8.02.2004
Dietary Impact on Alzheimer's Disease? Input from the South Pacific
Neurotoxins from blue-green algae present in certain foods or water can accumulate in proteins and might cause brain diseases like Alzheimer's after many years, suggests a new study.
The latest research explains how a devastating neurodegenerative disease common on the remote Pacific island of Guam can still strike people down decades after they have left the island.
The disease, called amyotrophic lateral sclerosis/Parkinsonism dementia complex (ALS/PDC), has symptoms resembling those of both Parkinson's and Alzheimer's disease. The brain damage it causes is similar to that found in Alzheimer's patients.
The latest theory is that the islanders' taste for flying foxes is to blame. A neurotoxin called BMAA found in the fruit of the cycads on which the flying foxes feed, is thought to become concentrated in the flying foxes' flesh. BMAA, in turn, is made by a blue-green alga, or cyanobacterium, that lives in the roots of the cycads.
But this theory does not explain everything. Many islanders who leave Guam develop ALS/PDC decades later. BMAA is a water-soluble chemical, which means the body should soon get rid of it. So how BMAA caused brain damage so long after exposure had puzzled scientists.
Now a team led by Paul Cox, director of the National Tropical Botanic Garden in Hawaii, has shown that that BMAA is sometimes incorporated into proteins in place of normal amino acids. BMAA's structure was already known to resemble that of the amino acids that make up the proteins in our body.
Levels of this protein-bound form of BMAA in the cycad flour eaten by islanders, in the flesh of flying foxes and in the brains of ALS/PDC victims, are typically around a hundred times higher than that of the free form, the team found.
Protein tangles
This BMAA would slowly be released as proteins are broken down, Cox suggests. So for years after eating contaminated food, people's brains would be exposed to low levels of the neurotoxin. What is more, the abnormal proteins containing BMAA could also damage the brain in several ways, for instance by binding together to form the protein tangles characteristic of both ALS/PDC and Alzheimer's.
The study also raises intriguing new questions. As controls, about 20 brain samples from Canada were also tested for BMAA alongside the eight samples from Guam. As expected, no BMAA was found in the brain of the 13 Canadians who had not died from neurological diseases. But protein-bound BMAA was found in the brains of eight Canadian victims of Alzheimer’s disease.
Cox stresses that the study does not prove that BMAA plays a role in Alzheimer's or other brain diseases. "The sample size that we have studied is too small," he says.
And it still has not been proven conclusively that BMAA is the cause of ALS/PDC on Guam, Cox adds. However, its presence in the brain could be a sign that people have been exposed to other, as-yet-unknown cyanobacterial toxins.
The idea is plausible, says cyanobacteria expert Hans Paerl of the University of North Carolina in Chapel Hill, US. Cyanobacteria are common in freshwaters and seas worldwide, and thrive in polluted, nutrient-rich waters. "Their influence is expanding as we nutrify the environment," he says.
For example, in China there is growing evidence that cyanobacterial contamination of drinking water is to blame for the high rates of liver cancer in some regions, says Paerl. "We are just starting to put the pieces of the puzzle together."
Proceedings of the National Academies of Sciences
Neurotoxins from blue-green algae present in certain foods or water can accumulate in proteins and might cause brain diseases like Alzheimer's after many years, suggests a new study.
The latest research explains how a devastating neurodegenerative disease common on the remote Pacific island of Guam can still strike people down decades after they have left the island.
The disease, called amyotrophic lateral sclerosis/Parkinsonism dementia complex (ALS/PDC), has symptoms resembling those of both Parkinson's and Alzheimer's disease. The brain damage it causes is similar to that found in Alzheimer's patients.
The latest theory is that the islanders' taste for flying foxes is to blame. A neurotoxin called BMAA found in the fruit of the cycads on which the flying foxes feed, is thought to become concentrated in the flying foxes' flesh. BMAA, in turn, is made by a blue-green alga, or cyanobacterium, that lives in the roots of the cycads.
But this theory does not explain everything. Many islanders who leave Guam develop ALS/PDC decades later. BMAA is a water-soluble chemical, which means the body should soon get rid of it. So how BMAA caused brain damage so long after exposure had puzzled scientists.
Now a team led by Paul Cox, director of the National Tropical Botanic Garden in Hawaii, has shown that that BMAA is sometimes incorporated into proteins in place of normal amino acids. BMAA's structure was already known to resemble that of the amino acids that make up the proteins in our body.
Levels of this protein-bound form of BMAA in the cycad flour eaten by islanders, in the flesh of flying foxes and in the brains of ALS/PDC victims, are typically around a hundred times higher than that of the free form, the team found.
Protein tangles
This BMAA would slowly be released as proteins are broken down, Cox suggests. So for years after eating contaminated food, people's brains would be exposed to low levels of the neurotoxin. What is more, the abnormal proteins containing BMAA could also damage the brain in several ways, for instance by binding together to form the protein tangles characteristic of both ALS/PDC and Alzheimer's.
The study also raises intriguing new questions. As controls, about 20 brain samples from Canada were also tested for BMAA alongside the eight samples from Guam. As expected, no BMAA was found in the brain of the 13 Canadians who had not died from neurological diseases. But protein-bound BMAA was found in the brains of eight Canadian victims of Alzheimer’s disease.
Cox stresses that the study does not prove that BMAA plays a role in Alzheimer's or other brain diseases. "The sample size that we have studied is too small," he says.
And it still has not been proven conclusively that BMAA is the cause of ALS/PDC on Guam, Cox adds. However, its presence in the brain could be a sign that people have been exposed to other, as-yet-unknown cyanobacterial toxins.
The idea is plausible, says cyanobacteria expert Hans Paerl of the University of North Carolina in Chapel Hill, US. Cyanobacteria are common in freshwaters and seas worldwide, and thrive in polluted, nutrient-rich waters. "Their influence is expanding as we nutrify the environment," he says.
For example, in China there is growing evidence that cyanobacterial contamination of drinking water is to blame for the high rates of liver cancer in some regions, says Paerl. "We are just starting to put the pieces of the puzzle together."
Proceedings of the National Academies of Sciences
Dr. Robert Heller, our Medical Advisor noticed the following article in Diagnostic Imaging which which I wanted to bring to your attention.
Patients in an early stage of Alzheimer's disease can benefit from disease-modifying treatments. Surrogate imaging markers of early AD pathology are needed for testing potential preventive therapies.
Mayo Clinic researchers suggest that FDG-PET distinguishes between patients with amnestic mild cognitive impairment (aMCI) and those with AD.
Dr. Kejal Kantarci and colleagues in Rochester, MN, used FDG-PET to image nine patients with AD, six with aMCI, and 12 healthy controls. FDG uptake was extracted using a 3D stereotactic surface projection technique (3D-SSP). The 3D-SSP maps of each group were compared against one another pixel by pixel.
Compared with normals, people with aMCI had decreased FDG uptake in the frontal pole, orbitofrontal cortices, and frontal, temporal, and parietal association cortices. Compared with normals, subjects with AD had decreased glucose uptake in the frontal and temporal lobes, parietal association cortex, posterior cingulate cortex, and precuneus.
FDG uptake in the primary sensory and motor cortices and in the occipital lobes were similar for all three groups.
An ROC curve analysis showed that FDG uptake in the right temporal lobe was the most accurate marker to differentiate patients with aMCI from normals, with 69% sensitivity and 80% specificity.
The same region distinguished patients with AD from normals with 91% and 85% sensitivity and specificity, respectively. Patients with AD showed the most significant decrease in FDG uptake in the temporal and parietal lobes, with a very high level of accuracy.
FDG uptake in all regions of interest in aMCI patients confirmed that MCI is a transitional stage between normal and AD, Kantarci said.
Using region of interest analysis, researchers unexpectedly found a decrease in FDG uptake in the medial temporal lobe of AD patients, while it remained normal in aMCI. This finding contradicts many structural MR studies showing hippocampal atrophy in MCI, she said. Previous FDG-PET studies also showed decreased FDG uptake in the medial temporal lobe.
One explanation Kantarci offered dealt with a flaw in the ROI analysis. Because of PET's low resolution, images could have included pixels from outside the medial temporal lobe structures, which might have affected the average FDG uptake. In aMCI, structures adjacent to the medial temporal lobe may have normal FDG uptake, and including them in the ROI may mask decreased glucose metabolism in the medial temporal lobe.
In AD, however, pixels adjacent to the medial temporal lobe may have decreased FDG uptake due to the extent of the pathologic temporal lobe involvement in AD. Therefore, medial temporal lobe uptake may be measured lower than normal in AD but not in aMCI.
"We will be using MR coregistration to trace the medial temporal region of interest as a result of this issue," Kantarci said.
Patients in an early stage of Alzheimer's disease can benefit from disease-modifying treatments. Surrogate imaging markers of early AD pathology are needed for testing potential preventive therapies.
Mayo Clinic researchers suggest that FDG-PET distinguishes between patients with amnestic mild cognitive impairment (aMCI) and those with AD.
Dr. Kejal Kantarci and colleagues in Rochester, MN, used FDG-PET to image nine patients with AD, six with aMCI, and 12 healthy controls. FDG uptake was extracted using a 3D stereotactic surface projection technique (3D-SSP). The 3D-SSP maps of each group were compared against one another pixel by pixel.
Compared with normals, people with aMCI had decreased FDG uptake in the frontal pole, orbitofrontal cortices, and frontal, temporal, and parietal association cortices. Compared with normals, subjects with AD had decreased glucose uptake in the frontal and temporal lobes, parietal association cortex, posterior cingulate cortex, and precuneus.
FDG uptake in the primary sensory and motor cortices and in the occipital lobes were similar for all three groups.
An ROC curve analysis showed that FDG uptake in the right temporal lobe was the most accurate marker to differentiate patients with aMCI from normals, with 69% sensitivity and 80% specificity.
The same region distinguished patients with AD from normals with 91% and 85% sensitivity and specificity, respectively. Patients with AD showed the most significant decrease in FDG uptake in the temporal and parietal lobes, with a very high level of accuracy.
FDG uptake in all regions of interest in aMCI patients confirmed that MCI is a transitional stage between normal and AD, Kantarci said.
Using region of interest analysis, researchers unexpectedly found a decrease in FDG uptake in the medial temporal lobe of AD patients, while it remained normal in aMCI. This finding contradicts many structural MR studies showing hippocampal atrophy in MCI, she said. Previous FDG-PET studies also showed decreased FDG uptake in the medial temporal lobe.
One explanation Kantarci offered dealt with a flaw in the ROI analysis. Because of PET's low resolution, images could have included pixels from outside the medial temporal lobe structures, which might have affected the average FDG uptake. In aMCI, structures adjacent to the medial temporal lobe may have normal FDG uptake, and including them in the ROI may mask decreased glucose metabolism in the medial temporal lobe.
In AD, however, pixels adjacent to the medial temporal lobe may have decreased FDG uptake due to the extent of the pathologic temporal lobe involvement in AD. Therefore, medial temporal lobe uptake may be measured lower than normal in AD but not in aMCI.
"We will be using MR coregistration to trace the medial temporal region of interest as a result of this issue," Kantarci said.
