging population, foreshadows an epidemic of Alzheimer's.” And although it makes sense to investigate the impact that diabetes treatment might have on cognition, an incredibly effective intervention already exists.

“Exercise is the most potent insulin-sensitizing agent we have,” said Dr. Craft, a geriatrician and Alzheimer's researcher at the Veterans Administration Puget Sound Health Care System, Seattle. “A single bout of aerobic exercise improves insulin sensitivity for 24 hours. It's much more potent than any medication. Caloric restriction also lowers hyperinsulinemia and improves insulin sensitivity.”

A large body of work now suggests that insulin resistance increases the risk of Alzheimer's by multiple mechanisms, Dr. Craft said. Far from being active only in the periphery, insulin readily crosses the blood-brain barrier and binds to receptors located throughout the brain. Once in the brain, insulin interacts with amyloid beta in several ways, increasing its intracellular clearance through insulin degrading enzyme and apparently even protecting neurons from the protein's toxic effects.

“This has been known for some time, but recent research has shown that amyloid beta may have its own independent effects on insulin signaling,” Dr. Craft said. A series of experiments by William L. Klein, Ph.D., concluded that soluble oligomers of amyloid beta can remove insulin receptors from the dendritic plasma membranes of hippocampal neurons. The study concluded that insulin receptor signaling downregulated the oligomeric binding sites. The addition of rosiglitazone potentiated this effect, suggesting that insulin-sensitizing agents may have some role in cognitive protection (Proc. Natl. Acad. Sci. U.S.A. 2009;106:1971-6).

“Insulin appears to mitigate many of the negative effects of amyloid and regulates its clearance, while beta amyloid appears to reduce insulin signaling. So high levels of insulin in the brain can induce a brain insulin-resistance by removing the insulin receptors from the nerve cell membranes,” Dr. Craft said.

She recently investigated insulin's effect on memory in a group of 33 patients with Alzheimer's or mild cognitive impairment and 59 elderly controls. The patients received placebo or five escalating doses of intranasal insulin, which travels directly into the central nervous system along the olfactory and trigeminal vasculature. Cognition was tested 15 minutes after each treatment. “We saw a 50% improvement in memory compared to baseline with the highest dose,” Dr. Craft said (J. Alz. Dis. 2008;13:323-31).

Insulin also affects vascular function in the brain. “It's very well known that insulin resistance is accompanied by peripheral vascular dysfunction, but the understanding that this may also manifest in the brain is very new and potentially important.”

In insulin resistance, there is a down-regulation of the phosphoinositide-3 (PI3) kinase pathway, which mediates vascular relaxation. But the mitogen-activated protein (MAP) kinase pathway, which mediates vasoconstriction, is driven by high levels of insulin and does not downregulate with insulin resistance. “You get a reduction in vasodilation and hyperactivation of vasoconstriction,” Dr. Craft said. “This imbalance is thought to underlie many of the vascular dysfunctions associated with insulin resistance.”

She saw this in a recent study of 196 brains (71 with dementia). The brains were divided into four groups: normal, diabetic without dementia, diabetic with dementia, and dementia without diabetes (Arch. Neuro. 2009;66:315-22).

“We saw a surprising pattern when we looked at plaques and tangles: The brains of the patients with dementia but no diabetes had a high load, as anticipated, but the brains of diabetic patients with dementia had a plaque load that was similar to the normal controls.”

The patients with both dementia and diabetes did, however, show high levels of microvascular lesions, which were absent in the other groups. “The volume of the lesions is small, so they are almost certainly not directly responsible for the cognitive impairment, but this finding may point to some broader based vascular dysfunction,” Dr. Craft said.

Memory loss in Alzheimer's may be tied to loss of insulin receptors (red).

Source Courtesy Fernanda G. De Felice and William L. Klein, Ph.D. (appeared in Proc. Natl. Acad. Sci. U.S.A. 2009;106:1971-6)

Benign positional vertigo appears to strongly correlate with osteopenia and osteoporosis in both men and women, researchers in a case-control study have concluded.

Compared to controls, patients with osteopenia were twice as likely to experience positional vertigo, and those with osteoporosis were three times as likely to experience the disorder, Dr. Ji Sook Kim and colleagues wrote.

“These findings suggest a deranged calcium metabolism in idiopathic benign positional vertigo,” Dr. Kim of the Seoul National University College of Medicine, Korea, said in an interview. “Restoring normal calcium metabolism may prevent recurrences of BPPV.”

The study compared bone mineral density in 209 patients with a diagnosis of idiopathic benign positional vertigo (BPV) and 202 controls. Most (142) were female; their mean age was 60 years.

Among female patients, only 28% had normal bone mineral density, while 47% had osteopenia and 25% had osteoporosis. Among female controls, normal bone mass was found in 57%; 33% had osteopenia and 9% had osteoporosis. (Percentages do not add up to 100% due to rounding.) The differences were significant at all points measured (Neurology 2009;72:1069-76).

In male patients, 48% had normal bone mass, while 40% had osteopenia and 12% had osteoporosis. In male controls, 67% had normal bone mass, 27% had osteopenia, and 6% had osteoporosis. The differences were significant at the femur and first lumbar vertebra, but not at the other lumbar measurements.

Benign positional vertigo appears to strongly correlate with osteopenia and osteoporosis in both men and women, researchers in a case-control study have concluded.

Compared to controls, patients with osteopenia were twice as likely to experience positional vertigo, and those with osteoporosis were three times as likely to experience the disorder, Dr. Ji Sook Kim and colleagues wrote.

“These findings suggest a deranged calcium metabolism in idiopathic benign positional vertigo,” Dr. Kim of the Seoul National University College of Medicine, Korea, said in an interview. “Restoring normal calcium metabolism may prevent recurrences of BPPV.”

The study compared bone mineral density in 209 patients with a diagnosis of idiopathic benign positional vertigo (BPV) and 202 controls. Most (142) were female; their mean age was 60 years.

Among female patients, only 28% had normal bone mineral density, while 47% had osteopenia and 25% had osteoporosis. Among female controls, normal bone mass was found in 57%; 33% had osteopenia and 9% had osteoporosis. (Percentages do not add up to 100% due to rounding.) The differences were significant at all points measured (Neurology 2009;72:1069-76).

In male patients, 48% had normal bone mass, while 40% had osteopenia and 12% had osteoporosis. In male controls, 67% had normal bone mass, 27% had osteopenia, and 6% had osteoporosis. The differences were significant at the femur and first lumbar vertebra, but not at the other lumbar measurements.

Benign positional vertigo appears to strongly correlate with osteopenia and osteoporosis in both men and women, researchers in a case-control study have concluded.

Compared to controls, patients with osteopenia were twice as likely to experience positional vertigo, and those with osteoporosis were three times as likely to experience the disorder, Dr. Ji Sook Kim and colleagues wrote.

“These findings suggest a deranged calcium metabolism in idiopathic benign positional vertigo,” Dr. Kim of the Seoul National University College of Medicine, Korea, said in an interview. “Restoring normal calcium metabolism may prevent recurrences of BPPV.”

The study compared bone mineral density in 209 patients with a diagnosis of idiopathic benign positional vertigo (BPV) and 202 controls. Most (142) were female; their mean age was 60 years.

Among female patients, only 28% had normal bone mineral density, while 47% had osteopenia and 25% had osteoporosis. Among female controls, normal bone mass was found in 57%; 33% had osteopenia and 9% had osteoporosis. (Percentages do not add up to 100% due to rounding.) The differences were significant at all points measured (Neurology 2009;72:1069-76).

In male patients, 48% had normal bone mass, while 40% had osteopenia and 12% had osteoporosis. In male controls, 67% had normal bone mass, 27% had osteopenia, and 6% had osteoporosis. The differences were significant at the femur and first lumbar vertebra, but not at the other lumbar measurements.

VIENNA — Valproate treatment over 2 years does nothing to delay the onset of agitation or psychosis in patients with Alzheimer's disease, and patients taking the anticonvulsant showed significantly more brain volume loss on MRI at year 1 than did those taking placebo, based on the results of a randomized trial.

But because the changes in brain volume did not correlate with any clinical differences between the groups, it's difficult to know just what to make of the observed volume loss, Dr. Pierre Tariot said at the International Conference on Alzheimer's Disease.

“Interpretation of these results really isn't possible at this juncture,” said Dr. Tariot of the Banner Alzheimer's Institute, Phoenix, in an interview. “It could theoretically represent damage to the brain, but that seems unlikely due to the absence of correlation with clinical decline that is seen in natural history studies. There are case reports of 'pseudoatrophy' associated with valproate use, which may be relevant here. We have an ongoing analysis, and the full details will be presented at a later time.”

The trial randomized 313 patients with mild-moderate Alzheimer's disease who lacked agitation or psychosis at baseline to either placebo or an extended-release form of divalproex sodium (Depakote ER) at a dose of 10-12 mg/kg per day. The primary outcome was time until the emergence of agitation and/or psychosis. The symptoms had to last at least 2 weeks, and had to be clinically significant in the opinion of the site physician.

MRI of the brain was performed on a subset of 90 patients at baseline and 1 year.

The patients' mean age was 75 years; their mean Mini Mental State Exam at baseline was 17 and the mean Neuropsychiatric Inventory score was 3. Most of the patients (70%) were positive for the high-risk apolipoprotein E e4 allele.

There were no between-group differences in time to agitation or psychosis. In fact, although the study assumed an incidence of 50% by the end of the trial, only 17% of the entire cohort developed either of these symptoms, said Dr. Tariot, who received consulting fees and research funding from Abbott Laboratories, which manufactures Depakote ER. Abbott supplied the drugs for the trial and funded the MRI portion of the trial.

There also were no between-group differences in any of the secondary end points, confirming that valproate confers no clinically discernible neuroprotective benefit. Patients taking placebo had a slightly better score on the Alzheimer's Disease Cooperative Study activities of daily living at 24 months, Dr. Tariot said, but that difference did not reach significance after adjustment for multiple comparisons.

Consistent with known effects of the medication, patients taking valproate had significantly more central nervous system side effects (gait disturbance, tremor, and sedation), and gastrointestinal side effects (abdominal pain, loose stool).

In the MRI substudy, total brain volume and bilateral hippocampal volume were significantly decreased in the valproate group, compared with placebo, while ventricular volume was significantly increased in the active treatment group, compared with the placebo group. However, Dr. Tariot noted, there were no differences in clinical outcomes between these two subgroups.

The conference was sponsored by the Alzheimer's Association.

Valproate appeared to reduce brain volume, but this difference did not correlate with clinical outcomes.

Source Dr. Tariot

VIENNA — Valproate treatment over 2 years does nothing to delay the onset of agitation or psychosis in patients with Alzheimer's disease, and patients taking the anticonvulsant showed significantly more brain volume loss on MRI at year 1 than did those taking placebo, based on the results of a randomized trial.

But because the changes in brain volume did not correlate with any clinical differences between the groups, it's difficult to know just what to make of the observed volume loss, Dr. Pierre Tariot said at the International Conference on Alzheimer's Disease.

“Interpretation of these results really isn't possible at this juncture,” said Dr. Tariot of the Banner Alzheimer's Institute, Phoenix, in an interview. “It could theoretically represent damage to the brain, but that seems unlikely due to the absence of correlation with clinical decline that is seen in natural history studies. There are case reports of 'pseudoatrophy' associated with valproate use, which may be relevant here. We have an ongoing analysis, and the full details will be presented at a later time.”

The trial randomized 313 patients with mild-moderate Alzheimer's disease who lacked agitation or psychosis at baseline to either placebo or an extended-release form of divalproex sodium (Depakote ER) at a dose of 10-12 mg/kg per day. The primary outcome was time until the emergence of agitation and/or psychosis. The symptoms had to last at least 2 weeks, and had to be clinically significant in the opinion of the site physician.

MRI of the brain was performed on a subset of 90 patients at baseline and 1 year.

The patients' mean age was 75 years; their mean Mini Mental State Exam at baseline was 17 and the mean Neuropsychiatric Inventory score was 3. Most of the patients (70%) were positive for the high-risk apolipoprotein E e4 allele.

There were no between-group differences in time to agitation or psychosis. In fact, although the study assumed an incidence of 50% by the end of the trial, only 17% of the entire cohort developed either of these symptoms, said Dr. Tariot, who received consulting fees and research funding from Abbott Laboratories, which manufactures Depakote ER. Abbott supplied the drugs for the trial and funded the MRI portion of the trial.

There also were no between-group differences in any of the secondary end points, confirming that valproate confers no clinically discernible neuroprotective benefit. Patients taking placebo had a slightly better score on the Alzheimer's Disease Cooperative Study activities of daily living at 24 months, Dr. Tariot said, but that difference did not reach significance after adjustment for multiple comparisons.

Consistent with known effects of the medication, patients taking valproate had significantly more central nervous system side effects (gait disturbance, tremor, and sedation), and gastrointestinal side effects (abdominal pain, loose stool).

In the MRI substudy, total brain volume and bilateral hippocampal volume were significantly decreased in the valproate group, compared with placebo, while ventricular volume was significantly increased in the active treatment group, compared with the placebo group. However, Dr. Tariot noted, there were no differences in clinical outcomes between these two subgroups.

The conference was sponsored by the Alzheimer's Association.

Valproate appeared to reduce brain volume, but this difference did not correlate with clinical outcomes.

Source Dr. Tariot

VIENNA — Valproate treatment over 2 years does nothing to delay the onset of agitation or psychosis in patients with Alzheimer's disease, and patients taking the anticonvulsant showed significantly more brain volume loss on MRI at year 1 than did those taking placebo, based on the results of a randomized trial.

But because the changes in brain volume did not correlate with any clinical differences between the groups, it's difficult to know just what to make of the observed volume loss, Dr. Pierre Tariot said at the International Conference on Alzheimer's Disease.

“Interpretation of these results really isn't possible at this juncture,” said Dr. Tariot of the Banner Alzheimer's Institute, Phoenix, in an interview. “It could theoretically represent damage to the brain, but that seems unlikely due to the absence of correlation with clinical decline that is seen in natural history studies. There are case reports of 'pseudoatrophy' associated with valproate use, which may be relevant here. We have an ongoing analysis, and the full details will be presented at a later time.”

The trial randomized 313 patients with mild-moderate Alzheimer's disease who lacked agitation or psychosis at baseline to either placebo or an extended-release form of divalproex sodium (Depakote ER) at a dose of 10-12 mg/kg per day. The primary outcome was time until the emergence of agitation and/or psychosis. The symptoms had to last at least 2 weeks, and had to be clinically significant in the opinion of the site physician.

MRI of the brain was performed on a subset of 90 patients at baseline and 1 year.

The patients' mean age was 75 years; their mean Mini Mental State Exam at baseline was 17 and the mean Neuropsychiatric Inventory score was 3. Most of the patients (70%) were positive for the high-risk apolipoprotein E e4 allele.

There were no between-group differences in time to agitation or psychosis. In fact, although the study assumed an incidence of 50% by the end of the trial, only 17% of the entire cohort developed either of these symptoms, said Dr. Tariot, who received consulting fees and research funding from Abbott Laboratories, which manufactures Depakote ER. Abbott supplied the drugs for the trial and funded the MRI portion of the trial.

There also were no between-group differences in any of the secondary end points, confirming that valproate confers no clinically discernible neuroprotective benefit. Patients taking placebo had a slightly better score on the Alzheimer's Disease Cooperative Study activities of daily living at 24 months, Dr. Tariot said, but that difference did not reach significance after adjustment for multiple comparisons.

Consistent with known effects of the medication, patients taking valproate had significantly more central nervous system side effects (gait disturbance, tremor, and sedation), and gastrointestinal side effects (abdominal pain, loose stool).

In the MRI substudy, total brain volume and bilateral hippocampal volume were significantly decreased in the valproate group, compared with placebo, while ventricular volume was significantly increased in the active treatment group, compared with the placebo group. However, Dr. Tariot noted, there were no differences in clinical outcomes between these two subgroups.

The conference was sponsored by the Alzheimer's Association.

Valproate appeared to reduce brain volume, but this difference did not correlate with clinical outcomes.

Source Dr. Tariot

VIENNA — Alzheimer's drug researchers served up a string of bad news at the International Conference on Alzheimer's disease, presenting one failed trial after another.

None of these strategies tested—blocking amyloid, improving insulin sensitivity in the brain, or even doubling up on agents that improve synaptic signaling—was able to alter the steady rate of cognitive and functional decline in patients with mild to moderate Alzheimer's disease (AD). The disappointments, combined with the failed omega-3 fatty acid study that was also presented at the meeting, left researchers wondering where to best focus their efforts.

Instead of searching for the compound that will alter the so-far inevitable decline seen in AD, the key will probably be preventing the disease from taking hold in the first place, Dr. Samuel Gandy, Mount Sinai Professor of Alzheimer's Disease Research at Mount Sinai Medical Center in New York, said in an interview. Unfortunately, those studies require very large cohorts and years of follow-up, making them logistically and financially intimidating.

Dr. Michael Gold presented the results of a phase II placebo-controlled trial of rosiglitazone that failed to show any benefit on cognition in a group of 553 patients with mild to moderate AD.

The 24-week trial, sponsored by GlaxoSmithKline, randomized the patients to placebo, a positive control group of donepezil 10 mg/day, or 2 mg or 8 mg daily of an experimental extended-release formulation of rosiglitazone.

At the 24-week end point, neither of the rosiglitazone doses was significantly different than placebo in either the AD Assessment Scale-cognitive domain (ADAS-cog) or the Clinicians' Interview-Based Impression of Change plus Caregiver Input, said Dr. Gold, global clinical vice president of neurology at GlaxoSmithKline, Durham, N.C.

Dr. Gordon Wilcock announced negative results in a second phase III trial with tarenflurbil, a selective amyloid-lowering agent. The results confirm those first seen in a phase III trial of the drug in 2008.

The results of the most recent trial, which randomized patients to placebo or to 800 mg tarenflurbil twice a day for 18 months, failed to show any statistically significant or clinically meaningful changes in any of the three outcomes it assessed: ADAS-cog, ADAS-activities of daily living (ADAS-ADL), or the Clinical Dementia Rating–sum of boxes (CDR-sb), said Dr. Wilcock of the University of Oxford (England). He is a consultant to Myriad Pharmaceuticals Inc., which sponsored the trial

A combination of two drugs already proven effective in AD worked no better than a single agent to slow the disorder's cognitive and functional decline, said Dr. Oliver Peters of Charité University Hospital Berlin.

Dr. Peters presented the results of a 1-year, randomized, controlled trial of a combination of 24 mg of galantamine daily and 20 mg memantine daily compared to 24 mg of galantamine alone in 233 patients with mild-moderate AD.

“At 16 weeks, we saw a little better effect in the combination group,” on the ADAS-cog, ADAS-ADL, and CDR-sb, although none of the differences were statistically significant, said Dr. Peters, who has no financial relationship with the trial sponsor, Janssen-Cilag of Buckinghamshire, England.

The negative results of an 18-month, randomized, placebo-controlled trial in 402 patients with mild-moderate AD may have sealed the fate of docosahexaenoic acid (DHA) as a treatment for AD, but a second study, which examined DHA's effect on memory performance in 485 normal subjects with mild, age-related memory difficulties, concluded that the supplement did significantly improve performance on a memory test.

“The data suggest that DHA may serve to reduce risk by perhaps facilitating neuronal health,” Dr. Marwan Sabbagh, director of clinical research at the Sun Health Research Institute, Sun City, Ariz., said in an interview. “However, it appears that once symptomatic Alzheimer's is present, the critical mass of pathology may be too much for even DHA to offset.”

VIENNA — Alzheimer's drug researchers served up a string of bad news at the International Conference on Alzheimer's disease, presenting one failed trial after another.

None of these strategies tested—blocking amyloid, improving insulin sensitivity in the brain, or even doubling up on agents that improve synaptic signaling—was able to alter the steady rate of cognitive and functional decline in patients with mild to moderate Alzheimer's disease (AD). The disappointments, combined with the failed omega-3 fatty acid study that was also presented at the meeting, left researchers wondering where to best focus their efforts.

Instead of searching for the compound that will alter the so-far inevitable decline seen in AD, the key will probably be preventing the disease from taking hold in the first place, Dr. Samuel Gandy, Mount Sinai Professor of Alzheimer's Disease Research at Mount Sinai Medical Center in New York, said in an interview. Unfortunately, those studies require very large cohorts and years of follow-up, making them logistically and financially intimidating.

Dr. Michael Gold presented the results of a phase II placebo-controlled trial of rosiglitazone that failed to show any benefit on cognition in a group of 553 patients with mild to moderate AD.

The 24-week trial, sponsored by GlaxoSmithKline, randomized the patients to placebo, a positive control group of donepezil 10 mg/day, or 2 mg or 8 mg daily of an experimental extended-release formulation of rosiglitazone.

At the 24-week end point, neither of the rosiglitazone doses was significantly different than placebo in either the AD Assessment Scale-cognitive domain (ADAS-cog) or the Clinicians' Interview-Based Impression of Change plus Caregiver Input, said Dr. Gold, global clinical vice president of neurology at GlaxoSmithKline, Durham, N.C.

Dr. Gordon Wilcock announced negative results in a second phase III trial with tarenflurbil, a selective amyloid-lowering agent. The results confirm those first seen in a phase III trial of the drug in 2008.

The results of the most recent trial, which randomized patients to placebo or to 800 mg tarenflurbil twice a day for 18 months, failed to show any statistically significant or clinically meaningful changes in any of the three outcomes it assessed: ADAS-cog, ADAS-activities of daily living (ADAS-ADL), or the Clinical Dementia Rating–sum of boxes (CDR-sb), said Dr. Wilcock of the University of Oxford (England). He is a consultant to Myriad Pharmaceuticals Inc., which sponsored the trial

A combination of two drugs already proven effective in AD worked no better than a single agent to slow the disorder's cognitive and functional decline, said Dr. Oliver Peters of Charité University Hospital Berlin.

Dr. Peters presented the results of a 1-year, randomized, controlled trial of a combination of 24 mg of galantamine daily and 20 mg memantine daily compared to 24 mg of galantamine alone in 233 patients with mild-moderate AD.

“At 16 weeks, we saw a little better effect in the combination group,” on the ADAS-cog, ADAS-ADL, and CDR-sb, although none of the differences were statistically significant, said Dr. Peters, who has no financial relationship with the trial sponsor, Janssen-Cilag of Buckinghamshire, England.

The negative results of an 18-month, randomized, placebo-controlled trial in 402 patients with mild-moderate AD may have sealed the fate of docosahexaenoic acid (DHA) as a treatment for AD, but a second study, which examined DHA's effect on memory performance in 485 normal subjects with mild, age-related memory difficulties, concluded that the supplement did significantly improve performance on a memory test.

“The data suggest that DHA may serve to reduce risk by perhaps facilitating neuronal health,” Dr. Marwan Sabbagh, director of clinical research at the Sun Health Research Institute, Sun City, Ariz., said in an interview. “However, it appears that once symptomatic Alzheimer's is present, the critical mass of pathology may be too much for even DHA to offset.”

VIENNA — Alzheimer's drug researchers served up a string of bad news at the International Conference on Alzheimer's disease, presenting one failed trial after another.

None of these strategies tested—blocking amyloid, improving insulin sensitivity in the brain, or even doubling up on agents that improve synaptic signaling—was able to alter the steady rate of cognitive and functional decline in patients with mild to moderate Alzheimer's disease (AD). The disappointments, combined with the failed omega-3 fatty acid study that was also presented at the meeting, left researchers wondering where to best focus their efforts.

Instead of searching for the compound that will alter the so-far inevitable decline seen in AD, the key will probably be preventing the disease from taking hold in the first place, Dr. Samuel Gandy, Mount Sinai Professor of Alzheimer's Disease Research at Mount Sinai Medical Center in New York, said in an interview. Unfortunately, those studies require very large cohorts and years of follow-up, making them logistically and financially intimidating.

Dr. Michael Gold presented the results of a phase II placebo-controlled trial of rosiglitazone that failed to show any benefit on cognition in a group of 553 patients with mild to moderate AD.

The 24-week trial, sponsored by GlaxoSmithKline, randomized the patients to placebo, a positive control group of donepezil 10 mg/day, or 2 mg or 8 mg daily of an experimental extended-release formulation of rosiglitazone.

At the 24-week end point, neither of the rosiglitazone doses was significantly different than placebo in either the AD Assessment Scale-cognitive domain (ADAS-cog) or the Clinicians' Interview-Based Impression of Change plus Caregiver Input, said Dr. Gold, global clinical vice president of neurology at GlaxoSmithKline, Durham, N.C.

Dr. Gordon Wilcock announced negative results in a second phase III trial with tarenflurbil, a selective amyloid-lowering agent. The results confirm those first seen in a phase III trial of the drug in 2008.

The results of the most recent trial, which randomized patients to placebo or to 800 mg tarenflurbil twice a day for 18 months, failed to show any statistically significant or clinically meaningful changes in any of the three outcomes it assessed: ADAS-cog, ADAS-activities of daily living (ADAS-ADL), or the Clinical Dementia Rating–sum of boxes (CDR-sb), said Dr. Wilcock of the University of Oxford (England). He is a consultant to Myriad Pharmaceuticals Inc., which sponsored the trial

A combination of two drugs already proven effective in AD worked no better than a single agent to slow the disorder's cognitive and functional decline, said Dr. Oliver Peters of Charité University Hospital Berlin.

Dr. Peters presented the results of a 1-year, randomized, controlled trial of a combination of 24 mg of galantamine daily and 20 mg memantine daily compared to 24 mg of galantamine alone in 233 patients with mild-moderate AD.

“At 16 weeks, we saw a little better effect in the combination group,” on the ADAS-cog, ADAS-ADL, and CDR-sb, although none of the differences were statistically significant, said Dr. Peters, who has no financial relationship with the trial sponsor, Janssen-Cilag of Buckinghamshire, England.

The negative results of an 18-month, randomized, placebo-controlled trial in 402 patients with mild-moderate AD may have sealed the fate of docosahexaenoic acid (DHA) as a treatment for AD, but a second study, which examined DHA's effect on memory performance in 485 normal subjects with mild, age-related memory difficulties, concluded that the supplement did significantly improve performance on a memory test.

“The data suggest that DHA may serve to reduce risk by perhaps facilitating neuronal health,” Dr. Marwan Sabbagh, director of clinical research at the Sun Health Research Institute, Sun City, Ariz., said in an interview. “However, it appears that once symptomatic Alzheimer's is present, the critical mass of pathology may be too much for even DHA to offset.”

VIENNA — Dimebon—the abandoned Russian antihistamine that burst onto the Alzheimer's study scene with the only positive clinical data of 2008—may throw yet another curve ball into a research world that for years has focused almost entirely on the amyloid hypothesis.

Rather than lowering amyloid beta (Abeta) levels, as two failed investigational drugs—tramiprosate and tarenflurbil—–have attempted, dimebon appears to almost immediately increase them, raising Abeta by as much as 200% in three mouse models of Alzheimer's disease (AD), Dr. Samuel Gandy reported at the International Conference on Alzheimer's Disease.

While preliminary, the findings—combined with the nearly unprecedented cognitive benefit dimebon conferred in its phase II trial—could be enough to dethrone the long-reigning amyloid hypothesis, according to Mark A. Smith, Ph.D., an AD researcher.

“This drug is clearly not targeting amyloid, but increasing it acutely,” said Dr. Smith of Case Western Reserve University, Cleveland. “If you believe the dogma, therefore, you should believe that this increase will cause Alzheimer's. These results question that dogma. If this holds up, it could be enough to wound the amyloid theory, potentially mortally.”

Dimebon's 2008 phase II study found that patients with mild to moderate AD who took the drug for 12 months gained about 2 points on the Alzheimer's Disease Assessment Scale-Cognition (ADAS-cog), while those taking placebo declined almost 6 points from baseline (Lancet 2008;372:207-15). A 6-month open-label extension trial found similarly positive results. Patients who completed a full 18 months of dimebon continued to show benefit on ADAS-cog. Former placebo patients who crossed over to dimebon stabilized their cognitive decline.

Dr. Gandy of the Mount Sinai School of Medicine, New York, investigated the drug's effect on amyloid in three models of the disease: cultured nerve cells, isolated synaptic terminals, and brains from mice that overexpress human amyloid.

“In every single system dimebon stimulated amyloid secretion,” Dr. Gandy said in an interview. “The levels of the amyloid peptides in the interstitial brain fluid roughly doubled whenever the drug was given. If we think about the increased risk of Alzheimer's in Down syndrome patients who have a 50% increase in amyloid, this acute increase with dimebon could be significant over a period of many years of use.”

Dr. Gandy noted that similar results were obtained by John Cirrito, Ph.D., and Dr. David Holtzman of Washington University, St. Louis, who collaborated with him in studying the brains of freely moving transgenic mice that overexpress human Abeta.

Dr. Gandy suggested that this acute release may be followed by a chronic lowering of Abeta—something he is now investigating. Combined with dimebon's positive clinical data, this finding would imply that neurons benefit from dumping their intracellular amyloid load.

This is reminiscent of the evidence gathered by Dr. Holtzman's group that suggested that healthy nerve cells released more amyloid as head-injured patients began to recover, Dr. Gandy said.

The clinical and lab data highlight the essential mystery of amyloid, both researchers said. “It all seemed so simple when we discovered genes that implicated amyloid,” Dr. Gandy said. “It was all amyloid toxicity and that was the end of it. But the truth is, we still don't really know what amyloid does locally. It is clear to me that amyloid beta causes the rare genetic forms of Alzheimer's, but there remains the possibility that some injurious event [e.g., calcium dysregulation or oxidative injury] is both directly neurotoxic and pro-amyloidogenic. Gary Gibson, Ph.D., of Cornell University and I have seen this in an experimental oxidative stress model, and if something like this is the case in common forms of AD, then lowering amyloid won't be sufficient. Still, I don't think we'll know that until we succeed in purging the brain of amyloid oligomers at an early age and follow the natural history of the amyloid-free brain.”

Some researchers, including Dr. Smith, have contended that amyloid isn't the direct cause of AD, but a down-stream product of some other dysfunction. The plaques themselves might be largely inert, or even be protecting the brain by binding and neutralizing neurotoxins.

“It could very well be that releasing Abeta is good, and that's why drugs that lower it are ineffective, or even damaging,” Dr. Smith said. A wealth of recent data seems to support that idea: In the last 2 years, four antiamyloid agents have failed their phase III trials, and both active and passive immunotherapy studies have seen about a 10% rate of vasogenic brain edema associated with plaque dissolution.

Researchers are not entirely sure how dimebon works, but are honing in on mitochondrial function. A 2003 Russian study suggested that the drug blocks the induction of the mitochondrial permeability transition pore. When the pore opens, the mitochondria lose their ability to generate energy, and can take in small molecules causing them to swell and burst, in turn destroying the cells that contain them (Ann. N.Y. Acad. Sci. 2003;993:334-44).

“Medivation and Pfizer [the companies developing dimebon] also have unpublished data showing that dimebon increases neurite outgrowth, which is a metabolically demanding process, and healthy mitochondria are essential for that,” Dr. Smith said.

But so far, he said, dimebon's method of action in improving cognition in AD remains unproven. “There are a lot of dots that form the shape of a mitochondria, but no one has connected them all yet.”

Neither Dr. Gandy nor Dr. Smith had any relevant disclosures to make.

'The levels of the amyloid peptides in the interstitial brain fluid roughly doubled whenever the drug was given.'

Source Dr. Gandy

VIENNA — Dimebon—the abandoned Russian antihistamine that burst onto the Alzheimer's study scene with the only positive clinical data of 2008—may throw yet another curve ball into a research world that for years has focused almost entirely on the amyloid hypothesis.

Rather than lowering amyloid beta (Abeta) levels, as two failed investigational drugs—tramiprosate and tarenflurbil—–have attempted, dimebon appears to almost immediately increase them, raising Abeta by as much as 200% in three mouse models of Alzheimer's disease (AD), Dr. Samuel Gandy reported at the International Conference on Alzheimer's Disease.

While preliminary, the findings—combined with the nearly unprecedented cognitive benefit dimebon conferred in its phase II trial—could be enough to dethrone the long-reigning amyloid hypothesis, according to Mark A. Smith, Ph.D., an AD researcher.

“This drug is clearly not targeting amyloid, but increasing it acutely,” said Dr. Smith of Case Western Reserve University, Cleveland. “If you believe the dogma, therefore, you should believe that this increase will cause Alzheimer's. These results question that dogma. If this holds up, it could be enough to wound the amyloid theory, potentially mortally.”

Dimebon's 2008 phase II study found that patients with mild to moderate AD who took the drug for 12 months gained about 2 points on the Alzheimer's Disease Assessment Scale-Cognition (ADAS-cog), while those taking placebo declined almost 6 points from baseline (Lancet 2008;372:207-15). A 6-month open-label extension trial found similarly positive results. Patients who completed a full 18 months of dimebon continued to show benefit on ADAS-cog. Former placebo patients who crossed over to dimebon stabilized their cognitive decline.

Dr. Gandy of the Mount Sinai School of Medicine, New York, investigated the drug's effect on amyloid in three models of the disease: cultured nerve cells, isolated synaptic terminals, and brains from mice that overexpress human amyloid.

“In every single system dimebon stimulated amyloid secretion,” Dr. Gandy said in an interview. “The levels of the amyloid peptides in the interstitial brain fluid roughly doubled whenever the drug was given. If we think about the increased risk of Alzheimer's in Down syndrome patients who have a 50% increase in amyloid, this acute increase with dimebon could be significant over a period of many years of use.”

Dr. Gandy noted that similar results were obtained by John Cirrito, Ph.D., and Dr. David Holtzman of Washington University, St. Louis, who collaborated with him in studying the brains of freely moving transgenic mice that overexpress human Abeta.

Dr. Gandy suggested that this acute release may be followed by a chronic lowering of Abeta—something he is now investigating. Combined with dimebon's positive clinical data, this finding would imply that neurons benefit from dumping their intracellular amyloid load.

This is reminiscent of the evidence gathered by Dr. Holtzman's group that suggested that healthy nerve cells released more amyloid as head-injured patients began to recover, Dr. Gandy said.

The clinical and lab data highlight the essential mystery of amyloid, both researchers said. “It all seemed so simple when we discovered genes that implicated amyloid,” Dr. Gandy said. “It was all amyloid toxicity and that was the end of it. But the truth is, we still don't really know what amyloid does locally. It is clear to me that amyloid beta causes the rare genetic forms of Alzheimer's, but there remains the possibility that some injurious event [e.g., calcium dysregulation or oxidative injury] is both directly neurotoxic and pro-amyloidogenic. Gary Gibson, Ph.D., of Cornell University and I have seen this in an experimental oxidative stress model, and if something like this is the case in common forms of AD, then lowering amyloid won't be sufficient. Still, I don't think we'll know that until we succeed in purging the brain of amyloid oligomers at an early age and follow the natural history of the amyloid-free brain.”

Some researchers, including Dr. Smith, have contended that amyloid isn't the direct cause of AD, but a down-stream product of some other dysfunction. The plaques themselves might be largely inert, or even be protecting the brain by binding and neutralizing neurotoxins.

“It could very well be that releasing Abeta is good, and that's why drugs that lower it are ineffective, or even damaging,” Dr. Smith said. A wealth of recent data seems to support that idea: In the last 2 years, four antiamyloid agents have failed their phase III trials, and both active and passive immunotherapy studies have seen about a 10% rate of vasogenic brain edema associated with plaque dissolution.

Researchers are not entirely sure how dimebon works, but are honing in on mitochondrial function. A 2003 Russian study suggested that the drug blocks the induction of the mitochondrial permeability transition pore. When the pore opens, the mitochondria lose their ability to generate energy, and can take in small molecules causing them to swell and burst, in turn destroying the cells that contain them (Ann. N.Y. Acad. Sci. 2003;993:334-44).

“Medivation and Pfizer [the companies developing dimebon] also have unpublished data showing that dimebon increases neurite outgrowth, which is a metabolically demanding process, and healthy mitochondria are essential for that,” Dr. Smith said.

But so far, he said, dimebon's method of action in improving cognition in AD remains unproven. “There are a lot of dots that form the shape of a mitochondria, but no one has connected them all yet.”

Neither Dr. Gandy nor Dr. Smith had any relevant disclosures to make.

'The levels of the amyloid peptides in the interstitial brain fluid roughly doubled whenever the drug was given.'

Source Dr. Gandy

VIENNA — Dimebon—the abandoned Russian antihistamine that burst onto the Alzheimer's study scene with the only positive clinical data of 2008—may throw yet another curve ball into a research world that for years has focused almost entirely on the amyloid hypothesis.

Rather than lowering amyloid beta (Abeta) levels, as two failed investigational drugs—tramiprosate and tarenflurbil—–have attempted, dimebon appears to almost immediately increase them, raising Abeta by as much as 200% in three mouse models of Alzheimer's disease (AD), Dr. Samuel Gandy reported at the International Conference on Alzheimer's Disease.

While preliminary, the findings—combined with the nearly unprecedented cognitive benefit dimebon conferred in its phase II trial—could be enough to dethrone the long-reigning amyloid hypothesis, according to Mark A. Smith, Ph.D., an AD researcher.

“This drug is clearly not targeting amyloid, but increasing it acutely,” said Dr. Smith of Case Western Reserve University, Cleveland. “If you believe the dogma, therefore, you should believe that this increase will cause Alzheimer's. These results question that dogma. If this holds up, it could be enough to wound the amyloid theory, potentially mortally.”

Dimebon's 2008 phase II study found that patients with mild to moderate AD who took the drug for 12 months gained about 2 points on the Alzheimer's Disease Assessment Scale-Cognition (ADAS-cog), while those taking placebo declined almost 6 points from baseline (Lancet 2008;372:207-15). A 6-month open-label extension trial found similarly positive results. Patients who completed a full 18 months of dimebon continued to show benefit on ADAS-cog. Former placebo patients who crossed over to dimebon stabilized their cognitive decline.

Dr. Gandy of the Mount Sinai School of Medicine, New York, investigated the drug's effect on amyloid in three models of the disease: cultured nerve cells, isolated synaptic terminals, and brains from mice that overexpress human amyloid.

“In every single system dimebon stimulated amyloid secretion,” Dr. Gandy said in an interview. “The levels of the amyloid peptides in the interstitial brain fluid roughly doubled whenever the drug was given. If we think about the increased risk of Alzheimer's in Down syndrome patients who have a 50% increase in amyloid, this acute increase with dimebon could be significant over a period of many years of use.”

Dr. Gandy noted that similar results were obtained by John Cirrito, Ph.D., and Dr. David Holtzman of Washington University, St. Louis, who collaborated with him in studying the brains of freely moving transgenic mice that overexpress human Abeta.

Dr. Gandy suggested that this acute release may be followed by a chronic lowering of Abeta—something he is now investigating. Combined with dimebon's positive clinical data, this finding would imply that neurons benefit from dumping their intracellular amyloid load.

This is reminiscent of the evidence gathered by Dr. Holtzman's group that suggested that healthy nerve cells released more amyloid as head-injured patients began to recover, Dr. Gandy said.

The clinical and lab data highlight the essential mystery of amyloid, both researchers said. “It all seemed so simple when we discovered genes that implicated amyloid,” Dr. Gandy said. “It was all amyloid toxicity and that was the end of it. But the truth is, we still don't really know what amyloid does locally. It is clear to me that amyloid beta causes the rare genetic forms of Alzheimer's, but there remains the possibility that some injurious event [e.g., calcium dysregulation or oxidative injury] is both directly neurotoxic and pro-amyloidogenic. Gary Gibson, Ph.D., of Cornell University and I have seen this in an experimental oxidative stress model, and if something like this is the case in common forms of AD, then lowering amyloid won't be sufficient. Still, I don't think we'll know that until we succeed in purging the brain of amyloid oligomers at an early age and follow the natural history of the amyloid-free brain.”

Some researchers, including Dr. Smith, have contended that amyloid isn't the direct cause of AD, but a down-stream product of some other dysfunction. The plaques themselves might be largely inert, or even be protecting the brain by binding and neutralizing neurotoxins.

“It could very well be that releasing Abeta is good, and that's why drugs that lower it are ineffective, or even damaging,” Dr. Smith said. A wealth of recent data seems to support that idea: In the last 2 years, four antiamyloid agents have failed their phase III trials, and both active and passive immunotherapy studies have seen about a 10% rate of vasogenic brain edema associated with plaque dissolution.

Researchers are not entirely sure how dimebon works, but are honing in on mitochondrial function. A 2003 Russian study suggested that the drug blocks the induction of the mitochondrial permeability transition pore. When the pore opens, the mitochondria lose their ability to generate energy, and can take in small molecules causing them to swell and burst, in turn destroying the cells that contain them (Ann. N.Y. Acad. Sci. 2003;993:334-44).

“Medivation and Pfizer [the companies developing dimebon] also have unpublished data showing that dimebon increases neurite outgrowth, which is a metabolically demanding process, and healthy mitochondria are essential for that,” Dr. Smith said.

But so far, he said, dimebon's method of action in improving cognition in AD remains unproven. “There are a lot of dots that form the shape of a mitochondria, but no one has connected them all yet.”

Neither Dr. Gandy nor Dr. Smith had any relevant disclosures to make.

'The levels of the amyloid peptides in the interstitial brain fluid roughly doubled whenever the drug was given.'

Source Dr. Gandy