The Food and Drug Administration (FDA) has given the Blanchette Rockefeller Neurosciences Institute (BRNI) the go-ahead to conduct Phase II clinical trials of Bryostatin for the treatment of Alzheimer’s disease patients.
The Phase II trials is slated to begin in approximately two to four months, so we will keep our eyes open and alert you to the locations and suitability criteria.
“With the potential to not just treat symptoms, but also stop the causes, the Bryostatin trial on Alzheimer's disease patients represents a new direction for the treatment of a disease with no current cure,” said Alkon. “
FDA Gives Clinical Trial Green Light On Drug To Treat Alzheimer’s Disease
Previous Studies Show Bryostatin Protects Against Alzheimer’s Protein, Rewires and Repairs Brain Damage
Morgantown, WV (April 22, 2009) - The Food and Drug Administration (FDA) has given the Blanchette Rockefeller Neurosciences Institute (BRNI) the go-ahead to conduct Phase II clinical trials of Bryostatin for the treatment of Alzheimer’s disease patients. The drug showed pre-clinical efficacy to not only treat Alzheimer’s disease symptoms, but also its underlying causes.
“We are very excited about the FDA’s agreement for BRNI to move forward with clinical trials,” said Dr. Daniel Alkon, Scientific Director of BRNI. “Bryostatin shows the promise to repair and protect against neurodegeneration caused by Alzheimer’s disease, stroke and other brain trauma, as well as enhance the brain’s normal memory functions.”
Bryostatin was originally created as an anti-cancer chemotherapy. When BRNI scientists extensively tested PKC activators against Alzheimer’s disease models, they discovered the drug’s hidden potential to stop Alzheimer’s disease.Over the past six years, the drug has shown remarkable possibilities. In preclinical testing, BRNI scientists experimented with Bryostatin on three species of Alzheimer’s disease transgenic mice, each species based on different human Alzheimer’s disease genes. The test results revealed that Bryostatin, and a related class of drugs discovered at BRNI, can reduce the toxic Alzheimer’s disease protein A Beta, restore lost synapses, and protect against the loss of memory functions. Bryostatin has been shown to enhance and restore memory by rewiring connections in the brain previously destroyed by stroke, head trauma, or aging itself.
The Phase II trials, slated to begin in approximately two to four months, will test these preclinical findings on human Alzheimer’s disease patients as well as controls, along with Bryostation’s effects on molecular targets in the human body, such as the signaling enzyme PKC. The drug’s side effects will also be carefully monitored using low doses that were previously found to be generally benign in human cancer patients.
“With the potential to not just treat symptoms, but also stop the causes, the Bryostatin trial on Alzheimer's disease patients represents a new direction for the treatment of a disease with no current cure,” said Alkon. “And the timing is crucial because as many as 5.3 million people live with Alzheimer’s disease in the United States alone, with a new American developing Alzheimer’s disease every 70 seconds.”
About BRNI
BRNI is the world’s only non-profit institute dedicated to the study of both human memory and diseases of memory. Its primary mission is to accelerate the transfer of neurological discoveries from the lab to the doctor’s office where it can benefit patients who suffer from neurological and psychiatric diseases.
BRNI is operated in alliance with West Virginia University in Morgantown as well as in collaboration with other academic institutions such as Johns Hopkins University. West Virginia Senator Jay Rockefeller founded the Institute in memory of his mother, Blanchette Hooker Rockefeller, who died of Alzheimer’s disease
Regular infusions of plasma-derived antibodies MAY WORK
FRIDAY, April 22 (HealthDay News) -- Regular infusions of plasma-derived antibodies appear to reduce levels of Alzheimer's disease-causing brain plaques while improving patients' thinking ability, researchers report.
Buildup of beta-amyloid protein plaques in the brain is a hallmark of Alzheimer's and toxicity related to this buildup is thought to be a major cause of the disease, for which there is currently no effective treatment.
In this phase I clinical study, conducted by a team from New York-Presbyterian Hospital/Weill Cornell Medical Center, researchers gave patients with mild to moderate Alzheimer's periodic infusions of a targeted antibody, called immunoglobulin (IVIg). The antibody makes its way to the brain where it targets beta-amyloid for removal.
The study included eight Alzheimer's patients treated with IVIg. After six months of treatment, seven of the patients underwent cognitive testing. The tests showed that cognitive function stopped declining in all seven patients and had actually improved in six of the seven patients.
"If these results are confirmed in larger, controlled trials, we might have a safe Alzheimer's treatment capable of clearing the amyloid protein away," senior researcher Dr. Marc E. Weksler said in a prepared statement.
The study was presented at the recent annual meeting of the American Academy of Neurology in Miami.
The researchers emphasize that it's too soon to describe IVIg as anything more than promising, and they do not recommend that doctors treat Alzheimer's patients with IVIg at this point in time. Preparations are already underway for a larger, controlled Phase II clinical trial of IVIg, the researchers said.
IVIg is an antibody product derived from human plasma. The U.S. Food and Drug Administration has long approved the use of IVIg to treat other conditions, but not Alzheimer's.
More information
The U.S. National Institute on Aging has more about Alzheimer's disease.
Alzheimer's, Cholesterol Gene Linked
By LINDSEY TANNER, AP Medical Writer
CHICAGO - A variation in a gene that is supposed to help the brain break down cholesterol may play a role in some cases of Alzheimer's disease (news - web sites), researchers say.
A study found that people with this variant form face double the risk of developing late-onset Alzheimer's, the most common form of the disease. It typically develops after age 65.
The gene, called CYP46, is involved in production of an enzyme that helps break down excess cholesterol in the brain. The research suggests that the variation might hamper production of the enzyme, resulting in a buildup in the brain of cholesterol and a gummy protein called beta amyloid.
The research, though preliminary, fits in with growing evidence that elevated cholesterol levels may raise the risk of Alzheimer's.
It also adds to evidence that genetics are involved. Late-onset Alzheimer's already has been linked to another genetic variation in a different gene involved in helping transport cholesterol throughout the body. That variation is called APOE-4.
In the new study, patients with both the CYP46 and APOE-4 variants were almost 10 times more likely to develop the mind-robbing disease than those with neither variation. They also had the highest brain levels of beta amyloid.
Autopsies also showed participants with just the CYP46 variant had significantly more beta amyloid deposits than those without the variant.
Dr. Andreas Papassotiropoulos at the University of Zurich and colleagues studied more than 400 European patients with or without Alzheimer's. The CYP46 variant was found in about 40 percent of participants.
The findings appear in January's Archives of Neurology.
Most of the estimated 4 million Americans with Alzheimer's have late-onset disease. It affects about one in 10 Americans over age 65 and nearly half of those over 85, according to the Alzheimer's Association.
An increasing number of studies suggest that cholesterol plays an important role in regulating beta amyloid.
Studies such as Papassotiropoulos' suggest that inhibiting cholesterol breakdown in the brain "might represent a viable treatment" for Alzheimer's, Dr. Benjamin Wolozin of Loyola University Medical Center in Maywood, Ill., said in an accompanying editorial.
Abnormality of Gait as a Predictor of Non-Alzheimer's Dementia
from NEW ENGLAND JOURNAL OF MEDICINE 11/28/2002
ABSTRACT
Background Neurologic abnormalities affecting gait occur early in several types of non-Alzheimer's dementias, but their value in predicting the development of dementia is uncertain.
Methods We analyzed the relation between neurologic gait status at base line and the development of dementia in a prospective study involving 422 subjects older than 75 years of age who lived in the community and did not have dementia at base line. Cox proportional-hazards regression analysis was used to calculate hazard ratios with adjustment for potential confounding demographic, medical, and cognitive variables.
Results At enrollment, 85 subjects had neurologic gait abnormalities of the following types: unsteady gait (in 31 subjects), frontal gait (in 12 subjects), hemiparetic gait (in 11 subjects), neuropathic gait (in 11 subjects), ataxic gait (in 10 subjects), parkinsonian gait (in 8 subjects), and spastic gait (in 2 subjects). During follow-up (median duration, 6.6 years), there were 125 newly diagnosed cases of dementia, 70 of them cases of Alzheimer's disease and 55 cases of non-Alzheimer's dementia (47 of which involved vascular dementia and 8 of which involved other types of dementia). Subjects with neurologic gait abnormalities had a greater risk of development of dementia (hazard ratio, 1.96 [95 percent confidence interval, 1.30 to 2.96]). These subjects had an increased risk of non-Alzheimer's dementia (hazard ratio, 3.51 [95 percent confidence interval, 1.98 to 6.24]), but not of Alzheimer's dementia (hazard ratio, 1.07 [95 percent confidence interval, 0.57 to 2.02]). Of non-Alzheimer's dementias, abnormal gait predicted the development of vascular dementia (hazard ratio, 3.46 [95 percent confidence interval, 1.86 to 6.42]). Among the types of abnormal gait, unsteady gait predicted vascular dementia (hazard ratio, 2.61), as did frontal gait (hazard ratio, 4.32) and hemiparetic gait (hazard ratio, 13.13).
Conclusions The presence of neurologic gait abnormalities in elderly persons without dementia at base line is a significant predictor of the risk of development of dementia, especially non-Alzheimer's dementia.
Source Information
From the Department of Neurology (J.V., R.B.L., C.B.H., G.K., M.J.K., H.B.) and the Department of Epidemiology and Social Medicine (R.B.L., C.B.H.), Albert Einstein College of Medicine, Bronx, N.Y.; and Innovative Medical Research and the Center for Healthier Aging (Advanced PCS), Hunt Valley, Md. (R.B.L.).
Address reprint requests to Dr. Verghese at the Einstein Aging Study, Albert Einstein College of Medicine, 1165 Morris Park Ave., Bronx, NY 10461, or at jverghes@aecom.yu.edu.
MEDLINE Abstracts: Antioxidants and the Aging Brain
Medscape Neurology & Neurosurgery 4(2), 2002. © 2002 Medscape
Posted 09/27/2002
Antioxidant Strategies for Alzheimer's Disease
Grundman M, Grundman M, Delaney P
Proc Nutr Soc. 2002;61:191-202
Oxidative damage is present within the brains of patients with Alzheimer's disease (AD), and is observed within every class of biomolecule, including nucleic acids, proteins, lipids and carbohydrates. Oxidative injury may develop secondary to excessive oxidative stress resulting from beta-amyloid-induced free radicals, mitochondrial abnormalities, inadequate energy supply, inflammation or altered antioxidant defences.
Treatment with antioxidants is a promising approach for slowing disease progression to the extent that oxidative damage may be responsible for the cognitive and functional decline observed in AD. Although not a uniformly consistent observation, a number of epidemiological studies have found a link between antioxidant intake and a reduced incidence of dementia, AD and cognitive decline in elderly populations. In AD clinical trials molecules with antioxidant properties such as vitamin E and Ginkgo biloba extract have shown modest benefit.
A clinical trial with vitamin E is currently ongoing to determine if it can delay progression to AD in individuals with mild cognitive impairment. Combinations of antioxidants might be of even greater potential benefit for AD, especially if the agents worked in different cellular compartments or had complementary activity (e.g. vitamins E, C and ubiquinone). Naturally-occurring compounds with antioxidant capacity are available and widely marketed (e.g. vitamin C, ubiquinone, lipoic acid, beta-carotene, creatine, melatonin, curcumin) and synthetic compounds are under development by industry. Nevertheless, the clinical value of these agents for AD prevention and treatment is ambiguous, and will remain so until properly designed human trials have been performed.
Nutrition Interventions in Aging and Age-Associated Disease
Meydani M, Meydani M
Proc Nutr Soc. 2002;61:165-171
Aging is a complex biological process, which usually is accompanied by changes in socio-economic status, which may have a great impact on the physical and nutritional status of the elderly. Decreased food intake and a sedentary lifestyle in the growing numbers of the elderly increase their risk for malnutrition, decline of bodily functions and developing chronic diseases.
Oxidative stress is believed to be an important factor in aging and many age-associated degenerative diseases. Modulation of oxidative stress by energy restriction in animals has been shown to be one of the mechanisms for retarding the aging process. Dietary antioxidants are regarded as being important in modulating oxidative stress of aging and age-associated diseases. Supplementation of the elderly with vitamin E has been shown to enhance immune response, delay onset of Alzheimer's disease, and increase resistance to oxidative injury associated with exercise. Vitamin E, in comparison with other antioxidants, is also effective in reducing viral titres, but not the longevity of middle-aged mice.
Our studies have indicated that polyphenols or vitamin E may assist in preventing cardiovascular disease, in part by decreasing expression by endothelial cells of proinflammatory cytokines, adhesion molecules, and monocyte adhesion. Most recently, we have found that some of these antioxidants may prevent tumour growth by inhibiting angiogenesis via suppression of interleukin 8 and modulation of the cell junction molecule, VE-cadherin. These findings provide further support for the consumption of fruit and vegetables, which contain several forms of phytochemicals with antioxidant activity, in order to reduce the risk of cardiovascular disease and cancer, the leading causes of morbidity and mortality among the elderly.
Vitamin e and Cognitive Decline in Older Persons
Morris MC, Evans DA, Bienias JL, et al
Arch Neurol. 2002;59:1125-1132
Background: Previous studies raise the possibility that antioxidants protect against neurodegenerative diseases.
Objective: To examine whether intake of antioxidant nutrients, including vitamin E, vitamin C, and carotene, is associated with reduced cognitive decline with age.
Design: Longitudinal population-based study conducted from September 17, 1993, to November 20, 2000, with an average follow-up of 3.2 years.
Patients: The patients were 2889 community residents, aged 65 to 102 years, who completed a food frequency questionnaire, on average 18 months after baseline.
Main Outcome Measure: Cognitive change as measured by 4 tests (the East Boston Memory Test, which tests immediate and delayed recall; the Mini-Mental State Examination; and the Symbol Digit Modalities Test) at baseline and 3 years for all participants, and at 6 months for 288 randomly selected participants.
Results: We used random-effects models to estimate nutrient effects on individual change in the average score of the 4 cognitive tests. The cognitive score declined on average by 5.0 x 10(-2) standardized units per year. There was a 36% reduction in the rate of decline among persons in the highest quintile of total vitamin E intake (-4.3 x 10(-2) standardized units per year) compared with those in the lowest quintile (-6.7 x 10(-2) standardized units per year) (P =.05), in a model adjusted for age, race, sex, educational level, current smoking, alcohol consumption, total calorie (energy) intake, and total intakes of vitamin C, carotene, and vitamin A. We also observed a reduced decline with higher vitamin E intake from foods (P =.03 for trend). There was little evidence of association with vitamin C or carotene intake.
Conclusion: Vitamin E intake, from foods or supplements, is associated with less cognitive decline with age.
Diets Enriched in Foods With High Antioxidant Activity Reverse Age-Induced Decreases in Cerebellar Beta -Adrenergic Function and Increases in Proinflammatory Cytokines
Gemma C, Mesches MH, Sepesi B, et al
J Neurosci. 2002;22:6114-6120
Antioxidants and diets supplemented with foods high in oxygen radical absorbance capacity (ORAC) reverse age-related decreases in cerebellar beta-adrenergic receptor function. We examined whether this effect was related to the antioxidant capacity of the food supplement and whether an antioxidant-rich diet reduced the levels of proinflammatory cytokines in the cerebellum.
Aged male Fischer 344 rats were given apple (5 mg dry weight), spirulina (5 mg), or cucumber (5 mg) either in 0.5 ml water by oral gavage or supplied in the rat chow daily for 14 d. Electrophysiologic techniques revealed a significant decrease in beta-adrenergic receptor function in aged control rats. Spirulina reversed this effect. Apple (a food with intermediate ORAC) had an intermediate effect on cerebellar beta-adrenergic receptor physiology, and cucumber (low ORAC) had no effect, indicating that the reversal of beta-adrenergic receptor function decreases might be related to the ORAC dose.
The mRNA of the proinflammatory cytokines tumor necrosis factor-alpha (TNFalpha) and TNFbeta was also examined. RNase protection assays revealed increased levels of these cytokines in the aged cerebellum. Spirulina and apple significantly downregulated this age-related increase in proinflammatory cytokines, whereas cucumber had no effect, suggesting that one mechanism by which these diets work is by modulation of an age-related increase in inflammatory responses. Malondialdehyde (MDA) was measured as a marker of oxidative damage. Apple and spirulina but not cucumber decreased MDA levels in the aged rats. In summary, the improved beta-adrenergic receptor function in aged rats induced by diets rich in antioxidants is related to the ORAC dose, and these diets reduce proinflammatory cytokine levels.
Antioxidant Property of Celastrus paniculatus willd.: A Possible Mechanism in Enhancing Cognition
Kumar MH, Gupta YK
Phytomedicine. 2002;9:302-311
In the present study aqueous, methanolic, chloroform and petroleum ether extracts of seeds of Celastrus paniculatus were investigated for their effect on cognitive functions in rats. Male Wistar rats weighing 200-250 g each were used to study effect on learning and memory through use of the shuttle-box, step-through, step-down and elevated plus maze paradigms. Only the aqueous seed extract (200 mg/kg body wt. for 14 days) showed an improvement in learning and memory in both the shuttle-box and step-through paradigms. Therefore, further experiments were conducted using the aqueous extract at 100, 200 and 300 mg/kg body wt. doses in different paradigms of cognition. All three doses of the aqueous extract increased the number of avoidances in the shuttle-box and step-through latency the in step-through apparatus, but no significant difference was observed between the doses tested. In the step-down apparatus, the 200- and 300-mg/kg body wt. doses of aqueous extract showed a significant increase in step-down latency, whereas no significant difference was observed in the elevated-plus-maze paradigm between drug-treated and vehicle-treated groups. Since the behavioral impairments are associated with oxidative stress, we investigated the effect of the aqueous extract on oxidative stress parameters. Among the three doses tested, only 200 and 300 mg/kg body wt. stimulated a significant decrease in the brain levels of malondialdehyde, with simultaneous significant increases in levels of glutathione and catalase. The present findings indicate that the aqueous extract of Celastrus paniculatus seed has cognitive-enhancing properties and an antioxidant effect might be involved.
Serum Antioxidant Capacity in Neurological, Psychiatric, Renal Diseases and Cardiomyopathy
Sofic E, Rustembegovic A, Kroyer G, Cao G
J Neural Transm. 2002;109:711-719
Summary: The role of free radicals (FR) in the pathogenesis and in the progression of many diseases has been often discussed, but not widely investigated. However, the total antioxidant capacity in the serum seems to be of great evidence. Total antioxidant capacity was determined using oxygen absorbance capacity assay (ORAC) in serum of patients suffering from depression, schizophrenia, Alzheimer's disease (AD), anorexia nervosa, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), AIDS-encephalopathy, diabetic polyneuropathy (PNP), cardiomyopathy (CM), renal disease, and healthy individuals as controls (C). The results showed that the total antioxidant capacity in serum decreased significantly (p < 0.01) by 24, 20, 13, and 17% for anorexia nervosa, AIDS-encephalopathy, PNP and CM respectively. In serum of patients with renal disease significantly elevated antioxidant capacity was found. The data indicated that increased oxidative stress can be involved in the pathogenesis or in the progression of PNP and CM. Decrease of serum antioxidant capacity in patients with anorexia nervosa and AIDS-encephalopathy are probably due primarily to malnutrition and secondly to insufficient antioxidant and immune system. In renal disease, the accumulation of urea in serum seems to be responsible for high antioxidant capacity. In contrast, there were no changes in PD, AD, depression syndrome and schizophrenia.
Treating High Blood Pressure May Stave Off Dementia
Mon Oct 14, 6:11 PM ET
By Linda Carroll
NEW YORK (Reuters Health) - Medications to lower blood pressure may help stave off dementia and Alzheimer's disease (news - web sites), two new studies show.
One, a large European trial, found that anti-hypertensive medications reduced the risk of dementia by 55% among patients who initially had high blood pressure, according to the report published in the Archives of Internal Medicine (news - web sites).
A second study published in the same journal found that blood-pressure lowering drugs were associated with a decrease in the risk of mental decline in elderly African Americans.
"It is important to make the point that, increasingly, the medical-scientific community is recognizing that common cardiovascular risk factors--such as high blood pressure, high cholesterol and diabetes--are predictive not only for the development of vascular dementia, but also for Alzheimer's disease, the more common form of neurodegenerative dementia," Dr. Jan Staessen, the European trial's co-author, said in an interview with Reuters Health. Staessen is a researcher with the University of Leuven in Belgium.
Staessen and his colleagues determined that the drugs protected best against Alzheimer's disease. "The majority of dementia cases prevented would have been Alzheimer's," he noted.
In the European study, researchers followed 2,902 patients, who were originally part of a trial to test the impact of anti-hypertensive medications on the risk of stroke. The patients all were at least 60 years old and had no observable mental impairment.
During the original trial, 1,417 of the patients received a placebo, while 1,485 were treated with blood-pressure lowering medications. At the end of the stroke study, all the patients were allowed to take the blood-pressure lowering medications and researchers continued to monitor all study participants for any decline in mental ability.
The researchers found that mental decline was most common among patients who had been assigned to the placebo group. Among these patients, there were 43 cases of dementia (29 were Alzheimer's), as compared to 21 cases (12 Alzheimer's) among study participants who had been taking anti-hypertensive medications all along.
Findings of the study of African Americans were similar. That study, led by Michael D. Murray, followed 1,900 patients 65 or older who had no signs of mental impairment at the study's outset.
Twice during the course of the five-year study, Murray and his colleagues tested patients' mental abilities and recorded medications patients were taking.
After five years, 288 patients showed some decline in their mental ability.
After factoring in the effects of age, sex, education, initial mental function scores and heart disease, the researchers found that patients who took anti-hypertensive medications were 38% less likely to show declines in their mental abilities. "The results of this longitudinal analysis of long-term drug effects indicate that antihypertensive medications reduce the risk of cognitive impairments in older African Americans," conclude Murray, a researcher with Indiana University School of Medicine in Indianapolis, and colleagues.
Murray and his team didn't speculate as to how the drugs might protect the brain.
And while Staessen and his colleagues aren't yet sure why the blood-pressure lowering drugs help, he's got some ideas.
"Two explanations for our findings are possible," he said. "A small difference in blood pressure persisted during most of the follow-up between patients initially randomized to placebo and active treatment--blood pressures were lower in the active treatment group. So lower blood pressure might explain the better outcome."
But not all studies have shown that anti-hypertensive medications reduce the risk of mental decline, he added. An alternative hypothesis, he said, is that one of the medications, a calcium-channel blocker, might offer specific protection against Alzheimer's disease.
"Laboratory experiments have shown that intracellular calcium plays an important role in causing the death of brain cells," Staessen added. Studies have also shown that the calcium channel blocker used in the study can enter the brain and "bind to receptors in those areas of the brain affected by Alzheimer's disease, and that it can restore the neurotransmitters that become deficient in Alzheimer's."
SOURCE: Archives of Internal Medicine 2002;162.
Company: Janssen Research
Approval Status: Approved February 2001
Treatment for: Mild to moderate dementia of the Alzheimer's type
Reminyl is an Alzheimer's treatment derived from the bulbs of the daffodil, Narcissus pseudonarcissus. It is believed that neurons producing the neurotransmitter acetylcholine degenerate in the brains of patients with Alzheimer's disease. This loss of acetylcholine has been correlated with decreased cognitive function (thinking, remembering and reasoning). Reminyl works to increase the concentration of acetylcholine by blocking the action of acetylcholinesterase, an enzyme that catalyzes the hydrolysis (break down) of acetylcholine.
An estimated four million Americans have Alzheimer's disease -- a progressive loss of cognitive function so severe that it interferes with an individual's ability to function. The number is expected to grow to 14 million by the middle of the next century. The disorder is the third-most expensive illness
Plasma Homocysteine and Alzheimer's Disease
A cohort of 1092 elderly subjects who were free of dementia were studied prospectively. After a median of eight years of follow-up, dementia had developed in 111 subjects. Even after adjustment for other known risk factors, an elevated plasma total homocysteine level at base line was an independent predictor of the development of clinical dementia, most cases of which were caused by Alzheimer's disease. The risk of Alzheimer's disease was nearly doubled for those with the highest plasma homocysteine levels.
This prospective, observational study greatly strengthens the evidence for an association between the plasma homocysteine level and the risk of dementia. Since folic acid supplementation can reduce plasma homocysteine levels, this report suggests an intervention that may help prevent dementia.
Study Gives Clues To Workings Of Anti-Alzheimer Antibody
St. Louis, July 3, 2001 — New research in mice may explain why certain antibodies could slow or reverse changes in the brain that are characteristic of Alzheimer’s disease.
The study, conducted by researchers at Washington University School of Medicine in St. Louis and Eli Lilly and Company, used an antibody that targets a particular region on the amyloid-beta protein. The amyloid-beta protein accumulates in the brain to form the amyloid plaques, a major feature of Alzheimer’s disease. The study is published in the July 3 issue of the Proceedings of the National Academy of Sciences Early Edition.
"We think the antibody is drawing amyloid-beta out of the brain and into the blood as a clearance mechanism," says senior author David M. Holtzman, M.D., associate professor of neurology at the School of Medicine. "Within hours of injecting the antibody into mice, the concentration of amyloid-beta in the bloodstream rose approximately 1,000 times higher than it had been before the injection. The antibody was binding all the amyloid-beta in the blood as well as additional amyloid-beta as it entered the blood from the brain. Since most of the amyloid-beta in the blood is derived from the brain in these mice, the antibody appeared to be facilitating the removal of amyloid-beta from the brain into the blood."
The team’s results support this theory since animals injected with the antibody over a period of months developed fewer amyloid plaques in the brain than did control animals.
The researchers found that after injection, the antibody m266 remained in the animals’ bloodstream and did not react directly with amyloid plaques in brain tissue. Typically, very little antibody in the blood (less than 0.1 percent) enters the brain or cerebral spinal fluid, the fluid that surrounds the brain. Nonetheless, the antibody, in addition to causing an increase in amyloid-beta in the blood, also transiently increased the amount of soluble amyloid-beta protein in the cerebral spinal fluid. "Our work is distinguished from previous research in that we have discovered that this particular antibody can be administered into the bloodstream and need not necessarily gain access to the brain and directly attack amyloid plaque to be effective in reducing plaques," says co-investigator Steven M. Paul, M.D., group vice president at Lilly Research Laboratories. "Thus, our work suggests a new mechanism by which certain anti-amyloid antibodies could be useful in preventing or treating Alzheimer’s."
The experiment involved two control groups of mice that received injections of either saline or a control antibody and a group of mice that received m266 antibody injections. The injections were administered every other week beginning at four months of age. At nine months of age, each mouse was examined for plaque development. In the control groups, about 40 percent of the animals had developed significant amounts of amyloid plaques. Only about seven percent of the mice in the m266 antibody-treated group developed significant plaques.
The difference between the two control groups and the group receiving the antibody was statistically significant.
The research team now is working to understand the detailed mechanism of how the antibody exerts its effect. The research has potential implications for both diagnosis and treatment of Alzheimer’s disease.
Reference: DeMattos RB, Bales KR, Cummins DJ, Dodart J-C, Paul SM, Holtzman DM. Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer’s disease, Proceedings of the National Academy of Sciences Early Edition, 2(27), July 3, 2001.
Eli Lilly and Company funded this research and provided the reagents for this study.
The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
Lilly, a leading innovation-driven corporation, is developing a growing portfolio of best-in-class pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations. Headquartered in Indianapolis, Ind., Lilly provides answers – through medicines and information – for some of the world's most urgent medical needs. Additional information about Lilly is available at http://www.lilly.com.
SOURCE: Nature 2002;417:231-233, 254-259.
Antioxidants Fight Alzheimer's
Eating foods rich in vitamins C and E may fend off Alzheimer's
disease. That's the finding of two studies published in the
Journal of the American Medical Association. The first study
looked at 815 Chicago residents aged 65 and older who initially
had no symptoms of mental decline. Researchers questioned them
about their diets and followed them for about four years, during
which time 131 of the people were diagnosed with Alzheimer's.
After taking into consideration other factors that affect
Alzheimer's risk, the researchers concluded that the people who
reported eating the most vitamin E-rich foods had a 70 percent
lower risk of developing the disease compared to those who
consumed the least dietary vitamin E. This study also suggested
some protective benefit from vitamin C, although the results were
not definitive. The second study looked at 5,395 people aged 55
and up in the Netherlands. They were followed for six years,
during which time 146 people developed Alzheimer's disease. The
researchers found that high intakes of vitamin C and E lowered
the risk of Alzheimer's, even in people who had a gene variant
linked to the disease. Taken together, the two studies suggest
that antioxidant rich foods have a protective effect, but not
vitamin supplements; however, the researchers say more study is
needed on the matter, The Associated Press reports.
