Michele G. Sullivan

PHILADELPHIA — Migraineurs—especially those with aura—have a significantly increased risk of developing deep matter white lesions and subclinical brain infarcts in the posterior circulation than do control subjects.

The findings of CAMERA II, a 9-year follow-up study, confirm those seen in the original Cerebral Abnormalities in Migraine, an Epidemiological Risk Analysis (CAMERA I): Patients with migraine are more likely to have subclinical brain lesions than were those without migraine.

CAMERA II wrapped up just days before the annual meeting of the International Headache Society, where Dr. Michel Ferrari presented the unadjusted data and said that a more refined analysis would be forthcoming.

CAMERA I included 140 controls, 164 migraine patients who experienced aura, and 134 migraine patients without aura who underwent magnetic resonance imaging, and clinical and cognitive testing. Although there were no significant overall differences in the prevalence of infarcts between controls and patients, patients with migraine and aura had a significantly higher prevalence of infarcts in the posterior circulation than controls (5% vs. 0.7%)—an adjusted odds ratio of 14. The highest risk was seen in patients with migraine and aura who experienced one attack or more per month (OR 16).

Women with migraine also had a significantly increased risk of a high volume of deep matter white lesions (OR 2). The risk increased with increasing attack frequency, being highest in those with more than one attack per month (OR 3).

“The most interesting finding in CAMERA I was this recurrent theme of higher risk with having had more migraine attacks,” said Dr. Ferrari, chairman of the Leiden (the Netherlands) Center for Translational Neuroscience at Leiden University. “That suggested to us that there must be progression, so we decided to do this follow-up study.

CAMERA II included 66% of the CAMERA I cohort (83 controls and 203 patients with migraine). Subjects underwent another MRI, cognitive testing, transcranial Doppler imaging for right-left shunting, and cerebellar test battery. The investigators used equipment and protocols similar to those used in CAMERA I.

In a comparison of volume of deep white matter lesions, patients with migraines had greater increases than controls from CAMERA I to CAMERA II. The difference was significant in patients with migraine and aura: In CAMERA I, the mean volume was 0.19 mL, increasing to 1.28 mL in CAMERA II.

There was also a significant increase between the studies in the percentage of migraineurs with infarcts. In CAMERA I, 9% of patients with migraine had any infarct, compared with 15% in CAMERA II. Posterior circulation infarcts increased as well, from 5% in CAMERA I patients to 9% in CAMERA II. “Among the 11 migraineurs in CAMERA I who had a posterior circulation infarct, 3 had had a new one by CAMERA II,” Dr. Ferrari said. “CAMERA II also showed seven incident posterior circulation infarcts in migraineurs, although there were no incident infarcts among the controls.”

The findings must be carefully considered, he said, since there were some significant baseline differences between those who developed infarcts and those who did not. Those with infarcts were older (62 vs. 57 years), more likely to be taking statins (39% vs. 17%) and antihypertensives (61% vs. 27%), and more likely to have hypertension (94% vs. 58%).

Without controlling for those factors, he said during the question-and-answer period, it's not possible to tell whether the migraines caused the infarcts, or whether they are more likely to be related to an unfavorable cardiovascular risk profile.

PHILADELPHIA — Migraineurs—especially those with aura—have a significantly increased risk of developing deep matter white lesions and subclinical brain infarcts in the posterior circulation than do control subjects.

The findings of CAMERA II, a 9-year follow-up study, confirm those seen in the original Cerebral Abnormalities in Migraine, an Epidemiological Risk Analysis (CAMERA I): Patients with migraine are more likely to have subclinical brain lesions than were those without migraine.

CAMERA II wrapped up just days before the annual meeting of the International Headache Society, where Dr. Michel Ferrari presented the unadjusted data and said that a more refined analysis would be forthcoming.

CAMERA I included 140 controls, 164 migraine patients who experienced aura, and 134 migraine patients without aura who underwent magnetic resonance imaging, and clinical and cognitive testing. Although there were no significant overall differences in the prevalence of infarcts between controls and patients, patients with migraine and aura had a significantly higher prevalence of infarcts in the posterior circulation than controls (5% vs. 0.7%)—an adjusted odds ratio of 14. The highest risk was seen in patients with migraine and aura who experienced one attack or more per month (OR 16).

Women with migraine also had a significantly increased risk of a high volume of deep matter white lesions (OR 2). The risk increased with increasing attack frequency, being highest in those with more than one attack per month (OR 3).

“The most interesting finding in CAMERA I was this recurrent theme of higher risk with having had more migraine attacks,” said Dr. Ferrari, chairman of the Leiden (the Netherlands) Center for Translational Neuroscience at Leiden University. “That suggested to us that there must be progression, so we decided to do this follow-up study.

CAMERA II included 66% of the CAMERA I cohort (83 controls and 203 patients with migraine). Subjects underwent another MRI, cognitive testing, transcranial Doppler imaging for right-left shunting, and cerebellar test battery. The investigators used equipment and protocols similar to those used in CAMERA I.

In a comparison of volume of deep white matter lesions, patients with migraines had greater increases than controls from CAMERA I to CAMERA II. The difference was significant in patients with migraine and aura: In CAMERA I, the mean volume was 0.19 mL, increasing to 1.28 mL in CAMERA II.

There was also a significant increase between the studies in the percentage of migraineurs with infarcts. In CAMERA I, 9% of patients with migraine had any infarct, compared with 15% in CAMERA II. Posterior circulation infarcts increased as well, from 5% in CAMERA I patients to 9% in CAMERA II. “Among the 11 migraineurs in CAMERA I who had a posterior circulation infarct, 3 had had a new one by CAMERA II,” Dr. Ferrari said. “CAMERA II also showed seven incident posterior circulation infarcts in migraineurs, although there were no incident infarcts among the controls.”

The findings must be carefully considered, he said, since there were some significant baseline differences between those who developed infarcts and those who did not. Those with infarcts were older (62 vs. 57 years), more likely to be taking statins (39% vs. 17%) and antihypertensives (61% vs. 27%), and more likely to have hypertension (94% vs. 58%).

Without controlling for those factors, he said during the question-and-answer period, it's not possible to tell whether the migraines caused the infarcts, or whether they are more likely to be related to an unfavorable cardiovascular risk profile.

PHILADELPHIA — Migraineurs—especially those with aura—have a significantly increased risk of developing deep matter white lesions and subclinical brain infarcts in the posterior circulation than do control subjects.

The findings of CAMERA II, a 9-year follow-up study, confirm those seen in the original Cerebral Abnormalities in Migraine, an Epidemiological Risk Analysis (CAMERA I): Patients with migraine are more likely to have subclinical brain lesions than were those without migraine.

CAMERA II wrapped up just days before the annual meeting of the International Headache Society, where Dr. Michel Ferrari presented the unadjusted data and said that a more refined analysis would be forthcoming.

CAMERA I included 140 controls, 164 migraine patients who experienced aura, and 134 migraine patients without aura who underwent magnetic resonance imaging, and clinical and cognitive testing. Although there were no significant overall differences in the prevalence of infarcts between controls and patients, patients with migraine and aura had a significantly higher prevalence of infarcts in the posterior circulation than controls (5% vs. 0.7%)—an adjusted odds ratio of 14. The highest risk was seen in patients with migraine and aura who experienced one attack or more per month (OR 16).

Women with migraine also had a significantly increased risk of a high volume of deep matter white lesions (OR 2). The risk increased with increasing attack frequency, being highest in those with more than one attack per month (OR 3).

“The most interesting finding in CAMERA I was this recurrent theme of higher risk with having had more migraine attacks,” said Dr. Ferrari, chairman of the Leiden (the Netherlands) Center for Translational Neuroscience at Leiden University. “That suggested to us that there must be progression, so we decided to do this follow-up study.

CAMERA II included 66% of the CAMERA I cohort (83 controls and 203 patients with migraine). Subjects underwent another MRI, cognitive testing, transcranial Doppler imaging for right-left shunting, and cerebellar test battery. The investigators used equipment and protocols similar to those used in CAMERA I.

In a comparison of volume of deep white matter lesions, patients with migraines had greater increases than controls from CAMERA I to CAMERA II. The difference was significant in patients with migraine and aura: In CAMERA I, the mean volume was 0.19 mL, increasing to 1.28 mL in CAMERA II.

There was also a significant increase between the studies in the percentage of migraineurs with infarcts. In CAMERA I, 9% of patients with migraine had any infarct, compared with 15% in CAMERA II. Posterior circulation infarcts increased as well, from 5% in CAMERA I patients to 9% in CAMERA II. “Among the 11 migraineurs in CAMERA I who had a posterior circulation infarct, 3 had had a new one by CAMERA II,” Dr. Ferrari said. “CAMERA II also showed seven incident posterior circulation infarcts in migraineurs, although there were no incident infarcts among the controls.”

The findings must be carefully considered, he said, since there were some significant baseline differences between those who developed infarcts and those who did not. Those with infarcts were older (62 vs. 57 years), more likely to be taking statins (39% vs. 17%) and antihypertensives (61% vs. 27%), and more likely to have hypertension (94% vs. 58%).

Without controlling for those factors, he said during the question-and-answer period, it's not possible to tell whether the migraines caused the infarcts, or whether they are more likely to be related to an unfavorable cardiovascular risk profile.

The prevalence and incidence of eosinophilic esophagitis appear to have increased over the past 30 years, with most of the cases being diagnosed in late summer and early fall, Dr. Ganapathy Prasad and his colleagues reported.

It's not entirely clear whether the increases represent a true spike in the disease or reflect the parallel increase in upper endoscopies performed over the study period, wrote Dr. Prasad of the Mayo Clinic, Rochester, Minn., and his coauthors. “Though the incidence of eosinophilic esophagitis appears to be increasing, it is possible that an increase in rates of endoscopic evaluation and acquisition of esophageal biopsies … may be responsible in part for this increase,” they wrote.

The researchers conducted a retrospective review of eosinophilic esophagitis in Olmsted County, Minn., using the Rochester Epidemiology Project. They examined data from 1976 through 2005. The incidence of eosinophilic esophagitis increased significantly over the last 15 years of the study, from 0.35/100,000 person-years in 1991-1995, to 9.45/100,000 person-years during 2001-2005. Prevalence was calculated to be 55 cases/100,000 person-years by the end of 2005.

Endoscopies increased during the same period, from about 100/year to about 2,000/year.

The researchers identified 55 adult cases and 23 pediatric cases. The mean age was 37 years among adults and 10 years among children. Dysphagia was the most common presenting symptom in adults and children (93% and 61%, respectively). Food impaction was more common in adults (42% vs. 22%), as was acid reflux regurgitation (38% vs. 22%).

Thirty-seven patients had both proximal and distal esophageal biopsies taken. Of these, 25 had more than 15 eosinophils/high-powered field in both samples, 10 had them in only the distal sample, and the remaining 2 patients had them only in the proximal sample. Of the five patients who had 24-hour pH studies done, distal esophageal acid exposure was normal in four and only mildly abnormal in one.

Treatment was mostly with inhaled steroids (51%); 40% also received a proton pump inhibitor and 20% received both medication and esophageal dilation.

Recurrences occurred in 32 patients, with 32% having a recurrence within 2 years of initial diagnosis and 49% having a recurrence within 4 years.

Among 56 patients contacted in a follow-up interview, 27 (48%) reported dysphagia within the past 3 months; 11 of these reported symptoms “usually” or “often” and the rest said dysphagia occurred “sometimes.” Five patients (9%) said they had visited an emergency department for food impaction within the last year, and 23 (41%) reported receiving either dilation or medications, or both.

The review showed that 60% of the diagnoses were confirmed in the late summer and fall. This may speak to an allergic component of the disease postulated by some researchers.

The study was supported in part by the National Institutes of Health and GlaxoSmithKline. Dr. Prasad reported no conflicts. However, two of the coauthors reported receiving research funding from GlaxoSmithKline and other drug companies.

The prevalence and incidence of eosinophilic esophagitis appear to have increased over the past 30 years, with most of the cases being diagnosed in late summer and early fall, Dr. Ganapathy Prasad and his colleagues reported.

It's not entirely clear whether the increases represent a true spike in the disease or reflect the parallel increase in upper endoscopies performed over the study period, wrote Dr. Prasad of the Mayo Clinic, Rochester, Minn., and his coauthors. “Though the incidence of eosinophilic esophagitis appears to be increasing, it is possible that an increase in rates of endoscopic evaluation and acquisition of esophageal biopsies … may be responsible in part for this increase,” they wrote.

The researchers conducted a retrospective review of eosinophilic esophagitis in Olmsted County, Minn., using the Rochester Epidemiology Project. They examined data from 1976 through 2005. The incidence of eosinophilic esophagitis increased significantly over the last 15 years of the study, from 0.35/100,000 person-years in 1991-1995, to 9.45/100,000 person-years during 2001-2005. Prevalence was calculated to be 55 cases/100,000 person-years by the end of 2005.

Endoscopies increased during the same period, from about 100/year to about 2,000/year.

The researchers identified 55 adult cases and 23 pediatric cases. The mean age was 37 years among adults and 10 years among children. Dysphagia was the most common presenting symptom in adults and children (93% and 61%, respectively). Food impaction was more common in adults (42% vs. 22%), as was acid reflux regurgitation (38% vs. 22%).

Thirty-seven patients had both proximal and distal esophageal biopsies taken. Of these, 25 had more than 15 eosinophils/high-powered field in both samples, 10 had them in only the distal sample, and the remaining 2 patients had them only in the proximal sample. Of the five patients who had 24-hour pH studies done, distal esophageal acid exposure was normal in four and only mildly abnormal in one.

Treatment was mostly with inhaled steroids (51%); 40% also received a proton pump inhibitor and 20% received both medication and esophageal dilation.

Recurrences occurred in 32 patients, with 32% having a recurrence within 2 years of initial diagnosis and 49% having a recurrence within 4 years.

Among 56 patients contacted in a follow-up interview, 27 (48%) reported dysphagia within the past 3 months; 11 of these reported symptoms “usually” or “often” and the rest said dysphagia occurred “sometimes.” Five patients (9%) said they had visited an emergency department for food impaction within the last year, and 23 (41%) reported receiving either dilation or medications, or both.

The review showed that 60% of the diagnoses were confirmed in the late summer and fall. This may speak to an allergic component of the disease postulated by some researchers.

The study was supported in part by the National Institutes of Health and GlaxoSmithKline. Dr. Prasad reported no conflicts. However, two of the coauthors reported receiving research funding from GlaxoSmithKline and other drug companies.

The prevalence and incidence of eosinophilic esophagitis appear to have increased over the past 30 years, with most of the cases being diagnosed in late summer and early fall, Dr. Ganapathy Prasad and his colleagues reported.

It's not entirely clear whether the increases represent a true spike in the disease or reflect the parallel increase in upper endoscopies performed over the study period, wrote Dr. Prasad of the Mayo Clinic, Rochester, Minn., and his coauthors. “Though the incidence of eosinophilic esophagitis appears to be increasing, it is possible that an increase in rates of endoscopic evaluation and acquisition of esophageal biopsies … may be responsible in part for this increase,” they wrote.

The researchers conducted a retrospective review of eosinophilic esophagitis in Olmsted County, Minn., using the Rochester Epidemiology Project. They examined data from 1976 through 2005. The incidence of eosinophilic esophagitis increased significantly over the last 15 years of the study, from 0.35/100,000 person-years in 1991-1995, to 9.45/100,000 person-years during 2001-2005. Prevalence was calculated to be 55 cases/100,000 person-years by the end of 2005.

Endoscopies increased during the same period, from about 100/year to about 2,000/year.

The researchers identified 55 adult cases and 23 pediatric cases. The mean age was 37 years among adults and 10 years among children. Dysphagia was the most common presenting symptom in adults and children (93% and 61%, respectively). Food impaction was more common in adults (42% vs. 22%), as was acid reflux regurgitation (38% vs. 22%).

Thirty-seven patients had both proximal and distal esophageal biopsies taken. Of these, 25 had more than 15 eosinophils/high-powered field in both samples, 10 had them in only the distal sample, and the remaining 2 patients had them only in the proximal sample. Of the five patients who had 24-hour pH studies done, distal esophageal acid exposure was normal in four and only mildly abnormal in one.

Treatment was mostly with inhaled steroids (51%); 40% also received a proton pump inhibitor and 20% received both medication and esophageal dilation.

Recurrences occurred in 32 patients, with 32% having a recurrence within 2 years of initial diagnosis and 49% having a recurrence within 4 years.

Among 56 patients contacted in a follow-up interview, 27 (48%) reported dysphagia within the past 3 months; 11 of these reported symptoms “usually” or “often” and the rest said dysphagia occurred “sometimes.” Five patients (9%) said they had visited an emergency department for food impaction within the last year, and 23 (41%) reported receiving either dilation or medications, or both.

The review showed that 60% of the diagnoses were confirmed in the late summer and fall. This may speak to an allergic component of the disease postulated by some researchers.

The study was supported in part by the National Institutes of Health and GlaxoSmithKline. Dr. Prasad reported no conflicts. However, two of the coauthors reported receiving research funding from GlaxoSmithKline and other drug companies.

PHILADELPHIA – OnabotulinumtoxinA appears to be a safe, effective, and well-tolerated headache prophylactic for patients with chronic migraine.

The PREEMPT 1 and 2 studies were conducted at centers in North America and Europe, and included 1,384 patients (average age 41 years). Each trial consisted of a 4-week baseline period, during which patients kept a headache diary, followed by 24 weeks of treatment during which patients received two injection cycles of either placebo or 155 U onabotulinumtoxinA (Botox), which has not been approved for migraine by the Food and Drug Administration. From 24 to 56 weeks, there was an open-label trial consisting of three injection cycles of the study drug, Dr. David W. Dodick of the Mayo Clinic Arizona, Phoenix, reported at the International Headache Congress.

At baseline, patients reported a mean of 20 headache-days a month, 19 of which were considered migraine days, with a mean of 290 cumulative headache-hours. The mean score on the Headache Impact Test-6 (HIT-6) survey was 65, indicating severe impact. Most of the patients (93%) also reported severe headache-related disability, and 65% were overusing acute pain medications. At 24 weeks, those in the active group had a significantly greater reduction in headache days and migraine days than those taking placebo (−8 vs. −6). The HIT-6 score also fell significantly more in the active group (−5 points vs. −2 points). The use of triptans did decrease significantly in the active group compared with the placebo group. The study was sponsored by Allergan Inc., maker of the study drug, and from which Dr. Dodick reported having received honoraria.

PHILADELPHIA – OnabotulinumtoxinA appears to be a safe, effective, and well-tolerated headache prophylactic for patients with chronic migraine.

The PREEMPT 1 and 2 studies were conducted at centers in North America and Europe, and included 1,384 patients (average age 41 years). Each trial consisted of a 4-week baseline period, during which patients kept a headache diary, followed by 24 weeks of treatment during which patients received two injection cycles of either placebo or 155 U onabotulinumtoxinA (Botox), which has not been approved for migraine by the Food and Drug Administration. From 24 to 56 weeks, there was an open-label trial consisting of three injection cycles of the study drug, Dr. David W. Dodick of the Mayo Clinic Arizona, Phoenix, reported at the International Headache Congress.

At baseline, patients reported a mean of 20 headache-days a month, 19 of which were considered migraine days, with a mean of 290 cumulative headache-hours. The mean score on the Headache Impact Test-6 (HIT-6) survey was 65, indicating severe impact. Most of the patients (93%) also reported severe headache-related disability, and 65% were overusing acute pain medications. At 24 weeks, those in the active group had a significantly greater reduction in headache days and migraine days than those taking placebo (−8 vs. −6). The HIT-6 score also fell significantly more in the active group (−5 points vs. −2 points). The use of triptans did decrease significantly in the active group compared with the placebo group. The study was sponsored by Allergan Inc., maker of the study drug, and from which Dr. Dodick reported having received honoraria.

PHILADELPHIA – OnabotulinumtoxinA appears to be a safe, effective, and well-tolerated headache prophylactic for patients with chronic migraine.

The PREEMPT 1 and 2 studies were conducted at centers in North America and Europe, and included 1,384 patients (average age 41 years). Each trial consisted of a 4-week baseline period, during which patients kept a headache diary, followed by 24 weeks of treatment during which patients received two injection cycles of either placebo or 155 U onabotulinumtoxinA (Botox), which has not been approved for migraine by the Food and Drug Administration. From 24 to 56 weeks, there was an open-label trial consisting of three injection cycles of the study drug, Dr. David W. Dodick of the Mayo Clinic Arizona, Phoenix, reported at the International Headache Congress.

At baseline, patients reported a mean of 20 headache-days a month, 19 of which were considered migraine days, with a mean of 290 cumulative headache-hours. The mean score on the Headache Impact Test-6 (HIT-6) survey was 65, indicating severe impact. Most of the patients (93%) also reported severe headache-related disability, and 65% were overusing acute pain medications. At 24 weeks, those in the active group had a significantly greater reduction in headache days and migraine days than those taking placebo (−8 vs. −6). The HIT-6 score also fell significantly more in the active group (−5 points vs. −2 points). The use of triptans did decrease significantly in the active group compared with the placebo group. The study was sponsored by Allergan Inc., maker of the study drug, and from which Dr. Dodick reported having received honoraria.

PHILADELPHIA – Migraine with or without aura is associated with a significant increase in the risk of cardiovascular disease, including stroke and heart attack.

Numerous studies have hinted at the association between migraine with aura and cardiovascular events, Dr. Marcelo E. Bigal reported at the International Headache Congress.

But the population-based study he performed with his colleague, Dr. Richard Lipton, was the first to examine the association in a large national sample in which migraine, with and without aura, had been officially diagnosed according to accepted standards.

Dr. Bigal of Merck Research Laboratories, Whitehouse Station, N.J., and his co-author, Dr. Lipton of Albert Einstein College of Medicine, New York, extracted their data from the American Migraine Prevalence and Progression Study.

The study by Dr. Bigal and Dr. Lipton was the largest of migraine sufferers ever conducted.

It analyzed symptoms and treatment patterns in a representative sample of 162,576 Americans aged 12 years and older.

The cardiovascular substudy included data on 6,102 adults with migraine and 5,243 controls.

Overall, the investigators found that migraineurs were significantly more likely than controls to have diabetes (13% vs. 9%, respectively), hypertension (33% vs. 26%), and hypercholesterolemia (33% vs. 26%).

In addition, Dr. Bigal and Dr. Lipton found that Framingham risk scores also were significantly higher for overall migraine and for those with migraine with and without aura (mean 11) than they were for controls (mean 9).

Myocardial infarction had occurred in 2% of controls and 4% of migraineurs, which yielded an unadjusted odds ratio of 2.2.

Stroke occurred in 1.2% of the controls and 2% of the migraineurs–a significant 60% increased odds.

Rates of stroke were higher in those who had migraine with aura (4%) than without aura (1%), Dr. Bigal and Dr. Lipton found.

The significantly increased risks remained after adjusting for gender, age, disability, triptan use, diabetes, smoking, hypertension, and high cholesterol.

Overall, migraineurs were twice as likely as controls to have experienced a heart attack and 50% more likely to have experienced a stroke, the investigators found.

Migraineurs with aura were three times more likely than controls to have experienced either of those outcomes.

Migraineurs without aura were twice as likely as controls to have had a heart attack. However, Dr. Bigal and Dr. Lipton found that migraineurs without aura had no increased risk of stroke.

“Both migraine with and without aura are associated with cardiovascular disease and providers should be aware of these association to properly identify individuals at particularly high risk, as well as to plan treatment that targets not only migraine, but the complications potentially associated with it,” Dr. Bigal said.

Dr. Bigal is a full-time employee of Merck Research Laboratories.

Dr. Lipton has received research grants and honoraria from Merck and is a member of its advisory board.

PHILADELPHIA – Migraine with or without aura is associated with a significant increase in the risk of cardiovascular disease, including stroke and heart attack.

Numerous studies have hinted at the association between migraine with aura and cardiovascular events, Dr. Marcelo E. Bigal reported at the International Headache Congress.

But the population-based study he performed with his colleague, Dr. Richard Lipton, was the first to examine the association in a large national sample in which migraine, with and without aura, had been officially diagnosed according to accepted standards.

Dr. Bigal of Merck Research Laboratories, Whitehouse Station, N.J., and his co-author, Dr. Lipton of Albert Einstein College of Medicine, New York, extracted their data from the American Migraine Prevalence and Progression Study.

The study by Dr. Bigal and Dr. Lipton was the largest of migraine sufferers ever conducted.

It analyzed symptoms and treatment patterns in a representative sample of 162,576 Americans aged 12 years and older.

The cardiovascular substudy included data on 6,102 adults with migraine and 5,243 controls.

Overall, the investigators found that migraineurs were significantly more likely than controls to have diabetes (13% vs. 9%, respectively), hypertension (33% vs. 26%), and hypercholesterolemia (33% vs. 26%).

In addition, Dr. Bigal and Dr. Lipton found that Framingham risk scores also were significantly higher for overall migraine and for those with migraine with and without aura (mean 11) than they were for controls (mean 9).

Myocardial infarction had occurred in 2% of controls and 4% of migraineurs, which yielded an unadjusted odds ratio of 2.2.

Stroke occurred in 1.2% of the controls and 2% of the migraineurs–a significant 60% increased odds.

Rates of stroke were higher in those who had migraine with aura (4%) than without aura (1%), Dr. Bigal and Dr. Lipton found.

The significantly increased risks remained after adjusting for gender, age, disability, triptan use, diabetes, smoking, hypertension, and high cholesterol.

Overall, migraineurs were twice as likely as controls to have experienced a heart attack and 50% more likely to have experienced a stroke, the investigators found.

Migraineurs with aura were three times more likely than controls to have experienced either of those outcomes.

Migraineurs without aura were twice as likely as controls to have had a heart attack. However, Dr. Bigal and Dr. Lipton found that migraineurs without aura had no increased risk of stroke.

“Both migraine with and without aura are associated with cardiovascular disease and providers should be aware of these association to properly identify individuals at particularly high risk, as well as to plan treatment that targets not only migraine, but the complications potentially associated with it,” Dr. Bigal said.

Dr. Bigal is a full-time employee of Merck Research Laboratories.

Dr. Lipton has received research grants and honoraria from Merck and is a member of its advisory board.

PHILADELPHIA – Migraine with or without aura is associated with a significant increase in the risk of cardiovascular disease, including stroke and heart attack.

Numerous studies have hinted at the association between migraine with aura and cardiovascular events, Dr. Marcelo E. Bigal reported at the International Headache Congress.

But the population-based study he performed with his colleague, Dr. Richard Lipton, was the first to examine the association in a large national sample in which migraine, with and without aura, had been officially diagnosed according to accepted standards.

Dr. Bigal of Merck Research Laboratories, Whitehouse Station, N.J., and his co-author, Dr. Lipton of Albert Einstein College of Medicine, New York, extracted their data from the American Migraine Prevalence and Progression Study.

The study by Dr. Bigal and Dr. Lipton was the largest of migraine sufferers ever conducted.

It analyzed symptoms and treatment patterns in a representative sample of 162,576 Americans aged 12 years and older.

The cardiovascular substudy included data on 6,102 adults with migraine and 5,243 controls.

Overall, the investigators found that migraineurs were significantly more likely than controls to have diabetes (13% vs. 9%, respectively), hypertension (33% vs. 26%), and hypercholesterolemia (33% vs. 26%).

In addition, Dr. Bigal and Dr. Lipton found that Framingham risk scores also were significantly higher for overall migraine and for those with migraine with and without aura (mean 11) than they were for controls (mean 9).

Myocardial infarction had occurred in 2% of controls and 4% of migraineurs, which yielded an unadjusted odds ratio of 2.2.

Stroke occurred in 1.2% of the controls and 2% of the migraineurs–a significant 60% increased odds.

Rates of stroke were higher in those who had migraine with aura (4%) than without aura (1%), Dr. Bigal and Dr. Lipton found.

The significantly increased risks remained after adjusting for gender, age, disability, triptan use, diabetes, smoking, hypertension, and high cholesterol.

Overall, migraineurs were twice as likely as controls to have experienced a heart attack and 50% more likely to have experienced a stroke, the investigators found.

Migraineurs with aura were three times more likely than controls to have experienced either of those outcomes.

Migraineurs without aura were twice as likely as controls to have had a heart attack. However, Dr. Bigal and Dr. Lipton found that migraineurs without aura had no increased risk of stroke.

“Both migraine with and without aura are associated with cardiovascular disease and providers should be aware of these association to properly identify individuals at particularly high risk, as well as to plan treatment that targets not only migraine, but the complications potentially associated with it,” Dr. Bigal said.

Dr. Bigal is a full-time employee of Merck Research Laboratories.

Dr. Lipton has received research grants and honoraria from Merck and is a member of its advisory board.

PHILADELPHIA – Men and women who experience migraine with aura were significantly more likely to die from cardiovascular disease and than were those without headache.

Women with nonmigraine headache were also significantly more likely to die from cardiovascular disease than were women without headache, but the hazard ratio was smaller, Dr. Larus S. Gudmundsson wrote in a poster presented at the annual meeting of the International Headache Society.

Dr. Gudmundsson of the University of Iceland, Reykjavik, and his colleagues used data extracted from the Reykjavik Studyckd, a population-based cohort of adults followed from middle age, representing 474,360 person-years of observation. The cohort comprised 18,882 subjects who were a mean of 53 years old at baseline. Baseline interviews took place between 1967 and 1991.

The investigators divided the cohort into four categories: those without a headache once or more per month; those with nonmigraine headache; those with migraine without aura; and those with migraine and aura. Auras were defined as visual, sensory or both.

Patients with nonaura headache symptoms, including nausea, unilateral location, and photophobia, were placed in the “with migrane without aura” category.

After entering the study, subjects were followed for up to 40 years (mean follow-up 26 years). Statistics on those who died during that time were obtained from the Icelandic government and hospital records.

The Cox regression analysis controlled for age, body mass index, smoking, blood pressure, hypertension medication, oral contraceptive use, diabetes, and lipid levels.

In an assessment of all-cause mortality, both men and women with migraine and aura were at a significantly increased risk of death, compared with subjects without headache (20%).

For men, the risk rose when only cardiovascular death was considered (hazard ratio 1.38). For women with migraine and aura, the risk of cardiovascular death dipped slightly (HR 1.18).

Migraine without aura did not increase the risk of cardiovascular death, compared with those without headache.

However, women with nonmigrainous headaches were at a slightly–though still statistically significant–elevated risk of cardiovascular mortality, compared with women without headache (HR 1.14).

The risk did not change significantly for men with nonmigrainous headache, Dr. Gudmundsson and his colleagues found.

The authors pointed out that the increased risk of death, while significant, was not as great as the risks conferred by other common factors.

“The risk is relatively low when compared with conventional risk factors such as hypertension, high cholesterol, and smoking,” they said.

PHILADELPHIA – Men and women who experience migraine with aura were significantly more likely to die from cardiovascular disease and than were those without headache.

Women with nonmigraine headache were also significantly more likely to die from cardiovascular disease than were women without headache, but the hazard ratio was smaller, Dr. Larus S. Gudmundsson wrote in a poster presented at the annual meeting of the International Headache Society.

Dr. Gudmundsson of the University of Iceland, Reykjavik, and his colleagues used data extracted from the Reykjavik Studyckd, a population-based cohort of adults followed from middle age, representing 474,360 person-years of observation. The cohort comprised 18,882 subjects who were a mean of 53 years old at baseline. Baseline interviews took place between 1967 and 1991.

The investigators divided the cohort into four categories: those without a headache once or more per month; those with nonmigraine headache; those with migraine without aura; and those with migraine and aura. Auras were defined as visual, sensory or both.

Patients with nonaura headache symptoms, including nausea, unilateral location, and photophobia, were placed in the “with migrane without aura” category.

After entering the study, subjects were followed for up to 40 years (mean follow-up 26 years). Statistics on those who died during that time were obtained from the Icelandic government and hospital records.

The Cox regression analysis controlled for age, body mass index, smoking, blood pressure, hypertension medication, oral contraceptive use, diabetes, and lipid levels.

In an assessment of all-cause mortality, both men and women with migraine and aura were at a significantly increased risk of death, compared with subjects without headache (20%).

For men, the risk rose when only cardiovascular death was considered (hazard ratio 1.38). For women with migraine and aura, the risk of cardiovascular death dipped slightly (HR 1.18).

Migraine without aura did not increase the risk of cardiovascular death, compared with those without headache.

However, women with nonmigrainous headaches were at a slightly–though still statistically significant–elevated risk of cardiovascular mortality, compared with women without headache (HR 1.14).

The risk did not change significantly for men with nonmigrainous headache, Dr. Gudmundsson and his colleagues found.

The authors pointed out that the increased risk of death, while significant, was not as great as the risks conferred by other common factors.

“The risk is relatively low when compared with conventional risk factors such as hypertension, high cholesterol, and smoking,” they said.

PHILADELPHIA – Men and women who experience migraine with aura were significantly more likely to die from cardiovascular disease and than were those without headache.

Women with nonmigraine headache were also significantly more likely to die from cardiovascular disease than were women without headache, but the hazard ratio was smaller, Dr. Larus S. Gudmundsson wrote in a poster presented at the annual meeting of the International Headache Society.

Dr. Gudmundsson of the University of Iceland, Reykjavik, and his colleagues used data extracted from the Reykjavik Studyckd, a population-based cohort of adults followed from middle age, representing 474,360 person-years of observation. The cohort comprised 18,882 subjects who were a mean of 53 years old at baseline. Baseline interviews took place between 1967 and 1991.

The investigators divided the cohort into four categories: those without a headache once or more per month; those with nonmigraine headache; those with migraine without aura; and those with migraine and aura. Auras were defined as visual, sensory or both.

Patients with nonaura headache symptoms, including nausea, unilateral location, and photophobia, were placed in the “with migrane without aura” category.

After entering the study, subjects were followed for up to 40 years (mean follow-up 26 years). Statistics on those who died during that time were obtained from the Icelandic government and hospital records.

The Cox regression analysis controlled for age, body mass index, smoking, blood pressure, hypertension medication, oral contraceptive use, diabetes, and lipid levels.

In an assessment of all-cause mortality, both men and women with migraine and aura were at a significantly increased risk of death, compared with subjects without headache (20%).

For men, the risk rose when only cardiovascular death was considered (hazard ratio 1.38). For women with migraine and aura, the risk of cardiovascular death dipped slightly (HR 1.18).

Migraine without aura did not increase the risk of cardiovascular death, compared with those without headache.

However, women with nonmigrainous headaches were at a slightly–though still statistically significant–elevated risk of cardiovascular mortality, compared with women without headache (HR 1.14).

The risk did not change significantly for men with nonmigrainous headache, Dr. Gudmundsson and his colleagues found.

The authors pointed out that the increased risk of death, while significant, was not as great as the risks conferred by other common factors.

“The risk is relatively low when compared with conventional risk factors such as hypertension, high cholesterol, and smoking,” they said.

PHILADELPHIA – An inhaled form of dihydroergotamine provided significant relief of migraine pain, with sustained pain reduction and few adverse events, according to a phase III, placebo-controlled trial.

The drug conferred 4 hours of pain relief on 65% of those who took it; 48 hours later, 39% still reported pain relief, Dr. Stephen D. Silberstein reported at the International Headache Congress.

Dihydroergotamine has been used in oral form and as an infusion for migraine. The inhaled version passes directly into the bloodstream through the lungs, working much more quickly, said Dr. Silberstein, director of the Jefferson Headache Center at Thomas Jefferson University in Philadelphia. It also bypasses the problem of nauseous patients vomiting an undigested tablet.

The FREEDOM 301 study randomized 903 patients with severe, recurrent migraine to either a placebo inhaler or to the inhaled dihydroergotamine; 792 were included in the intent-to-treat analysis. Patients were a mean of 40 years old; their Headache Impact Test-6 score was 66, indicating severe disability. Most of the patients (91%) were women.

The study consisted of a 28-day washout period, followed by 8 weeks of randomized treatment. Two 8-week, open-label, follow-up trials are underway.

The primary end point was pain relief at 2 hours. A pain curve separation began 30 minutes after dosing, but the groups were not significantly different.

At 1 hour, differences became significant and 48% of the active group and 28% of the placebo group reported relief. At 2 hours, pain relief was present in 59% of the active group and 35% of the placebo group. Significantly more patients treated with the study drug than with placebo sustained relief at 24 hours (44% vs. 20%,) and at 48 hours (36% vs. 17%).

Freedom from pain was an important secondary end point. Again, significantly more of those taking the drug were free of pain at 2 hours (28% vs. 10%), 4 hours (39% vs. 17%), 24 hours (23% vs. 7%), and 48 hours (18% vs. 6%).

Adverse events were mild, occurring in 31% of the study drug group and 25% of the placebo group, with the drug's taste being most commonly reported.

The study was sponsored by MAP Pharmaceuticals Inc., which hopes to market the inhaled formulation as Levadex. Dr. Silberstein disclosed he has received grants and honoraria from the company and he has also been an advisory board member or consultant.

Of those who took the drug, 65% reported 4 hours of pain relief; 48 hours later, 39% still reported pain relief.

Source Dr. Silberstein

PHILADELPHIA – An inhaled form of dihydroergotamine provided significant relief of migraine pain, with sustained pain reduction and few adverse events, according to a phase III, placebo-controlled trial.

The drug conferred 4 hours of pain relief on 65% of those who took it; 48 hours later, 39% still reported pain relief, Dr. Stephen D. Silberstein reported at the International Headache Congress.

Dihydroergotamine has been used in oral form and as an infusion for migraine. The inhaled version passes directly into the bloodstream through the lungs, working much more quickly, said Dr. Silberstein, director of the Jefferson Headache Center at Thomas Jefferson University in Philadelphia. It also bypasses the problem of nauseous patients vomiting an undigested tablet.

The FREEDOM 301 study randomized 903 patients with severe, recurrent migraine to either a placebo inhaler or to the inhaled dihydroergotamine; 792 were included in the intent-to-treat analysis. Patients were a mean of 40 years old; their Headache Impact Test-6 score was 66, indicating severe disability. Most of the patients (91%) were women.

The study consisted of a 28-day washout period, followed by 8 weeks of randomized treatment. Two 8-week, open-label, follow-up trials are underway.

The primary end point was pain relief at 2 hours. A pain curve separation began 30 minutes after dosing, but the groups were not significantly different.

At 1 hour, differences became significant and 48% of the active group and 28% of the placebo group reported relief. At 2 hours, pain relief was present in 59% of the active group and 35% of the placebo group. Significantly more patients treated with the study drug than with placebo sustained relief at 24 hours (44% vs. 20%,) and at 48 hours (36% vs. 17%).

Freedom from pain was an important secondary end point. Again, significantly more of those taking the drug were free of pain at 2 hours (28% vs. 10%), 4 hours (39% vs. 17%), 24 hours (23% vs. 7%), and 48 hours (18% vs. 6%).

Adverse events were mild, occurring in 31% of the study drug group and 25% of the placebo group, with the drug's taste being most commonly reported.

The study was sponsored by MAP Pharmaceuticals Inc., which hopes to market the inhaled formulation as Levadex. Dr. Silberstein disclosed he has received grants and honoraria from the company and he has also been an advisory board member or consultant.

Of those who took the drug, 65% reported 4 hours of pain relief; 48 hours later, 39% still reported pain relief.

Source Dr. Silberstein

PHILADELPHIA – An inhaled form of dihydroergotamine provided significant relief of migraine pain, with sustained pain reduction and few adverse events, according to a phase III, placebo-controlled trial.

The drug conferred 4 hours of pain relief on 65% of those who took it; 48 hours later, 39% still reported pain relief, Dr. Stephen D. Silberstein reported at the International Headache Congress.

Dihydroergotamine has been used in oral form and as an infusion for migraine. The inhaled version passes directly into the bloodstream through the lungs, working much more quickly, said Dr. Silberstein, director of the Jefferson Headache Center at Thomas Jefferson University in Philadelphia. It also bypasses the problem of nauseous patients vomiting an undigested tablet.

The FREEDOM 301 study randomized 903 patients with severe, recurrent migraine to either a placebo inhaler or to the inhaled dihydroergotamine; 792 were included in the intent-to-treat analysis. Patients were a mean of 40 years old; their Headache Impact Test-6 score was 66, indicating severe disability. Most of the patients (91%) were women.

The study consisted of a 28-day washout period, followed by 8 weeks of randomized treatment. Two 8-week, open-label, follow-up trials are underway.

The primary end point was pain relief at 2 hours. A pain curve separation began 30 minutes after dosing, but the groups were not significantly different.

At 1 hour, differences became significant and 48% of the active group and 28% of the placebo group reported relief. At 2 hours, pain relief was present in 59% of the active group and 35% of the placebo group. Significantly more patients treated with the study drug than with placebo sustained relief at 24 hours (44% vs. 20%,) and at 48 hours (36% vs. 17%).

Freedom from pain was an important secondary end point. Again, significantly more of those taking the drug were free of pain at 2 hours (28% vs. 10%), 4 hours (39% vs. 17%), 24 hours (23% vs. 7%), and 48 hours (18% vs. 6%).

Adverse events were mild, occurring in 31% of the study drug group and 25% of the placebo group, with the drug's taste being most commonly reported.

The study was sponsored by MAP Pharmaceuticals Inc., which hopes to market the inhaled formulation as Levadex. Dr. Silberstein disclosed he has received grants and honoraria from the company and he has also been an advisory board member or consultant.

Of those who took the drug, 65% reported 4 hours of pain relief; 48 hours later, 39% still reported pain relief.

Source Dr. Silberstein

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 the symptoms of Alzheimer's.

Dr. Tyas and her colleagues used the ongoing Nun Study as the basis of their analysis. The Nun 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–the time 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 the symptoms of Alzheimer's.

Dr. Tyas and her colleagues used the ongoing Nun Study as the basis of their analysis. The Nun 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–the time 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 the symptoms of Alzheimer's.

Dr. Tyas and her colleagues used the ongoing Nun Study as the basis of their analysis. The Nun 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–the time 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 – 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 signalling–was able to alter the steady rate of cognitive and functional decline in patients with mild to moderate Alzheimer's. also among the failures were the omega-3 fatty acid studies.

“We are again left to wonder whether clues from epidemiology are more related to delaying or protective factors rather than factors related to progression of established disease,” said Dr. Samuel Gandy, Mount Sinai Professor of Alzheimer's Disease Research at Mount Sinai Medical Center in New York.

Instead of searching for the compound that will alter the so-far inevitable decline seen in Alzheimer's, the key will probably be preventing the disease from taking hold in the first place, he said in an interview.

Among the failures was a phase II placebo-controlled trial of rosiglitazone that showed no benefit on cognition in a group of 553 patients with mild to moderate Alzheimer's.

The 24-week trial, sponsored by GlaxoSmithKline, randomized the patients (mean age 72 years) to placebo, a positive control group of donepezil 10 mg/day, or one of two rosiglitazone doses (2 mg or 8 mg daily). The extended-release formulation was an experimental one, and not the Food and Drug Administration–approved Avandia, Dr. Michael Gold said at the meeting.

The study examined each treatment's effect in the overall cohort, on those who were apolipoprotein E e4 (APOE e4) negative, and all subjects except those homozygous for the high-risk gene. The primary end points were changes in the Alzheimer's Disease Assessment Scale–cognitive domain (ADAS-cog) and Clinicians' Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus).

At 24 weeks, neither of the rosiglitazone doses was significantly different from placebo in either cognitive assessment for any of the populations. But in the overall population and in the group that included everyone except the APOE e4 homozygous carriers, CIBIC scores were significantly better for those on donepezil than for those taking placebo.

Since that finding had not been adjusted for covariates, “I don't think it's anything we can hang our hats on,” said Dr. Gold, global clinical vice president of neurology at GlaxoSmithKline, Durham, N.C.

Dr. Gordon Wilcock reported another failed phase III trial for tarenflurbil, this one conducted in the United States, Canada, and Western Europe. In 2008, tarenflurbil, a selective amyloid-lowering agent, failed its highly anticipated phase III U.S. trial.

“With two failed phase III trials, tarenflurbil has killed itself off completely,” Dr. Wilcock, of the University of Oxford (England), said at the meeting.

Tarenflurbil was the first gamma secretase modulator to be tested in a phase III trial. This class of drug is thought to reduce the levels of toxic amyloid beta (AB₄₂) in the brain by changing the point at which the enzyme gamma secretase cuts the amyloid precursor protein, shifting the ratio to less of the toxic AB₄₂ and more of the less-toxic AB₄₀.

The most recent trial failed to show statistically significant or clinically meaningful changes in any of the three outcomes it assessed: Alzheimer's Disease Assessment Scale–Cognitive subscale (ADAS-cog), ADAS-activities of daily living (ADAS-ADL), or the Clinical Dementia Rating–sum of boxes (CDR-sb).

“This was a well-powered, well-designed, and well-conducted trial,” that would have identified any benefit that existed, Dr. Wilcock said. Its message seems to be that researchers should investigate non–amyloid-centered therapies. The trial was sponsored by Myriad Pharmaceuticals Inc. of Salt Lake City, for which Dr. Wilcock is a consultant.

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

He presented results of a randomized, controlled trial of a combination of galantamine and memantine compared to galantamine alone in 233 patients with mild-moderate Alzheimer's. The patients (mean age 72 years) were naive to cholinesterase inhibitors and memantine. They were randomized to 24 mg of galantamine daily plus a placebo, or a combination of 24 mg galantamine and 20 mg memantine for 1 year. The primary end points were the ADAS-cog, ADAS-ADL, and CDR-sb.

The combination was well tolerated, but the addition of memantine did not significantly affect any of the clinical end points. “At 16 weeks, we saw a little better effect in the combination group,” on all three measures, although none of the differences were statistically significant, Dr. Peters said. After 16 weeks, patients in both arms experienced steady declines which, by week 52, were significantly worse than their baseline scores. APOE e4 status had no significant impact on the results.

Dr. Peters acknowledged that a larger group would have been preferable. Janssen-Cilag of Buckinghamshire, England, which sponsored the trial, thought that the study was sufficiently powered, he said, adding that he had no financial relationship with the company.

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 signalling–was able to alter the steady rate of cognitive and functional decline in patients with mild to moderate Alzheimer's. also among the failures were the omega-3 fatty acid studies.

“We are again left to wonder whether clues from epidemiology are more related to delaying or protective factors rather than factors related to progression of established disease,” said Dr. Samuel Gandy, Mount Sinai Professor of Alzheimer's Disease Research at Mount Sinai Medical Center in New York.

Instead of searching for the compound that will alter the so-far inevitable decline seen in Alzheimer's, the key will probably be preventing the disease from taking hold in the first place, he said in an interview.

Among the failures was a phase II placebo-controlled trial of rosiglitazone that showed no benefit on cognition in a group of 553 patients with mild to moderate Alzheimer's.

The 24-week trial, sponsored by GlaxoSmithKline, randomized the patients (mean age 72 years) to placebo, a positive control group of donepezil 10 mg/day, or one of two rosiglitazone doses (2 mg or 8 mg daily). The extended-release formulation was an experimental one, and not the Food and Drug Administration–approved Avandia, Dr. Michael Gold said at the meeting.

The study examined each treatment's effect in the overall cohort, on those who were apolipoprotein E e4 (APOE e4) negative, and all subjects except those homozygous for the high-risk gene. The primary end points were changes in the Alzheimer's Disease Assessment Scale–cognitive domain (ADAS-cog) and Clinicians' Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus).

At 24 weeks, neither of the rosiglitazone doses was significantly different from placebo in either cognitive assessment for any of the populations. But in the overall population and in the group that included everyone except the APOE e4 homozygous carriers, CIBIC scores were significantly better for those on donepezil than for those taking placebo.

Since that finding had not been adjusted for covariates, “I don't think it's anything we can hang our hats on,” said Dr. Gold, global clinical vice president of neurology at GlaxoSmithKline, Durham, N.C.

Dr. Gordon Wilcock reported another failed phase III trial for tarenflurbil, this one conducted in the United States, Canada, and Western Europe. In 2008, tarenflurbil, a selective amyloid-lowering agent, failed its highly anticipated phase III U.S. trial.

“With two failed phase III trials, tarenflurbil has killed itself off completely,” Dr. Wilcock, of the University of Oxford (England), said at the meeting.

Tarenflurbil was the first gamma secretase modulator to be tested in a phase III trial. This class of drug is thought to reduce the levels of toxic amyloid beta (AB₄₂) in the brain by changing the point at which the enzyme gamma secretase cuts the amyloid precursor protein, shifting the ratio to less of the toxic AB₄₂ and more of the less-toxic AB₄₀.

The most recent trial failed to show statistically significant or clinically meaningful changes in any of the three outcomes it assessed: Alzheimer's Disease Assessment Scale–Cognitive subscale (ADAS-cog), ADAS-activities of daily living (ADAS-ADL), or the Clinical Dementia Rating–sum of boxes (CDR-sb).

“This was a well-powered, well-designed, and well-conducted trial,” that would have identified any benefit that existed, Dr. Wilcock said. Its message seems to be that researchers should investigate non–amyloid-centered therapies. The trial was sponsored by Myriad Pharmaceuticals Inc. of Salt Lake City, for which Dr. Wilcock is a consultant.

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

He presented results of a randomized, controlled trial of a combination of galantamine and memantine compared to galantamine alone in 233 patients with mild-moderate Alzheimer's. The patients (mean age 72 years) were naive to cholinesterase inhibitors and memantine. They were randomized to 24 mg of galantamine daily plus a placebo, or a combination of 24 mg galantamine and 20 mg memantine for 1 year. The primary end points were the ADAS-cog, ADAS-ADL, and CDR-sb.

The combination was well tolerated, but the addition of memantine did not significantly affect any of the clinical end points. “At 16 weeks, we saw a little better effect in the combination group,” on all three measures, although none of the differences were statistically significant, Dr. Peters said. After 16 weeks, patients in both arms experienced steady declines which, by week 52, were significantly worse than their baseline scores. APOE e4 status had no significant impact on the results.

Dr. Peters acknowledged that a larger group would have been preferable. Janssen-Cilag of Buckinghamshire, England, which sponsored the trial, thought that the study was sufficiently powered, he said, adding that he had no financial relationship with the company.

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 signalling–was able to alter the steady rate of cognitive and functional decline in patients with mild to moderate Alzheimer's. also among the failures were the omega-3 fatty acid studies.

“We are again left to wonder whether clues from epidemiology are more related to delaying or protective factors rather than factors related to progression of established disease,” said Dr. Samuel Gandy, Mount Sinai Professor of Alzheimer's Disease Research at Mount Sinai Medical Center in New York.

Instead of searching for the compound that will alter the so-far inevitable decline seen in Alzheimer's, the key will probably be preventing the disease from taking hold in the first place, he said in an interview.

Among the failures was a phase II placebo-controlled trial of rosiglitazone that showed no benefit on cognition in a group of 553 patients with mild to moderate Alzheimer's.

The 24-week trial, sponsored by GlaxoSmithKline, randomized the patients (mean age 72 years) to placebo, a positive control group of donepezil 10 mg/day, or one of two rosiglitazone doses (2 mg or 8 mg daily). The extended-release formulation was an experimental one, and not the Food and Drug Administration–approved Avandia, Dr. Michael Gold said at the meeting.

The study examined each treatment's effect in the overall cohort, on those who were apolipoprotein E e4 (APOE e4) negative, and all subjects except those homozygous for the high-risk gene. The primary end points were changes in the Alzheimer's Disease Assessment Scale–cognitive domain (ADAS-cog) and Clinicians' Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus).

At 24 weeks, neither of the rosiglitazone doses was significantly different from placebo in either cognitive assessment for any of the populations. But in the overall population and in the group that included everyone except the APOE e4 homozygous carriers, CIBIC scores were significantly better for those on donepezil than for those taking placebo.

Since that finding had not been adjusted for covariates, “I don't think it's anything we can hang our hats on,” said Dr. Gold, global clinical vice president of neurology at GlaxoSmithKline, Durham, N.C.

Dr. Gordon Wilcock reported another failed phase III trial for tarenflurbil, this one conducted in the United States, Canada, and Western Europe. In 2008, tarenflurbil, a selective amyloid-lowering agent, failed its highly anticipated phase III U.S. trial.

“With two failed phase III trials, tarenflurbil has killed itself off completely,” Dr. Wilcock, of the University of Oxford (England), said at the meeting.

Tarenflurbil was the first gamma secretase modulator to be tested in a phase III trial. This class of drug is thought to reduce the levels of toxic amyloid beta (AB₄₂) in the brain by changing the point at which the enzyme gamma secretase cuts the amyloid precursor protein, shifting the ratio to less of the toxic AB₄₂ and more of the less-toxic AB₄₀.

The most recent trial failed to show statistically significant or clinically meaningful changes in any of the three outcomes it assessed: Alzheimer's Disease Assessment Scale–Cognitive subscale (ADAS-cog), ADAS-activities of daily living (ADAS-ADL), or the Clinical Dementia Rating–sum of boxes (CDR-sb).

“This was a well-powered, well-designed, and well-conducted trial,” that would have identified any benefit that existed, Dr. Wilcock said. Its message seems to be that researchers should investigate non–amyloid-centered therapies. The trial was sponsored by Myriad Pharmaceuticals Inc. of Salt Lake City, for which Dr. Wilcock is a consultant.

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

He presented results of a randomized, controlled trial of a combination of galantamine and memantine compared to galantamine alone in 233 patients with mild-moderate Alzheimer's. The patients (mean age 72 years) were naive to cholinesterase inhibitors and memantine. They were randomized to 24 mg of galantamine daily plus a placebo, or a combination of 24 mg galantamine and 20 mg memantine for 1 year. The primary end points were the ADAS-cog, ADAS-ADL, and CDR-sb.

The combination was well tolerated, but the addition of memantine did not significantly affect any of the clinical end points. “At 16 weeks, we saw a little better effect in the combination group,” on all three measures, although none of the differences were statistically significant, Dr. Peters said. After 16 weeks, patients in both arms experienced steady declines which, by week 52, were significantly worse than their baseline scores. APOE e4 status had no significant impact on the results.

Dr. Peters acknowledged that a larger group would have been preferable. Janssen-Cilag of Buckinghamshire, England, which sponsored the trial, thought that the study was sufficiently powered, he said, adding that he had no financial relationship with the company.

VIENNA — The presence of brain infarcts at age 60 strongly predicts later stroke and dementia, while the presence of white matter hyperintensities is related to a wider variety of outcomes, including stroke, cognitive decline, dementia, and death.

The relationships suggest that each imaging abnormality could be used as a risk marker for the various disorders, Dr. Stephanie Debette said at the International Conference on Alzheimer's Disease.

“The association of large-volume white matter hyperintensities with incident dementia and amnestic MCI [mild cognitive impairment] suggests that it could be a useful quantitative intermediate marker for risk factors of early-stage cognitive impairment and dementia, whereas brain infarcts may be a more appropriate intermediate marker for stroke,” said Dr. Debette of Boston University. “These imaging measures could potentially serve as intermediate end points in prevention trials.”

The study cohort consisted of 2,229 subjects (mean age 62 years) in the Framingham Heart Study Offspring Cohort who underwent brain MRI and neuropsychological testing between 1999 and 2005. Of these, 1,694 returned for a second neuropsychological assessment an average of 6 years later.

At baseline, 2% had evidence of an ischemic stroke and 0.3% had clinical dementia. Excess white matter hyperintensity volume was present in 14%, and 11% showed at least one brain infarct.

After 6 years, 7 subjects had developed dementia; 32 had experienced an ischemic stroke; and 187 had developed new-onset MCI, 94 cases of which were amnestic. During follow-up, 97 of the subjects died.

Two multivariate analyses that controlled for age, sex, and vascular risk factors revealed significant associations between the MRI markers, neurocognitive outcomes, stroke, and death.

Subjects with a large volume of white matter hyperintensities at baseline were significantly more likely than were those without a large volume of lesions to experience stroke and dementia (hazard ratio 2.0), amnestic mild MCI (HR 1.75), and death (HR 1.77). This association was particularly strong with cardiovascular death (HR 3.5).

Subjects with at least one brain infarct at baseline were significantly more likely to develop MCI of the executive function type (HR 2.3). Baseline brain infarcts also significantly predicted stroke (HR 3.0) and dementia (HR 9.0).

'These imaging measures could potentially serve as intermediate end points in prevention trials.'

Source DR. DEBETTE

VIENNA — The presence of brain infarcts at age 60 strongly predicts later stroke and dementia, while the presence of white matter hyperintensities is related to a wider variety of outcomes, including stroke, cognitive decline, dementia, and death.

The relationships suggest that each imaging abnormality could be used as a risk marker for the various disorders, Dr. Stephanie Debette said at the International Conference on Alzheimer's Disease.

“The association of large-volume white matter hyperintensities with incident dementia and amnestic MCI [mild cognitive impairment] suggests that it could be a useful quantitative intermediate marker for risk factors of early-stage cognitive impairment and dementia, whereas brain infarcts may be a more appropriate intermediate marker for stroke,” said Dr. Debette of Boston University. “These imaging measures could potentially serve as intermediate end points in prevention trials.”

The study cohort consisted of 2,229 subjects (mean age 62 years) in the Framingham Heart Study Offspring Cohort who underwent brain MRI and neuropsychological testing between 1999 and 2005. Of these, 1,694 returned for a second neuropsychological assessment an average of 6 years later.

At baseline, 2% had evidence of an ischemic stroke and 0.3% had clinical dementia. Excess white matter hyperintensity volume was present in 14%, and 11% showed at least one brain infarct.

After 6 years, 7 subjects had developed dementia; 32 had experienced an ischemic stroke; and 187 had developed new-onset MCI, 94 cases of which were amnestic. During follow-up, 97 of the subjects died.

Two multivariate analyses that controlled for age, sex, and vascular risk factors revealed significant associations between the MRI markers, neurocognitive outcomes, stroke, and death.

Subjects with a large volume of white matter hyperintensities at baseline were significantly more likely than were those without a large volume of lesions to experience stroke and dementia (hazard ratio 2.0), amnestic mild MCI (HR 1.75), and death (HR 1.77). This association was particularly strong with cardiovascular death (HR 3.5).

Subjects with at least one brain infarct at baseline were significantly more likely to develop MCI of the executive function type (HR 2.3). Baseline brain infarcts also significantly predicted stroke (HR 3.0) and dementia (HR 9.0).

'These imaging measures could potentially serve as intermediate end points in prevention trials.'

Source DR. DEBETTE

VIENNA — The presence of brain infarcts at age 60 strongly predicts later stroke and dementia, while the presence of white matter hyperintensities is related to a wider variety of outcomes, including stroke, cognitive decline, dementia, and death.

The relationships suggest that each imaging abnormality could be used as a risk marker for the various disorders, Dr. Stephanie Debette said at the International Conference on Alzheimer's Disease.

“The association of large-volume white matter hyperintensities with incident dementia and amnestic MCI [mild cognitive impairment] suggests that it could be a useful quantitative intermediate marker for risk factors of early-stage cognitive impairment and dementia, whereas brain infarcts may be a more appropriate intermediate marker for stroke,” said Dr. Debette of Boston University. “These imaging measures could potentially serve as intermediate end points in prevention trials.”

The study cohort consisted of 2,229 subjects (mean age 62 years) in the Framingham Heart Study Offspring Cohort who underwent brain MRI and neuropsychological testing between 1999 and 2005. Of these, 1,694 returned for a second neuropsychological assessment an average of 6 years later.

At baseline, 2% had evidence of an ischemic stroke and 0.3% had clinical dementia. Excess white matter hyperintensity volume was present in 14%, and 11% showed at least one brain infarct.

After 6 years, 7 subjects had developed dementia; 32 had experienced an ischemic stroke; and 187 had developed new-onset MCI, 94 cases of which were amnestic. During follow-up, 97 of the subjects died.

Two multivariate analyses that controlled for age, sex, and vascular risk factors revealed significant associations between the MRI markers, neurocognitive outcomes, stroke, and death.

Subjects with a large volume of white matter hyperintensities at baseline were significantly more likely than were those without a large volume of lesions to experience stroke and dementia (hazard ratio 2.0), amnestic mild MCI (HR 1.75), and death (HR 1.77). This association was particularly strong with cardiovascular death (HR 3.5).

Subjects with at least one brain infarct at baseline were significantly more likely to develop MCI of the executive function type (HR 2.3). Baseline brain infarcts also significantly predicted stroke (HR 3.0) and dementia (HR 9.0).

'These imaging measures could potentially serve as intermediate end points in prevention trials.'

Source DR. DEBETTE

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.

The disappointments, combined with the failed omega-3 fatty acid studies that were also presented at the meeting, left researchers wondering where to best focus their efforts.

“We are again left to wonder whether clues from epidemiology are more related to delaying or protective factors rather than factors related to progression of established disease,” said Dr. Samuel Gandy, Mount Sinai Professor of Alzheimer's Disease Research at Mount Sinai Medical Center in New York.

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

“The major barrier to primary prevention studies in Alzheimer's is cost,” Dr. Gandy said.

No Effect With Rosiglitazone

Although researchers around the world are busy exploring the pathologic links between Alzheimer's and diabetes, a phase II placebo-controlled trial of rosiglitazone failed to show any benefit on cognition in a group of 553 patients with mild to moderate Alzheimer's.

The 24-week trial, sponsored by GlaxoSmithKline, randomized the patients (mean age 72 years) to placebo, a positive control group of donepezil 10 mg/day, or one of two rosiglitazone doses (2 mg or 8 mg daily). The extended-release formulation was an experimental one, and not the Food and Drug Administration–approved Avandia, Dr. Michael Gold said at the meeting.

The study examined each treatment's effect in the overall cohort, on those who were apolipoprotein E e4 (APOE e4) negative, and all subjects except those homozygous for the high-risk gene. The primary end points were changes in the Alzheimer's Disease Assessment Scale–cognitive domain (ADAS-cog) and Clinicians' Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus).

At 24 weeks, neither of the rosiglitazone doses was significantly different from placebo in either cognitive assessment for any of the populations. However, in the overall population and in the group that included everyone except the APOE e4 homozygous carriers, CIBIC-plus scores were significantly better for those taking donepezil than for those taking placebo.

But since that finding had not been adjusted for covariates, “I don't think it's anything we can hang our hats on,” said Dr. Gold, global clinical vice president of neurology at GlaxoSmithKline.

End of the Road for Tarenflurbil

Dr. Gordon Wilcock announced the final nail in the coffin for tarenflurbil: another failed phase III trial, this one conducted in the United States, Canada, and Western Europe.

In 2008, tarenflurbil, a selective amyloid-lowering agent, failed its very highly anticipated phase III U.S. trial. The results of this second trial, which was unblinded in February, confirm last year's disappointment, said Dr. Wilcock of the University of Oxford (England).

“The results really mirror the failed U.S. trial very much,” Dr. Wilcock said at the meeting. “I'm afraid with two failed phase III trials, tarenflurbil has killed itself off completely.”

Tarenflurbil was the first gamma secretase modulator to be tested in a phase III trial. This class of drug is thought to reduce the levels of toxic amyloid beta (AB₄₂) in the brain by changing the point at which the enzyme gamma secretase cuts the amyloid precursor protein, shifting the ratio to less of the toxic AB₄₂ and more of the less-toxic AB₄₀.

However, the most recent trial 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).

Patients were randomized to placebo or to 800 mg tarenflurbil twice a day. After 18 months, the mean placebo decline rates were 6 points on the ADAS-cog, 11 points on the ADAS-ADL, and 2.7 points on the CDR-sb. “The picture with tarenflurbil was absolutely the same,” Dr. Wilcock said. “You can virtually superimpose the decline” on tarenflurbil over that on placebo.

“We also included a neuropsychiatric test battery, thinking it might be more sensitive to early changes, but this produced a similarly disappointing picture,” he said.

Adverse events were reported in 88% of the placebo patients and 85% of the tarenflurbil patients—again, not a significant difference. However, compared with placebo, the drug was associated with significantly more anemia (14% vs. 4%), infections (4% vs. 1%), and gastrointestinal ulcers (2% vs. 0%).

“This was a well-powered, well-designed, and well-conducted trial,” that would have identified any benefit that existed, Dr. Wilcock said. Instead, its message seems to be that researchers would do well to investigate non–amyloid-centered therapies.

“It's one of three different strategic approaches to deal with amyloid in the brain that have proved negative,” Dr. Wilcock said. “Whether that is due to the study design, or means we need to be rethinking what is going on with the amyloid cascade hypothesis is an interesting question.”

The trial was sponsored by Myriad Pharmaceuticals Inc. of Salt Lake City. Dr. Wilcock is a consultant with the company.

Drug Combo No Better Than One Drug

Finally, a combination of two drugs already proven effective in Alzheimer's disease worked no better than a single agent to slow the disorder's cognitive and functional decline, Dr. Oliver Peters said.

Dr. Peters of Charité University Hospital Berlin, presented the results of a trial of a combination of galantamine and memantine, compared with galantamine alone, in 233 patients with mild to moderate Alzheimer's.

The patients (mean age 72 years) were randomized to 24 mg of galantamine daily plus a placebo, or a combination of 24 mg galantamine and 20 mg memantine for 1 year. The primary end points were the ADAS-cog, ADAS-ADL, and CDR-sb.

The combination was well tolerated, but the addition of memantine did not significantly affect any of the clinical end points.

“At 16 weeks, we saw a little better effect in the combination group,” on all three measures, although none of the differences were statistically significant, Dr. Peters said. After 16 weeks, patients in both treatment arms experienced steady declines which, by week 52, were significantly worse than their baseline scores.

Janssen-Cilag sponsored the trial. Dr. Peters said he had no financial relationship with the company.

The key to Alzheimer's will probably be preventing the disease from taking hold in the first place.

Source DR. GANDY

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.

The disappointments, combined with the failed omega-3 fatty acid studies that were also presented at the meeting, left researchers wondering where to best focus their efforts.

“We are again left to wonder whether clues from epidemiology are more related to delaying or protective factors rather than factors related to progression of established disease,” said Dr. Samuel Gandy, Mount Sinai Professor of Alzheimer's Disease Research at Mount Sinai Medical Center in New York.

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

“The major barrier to primary prevention studies in Alzheimer's is cost,” Dr. Gandy said.

No Effect With Rosiglitazone

Although researchers around the world are busy exploring the pathologic links between Alzheimer's and diabetes, a phase II placebo-controlled trial of rosiglitazone failed to show any benefit on cognition in a group of 553 patients with mild to moderate Alzheimer's.

The 24-week trial, sponsored by GlaxoSmithKline, randomized the patients (mean age 72 years) to placebo, a positive control group of donepezil 10 mg/day, or one of two rosiglitazone doses (2 mg or 8 mg daily). The extended-release formulation was an experimental one, and not the Food and Drug Administration–approved Avandia, Dr. Michael Gold said at the meeting.

The study examined each treatment's effect in the overall cohort, on those who were apolipoprotein E e4 (APOE e4) negative, and all subjects except those homozygous for the high-risk gene. The primary end points were changes in the Alzheimer's Disease Assessment Scale–cognitive domain (ADAS-cog) and Clinicians' Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus).

At 24 weeks, neither of the rosiglitazone doses was significantly different from placebo in either cognitive assessment for any of the populations. However, in the overall population and in the group that included everyone except the APOE e4 homozygous carriers, CIBIC-plus scores were significantly better for those taking donepezil than for those taking placebo.

But since that finding had not been adjusted for covariates, “I don't think it's anything we can hang our hats on,” said Dr. Gold, global clinical vice president of neurology at GlaxoSmithKline.

End of the Road for Tarenflurbil

Dr. Gordon Wilcock announced the final nail in the coffin for tarenflurbil: another failed phase III trial, this one conducted in the United States, Canada, and Western Europe.

In 2008, tarenflurbil, a selective amyloid-lowering agent, failed its very highly anticipated phase III U.S. trial. The results of this second trial, which was unblinded in February, confirm last year's disappointment, said Dr. Wilcock of the University of Oxford (England).

“The results really mirror the failed U.S. trial very much,” Dr. Wilcock said at the meeting. “I'm afraid with two failed phase III trials, tarenflurbil has killed itself off completely.”

Tarenflurbil was the first gamma secretase modulator to be tested in a phase III trial. This class of drug is thought to reduce the levels of toxic amyloid beta (AB₄₂) in the brain by changing the point at which the enzyme gamma secretase cuts the amyloid precursor protein, shifting the ratio to less of the toxic AB₄₂ and more of the less-toxic AB₄₀.

However, the most recent trial 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).

Patients were randomized to placebo or to 800 mg tarenflurbil twice a day. After 18 months, the mean placebo decline rates were 6 points on the ADAS-cog, 11 points on the ADAS-ADL, and 2.7 points on the CDR-sb. “The picture with tarenflurbil was absolutely the same,” Dr. Wilcock said. “You can virtually superimpose the decline” on tarenflurbil over that on placebo.

“We also included a neuropsychiatric test battery, thinking it might be more sensitive to early changes, but this produced a similarly disappointing picture,” he said.

Adverse events were reported in 88% of the placebo patients and 85% of the tarenflurbil patients—again, not a significant difference. However, compared with placebo, the drug was associated with significantly more anemia (14% vs. 4%), infections (4% vs. 1%), and gastrointestinal ulcers (2% vs. 0%).

“This was a well-powered, well-designed, and well-conducted trial,” that would have identified any benefit that existed, Dr. Wilcock said. Instead, its message seems to be that researchers would do well to investigate non–amyloid-centered therapies.

“It's one of three different strategic approaches to deal with amyloid in the brain that have proved negative,” Dr. Wilcock said. “Whether that is due to the study design, or means we need to be rethinking what is going on with the amyloid cascade hypothesis is an interesting question.”

The trial was sponsored by Myriad Pharmaceuticals Inc. of Salt Lake City. Dr. Wilcock is a consultant with the company.

Drug Combo No Better Than One Drug

Finally, a combination of two drugs already proven effective in Alzheimer's disease worked no better than a single agent to slow the disorder's cognitive and functional decline, Dr. Oliver Peters said.

Dr. Peters of Charité University Hospital Berlin, presented the results of a trial of a combination of galantamine and memantine, compared with galantamine alone, in 233 patients with mild to moderate Alzheimer's.

The patients (mean age 72 years) were randomized to 24 mg of galantamine daily plus a placebo, or a combination of 24 mg galantamine and 20 mg memantine for 1 year. The primary end points were the ADAS-cog, ADAS-ADL, and CDR-sb.

The combination was well tolerated, but the addition of memantine did not significantly affect any of the clinical end points.

“At 16 weeks, we saw a little better effect in the combination group,” on all three measures, although none of the differences were statistically significant, Dr. Peters said. After 16 weeks, patients in both treatment arms experienced steady declines which, by week 52, were significantly worse than their baseline scores.

Janssen-Cilag sponsored the trial. Dr. Peters said he had no financial relationship with the company.

The key to Alzheimer's will probably be preventing the disease from taking hold in the first place.

Source DR. GANDY

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.

The disappointments, combined with the failed omega-3 fatty acid studies that were also presented at the meeting, left researchers wondering where to best focus their efforts.

“We are again left to wonder whether clues from epidemiology are more related to delaying or protective factors rather than factors related to progression of established disease,” said Dr. Samuel Gandy, Mount Sinai Professor of Alzheimer's Disease Research at Mount Sinai Medical Center in New York.

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

“The major barrier to primary prevention studies in Alzheimer's is cost,” Dr. Gandy said.

No Effect With Rosiglitazone

Although researchers around the world are busy exploring the pathologic links between Alzheimer's and diabetes, a phase II placebo-controlled trial of rosiglitazone failed to show any benefit on cognition in a group of 553 patients with mild to moderate Alzheimer's.

The 24-week trial, sponsored by GlaxoSmithKline, randomized the patients (mean age 72 years) to placebo, a positive control group of donepezil 10 mg/day, or one of two rosiglitazone doses (2 mg or 8 mg daily). The extended-release formulation was an experimental one, and not the Food and Drug Administration–approved Avandia, Dr. Michael Gold said at the meeting.

The study examined each treatment's effect in the overall cohort, on those who were apolipoprotein E e4 (APOE e4) negative, and all subjects except those homozygous for the high-risk gene. The primary end points were changes in the Alzheimer's Disease Assessment Scale–cognitive domain (ADAS-cog) and Clinicians' Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus).

At 24 weeks, neither of the rosiglitazone doses was significantly different from placebo in either cognitive assessment for any of the populations. However, in the overall population and in the group that included everyone except the APOE e4 homozygous carriers, CIBIC-plus scores were significantly better for those taking donepezil than for those taking placebo.

But since that finding had not been adjusted for covariates, “I don't think it's anything we can hang our hats on,” said Dr. Gold, global clinical vice president of neurology at GlaxoSmithKline.

End of the Road for Tarenflurbil

Dr. Gordon Wilcock announced the final nail in the coffin for tarenflurbil: another failed phase III trial, this one conducted in the United States, Canada, and Western Europe.

In 2008, tarenflurbil, a selective amyloid-lowering agent, failed its very highly anticipated phase III U.S. trial. The results of this second trial, which was unblinded in February, confirm last year's disappointment, said Dr. Wilcock of the University of Oxford (England).

“The results really mirror the failed U.S. trial very much,” Dr. Wilcock said at the meeting. “I'm afraid with two failed phase III trials, tarenflurbil has killed itself off completely.”

Tarenflurbil was the first gamma secretase modulator to be tested in a phase III trial. This class of drug is thought to reduce the levels of toxic amyloid beta (AB₄₂) in the brain by changing the point at which the enzyme gamma secretase cuts the amyloid precursor protein, shifting the ratio to less of the toxic AB₄₂ and more of the less-toxic AB₄₀.

However, the most recent trial 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).

Patients were randomized to placebo or to 800 mg tarenflurbil twice a day. After 18 months, the mean placebo decline rates were 6 points on the ADAS-cog, 11 points on the ADAS-ADL, and 2.7 points on the CDR-sb. “The picture with tarenflurbil was absolutely the same,” Dr. Wilcock said. “You can virtually superimpose the decline” on tarenflurbil over that on placebo.

“We also included a neuropsychiatric test battery, thinking it might be more sensitive to early changes, but this produced a similarly disappointing picture,” he said.

Adverse events were reported in 88% of the placebo patients and 85% of the tarenflurbil patients—again, not a significant difference. However, compared with placebo, the drug was associated with significantly more anemia (14% vs. 4%), infections (4% vs. 1%), and gastrointestinal ulcers (2% vs. 0%).

“This was a well-powered, well-designed, and well-conducted trial,” that would have identified any benefit that existed, Dr. Wilcock said. Instead, its message seems to be that researchers would do well to investigate non–amyloid-centered therapies.

“It's one of three different strategic approaches to deal with amyloid in the brain that have proved negative,” Dr. Wilcock said. “Whether that is due to the study design, or means we need to be rethinking what is going on with the amyloid cascade hypothesis is an interesting question.”

The trial was sponsored by Myriad Pharmaceuticals Inc. of Salt Lake City. Dr. Wilcock is a consultant with the company.

Drug Combo No Better Than One Drug

Finally, a combination of two drugs already proven effective in Alzheimer's disease worked no better than a single agent to slow the disorder's cognitive and functional decline, Dr. Oliver Peters said.

Dr. Peters of Charité University Hospital Berlin, presented the results of a trial of a combination of galantamine and memantine, compared with galantamine alone, in 233 patients with mild to moderate Alzheimer's.

The patients (mean age 72 years) were randomized to 24 mg of galantamine daily plus a placebo, or a combination of 24 mg galantamine and 20 mg memantine for 1 year. The primary end points were the ADAS-cog, ADAS-ADL, and CDR-sb.

The combination was well tolerated, but the addition of memantine did not significantly affect any of the clinical end points.

“At 16 weeks, we saw a little better effect in the combination group,” on all three measures, although none of the differences were statistically significant, Dr. Peters said. After 16 weeks, patients in both treatment arms experienced steady declines which, by week 52, were significantly worse than their baseline scores.

Janssen-Cilag sponsored the trial. Dr. Peters said he had no financial relationship with the company.

The key to Alzheimer's will probably be preventing the disease from taking hold in the first place.

Source DR. GANDY