Carotenoids are thought to protect against Alzheimer's disease because of their antioxidant properties and their accumulation in the brain. However, a new study from Tufts University is putting the theory into question.
More than a century has passed since the German physician Dr. Alois Alzheimer first presented evidence on the case of Auguste Deter, who at only 51 suffered from severe memory loss and other psychological changes. At autopsy, Dr. Alzheimer found his patient had severe shrinkage and abnormal deposits of the nerve cells.
"That was in 1906," said nutritionist Annie Roe, a USDA researcher at Tufts University, who presented her laboratory's findings on April 21 at Experimental Biology 2012 in San Diego. "There's still disparity among scientists as to the etiology of this rapidly growing disease as we now know as Alzheimer's disease."
Currently, in the United States there are 5.3 million people with Alzheimer's disease. Unless new methods of intervention are available, however, the number is expected to reach 16 million by 2050. While the cause of the disease is not known, the deposits that Dr. Alzheimer first noted are now known to be amyloid-beta peptide deposits.
These deposits, or plaques, are a "hallmark diagnostic feature" of Alzheimer’s disease. Within the same region amyloid-beta plaques are found, increased concentrations of oxidized proteins, lipids DNA are also observed. It’s not yet clear whether or not that these products of oxidative stress caused the amyloid-beta plaque build-up or vice versa.
However, Roe said, it is clear that oxidative damage promotes neurotoxicity and is involved in cognitive impairment. Epidemiological studies have found that a higher dietary intake of carotenoids from fruits and vegetables are associated with reduced risk of age-related chronic diseases including Alzheimer’s disease. Other studies measuring the concentration of carotenoids in plasma have found an inverse relationship with chronic diseases.
Fruits and vegetables are the major sources of carotenoids in the diet, the most common of which are beta-carotene and beta-cryptoxanthin—two provitamin-A carotenoids. There is also lycopene, lutein, and zeaxanthin, which have no vitamin A activity. There are several biological mechanisms being explored for carotenoids' potential protection to the brain.
However, Roe explained that her laboratory research focuses on the role of antioxidants and their relationship to Alzheimer's disease, clinically determined by increased cognitive impairment. Since Alzheimer's affects brain tissue, the researchers' study purpose was to determine the concentration and magnitude of lipid peroxidation in brains diagnosed with Alzheimer’s disease compared with age-matched controls.
The Tufts laboratory received brain tissue samples from the National Institute for Child Health and Human Development (NICHD) Brain and Tissue Bank for Developmental Disorders. The samples were obtained from 15 individuals with Alzheimer’s disease and half with no known dementia. The samples were from subjects in their late 70s or early 80s, most of whom were Caucasians. The samples were of four different brain regions: occipital cortex, frontal cortex, hippocampus, and auditory cortex. To assess lipid peroxidation, the researchers extracted malondialdehyde (MDA)—a marker of oxidative damage—through HPLC.
When looking at relative distribution of major carotenoids between Alzheimer’s disease and controls, the study found the provitamin A carotenoids contributed to a significantly higher percentage of total carotenoids in the Alzheimer’s brains compared to the controls. Non-provitamin-A carotenoids contributed to higher concentration in control brains compared to Alzheimer’s disease brains, but there was no statistically significant difference.
In addition, Roe said, the absolute concentrations of provitamin-A carotenoids were higher in Alzheimer’s diseased samples versus control samples. There was no difference in absolute concentrations of lutein, zeaxanthin, or lycopene. There was also no significant difference between malondialdehyde concentrations and carotenoid concentrations.
Consistent with findings of increased pro-vitamin A carotenoids, retinol (vitamin A) concentration was significantly greater in the Alzheimer’s disease brains. However, when the study looked at malondialdehyde concentrations, there was not a significant difference between the two groups.
The findings "were interesting but unexpected," Roe said, adding that when she looked at each region separately, she saw the same pattern in the hippocampus, a region that is highly vulnerable to the disease.
Since prior research has shown both in cell culture and in clinical studies that vitamin A can have a positive effect on beta-amyloid aggregation, it is possible that caregivers or physicians confounded results. For example, they may have encouraged their patients after diagnosis to consume more fruits and vegetables. It may be that carotenoids are beneficial to the brain, but simply not after the disease has set in. Roe suggests future studies should include dietary intake assessments and target people with earlier stages of dementia.
"This is just a snapshot view of a small group of people at the end of life, so we can't infer any type of causation and certainly should not interpret the results to mean that vitamin A is bad for the brain," Roe said.
The study's results contradicted that of previous research, also presented at the conference by Neal Craft of Craft Technologies, which found an age-related decline of carotenoids in elderly brains that suggested that diminishing levels may be associated with Alzheimer's disease.
Showing posts with label Alzheimer's. Show all posts
Showing posts with label Alzheimer's. Show all posts
Sunday, April 22, 2012
Friday, October 8, 2010
Helping the Brain Help Itself keynote by Mark Mattson
Now, for the second keynote at American College of Nutrition conference in New York City we're listening to Mark Mattson, Ph.D. He starts out talking about his work in the laboratory of neurosciences at National Institutes of Aging.
He talks about what happens during aging in the brain.
More and more as people get older, neurons age and die, predisposing us to Alzheimer's and other brain diseases. The mechanisms on how this happens are being shown and he discusses the different pathways.
Dietary energy restriction, exercise, cognitive enrichment promote neuroprotection (hormesis?) by reducing oxidative stress and inflammation.
Current trends in Alzheimer's showing it's a huge issue that's not being dealt with. We need a war on it like we have on cancer. Many people die from Alzheimer's and it's a tax on society.
He discusses amyloid plaques and neurofibrillary tangles (with tau) that is involved in AD pathogenesis.
There's a number of animal models for AD such as transgenic mice with overexpression of mutated amyloid-precursor protein. Also, PS1 mice.
Mattson manipulates diets of AD-prone mice to see how diet affects their cognitive function, memory, and amelioration of AD behavior.
Intermittent fasting and calorie restriction ameliorated AD behavior changes. He thinks that neurons can be stimulated by these diets to protect themselves against the amyloid protein. He shows us data on how CR reduced tau levels, but IF did not.
They also used "couch potato mice" model of AD: overfed, sedentary. Of course, these are great controls.
CR and IF showed gene expression in the brain (Martin et al, 2007, Endocrinology).
They wanted to show an effect in primates, so performed a study in rhesus monkeys. They took the monkeys and reduced their calories by 30 percent for 11 months. They tested their motor function, dopamine. They injected a toxin called MPTP.
Both the animals on the normal diet and CR diet had deficits in motor function, but CR had less seeming to have a protective effect from a functional endpoint. When measured for dopamine, there was major depletion in the striatum in both. When measured for BDNF, the CR had higher levels of BDNF.
In a stroke model, they took young, middle-aged, or old mice on either IF or normal diets. They then damaged the cerebral cortex and measured neurological deficit. There was significant benefit for the young and middle-aged mice on IF, but not in old.
"So start early," he says. Exercise, eat less when you're younger to prevent Alzheimer's in the future. IF reduced inflammation in the young and middle-aged, but not in old.
Mattson starts talking about type 2 diabetes now. The world prevalence of diabetes is rising. This disease leads to problems later on in the brain, as shown in more mice models (like leptin-receptor mutant mice), which he summarizes.
- reduced BDNF levels
- l wer neurogenesis
Diabetes reduces neurogenesis, but what about interactions with exercise or calorie restriction? Both exercise and CR increase BDNF levels.
Mattson talking about possibility of using drugs and phytochemicals now (Duen et al 2004; Nelson et al 2007).
Some drugs work by involving BDNF. There are also several fruits and vegetables, but he doesn't think they have an intrinsic factor as antioxidants. Instead, he said, they have toxins concentrated in the skin meant to repel insects. Lots of these plants have natural pesticides, so Mattson acquired many of these natural chemicals to see which produce resistance to neurogenerative disorders.
OK, back to talking about IF, this time about a study showing that IF improves cardiovascular risk factors under stress in animals.
-The body temperature is up on the feeding day, down low on the fasting day.
-Heart rate variability was measured too. Higher heart rate variability is a good thing, because it shows adaptability. IF improved heart rate variability.
-Higher levels of BDNF
Interesting thing, he notes, when they infused BDNF in mice, they showed better heart rate variability.
Human studies? Mattson talks of Jim Johnson's work on subjects with moderate asthma on alternate-day calorie restriction. The subjects adapted to the diet, lost bodyweight, their mood increased, but importantly their asthma improved.
Mattson begins discussing GLP1, a receptor that when stimulated reduces amyloid plaque accumulation, and drugs that stimulate it. GLP1 increases BDNF and insulin sensitivity.
He intends to conduct a 3-year double-blind, randomized trial on a drug (Exendin-4) to treat Alzheimer's disease, by testing CSF biomarkers. He is optimistic and says at least he knows the drug should help with blood glucose management.
---
Unfortunately, Mattson ran out of time, but the presentation was awesome! Good to know we have serious scientists like this working on AD.
Surprisingly, with all the talk about CR, IF and Alzheimer's, not a word was said about Sirtuin 1 activation, so I asked Dr. Mattson his opinion on the research, specifically Guarente's paper showing that SIRT1 activation inhibited two pathways in the progression of AD.
Mattson responded with a dose of skepticism about sirtuins and their potential, at least as a treatment in the diseased state when they'd use up a lot of NADPH at a time when the brain needs it.
hmm...
He talks about what happens during aging in the brain.
More and more as people get older, neurons age and die, predisposing us to Alzheimer's and other brain diseases. The mechanisms on how this happens are being shown and he discusses the different pathways.
Dietary energy restriction, exercise, cognitive enrichment promote neuroprotection (hormesis?) by reducing oxidative stress and inflammation.
Current trends in Alzheimer's showing it's a huge issue that's not being dealt with. We need a war on it like we have on cancer. Many people die from Alzheimer's and it's a tax on society.
He discusses amyloid plaques and neurofibrillary tangles (with tau) that is involved in AD pathogenesis.
There's a number of animal models for AD such as transgenic mice with overexpression of mutated amyloid-precursor protein. Also, PS1 mice.
Mattson manipulates diets of AD-prone mice to see how diet affects their cognitive function, memory, and amelioration of AD behavior.
Intermittent fasting and calorie restriction ameliorated AD behavior changes. He thinks that neurons can be stimulated by these diets to protect themselves against the amyloid protein. He shows us data on how CR reduced tau levels, but IF did not.
They also used "couch potato mice" model of AD: overfed, sedentary. Of course, these are great controls.
CR and IF showed gene expression in the brain (Martin et al, 2007, Endocrinology).
They wanted to show an effect in primates, so performed a study in rhesus monkeys. They took the monkeys and reduced their calories by 30 percent for 11 months. They tested their motor function, dopamine. They injected a toxin called MPTP.
Both the animals on the normal diet and CR diet had deficits in motor function, but CR had less seeming to have a protective effect from a functional endpoint. When measured for dopamine, there was major depletion in the striatum in both. When measured for BDNF, the CR had higher levels of BDNF.
In a stroke model, they took young, middle-aged, or old mice on either IF or normal diets. They then damaged the cerebral cortex and measured neurological deficit. There was significant benefit for the young and middle-aged mice on IF, but not in old.
"So start early," he says. Exercise, eat less when you're younger to prevent Alzheimer's in the future. IF reduced inflammation in the young and middle-aged, but not in old.
Mattson starts talking about type 2 diabetes now. The world prevalence of diabetes is rising. This disease leads to problems later on in the brain, as shown in more mice models (like leptin-receptor mutant mice), which he summarizes.
- reduced BDNF levels
- l wer neurogenesis
Diabetes reduces neurogenesis, but what about interactions with exercise or calorie restriction? Both exercise and CR increase BDNF levels.
Mattson talking about possibility of using drugs and phytochemicals now (Duen et al 2004; Nelson et al 2007).
Some drugs work by involving BDNF. There are also several fruits and vegetables, but he doesn't think they have an intrinsic factor as antioxidants. Instead, he said, they have toxins concentrated in the skin meant to repel insects. Lots of these plants have natural pesticides, so Mattson acquired many of these natural chemicals to see which produce resistance to neurogenerative disorders.
OK, back to talking about IF, this time about a study showing that IF improves cardiovascular risk factors under stress in animals.
-The body temperature is up on the feeding day, down low on the fasting day.
-Heart rate variability was measured too. Higher heart rate variability is a good thing, because it shows adaptability. IF improved heart rate variability.
-Higher levels of BDNF
Interesting thing, he notes, when they infused BDNF in mice, they showed better heart rate variability.
Human studies? Mattson talks of Jim Johnson's work on subjects with moderate asthma on alternate-day calorie restriction. The subjects adapted to the diet, lost bodyweight, their mood increased, but importantly their asthma improved.
Mattson begins discussing GLP1, a receptor that when stimulated reduces amyloid plaque accumulation, and drugs that stimulate it. GLP1 increases BDNF and insulin sensitivity.
He intends to conduct a 3-year double-blind, randomized trial on a drug (Exendin-4) to treat Alzheimer's disease, by testing CSF biomarkers. He is optimistic and says at least he knows the drug should help with blood glucose management.
---
Unfortunately, Mattson ran out of time, but the presentation was awesome! Good to know we have serious scientists like this working on AD.
Surprisingly, with all the talk about CR, IF and Alzheimer's, not a word was said about Sirtuin 1 activation, so I asked Dr. Mattson his opinion on the research, specifically Guarente's paper showing that SIRT1 activation inhibited two pathways in the progression of AD.
Mattson responded with a dose of skepticism about sirtuins and their potential, at least as a treatment in the diseased state when they'd use up a lot of NADPH at a time when the brain needs it.
hmm...
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