James Butcher

SALZBURG, AUSTRIA – Herpes simplex virus-type 1 may be the root cause of some cases of Alzheimer's disease, according to research presented at an international conference on Alzheimer's and Parkinson's diseases.

Dr. Matthew Wozniak and Dr. Ruth Itzhaki of the University of Manchester (England) found that human neural cells infected with HSV-1 had contained far more amyloid β than had uninfected cells. “We've examined both neuronal and glial cells, and the increase occurs in both cell types,” said Dr Wozniak.

HSV-1 causes several diseases, including cold sores and herpes simplex encephalitis. Most humans are infected, usually in infancy, and in some the virus is woken from its dormant phase in times of stress.

Previously, researchers from Dr. Itzhaki's laboratory demonstrated that HSV-1 DNA is present in brain tissue and that antibodies to the virus can be found in the cerebral spinal fluid in a high proportion of patients with Alzheimer's disease (AD) and elderly patients who do not show signs of the disease (J. Med. Virol. 2005;75:300–6). The study included 27 AD patients and 13 age-matched controls. Importantly, these same markers are generally absent in the brains of younger people.

Subsequently, the researchers increased the study population to 61 AD patients and 48 age-matched controls (Lancet 1997;349:241–4). They found that HSV-1 DNA in the brain and possession of an apolipoprotein E-α4 allele is a strong risk factor for AD (odds ratio 12).

More recently, the researchers demonstrated that HSV-1 infection decreases the concentration of full length amyloid precursor protein, Dr. Wozniak explained.

“A role for HSV-1 in AD points to the use of antiviral agents as a treatment for the symptoms of the disease,” he suggested.

SALZBURG, AUSTRIA – Herpes simplex virus-type 1 may be the root cause of some cases of Alzheimer's disease, according to research presented at an international conference on Alzheimer's and Parkinson's diseases.

Dr. Matthew Wozniak and Dr. Ruth Itzhaki of the University of Manchester (England) found that human neural cells infected with HSV-1 had contained far more amyloid β than had uninfected cells. “We've examined both neuronal and glial cells, and the increase occurs in both cell types,” said Dr Wozniak.

HSV-1 causes several diseases, including cold sores and herpes simplex encephalitis. Most humans are infected, usually in infancy, and in some the virus is woken from its dormant phase in times of stress.

Previously, researchers from Dr. Itzhaki's laboratory demonstrated that HSV-1 DNA is present in brain tissue and that antibodies to the virus can be found in the cerebral spinal fluid in a high proportion of patients with Alzheimer's disease (AD) and elderly patients who do not show signs of the disease (J. Med. Virol. 2005;75:300–6). The study included 27 AD patients and 13 age-matched controls. Importantly, these same markers are generally absent in the brains of younger people.

Subsequently, the researchers increased the study population to 61 AD patients and 48 age-matched controls (Lancet 1997;349:241–4). They found that HSV-1 DNA in the brain and possession of an apolipoprotein E-α4 allele is a strong risk factor for AD (odds ratio 12).

More recently, the researchers demonstrated that HSV-1 infection decreases the concentration of full length amyloid precursor protein, Dr. Wozniak explained.

“A role for HSV-1 in AD points to the use of antiviral agents as a treatment for the symptoms of the disease,” he suggested.

SALZBURG, AUSTRIA – Herpes simplex virus-type 1 may be the root cause of some cases of Alzheimer's disease, according to research presented at an international conference on Alzheimer's and Parkinson's diseases.

Dr. Matthew Wozniak and Dr. Ruth Itzhaki of the University of Manchester (England) found that human neural cells infected with HSV-1 had contained far more amyloid β than had uninfected cells. “We've examined both neuronal and glial cells, and the increase occurs in both cell types,” said Dr Wozniak.

HSV-1 causes several diseases, including cold sores and herpes simplex encephalitis. Most humans are infected, usually in infancy, and in some the virus is woken from its dormant phase in times of stress.

Previously, researchers from Dr. Itzhaki's laboratory demonstrated that HSV-1 DNA is present in brain tissue and that antibodies to the virus can be found in the cerebral spinal fluid in a high proportion of patients with Alzheimer's disease (AD) and elderly patients who do not show signs of the disease (J. Med. Virol. 2005;75:300–6). The study included 27 AD patients and 13 age-matched controls. Importantly, these same markers are generally absent in the brains of younger people.

Subsequently, the researchers increased the study population to 61 AD patients and 48 age-matched controls (Lancet 1997;349:241–4). They found that HSV-1 DNA in the brain and possession of an apolipoprotein E-α4 allele is a strong risk factor for AD (odds ratio 12).

More recently, the researchers demonstrated that HSV-1 infection decreases the concentration of full length amyloid precursor protein, Dr. Wozniak explained.

“A role for HSV-1 in AD points to the use of antiviral agents as a treatment for the symptoms of the disease,” he suggested.

SALZBURG, AUSTRIA – The investigational Pittsburgh B compound that binds to cerebral β-amyloid and is visible on positron emission tomography maintains its promise as a way to distinguish the elderly patients presenting with memory problems who will go on to develop Alzheimer's disease from those who won't progress.

A series of presentations at an international conference on Alzheimer's and Parkinson's diseases suggested that the ligand Pittsburgh B (PIB) compound, although still at the research stage, may also prove to be an invaluable biomarker to track disease modification in clinical trials.

Kerryn Pike, a research officer at Austin Health, Melbourne, presented the results of a study that examined the relationship between amyloid burden and cognitive function.

The researchers studied 108 individuals with varying degrees of cognitive impairment: 38 of the participants were healthy aging controls (mean Mini Mental State Examination [MMSE], 29.1), 34 had mild cognitive impairment (mean MMSE, 26.3), and 36 had mild Alzheimer's disease (mean MMSE, 22.1).

The average age of the participants was 72 years, and there was no significant difference in age among the three groups.

All the individuals were given neuropsychological tests, including the MMSE, California verbal learning test second edition, Rey complex figure test, digit span, verbal fluency, Boston naming test, and digit symbol coding tests.

The researchers calculated a composite episodic memory score and a composite nonmemory cognition score from these neuropsychological tests for each participant.

The participants also had a PET scan after being given an intravenous dose of the radiotracer 11C-PIB. A “positive” PIB test was noted in 26% of the 38 healthy aging controls, 59% of the 34 patients with mild cognitive impairment (MCI), and 97% of the 36 patients with Alzheimer's disease (AD), suggesting that they had amyloid deposited in their brains. “About a quarter of healthy elderly are known to have amyloid plaques at autopsy,” noted Ms. Pike.

Two of the MCI patients have gone on to develop AD, and the researchers plan to follow up the cohort over the coming years.

Individuals with MCI who had a positive PIB test did much worse in the neuropsychological memory tests than did participants with MCI who were negative for amyloid deposition (−2.95 standard deviations from control values vs. −1.1 standard deviations). “This suggests to us that amyloid deposition is a very early pathological process that affects memory specifically,” said Ms. Pike.

Indeed, those people with mild cognitive impairment who were PIB positive did almost as badly in the memory tests as did the patients with Alzheimer's disease (−3.22 standard deviations from control values). The researchers found a correlation of 0.72 between amyloid load and memory score.

In addition, participants with MCI who were PIB positive were significantly older than the PIB-negative participants (73.6 years vs. 66.1 years) and the 6 nonamnestic MCI participants were significantly younger than the 28 amnestic MCI participants (mean 63.7 years vs. 71.9 years).

“All our nonamnestic MCI participants were PIB negative, and this suggests to us that they have different underlying pathology such as frontotemporal dementia, which doesn't have amyloid plaques,” said Ms. Pike.

In a separate presentation, Dr. David Brooks, professor of neurology at Imperial College School of Medicine, London, presented data from a case series of 13 patients with dementia with Lewy bodies (DLB) and 13 patients with Parkinson's disease dementia (PDD) who were imaged using PIB.

The patients with DLB had a mean MMSE of 21, compared with 20 in the patients with PDD. The mean Unified Parkinson's Disease Rating Scale score was 31 in the patients with DLB and 35 in the patients with PDD.

Amyloid levels were raised in 11 of the 13 patients with DLB, although those levels were not as high as those seen previously in patients with AD. By contrast, only 2 of the 13 patients with PDD showed an increased amyloid burden, suggesting that PIB could potentially be used in the differential diagnosis of PDD and DLB.

SALZBURG, AUSTRIA – The investigational Pittsburgh B compound that binds to cerebral β-amyloid and is visible on positron emission tomography maintains its promise as a way to distinguish the elderly patients presenting with memory problems who will go on to develop Alzheimer's disease from those who won't progress.

A series of presentations at an international conference on Alzheimer's and Parkinson's diseases suggested that the ligand Pittsburgh B (PIB) compound, although still at the research stage, may also prove to be an invaluable biomarker to track disease modification in clinical trials.

Kerryn Pike, a research officer at Austin Health, Melbourne, presented the results of a study that examined the relationship between amyloid burden and cognitive function.

The researchers studied 108 individuals with varying degrees of cognitive impairment: 38 of the participants were healthy aging controls (mean Mini Mental State Examination [MMSE], 29.1), 34 had mild cognitive impairment (mean MMSE, 26.3), and 36 had mild Alzheimer's disease (mean MMSE, 22.1).

The average age of the participants was 72 years, and there was no significant difference in age among the three groups.

All the individuals were given neuropsychological tests, including the MMSE, California verbal learning test second edition, Rey complex figure test, digit span, verbal fluency, Boston naming test, and digit symbol coding tests.

The researchers calculated a composite episodic memory score and a composite nonmemory cognition score from these neuropsychological tests for each participant.

The participants also had a PET scan after being given an intravenous dose of the radiotracer 11C-PIB. A “positive” PIB test was noted in 26% of the 38 healthy aging controls, 59% of the 34 patients with mild cognitive impairment (MCI), and 97% of the 36 patients with Alzheimer's disease (AD), suggesting that they had amyloid deposited in their brains. “About a quarter of healthy elderly are known to have amyloid plaques at autopsy,” noted Ms. Pike.

Two of the MCI patients have gone on to develop AD, and the researchers plan to follow up the cohort over the coming years.

Individuals with MCI who had a positive PIB test did much worse in the neuropsychological memory tests than did participants with MCI who were negative for amyloid deposition (−2.95 standard deviations from control values vs. −1.1 standard deviations). “This suggests to us that amyloid deposition is a very early pathological process that affects memory specifically,” said Ms. Pike.

Indeed, those people with mild cognitive impairment who were PIB positive did almost as badly in the memory tests as did the patients with Alzheimer's disease (−3.22 standard deviations from control values). The researchers found a correlation of 0.72 between amyloid load and memory score.

In addition, participants with MCI who were PIB positive were significantly older than the PIB-negative participants (73.6 years vs. 66.1 years) and the 6 nonamnestic MCI participants were significantly younger than the 28 amnestic MCI participants (mean 63.7 years vs. 71.9 years).

“All our nonamnestic MCI participants were PIB negative, and this suggests to us that they have different underlying pathology such as frontotemporal dementia, which doesn't have amyloid plaques,” said Ms. Pike.

In a separate presentation, Dr. David Brooks, professor of neurology at Imperial College School of Medicine, London, presented data from a case series of 13 patients with dementia with Lewy bodies (DLB) and 13 patients with Parkinson's disease dementia (PDD) who were imaged using PIB.

The patients with DLB had a mean MMSE of 21, compared with 20 in the patients with PDD. The mean Unified Parkinson's Disease Rating Scale score was 31 in the patients with DLB and 35 in the patients with PDD.

Amyloid levels were raised in 11 of the 13 patients with DLB, although those levels were not as high as those seen previously in patients with AD. By contrast, only 2 of the 13 patients with PDD showed an increased amyloid burden, suggesting that PIB could potentially be used in the differential diagnosis of PDD and DLB.

SALZBURG, AUSTRIA – The investigational Pittsburgh B compound that binds to cerebral β-amyloid and is visible on positron emission tomography maintains its promise as a way to distinguish the elderly patients presenting with memory problems who will go on to develop Alzheimer's disease from those who won't progress.

A series of presentations at an international conference on Alzheimer's and Parkinson's diseases suggested that the ligand Pittsburgh B (PIB) compound, although still at the research stage, may also prove to be an invaluable biomarker to track disease modification in clinical trials.

Kerryn Pike, a research officer at Austin Health, Melbourne, presented the results of a study that examined the relationship between amyloid burden and cognitive function.

The researchers studied 108 individuals with varying degrees of cognitive impairment: 38 of the participants were healthy aging controls (mean Mini Mental State Examination [MMSE], 29.1), 34 had mild cognitive impairment (mean MMSE, 26.3), and 36 had mild Alzheimer's disease (mean MMSE, 22.1).

The average age of the participants was 72 years, and there was no significant difference in age among the three groups.

All the individuals were given neuropsychological tests, including the MMSE, California verbal learning test second edition, Rey complex figure test, digit span, verbal fluency, Boston naming test, and digit symbol coding tests.

The researchers calculated a composite episodic memory score and a composite nonmemory cognition score from these neuropsychological tests for each participant.

The participants also had a PET scan after being given an intravenous dose of the radiotracer 11C-PIB. A “positive” PIB test was noted in 26% of the 38 healthy aging controls, 59% of the 34 patients with mild cognitive impairment (MCI), and 97% of the 36 patients with Alzheimer's disease (AD), suggesting that they had amyloid deposited in their brains. “About a quarter of healthy elderly are known to have amyloid plaques at autopsy,” noted Ms. Pike.

Two of the MCI patients have gone on to develop AD, and the researchers plan to follow up the cohort over the coming years.

Individuals with MCI who had a positive PIB test did much worse in the neuropsychological memory tests than did participants with MCI who were negative for amyloid deposition (−2.95 standard deviations from control values vs. −1.1 standard deviations). “This suggests to us that amyloid deposition is a very early pathological process that affects memory specifically,” said Ms. Pike.

Indeed, those people with mild cognitive impairment who were PIB positive did almost as badly in the memory tests as did the patients with Alzheimer's disease (−3.22 standard deviations from control values). The researchers found a correlation of 0.72 between amyloid load and memory score.

In addition, participants with MCI who were PIB positive were significantly older than the PIB-negative participants (73.6 years vs. 66.1 years) and the 6 nonamnestic MCI participants were significantly younger than the 28 amnestic MCI participants (mean 63.7 years vs. 71.9 years).

“All our nonamnestic MCI participants were PIB negative, and this suggests to us that they have different underlying pathology such as frontotemporal dementia, which doesn't have amyloid plaques,” said Ms. Pike.

In a separate presentation, Dr. David Brooks, professor of neurology at Imperial College School of Medicine, London, presented data from a case series of 13 patients with dementia with Lewy bodies (DLB) and 13 patients with Parkinson's disease dementia (PDD) who were imaged using PIB.

The patients with DLB had a mean MMSE of 21, compared with 20 in the patients with PDD. The mean Unified Parkinson's Disease Rating Scale score was 31 in the patients with DLB and 35 in the patients with PDD.

Amyloid levels were raised in 11 of the 13 patients with DLB, although those levels were not as high as those seen previously in patients with AD. By contrast, only 2 of the 13 patients with PDD showed an increased amyloid burden, suggesting that PIB could potentially be used in the differential diagnosis of PDD and DLB.

SALZBURG, AUSTRIA – Eradication of Helicobacter pylori in patients with idiopathic parkinsonism modified the syndrome but did not arrest it, according to interim results from a randomized controlled trial presented at an international conference on Alzheimer's and Parkinson's Diseases.

Dr. Sylvia Dobbs presented an interim analysis of a 5-year trial of 30 patients with early disease who were either not on medication or were taking stable, long half-life antiparkinsonism medication. Patients using levodopa were excluded.

All the participants had biopsy-proven H. pylori infection. The researchers randomly and blindly assigned the patients to 1 week of triple therapy to eradicate H. pylori infection or placebo. The antimicrobials used in eradication were chosen according to in vitro sensitivity tests.

Unblinding occurred at 1 year or if the disease had progressed quickly and the researchers thought the patient's lifestyle was unsustainable. Patients on placebo who were breath-test positive at 1 year were given active treatment.

Dr. Dobbs of the Institute of Psychiatry, King's College London, reported follow-up to a mean of 468 days after unblinding. The primary outcome measure was time trend in mean stride length at free-walking speed.

“If you use global scores, which are very insensitive, you require huge numbers of patients,” Dr. Dobbs said in an interview. “If you objectively measure the outcome criteria, you require small numbers. If you do time trends in the outcome criteria, you require even smaller numbers.”

Protocol analysis on the primary outcome showed a clinically relevant effect in favor of biopsy-proven successful, blinded active eradication over placebo (7.3 cm/yr increase in mean stride length [95% confidence interval 1.4,13.2], P less than .01). The presence or absence of antiparkinsonism medication did not affect the results, she said.

Patients in the placebo group who received treatment to eradicate their H. pylori infection unblinding also improved in the primary outcome measure (9.5 cm/yr increase in mean stride length [95% confidence interval 1.2, 20.1], P = .04).

“We have some prima facie evidence pointing to a direct or surrogate but not necessarily unique, response to [H. pylori eradication],” said Dr. Dobbs. “The effect was sustained in the following year.”

SALZBURG, AUSTRIA – Eradication of Helicobacter pylori in patients with idiopathic parkinsonism modified the syndrome but did not arrest it, according to interim results from a randomized controlled trial presented at an international conference on Alzheimer's and Parkinson's Diseases.

Dr. Sylvia Dobbs presented an interim analysis of a 5-year trial of 30 patients with early disease who were either not on medication or were taking stable, long half-life antiparkinsonism medication. Patients using levodopa were excluded.

All the participants had biopsy-proven H. pylori infection. The researchers randomly and blindly assigned the patients to 1 week of triple therapy to eradicate H. pylori infection or placebo. The antimicrobials used in eradication were chosen according to in vitro sensitivity tests.

Unblinding occurred at 1 year or if the disease had progressed quickly and the researchers thought the patient's lifestyle was unsustainable. Patients on placebo who were breath-test positive at 1 year were given active treatment.

Dr. Dobbs of the Institute of Psychiatry, King's College London, reported follow-up to a mean of 468 days after unblinding. The primary outcome measure was time trend in mean stride length at free-walking speed.

“If you use global scores, which are very insensitive, you require huge numbers of patients,” Dr. Dobbs said in an interview. “If you objectively measure the outcome criteria, you require small numbers. If you do time trends in the outcome criteria, you require even smaller numbers.”

Protocol analysis on the primary outcome showed a clinically relevant effect in favor of biopsy-proven successful, blinded active eradication over placebo (7.3 cm/yr increase in mean stride length [95% confidence interval 1.4,13.2], P less than .01). The presence or absence of antiparkinsonism medication did not affect the results, she said.

Patients in the placebo group who received treatment to eradicate their H. pylori infection unblinding also improved in the primary outcome measure (9.5 cm/yr increase in mean stride length [95% confidence interval 1.2, 20.1], P = .04).

“We have some prima facie evidence pointing to a direct or surrogate but not necessarily unique, response to [H. pylori eradication],” said Dr. Dobbs. “The effect was sustained in the following year.”

SALZBURG, AUSTRIA – Eradication of Helicobacter pylori in patients with idiopathic parkinsonism modified the syndrome but did not arrest it, according to interim results from a randomized controlled trial presented at an international conference on Alzheimer's and Parkinson's Diseases.

Dr. Sylvia Dobbs presented an interim analysis of a 5-year trial of 30 patients with early disease who were either not on medication or were taking stable, long half-life antiparkinsonism medication. Patients using levodopa were excluded.

All the participants had biopsy-proven H. pylori infection. The researchers randomly and blindly assigned the patients to 1 week of triple therapy to eradicate H. pylori infection or placebo. The antimicrobials used in eradication were chosen according to in vitro sensitivity tests.

Unblinding occurred at 1 year or if the disease had progressed quickly and the researchers thought the patient's lifestyle was unsustainable. Patients on placebo who were breath-test positive at 1 year were given active treatment.

Dr. Dobbs of the Institute of Psychiatry, King's College London, reported follow-up to a mean of 468 days after unblinding. The primary outcome measure was time trend in mean stride length at free-walking speed.

“If you use global scores, which are very insensitive, you require huge numbers of patients,” Dr. Dobbs said in an interview. “If you objectively measure the outcome criteria, you require small numbers. If you do time trends in the outcome criteria, you require even smaller numbers.”

Protocol analysis on the primary outcome showed a clinically relevant effect in favor of biopsy-proven successful, blinded active eradication over placebo (7.3 cm/yr increase in mean stride length [95% confidence interval 1.4,13.2], P less than .01). The presence or absence of antiparkinsonism medication did not affect the results, she said.

Patients in the placebo group who received treatment to eradicate their H. pylori infection unblinding also improved in the primary outcome measure (9.5 cm/yr increase in mean stride length [95% confidence interval 1.2, 20.1], P = .04).

“We have some prima facie evidence pointing to a direct or surrogate but not necessarily unique, response to [H. pylori eradication],” said Dr. Dobbs. “The effect was sustained in the following year.”

SALZBURG, AUSTRIA – A risk score that predicts the likelihood of a middle-aged person developing dementia within 20 years has been independently validated in an ethnically diverse population, according to data presented at an international conference on Alzheimer's and Parkinson's diseases.

The Cardiovascular Risk Factors, Aging and Dementia (CAIDE) risk score originally was created using data from the CAIDE study, a population-based study of 1,409 individuals in a Finnish population in the 1970s (mean age 50.4 years). When the Finnish subjects were reexamined in 1998, 61 of the subjects were diagnosed with dementia.

Study participants with dementia were found to be older at the midlife examination (mean age 53.4 years vs. mean 50.2 years) and less well educated (6.7 years of formal education vs. 8.7 years), and they had more vascular risk factors–such as high blood pressure, high total cholesterol, and high body mass index, as well as a history of smoking–present at midlife than did participants without dementia.

Dr. Miia Kivipelto of the Aging Research Center at the Karolinska Institute, Stockholm, used the data from the CAIDE study to create a score that could predict the risk of developing dementia in later life.

The CAIDE dementia score uses age, years of formal education, sex, systolic blood pressure, total cholesterol, body mass index, and physical activity to determine an individual's likelihood of developing dementia within 20 years. The risk of dementia was found to be 1% for those with a score of 0–5; 1.9% for a score of 6–7; 4.2% for a score of 8–9; 7.4% for a score of 10–11; and 16.4% for a score of 12–15 (Lancet Neurol. 2006;5:735–41).

“When the cutoff was set at 9 points or more, the sensitivity was 0.77, the specificity was 0.63, and the negative predictive value was 0.98,” said Dr. Kivipelto at the conference.

Rachel Whitmer, Ph.D., an epidemiologist working at the Kaiser Permanente Division of Research, Oakland, Calif., validated the CAIDE dementia risk score in a sample of 9,480 long-term members of Kaiser Permanente's integrated health care delivery system, of whom 1,011 developed Alzheimer's disease or vascular dementia. The study sample was ethnically diverse (474 Asian, 1,401 black, and 7,605 white), and included people from a wide demographic range.

In addition, Dr. Whitmer added more variables to the score, including obesity, smoking, pulmonary function, and depression, but found that these did not improve the score's predictive value.

However, the addition of diabetes as a variable improved the predictability of the score for Asian patients, but not for black or white study patients.

“It seems like we're really onto something here,” said Dr. Whitmer.

“It replicated really well and is so predictive in such a different population.”

SALZBURG, AUSTRIA – A risk score that predicts the likelihood of a middle-aged person developing dementia within 20 years has been independently validated in an ethnically diverse population, according to data presented at an international conference on Alzheimer's and Parkinson's diseases.

The Cardiovascular Risk Factors, Aging and Dementia (CAIDE) risk score originally was created using data from the CAIDE study, a population-based study of 1,409 individuals in a Finnish population in the 1970s (mean age 50.4 years). When the Finnish subjects were reexamined in 1998, 61 of the subjects were diagnosed with dementia.

Study participants with dementia were found to be older at the midlife examination (mean age 53.4 years vs. mean 50.2 years) and less well educated (6.7 years of formal education vs. 8.7 years), and they had more vascular risk factors–such as high blood pressure, high total cholesterol, and high body mass index, as well as a history of smoking–present at midlife than did participants without dementia.

Dr. Miia Kivipelto of the Aging Research Center at the Karolinska Institute, Stockholm, used the data from the CAIDE study to create a score that could predict the risk of developing dementia in later life.

The CAIDE dementia score uses age, years of formal education, sex, systolic blood pressure, total cholesterol, body mass index, and physical activity to determine an individual's likelihood of developing dementia within 20 years. The risk of dementia was found to be 1% for those with a score of 0–5; 1.9% for a score of 6–7; 4.2% for a score of 8–9; 7.4% for a score of 10–11; and 16.4% for a score of 12–15 (Lancet Neurol. 2006;5:735–41).

“When the cutoff was set at 9 points or more, the sensitivity was 0.77, the specificity was 0.63, and the negative predictive value was 0.98,” said Dr. Kivipelto at the conference.

Rachel Whitmer, Ph.D., an epidemiologist working at the Kaiser Permanente Division of Research, Oakland, Calif., validated the CAIDE dementia risk score in a sample of 9,480 long-term members of Kaiser Permanente's integrated health care delivery system, of whom 1,011 developed Alzheimer's disease or vascular dementia. The study sample was ethnically diverse (474 Asian, 1,401 black, and 7,605 white), and included people from a wide demographic range.

In addition, Dr. Whitmer added more variables to the score, including obesity, smoking, pulmonary function, and depression, but found that these did not improve the score's predictive value.

However, the addition of diabetes as a variable improved the predictability of the score for Asian patients, but not for black or white study patients.

“It seems like we're really onto something here,” said Dr. Whitmer.

“It replicated really well and is so predictive in such a different population.”

SALZBURG, AUSTRIA – A risk score that predicts the likelihood of a middle-aged person developing dementia within 20 years has been independently validated in an ethnically diverse population, according to data presented at an international conference on Alzheimer's and Parkinson's diseases.

The Cardiovascular Risk Factors, Aging and Dementia (CAIDE) risk score originally was created using data from the CAIDE study, a population-based study of 1,409 individuals in a Finnish population in the 1970s (mean age 50.4 years). When the Finnish subjects were reexamined in 1998, 61 of the subjects were diagnosed with dementia.

Study participants with dementia were found to be older at the midlife examination (mean age 53.4 years vs. mean 50.2 years) and less well educated (6.7 years of formal education vs. 8.7 years), and they had more vascular risk factors–such as high blood pressure, high total cholesterol, and high body mass index, as well as a history of smoking–present at midlife than did participants without dementia.

Dr. Miia Kivipelto of the Aging Research Center at the Karolinska Institute, Stockholm, used the data from the CAIDE study to create a score that could predict the risk of developing dementia in later life.

The CAIDE dementia score uses age, years of formal education, sex, systolic blood pressure, total cholesterol, body mass index, and physical activity to determine an individual's likelihood of developing dementia within 20 years. The risk of dementia was found to be 1% for those with a score of 0–5; 1.9% for a score of 6–7; 4.2% for a score of 8–9; 7.4% for a score of 10–11; and 16.4% for a score of 12–15 (Lancet Neurol. 2006;5:735–41).

“When the cutoff was set at 9 points or more, the sensitivity was 0.77, the specificity was 0.63, and the negative predictive value was 0.98,” said Dr. Kivipelto at the conference.

Rachel Whitmer, Ph.D., an epidemiologist working at the Kaiser Permanente Division of Research, Oakland, Calif., validated the CAIDE dementia risk score in a sample of 9,480 long-term members of Kaiser Permanente's integrated health care delivery system, of whom 1,011 developed Alzheimer's disease or vascular dementia. The study sample was ethnically diverse (474 Asian, 1,401 black, and 7,605 white), and included people from a wide demographic range.

In addition, Dr. Whitmer added more variables to the score, including obesity, smoking, pulmonary function, and depression, but found that these did not improve the score's predictive value.

However, the addition of diabetes as a variable improved the predictability of the score for Asian patients, but not for black or white study patients.

“It seems like we're really onto something here,” said Dr. Whitmer.

“It replicated really well and is so predictive in such a different population.”

SALZBURG, AUSTRIA — Mutations in the progranulin gene are found in approximately 5% of patients with frontotemporal dementia, according to research presented at the 8th International Conference on Alzheimer's and Parkinson's Diseases.

Frontotemporal dementia (FTD) is the second most common cause of dementia, after Alzheimer's disease, in patients aged 65 years or less.

Approximately 35%–50% of those patients with frontotemporal dementia have a family history of dementia, a statistic which suggests that there is a strong genetic component to the disease.

In 1998, investigators reported that they found mutations in the gene encoding the microtubule-associated protein tau (MAPT) caused familial FTD with parkinsonism linked to chromosome 17 (FTDP-17).

However, not all families who showed linkage to the same region on chromosome 17 had mutations in MAPT, suggesting that mutations in at least one other gene were responsible for the disease in these patients.

In addition, these patients had ubiquitin-immunoreactive neuronal cytoplasmic inclusions (FTDU-17) but not tau-immunoreactive inclusion pathology.

In July 2006, two studies found that FTDU-17 is caused by mutations in progranulin, a polypeptide with growth-modulatory activity, leading to a loss of protein function (Nature 2006;442:916–9; Nature 2006;442:920–4).

Since then, researchers have been screening their patient populations for the mutations to determine their prevalence in the frontotemporal dementia community.

Stuart Pickering-Brown, Ph.D., who works at the University of Manchester (England), presented data from the Manchester Cohort that currently includes 272 patients with FTD; some of the included patients have been followed for more than 20 years.

“We recently finished sequencing for progranulin mutations and found 14 cases,” commented Dr. Pickering-Brown.

He also noted that this frequency (5%) is about the same as for tau gene mutations (6%) in his study cohort.

Clinically, the 14 patients with the progranulin mutations had been diagnosed with frontotemporal dementias, primary progressive aphasia, and corticobasal degeneration, according to Dr. Pickering-Brown.

He added that “All the cases had a family history of disease.”

The researchers also genotyped a number of single nucleotide polymorphisms (SNPs) spanning the progranulin gene to determine whether a common variation at the locus increases the risk of sporadic disease, but they reported finding no evidence of allelic association of any of the SNPs.

Dr. Brendan Kelley presented the latest data from the Mayo Clinic cohort of patients at the meeting.

He reported on the clinical characterization of eight kindreds, which included 31 individuals with progranulin mutations, of whom 16 were men.

The patients were aged 49–83 years at disease onset (mean age 63 years) and had a disease duration of 1–12 years (mean 6.5 years).

“Two individuals who died within 1 year both had accidents that may have been related to disinhibited behaviors,” said Dr. Kelley.

Like the Manchester cohort, the clinical diagnosis varied widely and included frontotemporal dementia with and without parkinsonism, mild cognitive impairment, Alzheimer's disease, corticobasal syndrome, and primary progressive aphasia.

“At this juncture, clinical practice will not be changed based on the discovery of this gene,” commented Dr. Zbigniew Wszolek, who is currently a professor of neurology at the Mayo Clinic College of Medicine, Jacksonville, Fla., and who chaired the session at the meeting.

“Clinical genetic testing, I believe, is not available yet, albeit patents have been filed,” noted Dr. Wszolek.

SALZBURG, AUSTRIA — Mutations in the progranulin gene are found in approximately 5% of patients with frontotemporal dementia, according to research presented at the 8th International Conference on Alzheimer's and Parkinson's Diseases.

Frontotemporal dementia (FTD) is the second most common cause of dementia, after Alzheimer's disease, in patients aged 65 years or less.

Approximately 35%–50% of those patients with frontotemporal dementia have a family history of dementia, a statistic which suggests that there is a strong genetic component to the disease.

In 1998, investigators reported that they found mutations in the gene encoding the microtubule-associated protein tau (MAPT) caused familial FTD with parkinsonism linked to chromosome 17 (FTDP-17).

However, not all families who showed linkage to the same region on chromosome 17 had mutations in MAPT, suggesting that mutations in at least one other gene were responsible for the disease in these patients.

In addition, these patients had ubiquitin-immunoreactive neuronal cytoplasmic inclusions (FTDU-17) but not tau-immunoreactive inclusion pathology.

In July 2006, two studies found that FTDU-17 is caused by mutations in progranulin, a polypeptide with growth-modulatory activity, leading to a loss of protein function (Nature 2006;442:916–9; Nature 2006;442:920–4).

Since then, researchers have been screening their patient populations for the mutations to determine their prevalence in the frontotemporal dementia community.

Stuart Pickering-Brown, Ph.D., who works at the University of Manchester (England), presented data from the Manchester Cohort that currently includes 272 patients with FTD; some of the included patients have been followed for more than 20 years.

“We recently finished sequencing for progranulin mutations and found 14 cases,” commented Dr. Pickering-Brown.

He also noted that this frequency (5%) is about the same as for tau gene mutations (6%) in his study cohort.

Clinically, the 14 patients with the progranulin mutations had been diagnosed with frontotemporal dementias, primary progressive aphasia, and corticobasal degeneration, according to Dr. Pickering-Brown.

He added that “All the cases had a family history of disease.”

The researchers also genotyped a number of single nucleotide polymorphisms (SNPs) spanning the progranulin gene to determine whether a common variation at the locus increases the risk of sporadic disease, but they reported finding no evidence of allelic association of any of the SNPs.

Dr. Brendan Kelley presented the latest data from the Mayo Clinic cohort of patients at the meeting.

He reported on the clinical characterization of eight kindreds, which included 31 individuals with progranulin mutations, of whom 16 were men.

The patients were aged 49–83 years at disease onset (mean age 63 years) and had a disease duration of 1–12 years (mean 6.5 years).

“Two individuals who died within 1 year both had accidents that may have been related to disinhibited behaviors,” said Dr. Kelley.

Like the Manchester cohort, the clinical diagnosis varied widely and included frontotemporal dementia with and without parkinsonism, mild cognitive impairment, Alzheimer's disease, corticobasal syndrome, and primary progressive aphasia.

“At this juncture, clinical practice will not be changed based on the discovery of this gene,” commented Dr. Zbigniew Wszolek, who is currently a professor of neurology at the Mayo Clinic College of Medicine, Jacksonville, Fla., and who chaired the session at the meeting.

“Clinical genetic testing, I believe, is not available yet, albeit patents have been filed,” noted Dr. Wszolek.

SALZBURG, AUSTRIA — Mutations in the progranulin gene are found in approximately 5% of patients with frontotemporal dementia, according to research presented at the 8th International Conference on Alzheimer's and Parkinson's Diseases.

Frontotemporal dementia (FTD) is the second most common cause of dementia, after Alzheimer's disease, in patients aged 65 years or less.

Approximately 35%–50% of those patients with frontotemporal dementia have a family history of dementia, a statistic which suggests that there is a strong genetic component to the disease.

In 1998, investigators reported that they found mutations in the gene encoding the microtubule-associated protein tau (MAPT) caused familial FTD with parkinsonism linked to chromosome 17 (FTDP-17).

However, not all families who showed linkage to the same region on chromosome 17 had mutations in MAPT, suggesting that mutations in at least one other gene were responsible for the disease in these patients.

In addition, these patients had ubiquitin-immunoreactive neuronal cytoplasmic inclusions (FTDU-17) but not tau-immunoreactive inclusion pathology.

In July 2006, two studies found that FTDU-17 is caused by mutations in progranulin, a polypeptide with growth-modulatory activity, leading to a loss of protein function (Nature 2006;442:916–9; Nature 2006;442:920–4).

Since then, researchers have been screening their patient populations for the mutations to determine their prevalence in the frontotemporal dementia community.

Stuart Pickering-Brown, Ph.D., who works at the University of Manchester (England), presented data from the Manchester Cohort that currently includes 272 patients with FTD; some of the included patients have been followed for more than 20 years.

“We recently finished sequencing for progranulin mutations and found 14 cases,” commented Dr. Pickering-Brown.

He also noted that this frequency (5%) is about the same as for tau gene mutations (6%) in his study cohort.

Clinically, the 14 patients with the progranulin mutations had been diagnosed with frontotemporal dementias, primary progressive aphasia, and corticobasal degeneration, according to Dr. Pickering-Brown.

He added that “All the cases had a family history of disease.”

The researchers also genotyped a number of single nucleotide polymorphisms (SNPs) spanning the progranulin gene to determine whether a common variation at the locus increases the risk of sporadic disease, but they reported finding no evidence of allelic association of any of the SNPs.

Dr. Brendan Kelley presented the latest data from the Mayo Clinic cohort of patients at the meeting.

He reported on the clinical characterization of eight kindreds, which included 31 individuals with progranulin mutations, of whom 16 were men.

The patients were aged 49–83 years at disease onset (mean age 63 years) and had a disease duration of 1–12 years (mean 6.5 years).

“Two individuals who died within 1 year both had accidents that may have been related to disinhibited behaviors,” said Dr. Kelley.

Like the Manchester cohort, the clinical diagnosis varied widely and included frontotemporal dementia with and without parkinsonism, mild cognitive impairment, Alzheimer's disease, corticobasal syndrome, and primary progressive aphasia.

“At this juncture, clinical practice will not be changed based on the discovery of this gene,” commented Dr. Zbigniew Wszolek, who is currently a professor of neurology at the Mayo Clinic College of Medicine, Jacksonville, Fla., and who chaired the session at the meeting.

“Clinical genetic testing, I believe, is not available yet, albeit patents have been filed,” noted Dr. Wszolek.

MADRID – The use of coercive interventions–such as physical or mechanical restraint–to control imminent and actual dangerous behavior by people with acute mental illness was discussed at a symposium at the 15th European Congress of Psychiatry.

Dr. Tilman Steinert, of the University of Ulm (Germany), presented data obtained by the European Violence in Psychiatry Research Group. Those data looked at the way in which violent patients are managed across Europe, and whether real-life practice followed legislative guidelines.

The researchers prepared three representative case vignettes and asked experts from 14 European countries (Ireland, Scotland, Wales, England, the Netherlands, Luxembourg, Germany, Switzerland, Austria, Italy, Slovenia, Turkey, Finland, and Estonia) to describe how they would treat each patient and whether legislation in each country would allow the use of different forms of restraint.

The first case was that of a voluntary inpatient who assaults a staff member. Experts from all of the countries except Switzerland would treat such a patient with an involuntary intramuscular injection, but experts from only five of the countries would use an involuntary intravenous medication. Physical restraint was used in five countries and mechanical restraint in seven. Net beds are banned by legislation in most European countries, but psychiatric staffs in Luxembourg and Austria use them.

The second case involved that of an involuntary patient who does not behave violently, but who refuses medication. In cases like this, involuntary intramuscular injection is given in seven European countries, and involuntary intravenous medication is given in just two. Any form of involuntary medication is banned in the Netherlands and in Switzerland.

The researchers concluded that there is wide diversity of legislation and practice across Europe, and, importantly, in the way in which psychiatric professionals interpret their own legislation. “We need evidence on what is the best practice before we enforce uniformity,” Dr. Steinert said.

In a separate presentation, Richard Whittington, Ph.D., of the health and community care research unit at the University of Liverpool (England), presented data on the psychological and social context surrounding the decision by staff to restrain a patient on the floor.

Dr. Whittington and his colleagues did an audit study of 20,000 incident forms, describing incidents involving 5,000 patients from 46 secure and general wards over a 5-year period. They looked to see how often control and restraint procedures were used, and found that 20% of all incidents were managed in this way. However, 50% of reported incidents involving interpersonal violence resulted in the use of control and restraint procedures.

Interestingly, restraint was used in 42% of “first incidents” but was used only 24% of the time when the patient had been involved in more than five incidents in the past. “If a staff member does not know a patient, he or she is more likely to use control and restraint,” he said.

MADRID – The use of coercive interventions–such as physical or mechanical restraint–to control imminent and actual dangerous behavior by people with acute mental illness was discussed at a symposium at the 15th European Congress of Psychiatry.

Dr. Tilman Steinert, of the University of Ulm (Germany), presented data obtained by the European Violence in Psychiatry Research Group. Those data looked at the way in which violent patients are managed across Europe, and whether real-life practice followed legislative guidelines.

The researchers prepared three representative case vignettes and asked experts from 14 European countries (Ireland, Scotland, Wales, England, the Netherlands, Luxembourg, Germany, Switzerland, Austria, Italy, Slovenia, Turkey, Finland, and Estonia) to describe how they would treat each patient and whether legislation in each country would allow the use of different forms of restraint.

The first case was that of a voluntary inpatient who assaults a staff member. Experts from all of the countries except Switzerland would treat such a patient with an involuntary intramuscular injection, but experts from only five of the countries would use an involuntary intravenous medication. Physical restraint was used in five countries and mechanical restraint in seven. Net beds are banned by legislation in most European countries, but psychiatric staffs in Luxembourg and Austria use them.

The second case involved that of an involuntary patient who does not behave violently, but who refuses medication. In cases like this, involuntary intramuscular injection is given in seven European countries, and involuntary intravenous medication is given in just two. Any form of involuntary medication is banned in the Netherlands and in Switzerland.

The researchers concluded that there is wide diversity of legislation and practice across Europe, and, importantly, in the way in which psychiatric professionals interpret their own legislation. “We need evidence on what is the best practice before we enforce uniformity,” Dr. Steinert said.

In a separate presentation, Richard Whittington, Ph.D., of the health and community care research unit at the University of Liverpool (England), presented data on the psychological and social context surrounding the decision by staff to restrain a patient on the floor.

Dr. Whittington and his colleagues did an audit study of 20,000 incident forms, describing incidents involving 5,000 patients from 46 secure and general wards over a 5-year period. They looked to see how often control and restraint procedures were used, and found that 20% of all incidents were managed in this way. However, 50% of reported incidents involving interpersonal violence resulted in the use of control and restraint procedures.

Interestingly, restraint was used in 42% of “first incidents” but was used only 24% of the time when the patient had been involved in more than five incidents in the past. “If a staff member does not know a patient, he or she is more likely to use control and restraint,” he said.

MADRID – The use of coercive interventions–such as physical or mechanical restraint–to control imminent and actual dangerous behavior by people with acute mental illness was discussed at a symposium at the 15th European Congress of Psychiatry.

Dr. Tilman Steinert, of the University of Ulm (Germany), presented data obtained by the European Violence in Psychiatry Research Group. Those data looked at the way in which violent patients are managed across Europe, and whether real-life practice followed legislative guidelines.

The researchers prepared three representative case vignettes and asked experts from 14 European countries (Ireland, Scotland, Wales, England, the Netherlands, Luxembourg, Germany, Switzerland, Austria, Italy, Slovenia, Turkey, Finland, and Estonia) to describe how they would treat each patient and whether legislation in each country would allow the use of different forms of restraint.

The first case was that of a voluntary inpatient who assaults a staff member. Experts from all of the countries except Switzerland would treat such a patient with an involuntary intramuscular injection, but experts from only five of the countries would use an involuntary intravenous medication. Physical restraint was used in five countries and mechanical restraint in seven. Net beds are banned by legislation in most European countries, but psychiatric staffs in Luxembourg and Austria use them.

The second case involved that of an involuntary patient who does not behave violently, but who refuses medication. In cases like this, involuntary intramuscular injection is given in seven European countries, and involuntary intravenous medication is given in just two. Any form of involuntary medication is banned in the Netherlands and in Switzerland.

The researchers concluded that there is wide diversity of legislation and practice across Europe, and, importantly, in the way in which psychiatric professionals interpret their own legislation. “We need evidence on what is the best practice before we enforce uniformity,” Dr. Steinert said.

In a separate presentation, Richard Whittington, Ph.D., of the health and community care research unit at the University of Liverpool (England), presented data on the psychological and social context surrounding the decision by staff to restrain a patient on the floor.

Dr. Whittington and his colleagues did an audit study of 20,000 incident forms, describing incidents involving 5,000 patients from 46 secure and general wards over a 5-year period. They looked to see how often control and restraint procedures were used, and found that 20% of all incidents were managed in this way. However, 50% of reported incidents involving interpersonal violence resulted in the use of control and restraint procedures.

Interestingly, restraint was used in 42% of “first incidents” but was used only 24% of the time when the patient had been involved in more than five incidents in the past. “If a staff member does not know a patient, he or she is more likely to use control and restraint,” he said.

SALZBURG, AUSTRIA – Mutations in the progranulin gene are found in about 5% of patients with frontotemporal dementia, according to research presented at the 8th International Conference on Alzheimer's and Parkinson's Diseases.

Frontotemporal dementia (FTD) is the second most common cause of dementia, after Alzheimer's disease, in patients aged 65 years or younger. About 35%–50% of patients with FTD have a family history of dementia, which suggests the existence of a strong genetic component to the disease.

In 1998, researchers reported that mutations in the gene encoding the microtubule-associated protein tau (MAPT) caused familial FTD with parkinsonism linked to chromosome 17 (FTDP-17). However, not all families who showed linkage to the same region on chromosome 17 had mutations in MAPT, suggesting that mutations in at least one other gene were responsible for the disease in these patients. In addition, these patients had ubiquitin-immunoreactive neuronal cytoplasmic inclusions (FTDU-17) but not tau-immunoreactive inclusion pathology.

In July 2006, two studies found that FTDU-17 is caused by mutations in progranulin, a polypeptide with growth-modulatory activity, leading to a loss of protein function (Nature 2006;442:916–9; Nature 2006;442:920–4). Since then, researchers have been screening their patient populations for the mutations to determine their prevalence in the FTD community.

Stuart Pickering-Brown, Ph.D., who works at the University of Manchester (England), presented data from the Manchester Cohort that currently includes 272 patients with FTD, with some being followed for over 20 years.

“We recently finished sequencing for progranulin mutations and found 14 cases,” said Dr. Pickering-Brown, who noted that this frequency (5%) is about the same as for tau gene mutations (6%) in his cohort.

Clinically, the 14 patients had been diagnosed with frontotemporal dementias, primary progressive aphasia, and corticobasal degeneration, said Dr. Pickering-Brown. “All the cases had a family history of disease,” he added.

The researchers also genotyped several single nucleotide polymorphisms (SNPs) spanning the progranulin gene to determine whether a common variation at the locus increases the risk of sporadic disease, but they found no evidence of allelic association of any of the SNPs.

Dr. Brendan Kelley presented the latest data from the Mayo Clinic cohort of patients. He reported on the clinical characterization of eight kindreds, which included 31 individuals with progranulin mutations, of whom 16 were men. The patients were aged 49–83 years at disease onset (mean age 63 years) and had a disease duration of 1–12 years (mean 6.5 years). “Two individuals who died within 1 year both had accidents that may have been related to disinhibited behaviors,” Dr. Kelley said.

Like the Manchester cohort, the clinical diagnosis varied widely and included FTD with and without parkinsonism, mild cognitive impairment, and Alzheimer's.

The discovery of this gene will not change clinical practice at this point, said Dr. Zbigniew Wszolek, a professor of neurology at the Mayo Clinic College of Medicine, Jacksonville, Fla., who chaired the session. In addition, Dr. Wszolek said he did not think clinical genetic testing was available yet, but patents have been filed.

SALZBURG, AUSTRIA – Mutations in the progranulin gene are found in about 5% of patients with frontotemporal dementia, according to research presented at the 8th International Conference on Alzheimer's and Parkinson's Diseases.

Frontotemporal dementia (FTD) is the second most common cause of dementia, after Alzheimer's disease, in patients aged 65 years or younger. About 35%–50% of patients with FTD have a family history of dementia, which suggests the existence of a strong genetic component to the disease.

In 1998, researchers reported that mutations in the gene encoding the microtubule-associated protein tau (MAPT) caused familial FTD with parkinsonism linked to chromosome 17 (FTDP-17). However, not all families who showed linkage to the same region on chromosome 17 had mutations in MAPT, suggesting that mutations in at least one other gene were responsible for the disease in these patients. In addition, these patients had ubiquitin-immunoreactive neuronal cytoplasmic inclusions (FTDU-17) but not tau-immunoreactive inclusion pathology.

In July 2006, two studies found that FTDU-17 is caused by mutations in progranulin, a polypeptide with growth-modulatory activity, leading to a loss of protein function (Nature 2006;442:916–9; Nature 2006;442:920–4). Since then, researchers have been screening their patient populations for the mutations to determine their prevalence in the FTD community.

Stuart Pickering-Brown, Ph.D., who works at the University of Manchester (England), presented data from the Manchester Cohort that currently includes 272 patients with FTD, with some being followed for over 20 years.

“We recently finished sequencing for progranulin mutations and found 14 cases,” said Dr. Pickering-Brown, who noted that this frequency (5%) is about the same as for tau gene mutations (6%) in his cohort.

Clinically, the 14 patients had been diagnosed with frontotemporal dementias, primary progressive aphasia, and corticobasal degeneration, said Dr. Pickering-Brown. “All the cases had a family history of disease,” he added.

The researchers also genotyped several single nucleotide polymorphisms (SNPs) spanning the progranulin gene to determine whether a common variation at the locus increases the risk of sporadic disease, but they found no evidence of allelic association of any of the SNPs.

Dr. Brendan Kelley presented the latest data from the Mayo Clinic cohort of patients. He reported on the clinical characterization of eight kindreds, which included 31 individuals with progranulin mutations, of whom 16 were men. The patients were aged 49–83 years at disease onset (mean age 63 years) and had a disease duration of 1–12 years (mean 6.5 years). “Two individuals who died within 1 year both had accidents that may have been related to disinhibited behaviors,” Dr. Kelley said.

Like the Manchester cohort, the clinical diagnosis varied widely and included FTD with and without parkinsonism, mild cognitive impairment, and Alzheimer's.

The discovery of this gene will not change clinical practice at this point, said Dr. Zbigniew Wszolek, a professor of neurology at the Mayo Clinic College of Medicine, Jacksonville, Fla., who chaired the session. In addition, Dr. Wszolek said he did not think clinical genetic testing was available yet, but patents have been filed.

SALZBURG, AUSTRIA – Mutations in the progranulin gene are found in about 5% of patients with frontotemporal dementia, according to research presented at the 8th International Conference on Alzheimer's and Parkinson's Diseases.

Frontotemporal dementia (FTD) is the second most common cause of dementia, after Alzheimer's disease, in patients aged 65 years or younger. About 35%–50% of patients with FTD have a family history of dementia, which suggests the existence of a strong genetic component to the disease.

In 1998, researchers reported that mutations in the gene encoding the microtubule-associated protein tau (MAPT) caused familial FTD with parkinsonism linked to chromosome 17 (FTDP-17). However, not all families who showed linkage to the same region on chromosome 17 had mutations in MAPT, suggesting that mutations in at least one other gene were responsible for the disease in these patients. In addition, these patients had ubiquitin-immunoreactive neuronal cytoplasmic inclusions (FTDU-17) but not tau-immunoreactive inclusion pathology.

In July 2006, two studies found that FTDU-17 is caused by mutations in progranulin, a polypeptide with growth-modulatory activity, leading to a loss of protein function (Nature 2006;442:916–9; Nature 2006;442:920–4). Since then, researchers have been screening their patient populations for the mutations to determine their prevalence in the FTD community.

Stuart Pickering-Brown, Ph.D., who works at the University of Manchester (England), presented data from the Manchester Cohort that currently includes 272 patients with FTD, with some being followed for over 20 years.

“We recently finished sequencing for progranulin mutations and found 14 cases,” said Dr. Pickering-Brown, who noted that this frequency (5%) is about the same as for tau gene mutations (6%) in his cohort.

Clinically, the 14 patients had been diagnosed with frontotemporal dementias, primary progressive aphasia, and corticobasal degeneration, said Dr. Pickering-Brown. “All the cases had a family history of disease,” he added.

The researchers also genotyped several single nucleotide polymorphisms (SNPs) spanning the progranulin gene to determine whether a common variation at the locus increases the risk of sporadic disease, but they found no evidence of allelic association of any of the SNPs.

Dr. Brendan Kelley presented the latest data from the Mayo Clinic cohort of patients. He reported on the clinical characterization of eight kindreds, which included 31 individuals with progranulin mutations, of whom 16 were men. The patients were aged 49–83 years at disease onset (mean age 63 years) and had a disease duration of 1–12 years (mean 6.5 years). “Two individuals who died within 1 year both had accidents that may have been related to disinhibited behaviors,” Dr. Kelley said.

Like the Manchester cohort, the clinical diagnosis varied widely and included FTD with and without parkinsonism, mild cognitive impairment, and Alzheimer's.

The discovery of this gene will not change clinical practice at this point, said Dr. Zbigniew Wszolek, a professor of neurology at the Mayo Clinic College of Medicine, Jacksonville, Fla., who chaired the session. In addition, Dr. Wszolek said he did not think clinical genetic testing was available yet, but patents have been filed.

SALZBURG, AUSTRIA — The investigational Pittsburgh B compound that binds to cerebral β-amyloid and is visible on positron emission tomography maintains its promise as a way to distinguish the elderly patients presenting with memory problems who will go on to develop Alzheimer's disease from those who won't progress.

A series of presentations at an international conference on Alzheimer's and Parkinson's diseases suggested that the ligand Pittsburgh B (PIB) compound, although still at the research stage, may also prove to be an invaluable biomarker to track disease modification in clinical trials.

Kerryn Pike, a research officer at Austin Health, Melbourne, presented the results of a study that examined the relationship between amyloid burden and cognitive function.

The researchers studied 108 individuals with varying degrees of cognitive impairment: 38 of the participants were healthy aging controls (mean Mini Mental State Examination [MMSE], 29.1), 34 had mild cognitive impairment (mean MMSE, 26.3), and 36 had mild Alzheimer's disease (mean MMSE, 22.1).

The average age of the participants was 72 years, and there was no significant difference in age among the three groups. All the individuals were given neuropsychological tests, including the MMSE, California verbal learning test second edition, Rey complex figure test, digit span, verbal fluency, Boston naming test, and digit symbol coding tests.

The researchers calculated a composite episodic memory score and a composite nonmemory cognition score from these neuropsychological tests for each participant. The participants also had a PET scan after being given an intravenous dose of the radiotracer 11C-PIB. A “positive” PIB test was noted in 26% of the 38 healthy aging controls, 59% of the 34 patients with mild cognitive impairment (MCI), and 97% of the 36 patients with Alzheimer's disease (AD), suggesting that they had amyloid deposited in their brains. “About a quarter of healthy elderly are known to have amyloid plaques at autopsy,” noted Ms Pike.

Two of the MCI patients have gone on to develop AD and the researchers plan to follow up the cohort over the coming years.

Individuals with MCI who had a positive PIB test did much worse in the neuropsychological memory tests than did participants with MCI who were negative for amyloid deposition (−2.95 standard deviations from control values vs. −1.1 standard deviations). “This suggests to us that amyloid deposition is a very early pathological process that affects memory specifically,” said Ms Pike.

Indeed, those people with mild cognitive impairment who were PIB positive did almost as badly in the memory tests as did the patients with Alzheimer's disease (−3.22 standard deviations from control values). The researchers found a correlation of 0.72 between amyloid load and memory score.

In addition, participants with MCI who were PIB positive were significantly older than the PIB-negative participants (73.6 years vs. 66.1 years), and the 6 nonamnestic MCI participants were significantly younger than the 28 amnestic MCI participants (mean 63.7 years vs. 71.9 years).

“All our nonamnestic MCI participants were PIB negative and this suggests to us that they have different underlying pathology such as frontotemporal dementia, which doesn't have amyloid plaques,” said Ms Pike.

In a separate presentation, Dr. David Brooks, professor of neurology at Imperial College School of Medicine, London, presented data from a case series of 13 patients with dementia with Lewy bodies (DLB) and 13 patients with Parkinson's disease dementia (PDD) who were imaged using PIB.

The patients with DLB had a mean MMSE of 21, compared with 20 in the patients with PDD. The mean Unified Parkinson's Disease Rating Scale score was 31 in the patients with DLB and 35 in the patients with PDD.

Amyloid levels were raised in 11 of the 13 patients with DLB, although those levels were not as high as those seen previously in patients with AD.

By contrast, only 2 of the 13 patients with PDD showed an increased amyloid burden, suggesting that PIB could potentially be used in the differential diagnosis of PDD and DLB.

SALZBURG, AUSTRIA — The investigational Pittsburgh B compound that binds to cerebral β-amyloid and is visible on positron emission tomography maintains its promise as a way to distinguish the elderly patients presenting with memory problems who will go on to develop Alzheimer's disease from those who won't progress.

A series of presentations at an international conference on Alzheimer's and Parkinson's diseases suggested that the ligand Pittsburgh B (PIB) compound, although still at the research stage, may also prove to be an invaluable biomarker to track disease modification in clinical trials.

Kerryn Pike, a research officer at Austin Health, Melbourne, presented the results of a study that examined the relationship between amyloid burden and cognitive function.

The researchers studied 108 individuals with varying degrees of cognitive impairment: 38 of the participants were healthy aging controls (mean Mini Mental State Examination [MMSE], 29.1), 34 had mild cognitive impairment (mean MMSE, 26.3), and 36 had mild Alzheimer's disease (mean MMSE, 22.1).

The average age of the participants was 72 years, and there was no significant difference in age among the three groups. All the individuals were given neuropsychological tests, including the MMSE, California verbal learning test second edition, Rey complex figure test, digit span, verbal fluency, Boston naming test, and digit symbol coding tests.

The researchers calculated a composite episodic memory score and a composite nonmemory cognition score from these neuropsychological tests for each participant. The participants also had a PET scan after being given an intravenous dose of the radiotracer 11C-PIB. A “positive” PIB test was noted in 26% of the 38 healthy aging controls, 59% of the 34 patients with mild cognitive impairment (MCI), and 97% of the 36 patients with Alzheimer's disease (AD), suggesting that they had amyloid deposited in their brains. “About a quarter of healthy elderly are known to have amyloid plaques at autopsy,” noted Ms Pike.

Two of the MCI patients have gone on to develop AD and the researchers plan to follow up the cohort over the coming years.

Individuals with MCI who had a positive PIB test did much worse in the neuropsychological memory tests than did participants with MCI who were negative for amyloid deposition (−2.95 standard deviations from control values vs. −1.1 standard deviations). “This suggests to us that amyloid deposition is a very early pathological process that affects memory specifically,” said Ms Pike.

Indeed, those people with mild cognitive impairment who were PIB positive did almost as badly in the memory tests as did the patients with Alzheimer's disease (−3.22 standard deviations from control values). The researchers found a correlation of 0.72 between amyloid load and memory score.

In addition, participants with MCI who were PIB positive were significantly older than the PIB-negative participants (73.6 years vs. 66.1 years), and the 6 nonamnestic MCI participants were significantly younger than the 28 amnestic MCI participants (mean 63.7 years vs. 71.9 years).

“All our nonamnestic MCI participants were PIB negative and this suggests to us that they have different underlying pathology such as frontotemporal dementia, which doesn't have amyloid plaques,” said Ms Pike.

In a separate presentation, Dr. David Brooks, professor of neurology at Imperial College School of Medicine, London, presented data from a case series of 13 patients with dementia with Lewy bodies (DLB) and 13 patients with Parkinson's disease dementia (PDD) who were imaged using PIB.

The patients with DLB had a mean MMSE of 21, compared with 20 in the patients with PDD. The mean Unified Parkinson's Disease Rating Scale score was 31 in the patients with DLB and 35 in the patients with PDD.

Amyloid levels were raised in 11 of the 13 patients with DLB, although those levels were not as high as those seen previously in patients with AD.

By contrast, only 2 of the 13 patients with PDD showed an increased amyloid burden, suggesting that PIB could potentially be used in the differential diagnosis of PDD and DLB.

SALZBURG, AUSTRIA — The investigational Pittsburgh B compound that binds to cerebral β-amyloid and is visible on positron emission tomography maintains its promise as a way to distinguish the elderly patients presenting with memory problems who will go on to develop Alzheimer's disease from those who won't progress.

A series of presentations at an international conference on Alzheimer's and Parkinson's diseases suggested that the ligand Pittsburgh B (PIB) compound, although still at the research stage, may also prove to be an invaluable biomarker to track disease modification in clinical trials.

Kerryn Pike, a research officer at Austin Health, Melbourne, presented the results of a study that examined the relationship between amyloid burden and cognitive function.

The researchers studied 108 individuals with varying degrees of cognitive impairment: 38 of the participants were healthy aging controls (mean Mini Mental State Examination [MMSE], 29.1), 34 had mild cognitive impairment (mean MMSE, 26.3), and 36 had mild Alzheimer's disease (mean MMSE, 22.1).

The average age of the participants was 72 years, and there was no significant difference in age among the three groups. All the individuals were given neuropsychological tests, including the MMSE, California verbal learning test second edition, Rey complex figure test, digit span, verbal fluency, Boston naming test, and digit symbol coding tests.

The researchers calculated a composite episodic memory score and a composite nonmemory cognition score from these neuropsychological tests for each participant. The participants also had a PET scan after being given an intravenous dose of the radiotracer 11C-PIB. A “positive” PIB test was noted in 26% of the 38 healthy aging controls, 59% of the 34 patients with mild cognitive impairment (MCI), and 97% of the 36 patients with Alzheimer's disease (AD), suggesting that they had amyloid deposited in their brains. “About a quarter of healthy elderly are known to have amyloid plaques at autopsy,” noted Ms Pike.

Two of the MCI patients have gone on to develop AD and the researchers plan to follow up the cohort over the coming years.

Individuals with MCI who had a positive PIB test did much worse in the neuropsychological memory tests than did participants with MCI who were negative for amyloid deposition (−2.95 standard deviations from control values vs. −1.1 standard deviations). “This suggests to us that amyloid deposition is a very early pathological process that affects memory specifically,” said Ms Pike.

Indeed, those people with mild cognitive impairment who were PIB positive did almost as badly in the memory tests as did the patients with Alzheimer's disease (−3.22 standard deviations from control values). The researchers found a correlation of 0.72 between amyloid load and memory score.

In addition, participants with MCI who were PIB positive were significantly older than the PIB-negative participants (73.6 years vs. 66.1 years), and the 6 nonamnestic MCI participants were significantly younger than the 28 amnestic MCI participants (mean 63.7 years vs. 71.9 years).

“All our nonamnestic MCI participants were PIB negative and this suggests to us that they have different underlying pathology such as frontotemporal dementia, which doesn't have amyloid plaques,” said Ms Pike.

In a separate presentation, Dr. David Brooks, professor of neurology at Imperial College School of Medicine, London, presented data from a case series of 13 patients with dementia with Lewy bodies (DLB) and 13 patients with Parkinson's disease dementia (PDD) who were imaged using PIB.

The patients with DLB had a mean MMSE of 21, compared with 20 in the patients with PDD. The mean Unified Parkinson's Disease Rating Scale score was 31 in the patients with DLB and 35 in the patients with PDD.

Amyloid levels were raised in 11 of the 13 patients with DLB, although those levels were not as high as those seen previously in patients with AD.

By contrast, only 2 of the 13 patients with PDD showed an increased amyloid burden, suggesting that PIB could potentially be used in the differential diagnosis of PDD and DLB.

SALZBURG, AUSTRIA — A risk score that predicts the likelihood of a middle-aged person developing dementia within 20 years has been independently validated in an ethnically diverse population, according to data presented at an international conference on Alzheimer's and Parkinson's diseases.

The Cardiovascular Risk Factors, Aging and Dementia (CAIDE) risk score originally was created using data from the CAIDE study, a population-based study of 1,409 individuals in a Finnish population in the 1970s (mean age 50.4 years). When the Finnish subjects were reexamined in 1998, 61 of the subjects were diagnosed with dementia.

Study participants with dementia were found to be older at the midlife examination (mean age 53.4 years vs. mean 50.2 years), less well educated (6.7 years of formal education vs. 8.7 years), and had more vascular risk factors—such as high blood pressure, high total cholesterol, and high body mass index, as well as a history of smoking—present at midlife than did participants without dementia.

Dr. Miia Kivipelto of the Aging Research Center at the Karolinska Institute, Stockholm, used the data from the CAIDE study to create a score that could predict the risk of developing dementia in later life.

The CAIDE dementia score uses age, years of formal education, sex, systolic blood pressure, body mass index, total cholesterol, and physical activity to determine an individual's likelihood of developing dementia within 20 years. (See table.) The risk of dementia was found to be 1% for patients with a score of 0–5; 1.9% for patients with a score of 6–7; 4.2% for those with a score of 8–9; 7.4% for a score of 10–11; and 16.4% for patients with a score of 12–15 (Lancet Neurol. 2006;5:735–41).

“When the cutoff was set at 9 points or more, the sensitivity was 0.77, the specificity was 0.63, and the negative predictive value was 0.98,” said Dr. Kivipelto at the conference.

Rachel Whitmer, Ph.D., an epidemiologist working at the Kaiser Permanente Division of Research, Oakland, Calif., validated the CAIDE dementia risk score in a sample of 9,480 long-term members of Kaiser Permanente's integrated health care delivery system, of whom 1,011 developed Alzheimer's disease or vascular dementia.

The study sample was ethnically diverse (474 Asian, 1,401 black, and 7,605 white) and included people from a wide demographic range.

According to Dr. Whitmer, she obtained results similar to those of Dr. Kivipelto by using the CAIDE score on the Kaiser Permanente sample.

In addition, Dr. Whitmer added more variables to the dementia risk score, including obesity, smoking, pulmonary function, and depression, but found that these did not improve the score's predictive value.

However, the addition of diabetes as a variable improved the predictability of the score for Asian patients, but not for black or white study patients.

“It seems like we're really onto something here,” said Dr. Whitmer. “It replicated really well and is so predictive in such a different population.”

ELSEVIER GLOBAL MEDICAL NEWS

SALZBURG, AUSTRIA — A risk score that predicts the likelihood of a middle-aged person developing dementia within 20 years has been independently validated in an ethnically diverse population, according to data presented at an international conference on Alzheimer's and Parkinson's diseases.

The Cardiovascular Risk Factors, Aging and Dementia (CAIDE) risk score originally was created using data from the CAIDE study, a population-based study of 1,409 individuals in a Finnish population in the 1970s (mean age 50.4 years). When the Finnish subjects were reexamined in 1998, 61 of the subjects were diagnosed with dementia.

Study participants with dementia were found to be older at the midlife examination (mean age 53.4 years vs. mean 50.2 years), less well educated (6.7 years of formal education vs. 8.7 years), and had more vascular risk factors—such as high blood pressure, high total cholesterol, and high body mass index, as well as a history of smoking—present at midlife than did participants without dementia.

Dr. Miia Kivipelto of the Aging Research Center at the Karolinska Institute, Stockholm, used the data from the CAIDE study to create a score that could predict the risk of developing dementia in later life.

The CAIDE dementia score uses age, years of formal education, sex, systolic blood pressure, body mass index, total cholesterol, and physical activity to determine an individual's likelihood of developing dementia within 20 years. (See table.) The risk of dementia was found to be 1% for patients with a score of 0–5; 1.9% for patients with a score of 6–7; 4.2% for those with a score of 8–9; 7.4% for a score of 10–11; and 16.4% for patients with a score of 12–15 (Lancet Neurol. 2006;5:735–41).

“When the cutoff was set at 9 points or more, the sensitivity was 0.77, the specificity was 0.63, and the negative predictive value was 0.98,” said Dr. Kivipelto at the conference.

Rachel Whitmer, Ph.D., an epidemiologist working at the Kaiser Permanente Division of Research, Oakland, Calif., validated the CAIDE dementia risk score in a sample of 9,480 long-term members of Kaiser Permanente's integrated health care delivery system, of whom 1,011 developed Alzheimer's disease or vascular dementia.

The study sample was ethnically diverse (474 Asian, 1,401 black, and 7,605 white) and included people from a wide demographic range.

According to Dr. Whitmer, she obtained results similar to those of Dr. Kivipelto by using the CAIDE score on the Kaiser Permanente sample.

In addition, Dr. Whitmer added more variables to the dementia risk score, including obesity, smoking, pulmonary function, and depression, but found that these did not improve the score's predictive value.

However, the addition of diabetes as a variable improved the predictability of the score for Asian patients, but not for black or white study patients.

“It seems like we're really onto something here,” said Dr. Whitmer. “It replicated really well and is so predictive in such a different population.”

ELSEVIER GLOBAL MEDICAL NEWS

SALZBURG, AUSTRIA — A risk score that predicts the likelihood of a middle-aged person developing dementia within 20 years has been independently validated in an ethnically diverse population, according to data presented at an international conference on Alzheimer's and Parkinson's diseases.

The Cardiovascular Risk Factors, Aging and Dementia (CAIDE) risk score originally was created using data from the CAIDE study, a population-based study of 1,409 individuals in a Finnish population in the 1970s (mean age 50.4 years). When the Finnish subjects were reexamined in 1998, 61 of the subjects were diagnosed with dementia.

Study participants with dementia were found to be older at the midlife examination (mean age 53.4 years vs. mean 50.2 years), less well educated (6.7 years of formal education vs. 8.7 years), and had more vascular risk factors—such as high blood pressure, high total cholesterol, and high body mass index, as well as a history of smoking—present at midlife than did participants without dementia.

Dr. Miia Kivipelto of the Aging Research Center at the Karolinska Institute, Stockholm, used the data from the CAIDE study to create a score that could predict the risk of developing dementia in later life.

The CAIDE dementia score uses age, years of formal education, sex, systolic blood pressure, body mass index, total cholesterol, and physical activity to determine an individual's likelihood of developing dementia within 20 years. (See table.) The risk of dementia was found to be 1% for patients with a score of 0–5; 1.9% for patients with a score of 6–7; 4.2% for those with a score of 8–9; 7.4% for a score of 10–11; and 16.4% for patients with a score of 12–15 (Lancet Neurol. 2006;5:735–41).

“When the cutoff was set at 9 points or more, the sensitivity was 0.77, the specificity was 0.63, and the negative predictive value was 0.98,” said Dr. Kivipelto at the conference.

Rachel Whitmer, Ph.D., an epidemiologist working at the Kaiser Permanente Division of Research, Oakland, Calif., validated the CAIDE dementia risk score in a sample of 9,480 long-term members of Kaiser Permanente's integrated health care delivery system, of whom 1,011 developed Alzheimer's disease or vascular dementia.

The study sample was ethnically diverse (474 Asian, 1,401 black, and 7,605 white) and included people from a wide demographic range.

According to Dr. Whitmer, she obtained results similar to those of Dr. Kivipelto by using the CAIDE score on the Kaiser Permanente sample.

In addition, Dr. Whitmer added more variables to the dementia risk score, including obesity, smoking, pulmonary function, and depression, but found that these did not improve the score's predictive value.

However, the addition of diabetes as a variable improved the predictability of the score for Asian patients, but not for black or white study patients.

“It seems like we're really onto something here,” said Dr. Whitmer. “It replicated really well and is so predictive in such a different population.”

ELSEVIER GLOBAL MEDICAL NEWS