35 replies to this topic

[kevin]

As it is with many diseases, forewarned is forearmed, and such is the case with Alzheimers. Soon we will have DNA testing that will be able to tell us whether or not we are predisposed to many many possible disorders that we may be adjust our lifestyles to avoid promoting their progression or prevent their occurence altogether. At this point it is nice to know that there are emerging technologies which will allow for the diagnosis of one of the most deblilitating and heart breaking old-age related diseases at unprecedented earlier stages.

----------------------------------
Finding Alzheimer's earlier
August 11, 2003

------------------------------
A new electrical brain test can detect the onset of Alzheimer's disease at stages earlier than ever before.
So says a study in the new issue of the Journal of Clinical Electroencephalography.

The study by brain researcher Dr Eric Braverman suggests the 10-minute electrical brain-mapping test could be an important aid for doctors. That's because early detection of Alzheimer's means more effective treatment options with higher rates of success.

Through targeted interventions - including drugs, natural hormones, nutrition and diet - we can reverse the onset of disease, but the results are far better early on, before the condition progresses. That's why early detection is critical, Braverman says in a news release.

He tested more than 1 500 people who were patients at his New York City practice.

For the first time, this test gives us the ability to identify patients who are developing Alzheimer's before they actually get the disease, says Braverman, who is physician-director of PATH Medical, a neuro-psychiatric research group. - (HealthDayNews

Edited by kevin, 14 August 2003 - 07:35 PM.

[kevin]

Public release date: 30-Jul-2003

Contact: Holly Korschun
hkorsch@emory.edu
404-727-3990
Emory University Health Sciences Center

Emory scientists contribute to study of key regulatory protein in neurodegeneration

ATLANTA--A multi-institutional team of scientists has gained important new knowledge about the regulatory role played in Alzheimer's disease by Pin1, a protein that coaxes other proteins into untwisting. The research is published in the July 31 issue of Nature.
The team of researchers, including a group from the Department of Human Genetics at Emory University School of Medicine, examined slices of brain and found an inverse relationship between the abundance of Pin1 and both the susceptibility of neurons to degenerative damage and the amount of protein tangles. They also found that mice with an artificial disruption of Pin1 develop a neurodegenerative disease that resembles Alzheimer's.

Lead authors are Drs. Yih-cherng Liou, Anyang Sun, and Kun Ping Lu from Harvard Medical School. Xiaojiang Li, PhD and Zhao-Xue Yu, PhD from Emory School of Medicine studied the degeneration in the brains of Pin1-deficient mice using electron microscopy and immunogold staining. Scientists from the University of Kentucky, the Salk Institute, and Tufts University also contributed to the study.

Scientists studying Alzheimer's disease and other neurodegenerative diseases resemble detectives poring over a crime scene in a mystery novel. They have identified a couple of suspicious individuals––proteins that form disruptive tangles and knots in the brain. The detectives can piece together how the crime was committed, but they still have questions about some characters standing in the shadows. They want to know not only how, but why.

In Alzheimer's disease, amyloid precursor protein (APP) and tau form aggregated tangles in the brain: APP outside and between cells, tau within the neurons. "It is clear that both proteins play a role in the Alzheimer's disease mechanism, but there is some disagreement about which one is more important," says Dr. Li.

Pin1, part of a class of enzymes called prolyl isomerases, is known to regulate many proteins critical for cell division. Pin1 twists the joints of proteins in specific creaky places, allowing them to change shape. However, it previously was unclear whether Pin1 helped to promote or prevent tangles. Dr. Lu's laboratory at Harvard had the opportunity to examine the situation in the living brain using Pin1-deficient mice. They had previously found that Pin1 is necessary for proper development of the retina and mammary glands.

Dr. Li's group joined the effort to analyze the Pin1-deficient brains in a way that was complementary to the biochemical methods used by the Harvard group. They found that the Pin-1-negative mice had degenerating neurons similar to those in Alzheimer's disease. Dr. Li says it is also important to investigate the connection between Pin1 and APP, which clogs up the brain outside the neurons in Alzheimer's disease. "The access of many enzymes to tau and APP could be regulated by Pin1," he says. "And Pin1 regulates many proteins, not just tau and APP. This research is really at the crossroads." Dr. Li hypothesizes that Pin1 loss of function could contribute to other neurodegenerative diseases like Parkinson's and Huntington disease.


###

[kevin]

Public release date: 30-Jul-2003
http://www.eurekaler...--urc072803.php

Contact: Tom Vasich
tmvasich@uci.edu
949-824-6455
University of California - Irvine

UCI resarchers create first living model to exhibit
Unique triple-transgenic mouse offers chance to develop single class of drugs

Irvine, Calif. -- A newly engineered, genetically altered mouse will allow researchers for the first time to study the two signature lesions of Alzheimer's disease in a single organism [- a model that closely matches how the disease develops in the human brain. Created by UC Irvine neurobiologists Frank LaFerla and Salvatore Oddo, the mouse is expected to provide a better "living laboratory" for understanding how these lesions grow, aiding efforts to find an effective treatment for both the sporadic and inherited forms of the disease.
"For the first time, plaque and tangle lesion formations can be studied together, letting us understand the relationship between the two lesions and dissect the processes by which they may be connected," said LaFerla, a professor of neurobiology and behavior, and senior author of the study, which appears in the July 31 issue of Neuron.

Plaque lesions grow on the outside of healthy cells, cutting off their ability to communicate with other cells, while tangle lesions grow inside of neural cells and clog signaling pathways. Plaque lesions are factors in the early-onset inherited and sporadic forms of the disease, and tangle lesions are found primarily in the sporadic form.

According to LaFerla, the mouse will be valuable in the search for drugs that can target both lesions. "This may eventually lead to a single class of drugs for treating both the inherited and sporadic forms of the disease," he said. "We now have the ability to study a wider spectrum of Alzheimer's disease than previously possible."

LaFerla and Oddo created the mouse by genetically altering it to host three mutant human genes that foster lesion growth: beta-amyloid precursor protein (âAPP), presenilin-1 and tau. âAPP is the source of the beta-amyloid protein that forms into brain plaques, while presenilin-1 is needed for this protein to form. Tau is the critical component of tangles.

Using the triple-transgenic mouse, the UCI researchers have already traced the sequence of molecular events leading to the disease. Significantly, they found that beta-amyloid plaques appeared first in the mouse brain, and tau-laden tangles appeared later. This suggests that beta-amyloid may be the initiating component of both sporadic and familial Alzheimer's disease.

"This finding confirms the human genetic data indicating that plaques are the earliest pathological feature of the disease," said LaFerla. The UCI researchers also found that beta-amyloid can accumulate in neural cells before plaques or tangles form. This appears to diminish the function of brain synapses, which may lead to memory impairments, the signature feature of Alzheimer's disease. The researchers found this was the earliest pathological change that occurred in their mice and will further investigations into the condition in humans.

Alzheimer's disease is the most common cause of dementia, afflicting more than four million Americans. The majority of Alzheimer's cases are sporadic, striking individuals at random as opposed to running in families. Generally, the sporadic form afflicts individuals older than 65. A small percentage of cases are passed down from one generation to another and generally have a much earlier onset, usually in the 40s or 50s, but sometimes as young as 16 years of age. Other than the age of onset, both forms are fairly similar.

The National Institute for Aging and the Alzheimer's Association funded the research.

About the triple-transgenic mouse

Transgenic mice have enabled researchers to observe experimentally what happens to an entire organism during the progression of a disease. In many areas, they are already the leading models for studying human diseases and their treatments.

To create these mice, UCI researchers injected foreign genetic material (generally, human genes harboring disease-causing mutations) into fertilized mouse eggs. When the mice were born, the ones producing the human proteins typically developed the designated traits or disease phenotype, and in the case for the mice in this study, the Alzheimer-type pathology.

Because mice don't normally develop Alzheimer's pathology, the only way to reproduce it in mice was to have them overproduce the human proteins associated with the disease. LaFerla and Oddo created the model for this study by injecting âAPP and tau genes into single-cell embryos from single-transgenic mice already harboring the presenilin-1 gene. This method assured that future generations would inherit the genetic material as one unit.

Because of this, the mice will be easy to breed and have the same genetic background. This is an important feature for analyzing the behavior of these mice and for evaluating drugs, since the researchers won't have to worry about the confounding effects associated with mice with different genetic backgrounds. It is anticipated that this unique mouse model will prove to be extremely useful in the preclinical evaluation of potential Alzheimer drugs.

[shpongled]

Alpha lipoic acid aids in the reduction of AGEs and beta-amyloid peptides, both features of Alzheimer's disease.

=====================================================
Alzheimers Dis. 2003 Feb;5(1):25-30.


Advanced glycation endproducts cause lipid peroxidation in the human neuronal cell line SH-SY5Y.

Gasic-Milenkovic J, Loske C, Munch G.

Neuroimmunological Cell Biology Unit, Interdisciplinary Center for Clinical Research (IZKF) Leipzig, Germany.

Advanced glycation endproducts (AGEs), sugar-derived protein modifications and lipid peroxidation products are prominent features of Alzheimer's disease. AGEs accumulate on beta-amyloid plaques during the course of the disease and can exert chronic oxidative stress via receptor-mediated mechanisms. Lipid peroxidation products such as hydroxynonenal, further markers of oxidative stress, are also increased in Alzheimer's diesease. In this study we present evidence for a direct biochemical link between AGEs and lipid peroxidation. Our results show that AGEs induce lipid peroxidation in a neuronal cell line in a dose-dependant manner, and that blocking the specific AGE-receptor RAGE, as well as using different antioxidants (alpha-lipoic acid, N-acetylcysteine, 17 beta-estradiol or aminoguanidine) can reduce the AGE-mediated formation of lipid peroxidation products. Thus, both RAGE antagonists and scavengers of oxygen free radicals could be useful in protecting brain tissue from lipid peroxidation and its pathophysilogical consequences that occur in Alzheimer's disease.
=====================================================
Neurosci Lett. 2001 Oct 26;312(3):125-8.


Alpha-lipoic acid protects rat cortical neurons against cell death induced by amyloid and hydrogen peroxide through the Akt signalling pathway.

Zhang L, Xing GQ, Barker JL, Chang Y, Maric D, Ma W, Li BS, Rubinow DR.

Behavioral Endocrinology Branch, NIMH, NIH, Building 10, Room 3N238, Bethesda, MD 20892, USA. zhangl@codon.nih.gov

Substantial evidence suggests that the accumulation of beta-amyloid (Abeta)-derived peptides contributes to the aetiology of Alzheimer's disease (AD) by stimulating formation of free radicals. Thus, the antioxidant alpha-lipoate, which is able to cross the blood-brain barrier, would seem an ideal substance in the treatment of AD. We have investigated the potential effectiveness of alpha-lipoic acid (LA) against cytotoxicity induced by Abeta peptide (31-35) (30 microM) and hydrogen peroxide (H(2)O(2)) (100 microM) with the cellular 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) reduction and fluorescence dye propidium iodide assays in primary neurons of rat cerebral cortex. We found that treatment with LA protected cortical neurons against cytotoxicity induced by Abeta or H(2)O(2). In addition, LA-induced increase in the level of Akt in the neurons was observed by Western blot. The LA-induced neuroprotection and Akt increase were attenuated by pre-treatment with the phosphatidylinositol 3-kinase inhibitor, LY294002 (50 microM). Our data suggest that the neuroprotective effects of the antioxidant LA are partly mediated through activation of the PKB/Akt signaling pathway.
=====================================================

[shpongled]

A snippet on a possible beneficial role of creatine supplementation in Alzheimer's. From [Curr Opin Clin Nutr Metab Care. 2000 Nov;3(6):497-502]. The abstract is available here: http://www.ncbi.nlm....7&dopt=Abstract. The studies they referenced are below, as well.
=====================================================
Diseases such as Alzheimer's and Parkinson's disease are associated with aging, and an increase in oxidative stress is noted in both of these conditions [48,49]. Animal studies have shown neuroprotection from glutamate and amyloid toxicity (the latter being seen in Alzheimer's disease) [50], as well as 1-methyl-4-phenyl-1,2,3 6-tetrahydopyridine (MPTP) toxicity (a model of Parkinson's disease) [25], and in a transgenic murine familial amyotrophic lateral sclerosis model (FALS G93A transgenic) [26••]. Studies have also shown neuronal cytoprotection during hypoxia [51,52] with creatine monohydrate in animal models [53].
=====================================================
25 Matthews RT, Ferrante RJ, Klivenyi P, et al. Creatine and cyclocreatine attenuate MPTP neurotoxicity. Exp Neurol 1999; 157:142-149. [Medline Link] [BIOSIS Previews Link] [Context Link]

26•• Klivenyi P, Ferrante RJ, Matthews RT, et al. Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis. Nat Med 1999; 5:347-350. [Medline Link] [BIOSIS Previews Link] A very interesting study reporting that creatine monohydrate supplementation delayed the onset of motor dysfunction in an animal model of amyotrophic lateral sclerosis. This study also demonstrated a lesser oxidative stress and a higher energy charge in the animals supplemented with creatine monohydrate. [Context Link]

48 Mecocci P, MacGarvey U, Beal MF. Oxidative damage to mitochondrial DNA is increased in Alzheimer's disease. Ann Neurol 1994; 36:747-751. [Medline Link] [Context Link]

49 Pennathur S, Jackson-Lewis V, Przedborski S, Heinecke JW. Mass spectrometric quantification of 3-nitrotyrosine, ortho-tyrosine, and o,o'-dityrosine in brain tissue of 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-treated mice, a model of oxidative stress in Parkinson's disease. J Biol Chem 1999; 274:34621-34628. [Medline Link] [BIOSIS Previews Link] [Context Link]

50 Brewer GJ, Wallimann TW. Protective effect of the energy precursor creatine against toxicity of glutamate and beta-amyloid in rat hippocampal neurons. J Neurochem 2000; 74:1968-1978. [Medline Link] [BIOSIS Previews Link] [Context Link]

51 Carter AJ, Muller RE, Pschorn U, Stransky W. Preincubation with creatine enhances levels of creatine phosphate and prevents anoxic damage in rat hippocampal slices. J Neurochem 1995; 64:2691-2699. [Medline Link] [BIOSIS Previews Link] [Context Link]

52 Balestrino M, Rebaudo R, Lunardi G. Exogenous creatine delays anoxic depolarization and protects from hypoxic damage: dose-effect relationship. Brain Res 1999; 816:124-130. [Medline Link] [BIOSIS Previews Link] [Context Link]

53 Wilken B, Ramirez JM, Probst I, Richter DW, Hanefeld F. Anoxic ATP depletion in neonatal mice brainstem is prevented by creatine supplementation. Arch Dis Child Fetal Neonatal Ed 2000; 2:F224-F227. [Fulltext Link] [Medline Link] [Context Link]

[kevin]

http://www.eurekaler...u-tpc081803.php

Public release date: 18-Aug-2003
Contact: Megan Fellman
fellman@northwestern.edu
847-491-3115
Northwestern University

Toxic protein could explain Alzheimer's and lead to breakthroughs

EVANSTON, Ill. -- Researchers at Northwestern University have discovered for the first time in humans the presence of a toxic protein that they believe to be responsible for the devastating memory loss found in individuals suffering from Alzheimer's disease.
An understanding of this key molecular link in the progression of Alzheimer's could lead to the development of new therapeutic drugs capable of reversing memory loss in patients who are treated early, in addition to preventing or delaying the disease. Help for individuals with pre-Alzheimer's memory failure (mild cognitive impairment) also is envisioned. The findings will be published online by the Proceedings of the National Academy of Sciences during the week of Aug. 18.

The research team, led by William L. Klein, professor of neurobiology and physiology, found up to 70 times more small, soluble aggregated proteins called "amyloid b-derived diffusible ligands" (ADDLs, pronounced "addles") in the brain tissue of individuals with Alzheimer's disease compared to that of normal individuals.

The clinical data strongly support a recent theory in which ADDLs accumulate at the beginning of Alzheimer's disease and block memory function by a process predicted to be reversible. ADDLs have the ability to attack the memory-building activity of synapses, points of communication where neurons exchange information, without killing neurons.

"Researchers for more than a decade thought it was big molecules, the 'amyloid fibrils,' that caused memory problems, but we think the real culprits are extremely small molecules, what we call ADDLs," said Klein, who is a member of Northwestern's Cognitive Neurology and Alzheimer's Disease Center. "Now we've shown that ADDLs are present in humans and are a clinically valid part of Alzheimer's pathology. If we can develop drugs that target and neutralize these neurotoxins, it might be possible to not only slow down memory loss, but to actually reverse it, to bring memory function back to normal."

Although both are a form of amyloid beta, ADDLs and their properties differ significantly from the amyloid fibrils (known as plaques) that are a diagnostic hallmark of Alzheimer's. ADDLs found in human brains, mostly 12 or 24 amyloid beta proteins clumped together, are tiny and undetectable in conventional neuropathology; fibrils are much, much larger. While fibrils are immobile toxic waste dumps, ADDLs are soluble and diffuse between brain cells until they find vulnerable synapses. (Single pieces of amyloid beta protein in the brain is normal.)

"The difference between ADDLs and fibrils is like comparing four eggs, over easy, to an enormous omelet that could feed the entire Chicago Bears team," said Klein. ""You start with eggs, but the final product taste, texture and size are all different."

The existence of ADDLs may help explain the poor correlation between plaques and neurological deficits. Studies by other researchers have shown a reversal of memory failure in mouse models treated with amyloid beta antibodies -- but without any reduction in plaque. The antibodies appear to restore memory because they neutralize ADDLs, which Klein's group has found in mouse models with Alzheimer's as well as in human brains with Alzheimer's.

Klein's research team recently began a study funded by the National Institutes of Health to continue investigating ADDLs in humans and further characterize these molecules. In addition to Alzheimer's disease, ADDL-like molecules could be the cause of other degenerative diseases.

Klein also is working with researchers at Northwestern's Institute for Nanotechnology on clinical diagnostics capable of detecting ADDLs in blood or cerebral spinal fluid. Currently diagnosis of Alzheimer's is based primarily on a battery of psychological tests.

"Now that ADDLs have been discovered in humans we would like to develop effective diagnostics and that means employing nanotechnology," said Klein. "That's because ADDLs are present in very low concentrations, and nanotechnology has the potential to provide the ultra-sensitive assays needed for the clinic."

Klein, Grant A. Krafft, formerly at Northwestern University Medical School and now chief scientific officer at Acumen Pharmaceuticals, Inc., and Caleb E. Finch, professor of biological sciences and gerontology at the University of Southern California, reported the discovery of ADDLs in 1998. Krafft and Finch are co-authors on the PNAS paper. Northwestern and USC hold joint patents on the composition and use of ADDLs in neurodisorders.

The patent rights have been licensed to Acumen Pharmaceuticals, based in Glenview, Ill., for the development of drugs that treat Alzheimer's disease and other memory-related disorders. Clinical trials could be two or three years away.

In addition to Klein, Krafft and Finch, other authors on the paper are Yuesong Gong (lead author), Lei Chang, Kirsten L. Viola, Pascale N. Lacor and Mary P. Lambert, from Northwestern University.


###
The research was supported by the National Institutes of Health, the Boothroyd, Feiger and French foundations, and the Institute for the Study of Aging.





--------------------------------------------------------------------------------
[ Print This Article | Close This Window ]

[kevin]

Link: http://health.ucsd.e..._08_Martin.html
Date: 09-08-03
Author: Paul Martin
Source: University of California, San Diego
Title: UCSD Researchers ID Peptides That Bind to Alzheimer’s Plaques

---

Paul T. Martin, Ph.D.

September 8, 2003
UCSD Researchers ID Peptides That Bind to Alzheimer’s Plaques

Two short protein segments, called peptides, have been identified by researchers at the University of California, San Diego (UCSD) School of Medicine, for their ability to recognize and bind to beta-amyloid-containing plaques that accumulate abnormally in the brains of Alzheimer’s disease patients, providing a possible “Trojan horse” mechanism to diagnose and treat the disorder.

“These peptide sequences are potential new tools for the delivery of medication to the amyloid plaques that are found in Alzheimer’s disease, or for new diagnostic tests that would allow early identification and treatment of the disease,” said the study’s senior author, Paul T. Martin, Ph.D., UCSD assistant professor of neurosciences.

In studies published in the September issue of the journal Neurobiology of Disease (published online Aug. 27, 2003), Martin and colleagues found that natural and synthetic versions of the peptides attach themselves to the abnormal plaque, while ignoring normal brain tissue.

Although past research has identified larger non-antibody and antibody proteins and small organic molecules that can bind to the amyloid plaques, the UCSD team said the newly discovered peptides may be a better choice for diagnosis and treatment. Smaller in size than previously identified proteins, the peptides may more easily cross the blood-brain barrier. In addition, some of the previously identified organic molecules could cause toxic side effects if given to people.

The scientists used a laboratory technique called phage peptide display to identify the two peptide sequences from a starting library of 50 million peptide sequences. These peptides were engineered to be exposed on the surface of bacteria by infecting the bacteria with bacteriophage (a bacterial virus). The peptide-expressing bacteria were then used to select for peptide sequences that bound amyloid plaques. An analysis of the bacteriophage showed that only the two peptides were able to seek out and bind to abnormal beta-amyloid.

“It is striking that we found only two peptide sequences, and that they were very similar in structure to one another,” Martin said. “This suggests that if other sequences do exist, they would most likely be variations on the structures we have already identified.”

He added that the UCSD team sees several potential applications for the peptides. First, they could be coupled to molecules designed to inhibit the toxicity of beta-amyloid plaques. The peptides might also be coupled to substances that stimulate the breakdown of plaques, or inhibit them from forming. A final application would be coupling the peptides to other markers that would highlight the abnormal plaque in imaging diagnostic tests. Currently, Alzheimer’s disease is diagnosed by cognitive tests involving patient interview, and a conclusive diagnosis requires postmortem analysis of the brain itself.

In addition to Martin, authors of the study included Christine Kang, staff research associate, and Vianney Jayasinha, an undergraduate student, in the UCSD Department of Neurosciences. The study was funded by the National Institutes of Health.

# # #

Contact:
Sue Pondrom
(619) 543-6163
spondrom@ucsd.edu

[Cyto]

Understanding Alzheimer's: New Direction For Therapy

Saint Louis University study suggests protein can't cross blood brain barrier
-From Bio.com-

10/03/2003 -- Alzheimer's disease may be caused by a problem transporting a certain protein across the blood brain barrier and out of the brain, according to new Saint Louis University research published in the October issue of Neuroscience.

The findings are important, says William A. Banks, M.D., a Saint Louis University professor and the lead author of the article, because they give us a new approach for treating Alzheimer's disease.

"It's going to be a big piece to solving the Alzheimer's disease puzzle," says Dr. Banks, a professor of geriatrics in the department of internal medicine and professor of pharmacological science at Saint Louis University School of Medicine. "If one could reverse the transport deficit problem, the system should be able to pump the protein out again. The impaired transporter problem may be an easier therapeutic target."

Normally, amyloid beta protein, the protein thought to cause Alzheimer's disease, leaves the brain and crosses the blood brain barrier, which is a wall of blood vessels that feed the brain and regulate the entry and exit of brain chemicals. But in persons with Alzheimer's disease, amyloid beta protein becomes blocked in the brain and can't make it across the blood brain barrier. The more amyloid beta protein accumulates, the tougher it is for the blood brain barrier to move it out, and the more disabled a person becomes.

Because the transport deficit causes the amyloid beta protein to accumulate, scientists should focus on finding ways to destroy the protein with enzymes or pushing the protein across the blood brain barrier and out of the brain. Dr. Banks says fixing the system that transports amyloid beta protein across the blood brain barrier is "a viable therapeutic target."

"We need to find therapies to bring the transportation system back on line to pump the amyloid beta protein out of the brain," says Dr. Banks, who also is a staff physician at Veterans Affairs Medical Center in St. Louis.

The research analyzed the accumulation of amyloid beta protein in a mouse model of Alzheimer's disease.

Source: Saint Louis University
---------------------------------------------------------
Rusty hatches in the Blood Brain Barrier too? mmm.

[kevin]

Link: http://www.reuters.c...storyID=3638866
Date: 10-17-03
Author: Lisa Richwine
Source: Reuters
Title: US OKs First Drug for Late-Stage Alzheimer's

---

US OKs First Drug for Late-Stage Alzheimer's
Fri October 17, 2003 05:04 PM ET
By Lisa Richwine
WASHINGTON (Reuters) - U.S. health officials on Friday approved the first medicine for the late stages of Alzheimer's, the degenerative brain disease that afflicts an estimated 4 million Americans.

Namenda, made by Forest Laboratories Inc., slowed the decline in awareness, reasoning and daily function experienced by patients with moderate to severe Alzheimer's who were treated in clinical trials, the Food and Drug Administration said.

The disease causes a gradual loss of brain cells that results in memory loss and dementia, and can eventually lead to death.

In the studies, most patients' mental and functional ability did deteriorate. But on average those given Namenda were better able to perform tasks such as feeding themselves or dialing a phone than those given a placebo, the FDA said.

Forest said Namenda will address an important medical need because the moderate to severe stages of Alzheimer's can last years.

"It certainly provides a modest, but we think meaningful, benefit," said Charles Triano, Forest's vice president for investor relations.

The drug should be available in January, Triano said.

The FDA action follows last month's unanimous recommendation for approval from an FDA advisory panel. Members of the panel agreed the drug was safe and effective but stressed that benefits appeared limited.

Namenda, known generically as memantine, is the first of a new type of medicines for treating Alzheimer's disease.

Researchers believe Namenda calms overstimulated nerve cells in the brain by blocking activity of the chemical glutamate.

The four other approved Alzheimer's drugs are cleared only for treating mild to moderate forms of the illness, and they also offer modest benefits.

Those drugs, which include Aricept from Pfizer Inc. and Eisai Co Ltd., work by helping to make the chemical acetylcholine more available in the brain. Acetylcholine plays an important role in learning and memory.

In clinical trials, Namenda was used alone or with another Alzheimer's treatment. Side effects were minor and included dizziness, headache and constipation, the FDA said.

Alzheimer's patients, families and caregivers had been waiting for regulatory approval of Namenda. At last month's advisory panel meeting, some said they had sought out supplies of the drug overseas.

Namenda is Forest's most important new drug, analysts have said. SG Cowen expects annual sales to reach up to $800 million, assuming that half of all people treated for Alzheimer's use the drug.

Shares of New York-based Forest Laboratories, also the maker of antidepressants Lexapro and Celexa, gained 46 cents to close at $49.92 on the New York Stock Exchange. (Additional reporting by Jed Seltzer in New York)

---

Link: http://www.commentwi...entwire_ID=4936
Date: 10-20-03
Author: -
Source: DataMonitor
Title: The FDA has approved Forest Laboratories' Namenda (memantine) for severe Alzheimer's.

---

Forest: Namenda finally approved for Azheimer's
The FDA has approved Forest Laboratories' Namenda (memantine) for severe Alzheimer's.
October 20, 2003 6:47 PM GMT (Datamonitor) - Namenda is the first drug aimed at treating severe Alzheimer's disease sufferers in the US, and is expected to experience strong uptake in the market. Despite delays to its launch, Namenda will be crucial to the growth of Forest's [FRX] CNS franchise, which includes the blockbuster antidepressant Cipramil.

The Alzheimer's field is becoming increasingly attractive to investors as the effects of an ageing global population take hold. The degenerative brain disease affects over four million elderly in the US alone. At present, Pfizer [PFE]/Eisai [ESALY.PK]'s Aricept (donepezil) is the gold-standard therapy, and has dominated the market since its launch in 1997. Sales of Aricept reached $995 million in 2002.

However, Aricept and other AD drugs are only approved for the treatment of mild to moderate AD in the US. Severe sufferers represent around 20% of the overall AD population, and, until now, this segment has been underserved by approved drug therapy. After a long approval process, Forest's Namenda will finally benefit from 'first-to-market' status in this niche sector. Forest claims Namenda will address an important medical need because the moderate to severe stages of Alzheimer's can last for years. FDA approval follows last month's unanimous recommendation from an FDA advisory panel, which agreed the drug was safe and effective.

Namenda, known generically as memantine, is the first of a new type of medicines for treating Alzheimer's disease. Researchers believe Namenda calms overstimulated nerve cells in the brain by blocking activity of the chemical glutamate.

However, from clinical data, it is unclear whether Namenda offers an improved ability to alleviate cognitive deficits compared to existing therapies. Potential beneficial effects are therefore unlikely to be great, although the drug is well tolerated. For example, Namenda is not as effective as Aricept at treating cognitive impairments. It is this lack of perceived cognitive efficacy that forced Forest to voluntarily withdraw its initial New Drug Application in September 2002.

Nevertheless, the fact that Forest will market the drug in the US (Lundbeck [LUN.CO] will market the drug under the brand Ebixa in Europe) will strongly enhance the sales potential of Namenda. Forest's strength in the CNS pharmaceutical arena is exemplified by the company's success in the multibillion-dollar antidepressant market with Cipramil (citalopram).

[JonesGuy]

An audio primer on Alzheimers and a vaccine for it.

ta da!

Quote:
Alzheimer's disease is one of the serious problems associated with aging. There's no way to prevent it, and there's no cure.

When a pharmaceutical company announced clinical trials of a vaccine, it offered the first hope that we might be able to deal with the disease. But earlier this year the vaccine trials were canceled. Some of the patients had developed inflammation in their brains.

Now a new study from the University of Toronto has revived some of the hope. Dr. Jo Ann McLaurin is an assistant professor in the department of Laboratory Medicine and Pathobiology, and a researcher at the Centre for Research in Neurodegenerative Diseases at the University of Toronto.

She's part of a team that's come up with a refined vaccine that they think won't have the negative side effects of the original one.

[chubtoad]

http://www.scienceda...31022061239.htm
Source: Duke University Medical Center
Date: 2003-10-22

Gene Controls Age At Onset Of Alzheimer's And Parkinson's Diseases
DURHAM, N.C. - By applying a new technique that combines independent lines of genomic evidence, Duke University Medical Center researchers and colleagues have identified a single gene that influences the age at which individuals first show symptoms of Alzheimer's and Parkinson's diseases.

Such genes that can impact patients' age at onset for the two very prevalent neurological disorders are of particular interest as alternative targets for treatment, said Margaret Pericak-Vance, Ph.D., director of the Duke Center for Human Genetics. Drugs that delay the onset of Alzheimer's or Parkinson's diseases beyond the normal human lifespan would effectively prevent them in patients at risk for the disorders, she added.

Alzheimer's disease is the most common cause of dementia among people over the age of 65, affecting up to 4 million Americans. Parkinson's disease -- characterized by tremors, stiffness of the limbs and trunk, slow movements and a lack of balance -- afflicts approximately 50,000 Americans each year. Both are complex disorders involving multiple genes.

"Although physicians generally consider Alzheimer and Parkinson diseases to be distinct disorders, the two exhibit a lot of overlap both clinically and pathophysiologically," said Jeffery Vance, M.D., director of Duke's Morris K. Udall Parkinson's Disease Research Center and associate director of the Duke Center for Human Genetics. "This study emphasizes the similarity between the two diseases by highlighting a single gene that influences their age of onset."

The team reports their findings in the Dec. 15, 2003, issue (available online Oct. 21) of Human Molecular Genetics and will present the work as a keynote paper at the annual meeting of the American Society of Human Genetics, which will be held Nov. 4-8, in Los Angeles. The major funding for the study was provided by the National Institute on Aging, the National Institute of Neurological Disorders and Stroke, the Alzheimer's Association, the Institute de France, and the American Federation for Aging Research.

The team's earlier work identified a broad chromosomal region linked to the age at onset of Alzheimer's and Parkinson's diseases. The new research -- led by Pericak-Vance, Vance, John Gilbert, Ph.D. and Yi-Ju Li, Ph.D., of the Duke Center for Human Genetics and Jonathan Haines, Ph.D., of Vanderbilt University Medical Center -- narrows that region of the genome, which contained many hundreds of genes, to a single gene known as glutathione S-transferase omega-1 or GSTO1.

The researchers overlaid three independent lines of genetic evidence to reveal those genes more likely to play a role in the disorders' age at onset -- a method, called genomic convergence, which the Duke team developed.

The researchers first focused on Alzheimer's disease by comparing the activity of genes in the hippocampus -- a part of the brain affected by the disorder -- of unaffected individuals and Alzheimer's patients. The experiment uncovered four genes, including GSTO1, located in the region of the genome earlier linked to age at onset, the researchers report.

An additional analysis involving 1,773 patients with Alzheimer's disease and 635 patients with Parkinson's disease later found that of those four genes, only GSTO1 showed genetic differences associated with age at onset.

"By combining evidence based on gene expression and genetic association, we found a gene that modifies when the diseases start," said Li, the study's first author. "Understanding the role this gene plays in Alzheimer and Parkinson diseases may, in the future, lead to a means to delay the disorders' onset," she added, noting that even a short delay would benefit at-risk patients.

The Center for Human Genetics is one of five centers within Duke's Institute for Genome Sciences and Policy. The institute represents Duke University's comprehensive response to the broad challenges of the genomic revolution.

The international research team included scientists representing 17 institutions in the United States, the United Kingdom and Australia. Additional funding was provided by the Hilles Families Foundation, the U.S. Public Health Service, the California Department of Health Services, the Fran and Ray Stark Foundation Fund for Alzheimer's Disease Research and GlaxoSmithKline.

[chubtoad]

http://www.scienceda...31030064649.htm
Source: Harvard Medical School
Date: 2003-10-31

Mouse Model Of Alzheimer’s, Other Diseases May Clarify Steps Of Brain Degeneration

A new mouse model developed by Harvard Medical School researchers and reported in the October 30 Neuron may allow scientists for the first time to spotlight two key proteins in a living animal and see how they contribute to the neuronal death and atrophy found in neurodegenerative diseases. The two proteins are dubbed p25 and cyclin-dependent kinase 5 (Cdk5).

“This is an excellent animal model for any therapeutic approach toward p25 and its link to Alzheimer’s and similar neurodegenerative diseases,” says Li-Huei Tsai, HMS professor of pathology and Howard Hughes Medical Institute associate investigator, the study’s lead author. “We know that p25 causes neurodegeneration, and we want to figure out how that mechanism works.”

The new model is the latest in Cdk5 research from the lab of Li-Huei Tsai. Over the past nine years, Tsai and her colleagues have defined many of Cdk5’s functions and noted the role its usual regulator p35 plays in orienting neuronal migration and growth. Their latest challenge is deciphering how Cdk5 and the pernicious regulator p25 lead to neurodegenerative diseases.

The protein p25 is usually not found in healthy brains, but is formed when a stroke or another oxygen-restricting event cuts p35—a beneficial protein found in healthy brains—to form p25, starting a domino effect that leads to neuronal death and malformation. Once present, p25 activates Cdk5 and alters its normally constructive behavior to kill neurons. To make matters worse, p25 is longer-lived than p35, so it accumulates in the brain and continues to keep Cdk5 active. Overactive Cdk5 and accumulated p25 have been noted in the brain tissue of people with the neurodegenerative diseases Alzheimer’s and Niemann–Pick type C. But the lack of a mouse model prevented researchers from demonstrating in vivo the effects of Cdk5 and p25 in the brain.

Tsai’s model exhibits the two characteristics researchers want to study: profound neuronal death and tau-associated degeneration. Some forms of the tau protein are associated with neurodegenerative diseases. In the model, Tsai turns on the production of p25 when the mice are mature. The mice were created with a gene that overproduces p25, but this gene is inhibited in the presence of the chemical doxycycline. The mice were conceived and raised for four to six weeks on doxycycline, which allowed their brains to develop normally. Once the mice were mature, Tsai turned on the p25 gene by removing doxycycline from their food.

Tsai’s model produces the results she expected. The mouse brains show a high accumulation of p25, substantial atrophy, progressive neuronal loss and tau pathology. After only 12 weeks of p25 exposure, the mouse brains were disintegrating, with a 40 percent decrease in neuronal density. By 30 weeks after p25 induction, the aggregation of tau proteins caused neurofibrillary tangles in the brain, a symptom of Alzheimer’s disease. The brains also showed neurodegeneration and neuronal cell death similar to earlier in vitro work.

Other labs have created mouse models that overproduce p25 throughout their lives, but these models fail to exhibit high brain cell p25 levels and neuronal death. Tsai explains that mice in these earlier models may have found a way to cope with the overexpression of toxic p25 during development, thereby lowering the accumulated p25 levels in their brains. These p25 levels may not have reached the threshold to induce the neuronal death and substantial tau pathology associated with aberrant p25. Without the high levels of accumulated p25 or evidence of neuronal death, these mice are not useful as models of neurodegeneration.

[chubtoad]

http://www.scienceda...31103070129.htm
Source: Duke University Medical Center
Date: 2003-11-03


Drug Improves Brain Structure In Alzheimer's Patients


DURHAM, N.C. -- Researchers at Duke University Medical Center have determined that a medication commonly prescribed for mild to moderate Alzheimer's disease (AD) appears to cause physical improvements in the hippocampus and other brain regions of patients with the disease. These improvements could explain why the drug, donepezil (trade name Aricept), a cholinesterase inhibitor, is beneficial in treating the symptoms of some Alzheimer's patients, the researchers said.

The findings were made by using magnetic resonance (MR) technology to track brain changes among patients taking the drug. According to the researchers, this is the first time MR has been used to observe the effects of a medication on brain structures of patients living with AD. The feasibility of using MR for such studies is likely to improve future research into treatments for AD and other brain disorders, the researchers said.

The study results appear in the Nov. 1, 2003, issue of the American Journal of Psychiatry.

"We wanted to know if the drugs available for Alzheimer's disease alter the brain or the progression of the disease in any way," said Ranga Krishnan, M.D., lead author of the study and chairman of psychiatry at Duke University Medical Center. "We discovered that, among the patients taking donepezil, levels of a brain chemical called N-acetylaspartate increased and the hippocampus deteriorated more slowly than among the patients who received a placebo. The implication is that we may be able to do something to change the progression of this disease."

The researchers believe the drug may have a protective effect on the brains of Alzheimer's patients because it appears to slow the progression of the disease by reducing atrophy in the hippocampus, a region of the brain that is critical to memory function and is affected earliest in AD.

"When someone has Alzheimer's disease, the brain begins to deteriorate as the gray matter shrinks and the disease progresses," Krishnan said. "We are unsure of why and how donepezil slowed the loss of hippocampal volume but we think the drug may help to improve cognition by increasing the levels of N-acetylaspartate in the brain, at least temporarily."

This is important, the researchers say, because the data raise the possibility that a medication could affect the progression of brain changes in Alzheimer's disease.

According to the researchers, this is the first longitudinal study to use magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (MRS) to assess brain function and the impact of a medication upon brain structures of patients with AD.

The study is a follow up to the team's 1999 report that MRS could be used to track levels of the brain chemical called N-acetylaspartate, an amino acid found in the neurons of the central nervous system in patients with AD. The team had determined that the chemical could serve as a useful "marker" of the functional and structural integrity of neurons when proton magnetic resonance spectroscopy is used to view brain structures.

Since MR had already proven to be an excellent tool for observing function and the changes in brain structures affected by AD, Krishnan and his team wondered if it would be possible to see how a drug affects those same structures.

In the patients enrolled in this study, the researchers discovered that hippocampal volume decreased by 8.2 percent in the placebo group compared with a 0.4 percent decrease in those taking donepezil. Those on placebo also showed evidence of declining concentrations of N-acetylaspartate along with some cognitive decline. Those in the donepezil group showed evidence of increasing levels of N-acetylaspartate concentrations in two brain regions, the subcortical gray matter and the periventricular matter, which peaked between weeks six and 18. Donepezil treatment was associated with significantly greater improvements in cognition, relative to placebo, at every point during the study.

Among those on placebo, the researchers found a significant relationship between the decline in N-acetylaspartate concentrations in the noncortical gray matter region of the brain and reductions in the patients' scores on cognition tests. The drug appeared to increase concentrations of N-acetylaspartate, although the mechanisms that underlie this are uncertain. The researchers are also unsure why donepezil appears to slow the deterioration of hippocampal tissue, uncertainty they say is compounded by a general lack of understanding about the cause of neuron loss in Alzheimer's disease.

The researchers enrolled 67 patients aged 50 and older with a diagnosis of mild to moderate AD. Prior to the study, all of the participants received a comprehensive medical examination and verification of an Alzheimer's disease diagnosis. At baseline, the physical exam was repeated and an MRI scan of the brain was performed. Patients were administered two identical pills -- either donepezil or placebo -- each evening for 24 weeks. Patients in the donepezil group received five milligrams per day (a five-milligram pill plus a dummy pill) for the first 28 days and 10 milligrams (two five-milligram pills) per day thereafter. Daily doses consisted of two identical tablets so as to not reveal the dosage scheme.

The randomized, double-blind, placebo-controlled study was conducted over a 24-week period followed by a six-week period in which all participants received only placebo pills. Each participant was treated and clinically evaluated at one of three outpatient sites –- Duke University Medical Center, the Medical University of South Carolina or a private psychiatrist's office in Raleigh, N.C. All of the MR scans were performed at Duke University Medical Center and all data were processed by the Duke Image Analysis Laboratory.

Patients were required to return at six-week intervals for routine physical examinations, laboratory assessments, a medication compliance check, adverse events monitoring and an MRI scan. Of the 67 participants who enrolled, 34 received donepezil and 33 were given placebo. Fifty-one patients (76 percent) completed the study. Ten patients (30 percent) in the placebo group discontinued the study compared with six (18 percent) from the donepezil group.

"The study was challenging in that subjects were required to be scanned every six weeks and the MRI methods needed to be standardized," said Cecil Charles, co-director of the Center for Advanced Magnetic Resonance Development at Duke. "This study will set the stage for more effective studies of medications used for Alzheimer's disease.

"Clearly, more effective treatments are needed for Alzheimer's disease," Charles added. "This study further suggests that MRI and MRS may be useful tools to assess brain changes in patients with Alzheimer's disease."

The researchers stressed the limitations of their study, saying additional placebo-controlled studies with larger numbers of patients are necessary to confirm and expand their findings.

Alzheimer's disease is the most common form of dementia among Americans over the age of 80. Donepezil is one of four drugs currently approved by the Food and Drug Administration for the treatment of mild to moderate Alzheimer's disease.

[chubtoad]

http://www.scienceda...31104064534.htm
Source: Duke University Medical Center
Date: 2003-11-04

Distinct Genes Influence Alzheimer's Risk At Different Ages


DURHAM, N.C. -- The genes that influence the risk of developing Alzheimer's disease may vary over the course of an individual's lifetime, a new study by Duke University Medical Center researchers finds. The team's results revealed two chromosomal regions not previously known to influence Alzheimer's disease: one linked to the disorder in families that first show symptoms early in life and another in families with very late onset of the disorder's symptoms.

While earlier studies have identified genes that underlie early- versus late-onset Alzheimer's disease, the new study is the first to indicate that distinct genes might also determine the very late onset of Alzheimer's disease, in which symptoms first appear after the age of 80, said Duke Center for Human Genetics researcher William Scott, Ph.D., the study's first author.

The team's findings will appear in the November 2003 issue of The American Journal of Human Genetics. The research was supported by the National Institute on Aging and the Alzheimer's Association. The study immediately follows another in which the Duke team identified a single gene that influences the age at onset of both Alzheimer's and Parkinson's diseases.

Alzheimer's disease affects up to 4 million Americans and is the most common cause of dementia among people over the age of 65. However, some patients first experience at age 50 the mild forgetfulness characteristic of the disease's earliest stages; for others, symptoms appear at age 80 or older.
Multiple genes underlie an individual's risk for Alzheimer's disease, explained Margaret Pericak-Vance, Ph.D., director of the Duke Center for Human Genetics and leader of the study. Still other genes determine the age at which individuals first show signs of the disorder.

In their study, the team conducted a genomic screen of 437 families in which at least two members had Alzheimer's disease.

The researchers then applied a novel method of analysis, called "ordered subsets linkage analysis," that allowed them to identify genetic regions linked to Alzheimer's disease specifically in families that differed in terms of their average age at onset -- without making assumptions about how those age groups should be defined. In contrast, earlier methods have generally lumped people with Alzheimer's disease into two predefined groups: early and late onset, Scott explained.

The analysis identified a region on chromosome 2 linked to Alzheimer's disease in families with a minimum age at onset between 50 and 60 years, the researchers reported. The researchers also uncovered a second region, located on chromosome 15, linked to the disorder only in families with a minimum age at onset of 80 years.

A third region on chromosome 9, identified in an earlier genomic screen conducted by the Duke team, was found to influence late onset Alzheimer's disease in families that experience symptoms between the ages of 60 and 75.

"By including age at onset in our analysis using this new method, we have identified genetic regions that may be associated with Alzheimer's disease that we wouldn't have found otherwise," Scott said.
The researchers' next step will be to apply additional genomic tools to identify candidate genes located in the newly identified chromosomal regions that might influence risk of Alzheimer's disease.

[chubtoad]

http://www.scienceda...31107055048.htm
Source: Brown University
Date: 2003-11-07


Herpes Research Uncovers Possible Clue To Alzheimer's Disease

Providence, R.I. -- Researchers at Brown University and the Marine Biological Laboratory at Woods Hole, Mass., have found a physical connection between the herpes simplex virus and amyloid precursor protein, a protein that breaks down to form a major component of the amyloid plaques that are consistently present in the brains of persons with Alzheimer's disease.

Amyloid precursor protein – or APP – breaks down to form beta-amyloid. There is strong evidence, according to the researchers, that beta-amyloid is the underlying cause of Alzheimer's.

While the scientists caution that no conclusions about Alzheimer's can be drawn from their findings, Dr. Elaine Bearer, senior research scientist and associate professor in Brown's Department of Pathology and Laboratory Medicine, believes the work does in fact link the common herpes virus of cold sores with the neurodegenerative disorder. Bearer isalso a summer investigator at the Marine Biological Laboratory at Woods Hole, Mass.

Past studies have implicated the herpes virus in the onset of Alzheimer's disease, but agreement within the scientific community on the value of that research is far from universal. Bearer expects that the discovery of a physical interaction between APP and the herpes virus will trigger further investigations into the role the virus may play in the disease, and even into possible uses of the virus in therapy.

The scientists stress that none of what they found should cause alarm among those who have at one time had a cold sore. According to Bearer, nearly 85 percent of us harbor the herpes simplex virus and most of us never develop Alzheimer's.

The researchers discovered the interaction between the herpes simplex virus (HSV) and APP while conducting experiments in the giant axon of squid at the Marine Biological Laboratory. Prasanna Satpute-Krishnan and Joseph A. DeGiorgis, both doctoral candidates in Brown's graduate program at the time of the research, were seeking to learn how viruses are carried around the body – within cells and from one cell to another. Specifically, they were examining how the herpes simplex virus travels back to the lip area to form a recurring blister after remaining latent for some time in the trigeminal ganglion, a collection of nerve cells next to the brain.

What they found was that the herpes virus was interacting with APP, a putative motor receptor that recruits a microtubular motor, kinesin, for transport through neurons. This was the first time scientists had observed any physical interaction between the herpes virus and APP.

Without the APP, the virus moves backward up an axon (a long extension of a neuron) from the area of the lip towards the trigeminal ganglion. But the Brown researchers discovered that once it interacts with the APP, the virus travels in the opposite direction – what scientists describe as anterograde transport – back down to the lip. The researchers also found that once coupled with the APP, the virus moves remarkably fast.

"It's as if the virus hijacks a car – which in this case would be the kinesin – and the APP is the driver," explains Bearer. "The virus takes the APP where it wants to be, not where the APP wants to be."
The build-up of beta-amyloid (formed in the breakdown of APP) is found consistently in the brains of Alzheimer's patients, and many scientists are now convinced it is involved in the disease, according to Satpute-Krishnan. Questions persist, however, as to what that involvement is, and why, when APP is found in all of us, it causes problems only in a few.

Perhaps, Bearer speculates, when the APP is co-opted by the herpes virus, the APP breaks down at a location where it would not normally appear – and at a very different rate. "When APP piles up around neurons, the neurons die," she explains. "But we don't yet know if this is a secondary or a primary cause of Alzheimer's."

"At this point, of course, we don't yet know whether herpes plays a causal role in Alzheimer's disease," DeGiorgis notes. "But our research does provide some interesting new insight into both diseases."

A paper outlining the findings of the Brown/MBL researchers – titled "Fast Anterograde Transport of Herpes Simplex Virus: Role of Amyloid Precursor Protein" – will appear in the December issue of Aging Cell, published by Blackwell Publishing in England and at the publisher's "OnlineEarly" site [http://www.blackwell...links/toc/ace].

Satpute-Krishnan, the first author of the paper, is a graduate student in Brown's Molecular Biology, Cell Biology and Biochemistry Graduate Program. Bearer, who holds both an M.D. and a Ph.D., is an experimental pathologist. DeGiorgis, who earned his Ph.D. in Bearer's lab last year, is now with the National Institutes of Health.

Experiments in this study were conducted in the giant axon of squid, a model widely used in research because with a diameter of nearly a millimeter it is 1,000 times thicker than a human axon. Researchers are able to inject substances into the giant axon and then observe the behavior of those substances through high-powered microscopes.

"It is pretty extraordinary that breakthroughs in Alzheimer's disease and in the pathogenesis of herpes virus should be made using the squid of the North Atlantic sea," notes Bearer.

[chubtoad]

http://www.scienceda...31106051400.htm
Source: University Of California - Los Angeles
Date: 2003-11-06


PET Scan Predicts Alzheimer's More Accurately


Scanning a patient's brain metabolism with positron-emission tomography (PET) can improve a doctor's ability to forecast the patient's future cognitive functions by up to 30 percent, a new UCLA study discovered. Published in the November issue of the journal Molecular Genetics and Metabolism, the findings suggest that PET may offer physicians a new tool to help with earlier diagnosis and treatment of Alzheimer's disease and dementia.
The study showed that use of a PET scan sharply increased the ability of physicians to predict whether the condition of patients with early memory complaints would significantly worsen in the years after their initial examination.

"Adding PET to the diagnostic evaluation of patients with mild cognitive changes can improve our accuracy in predicting what will happen to them in the future and enhance our ability to intervene earlier," said Dr. Dan Silverman, associate director of imaging at the UCLA Alzheimer's Disease Center and assistant professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA.

Silverman and his colleagues studied the results of PET scans performed between 1991 and 1999 on 167 UCLA patients being evaluated by their neurologists for mild cognitive complaints, such as memory loss, behavioral changes and changes in language ability. The average age of the patients was 66.

A PET scan images the brain for a metabolic pattern indicative of progressive dementia. Based on the PET scan results, the UCLA researchers predicted each of the 167 patients' future cognitive abilities. The research team then compared those predictions to the neurologists' original clinical diagnoses and to patients' cognitive conditions two to 10 years after their initial evaluation.

According to Silverman, the accuracy of the prognoses significantly increased when doctors took the PET scan results into account.

"Adding PET substantially boosted how often physicians were correct in predicting patients' future cognitive decline or stability," he noted.

For example, neurologists who diagnosed their patients as free of a progressive disease were correct 66 percent of the time. When patients' PET scans revealed a negative diagnosis, the accuracy of the doctor's predictions rose to 96 percent. However, patients in this group who had positives PET scan were 18 times more likely to develop progressive dementia in the future than those whose scans were negative.

Neurologists who diagnosed their patients with progressive dementia were correct 84 percent of the time. Adding a positive diagnosis from a PET scan boosted the accuracy of those predictions to 94 percent. Patients in this group with negative PET scans were 12 times more likely to remain cognitively stable during the follow-up period than those with positive scans.

Overall, patients with positive PET scans experienced a significant decline in general brain function years later. Those patients' performance fell significantly on the Mini-Mental State Examination (MMSE), a standard clinical test used to gauge general mental abilities.
"The predictive power of brain PET scans may prove most helpful to people with early cognitive problems who would not otherwise be suspected to have progressive dementia," Dr. Silverman said.

Patients whose doctors predicted they would maintain a stable mental course – but who received positive PET scans – experienced an average eight-point decline on the MMSE test. In comparison, patients in this group who had negative PET scans declined by an average of only two points.

This UCLA study is the first to follow a large number of clinical patients with early cognitive complaints through PET and several years of clinical monitoring, and to measure the accuracy added to clinical evaluation by visually interpreted PET scans.

Alzheimer's disease is the most common form of dementia. It often begins with mild memory lapses and gradually advances to a progressive deterioration of memory, language and mental functions. Alzheimer's affects approximately 400 million people in the United States, and the nation spends roughly $100 billion on the disease each year.

[chubtoad]

http://www.scienceda...31113065542.htm
Source: Society For Neuroscience
Date: 2003-11-13


New Vaccine Tested In Animals May Hold Hope For Alzheimer's Patients


In new research, scientists show that two dramatically different approaches may be effective in treating or preventing Alzheimer's disease. One approach involves development of a vaccine that clears deposits of a sticky substance called amyloid beta protein from monkey brains. The amyloid beta protein in monkey brains is the same as that in the brains of Alzheimer's patients, so the hope is that such a vaccine may be effective in humans.

The other research centers on finding out how and to what extent reducing caloric intake can help diminish the pathological symptoms of Alzheimer's disease. Researchers are also working on newer and safer forms of immunization for this devastating disease that afflicts 4.5 million Americans.

Alzheimer's disease is a progressive, degenerative disorder of the brain that results in loss of memory and the ability to think logically and clearly. During its end stages, the brain is littered with dying and dysfunctional neurons, plaques containing the amyloid beta protein, and a profusion of enlarged processes from these neurons. In response to these pathological events, glial cells release proinflammatory proteins involved in nerve cell dysfunction and loss. Although aging is the greatest risk factor for Alzheimer's--its prevalence in the general population doubles every five years after the age of 65--there are a number of other risk factors that might be controlled by changes in lifestyle.

One prominent theory for how Alzheimer's disease develops is that it results from an imbalance in production or clearance of amyloid beta protein, resulting in its accumulation outside of nerve cells to form plaques. As the protein becomes more tightly clumped, it is difficult to clear, diminishing the connections between neurons, and ultimately leading to the dementia associated with Alzheimer's disease.

Several groups are exploring the possibility that vaccines can help the brain in Alzheimer's disease either lower the production of amyloid beta protein or increase its clearance.

Work by Cynthia Lemere, PhD, and her associates at Harvard Medical School shows that vaccinating monkeys with synthetic amyloid beta peptide enhanced the clearance of amyloid beta protein from the brain and into the blood. Although this finding confirms what had already been shown in mice, it is significant because monkeys have the same amyloid beta protein as humans, making them a more natural model for studying clearance of the protein. Dennis Selkoe, co-author, is director and co-founder of Elan, a company that does research and development in neurological disorders such as Alzheimer's disease. The Harvard group's research was not sponsored by Elan.

Over a nine-month period, five aged Caribbean vervet monkeys were given eight injections of the amyloid beta peptide. Five control monkeys did not receive the treatment. All of the immunized monkeys made antibodies to amyloid beta peptide, which were found in blood and, in lower amounts, in cerebrospinal fluid (CSF). Between 22 and 42 days after immunization, levels of amyloid beta protein dropped in the CSF and increased in the blood, suggesting that the antibodies bound to amyloid beta protein and increased its slow release from the CSF to the blood for clearance. In addition, no plaques were found in the immunized animals.

"Our study is the first to show clearance of amyloid beta by vaccination in a primate model," said Lemere, "thus providing further evidence for the potential use of such a vaccine in humans."
Earlier studies that showed mice had increased amyloid clearance after vaccination led to clinical trials to test the treatment in humans. However, the trials were stopped midway because some patients developed cerebral inflammation. While no signs of inflammation were found in any of the immunized monkey brains, Lemere and her team are now attempting an even safer vaccine by developing new amyloid beta compounds.

Investigators at New York University School of Medicine are also working on a safer vaccine. They have altered a portion of the sequence of amyloid beta protein, and preliminary studies show behavioral improvements in mice given the altered amyloid beta, which does not form amyloid fibrils, as does full-length amyloid beta. These amyloid beta derivatives, used in small amounts, result in a lower antibody response than that generated by full-length amyloid beta. A new turn in the research is to determine whether the region of the compound that has been altered is important for lessening the potentially toxic inflammatory autoimmune response, and thus contributing to a safer vaccine.

"Our work shows that relatively low levels of circulating antibodies to amyloid beta may benefit Alzheimer's disease patients," said NYU's Einar Sigurdsson, PhD. "Use of amyloid beta derivatives can potentially reduce the toxicity associated with the full-length native amyloid beta vaccine."

These investigators are now working on a new memory test for mice and on characterizing the antibodies generated toward the vaccines. They hope that together these studies will help show if any particular properties of the antibodies correlate with cognitive improvement.

In other work, researchers at the National Institute for Longevity Sciences in Japan have developed a new oral vaccine for Alzheimer's disease in mice using adeno-associated virus vector. The advantage of an oral vaccine is that it will not result in a potentially toxic autoimmune response. The group, led by Hideo Hara, PhD, plans next to give the vaccine to aged monkeys to test its effectiveness in primates.

On a different front, other researchers are looking at a change-in-lifestyle approach to preventing Alzheimer's disease. While trying to identify factors that contribute to aging and thereby might contribute to the development of Alzheimer's disease, Todd Morgan, PhD, Caleb Finch, PhD, and other colleagues at the University of Southern California, Los Angeles, used a remarkably effective and simple means of delaying aging: caloric restriction.

By reducing food intake by 10 to 40 percent in experimental animals, inflammatory changes are suppressed in the aging brain and other tissues. In collaboration with David Morgan and his colleagues at the University of Southern Florida in Tampa, the two research teams showed that six weeks of caloric restriction reduced the glial inflammatory response as well as the number of amyloid beta plaques in a transgenic experimental animal model of Alzheimer's disease.
The researchers examined the effects of caloric restriction in two different lines of transgenic mice that are bioengineered to express either mutated human amyloid beta precursor protein alone or in combination with mutated presenilin1. Mutations in these two genes are responsible for causing inherited forms of Alzheimer's disease in humans. Mouse brains from both groups showed decreased amyloid beta deposits and decreased glial inflammation.

"These ameliorating influences of caloric restriction on development of amyloid plaques and inflammation in these transgenic mice are consistent with clinical reports that people with high calorie diets are at increased risk for developing Alzheimer's disease," said Morgan. "These results suggest that dietary changes, even in adulthood, may be an approach to prevention and treatment of Alzheimer's disease."

[chubtoad]

http://www.scienceda...31126064727.htm
Source: Washington University In St. Louis
Date: 2003-11-26

Brain's 'Daydream' Network Offers Detection For Alzheimer's Diagnosis

Researchers tracking the ebb and flow of cognitive function in the human brain have discovered surprising differences in the ability of younger and older adults to shut down a brain network normally active during periods of passive daydreaming. The differences, which are especially pronounced in people with dementia, may provide a clear and powerful new method for diagnosing individuals in the very early stages of Alzheimer's disease.

"In young adults, there are parts of the brain that are very active during a passive free-thinking state, but these areas appear to shut down dramatically or 'turn off' when the person is asked to do something," said Cindy Lustig, research team member and post-doctoral fellow in psychology at Washington University in St. Louis. "Interestingly, older people, especially those with Alzheimer's disease, don't show this same kind of brain activity during free- thinking, resting conditions."
In a study published Nov. 25 in the Proceedings of the National Academies of Science, Lustig and colleagues detail results of functional magnetic resonance imaging (fMRI) tests conducted on groups of young adults, older adults and adults experiencing early signs of Alzheimer's-related dementia.

Although fMRI testing is widely used to track regional increases in brain activity during completion of specific mental tasks, such as language, memory or problem solving, this study focuses on what happens in regions that are active when the brain has no particular task at hand, regions that are focal points for a baseline, passive processing mode, one that seems to operate when the mind free to wander and daydream.

"What we found in our study is that rather than turning these regions off when asked to concentrate, as young adults do, people with Alzheimer's seem to turn them on," Lustig said. "This might reflect a 'broken brain' in Alzheimer's, making it hard for people to turn these brain regions on or off appropriately; more optimistically, it might be an attempt to compensate for the memory problems that come with Alzheimer's."

Other members of the Washington University in St. Louis / Howard Hughes Medical Institute research team include Abraham Z. Snyder, Mehul Bhakta, Katherine O'Brien, Mark McAvoy, Marcus E. Raichle, John C. Morris and Randy L. Buckner, all of whom are affiliated with the departments of psychology in Arts and Sciences and/or the departments of neurology and radiology in the School of Medicine.

Raichle, a pioneer in the use of positron emission tomography (PET) to image changes in brain activity, has been an advocate for more research into brain deactivations, a process by which the brain reduces activity in one region so that resources can be shifted to other areas where more challenging mental tasks are currently being processed. Irregularities in brain deactivation patterns have been noted in other neurological illnesses, including amnesia, schizophrenia and Fragile X syndrome.

Recent research has provided mounting evidence supporting the existence within the brain of a "default network," a set of interconnected brain areas that carry out routine, passive mental processes, such as monitoring the environment, registering internal emotions and other forms of largely undirected thought and reflection. Brain areas thought to be included in this network are the medial frontal, the lateral parietal and the posterior cingulate regions of the cortex.

"The posterior cingulate cortex was the site of the largest and most intriguing differences between the groups," Buckner said. "Whereas young adults showed decreases in this region after a transient initial activation, Alzheimer's participants maintained an above-baseline activation throughout the task period."

The study also identified a number of other significant differences in the timing and magnitude of changes in default network activity among young adults, older adults and older adults with early stages of Alzheimer's.

Other studies have shown that young adults have more activity in this default network than do older adults during so-called passive conditions where they are not given any particular task to think about. What this new study found is that older adults also do not seem to shut down or "deactivate" the default network as much when they are given something to concentrate on.

"The reduced deactivation in the older adult groups are especially surprising, given that the performance data suggested that they found the task more difficult than did the young adults, " Buckner noted. "In young adults, greater task difficulty is usually associated with greater deactivation in these areas."
Interestingly, there is one situation in which young adults exhibit some activity in the default or daydreaming regions even while they are actively tackling a mental task elsewhere in the brain; that is when the task at hand involves a person's autobiographical memory. For instance, if someone asks what you had for breakfast or how you feel about something that happened in your past, then you might activate parts of the default passive processing network as you search for the answer.

"Since the brain's default processing network is connected to brain areas that are heavily involved with memory, it could be that people with memory problems are turning the network on in an attempt to compensate for the memory damage caused by normal aging or Alzheimer's," Lustig said.

"The biggest, most obvious thing that we know about these default regions is that older adults, especially those with Alzheimer's, are doing something different with them when they're in a free-thinking mode. The reasons for this aren't entirely clear, but may have something to do with their memory problems.

"In the long run, this quirk may help us understand what's going wrong with fundamental cognitive processes that underlie mental declines associated with aging and Alzheimer's. In the meantime, we're very interested in whether these changes can be used to identify older adults in the earliest stages of Alzheimer's disease so that they can begin treatment as soon as possible."

[Cyto]

Findings on nerve cell proteins show promise for reducing disability

Tytell said that over the years, there has been little progress in research on traumatic injury to the nervous system. One approach that is being studied is to replace the damaged cells with stem cells. However, there are technical problems getting the nerve 'circuitry' to grow back to normal. He believes the idea of protecting cells from secondary cell death deserves additional research attention.

The research showed that up to 50 percent of the motor and sensory nerve cell death could be prevented in mice with sciatic nerve injury. It is reported in the current issue of Cell Stress and Chaperones, a journal of stress biology and medicine.

'We are on our way to developing a treatment that is effective in preventing motor nerve cell death, which is significant to people because loss of motor neurons means paralysis,' said Tytell, professor of neurobiology and anatomy at Wake Forest Baptist.

A long-range goal is to determine if the proteins could be useful in the treatment of degenerative diseases of the brain, such as Alzheimer's disease and Huntington's disease.

The sidenote here is that Hsp70 binds to Bax, which is involved in pore formation on the outter mitochondrial membrane (OMM), and keeps the Bak/Bax focal complexes from apoptizing the cell.

[Cyto]

AD Genetic Factors

ApoE4 is the best known genetic risk factor for Alzheimer's disease, but, until now, the mechanism by which it increases that risk has remained a mystery. The key finding of the current study relates to apoE4's tendency to be broken down into toxic fragments when it is produced in neurons, the brain cells responsible for cognitive functions.

In the new study, involving the examination of genetically engineered mice, Gladstone researchers have established that:

* only apoE4 produced by neurons is susceptible to fragmentation, unlike apoE4 produced by other brain cells;

* fragmentation is correlated with age, occurring more frequently the older the animal, similar to the effect of age on Alzheimer disease risk in humans;

* fragmentation of apoE4 occurs predominantly in the very parts of the brain that are most vulnerable to Alzheimer's disease, the neocortex and hippocampus. In contrast, fragmentation does not occur in the cerebellum, which is much less vulnerable to Alzheimer's disease;

* the apoE4 fragments cause an abnormal change to the protein tau, which is also heavily affected by Alzheimer's disease. Both apoE4 fragments and Alzheimer's disease lead to the abnormal attachment of phosphate groups on tau that can end up contorting the shape of brain cells.

The investigators suspect that the fragmentation of apoE4 is caused by a neuron-specific enzyme, which they are now trying to identify and block with drugs.

[chubtoad]

http://nia.nih.gov/n...2004/040504.htm

Study Identifies Predictors of Alzheimer’s Disease Longevity

It’s among the first questions asked after someone is diagnosed with Alzheimer’s disease: “What can we expect?” It’s a tough question that has been difficult to answer. But a new study suggests that assessing several key clinical aspects of the disease soon after diagnosis could help families and physicians better predict long-term survival in individuals with AD. These insights also could help public health officials refine cost projections and plan services for the growing number of older Americans at risk for the disease.

The study, funded by the National Institute on Aging (NIA) of the National Institutes of Health (NIH), appears in the April 6, 2004 issue of the journal Annals of Internal Medicine.

The researchers from Seattle's Group Health Cooperative and the University of Washington found that in the years following diagnosis, people with AD survived about half as long as those of similar age in the U.S population. Women tended to live longer than men, surviving about 6 years compared to men who lived for about 4 years after diagnosis. But this gender gap narrowed with age. Age at diagnosis was also a factor. Those who were diagnosed with AD in their 70s had longer survival times than those diagnosed at age 85 or older.

“This finding moves us toward a more precise vision of the course that Alzheimer’s may take in people with certain clinical characteristics,” says Eric B. Larson, M.D., M.P.H., director of Group Health Cooperative’s Center for Health Studies in Seattle and former medical director at the University of Washington Medical Center. “For doctors, this provides very useful data for gauging the prognosis of an AD patient. For patients and their caregivers, as difficult as this may be to hear, it can help in making appropriate plans for the future.”

During the study, Dr. Larson and his colleagues followed 521 community-dwelling men and women aged 60 and older who had been recently diagnosed with Alzheimer’s disease. They were recruited from a database of 23,000 people listed in an Alzheimer’s Disease Patient Registry in the Seattle area. The average follow-up period was about 5 years, with an approximate range from 2 1/2 months to 14 years.

As they entered the study, each person was evaluated for cognitive and memory problems and examined for other conditions including heart disease, heart failure, diabetes, stroke, depression, and urinary incontinence. They were also assessed for a history of agitation, wandering, paranoia, falls and walking difficulties. Survival was measured from the time of initial diagnosis until death or when the study ended in 2001.

When compared to the life expectancy of the general U.S. population, overall survival was lower for people with AD in all age groups. For instance, median* survival was 8 years for women aged 70 diagnosed with AD, which is about half the life expectancy of similarly aged American women who do not have the disease. Similar trends were found among 70-year old men with AD who had a median survival time of 4.4 years compared with 9.3 years for the U.S. population.

Survival was poorest among those aged 85 and older who wandered, had walking problems and had histories of diabetes and congestive heart failure. However, the difference in the life expectancy between those who were diagnosed with AD and the general population progressively diminished with age. At 85, for example, median life expectancy for women with AD was 3.9 years after diagnosis compared to about 6 years for women who didn’t have the disease. Similarly, 85-year-old men with newly diagnosed AD had a median life expectancy of 3.3 years compared to 4.7 for men of the same age who didn’t have AD.

Poor scores on the initial tests of memory and cognitive performance predicted shorter survival time after diagnosis. In fact, a five-point drop in one key test, the Mini-Mental State Exam, during the first year following diagnosis predicted up to a 66 percent increase in the risk of death after that initial year. Walking problems, congestive heart failure, and a history of falls, diabetes and ischemic heart disease were other important predictors of reduced life expectancy after AD diagnosis.

“This study suggests that several critical factors can be evaluated to help answer some of the important questions posed by Alzheimer’s disease patients and their families,” says Neil Buckholtz, Ph.D., chief of the NIA’s Dementias of Aging Branch. “These conversations are never easy. But these findings could help clarify what patients and families can expect. And ultimately, families who have more precise information on the likely course of the disease should be better prepared to deal with it as it progresses.”

AD is an irreversible disorder of the brain, robbing those who have it of memory, and eventually, overall mental and physical function, leading to death. It is the most common cause of dementia among people over age 65. Recent studies estimate that up to 4.5 million people currently have the disease, and the prevalence (the number of people with the disease at any one time) doubles every 5 years after the age of 65. By 2050, if current population trends continue and no preventive treatments become available, some 13.5 million Americans will have Alzheimer’s disease.

The annual national direct and indirect costs of caring for AD patients are estimated to be as much as $100 billion. This suggests that the economic burden will grow as the population ages and the number of AD patients increases.

[chubtoad]

http://www.nature.co...2/040412-7.html
16 April 2004
ERIKA CHECK

Anti-stroke drug eases Alzheimer's symptoms

Atorvastatin unclogs arteries and may help memory too.

Statins may keep your memory keen in old age.
People with Alzheimer's disease may benefit from taking a popular cholesterol-lowering medication, scientists announced on Wednesday.

In a study of 63 people with mild to moderate Alzheimer's disease, the performance of those who took a drug called atorvastatin declined less on tests of memory and brain function than that of those who did not take the drug.

The researchers, led by Larry Sparks of the Sun Health Research Institute in Sun City, Arizona, say the result is a sign that atorvastatin and similar drugs might slow the devastation caused by Alzheimer's disease.

"This fact that this trial showed a benefit is very exciting," says Benjamin Wolozin, a professor of pharmacology at the Loyola University Chicago Stritch School of Medicine. "But it is not big enough to be definitive," he adds.

No more tangles

Atorvastatin, one of a class of common cholesterol-reducing drugs called statins, is taken by millions of people every year. Statins are usually used to lower the risk of heart disease and stroke.

Four years ago, Wolozin analyzed 56,000 patient records in a database and found that people on statins were 70% less likely to be diagnosed with Alzheimer's than those who were not. Other similar studies since then have also found a lower incidence of Alzheimer's in patients who take statin drugs.

Scientists are not sure how the statins work to ease Alzheimer's symptoms. Animal studies suggest they might interfere with processes that create plaques and tangles, which are clumps of protein that accumulate in the brains of patients with the disease. Or the drugs may decrease harmful inflammation in the brain: other anti-inflammatory drugs, such as ibuprofen, have previously been shown to delay or reduce the onset of Alzheimer's.

But while statins appear to ease Alzheimer's symptoms, they might not prevent people from developing the disease in the first place. Previous studies have failed to find any evidence of a protective effect, though these involved smaller numbers of patients and were not designed to look specifically at Alzheimer's, says Sparks.

Sparks presented his results at the 8th International Montreal/Springfield Symposium on Advances in Alzheimer Therapy in Montreal, Canada. The work was paid for in part by Pfizer, a drug company that sells atorvastatin under the brand name Lipitor.

Sparks and his colleagues have now begun a larger, 600-patient trial of atorvastatin.

The US National Institute on Aging is enrolling 400 patients in a separate study to investigate the effects of simvastatin on Alzheimer's. The leader of that trial, Mary Sano, director of the Alzheimer's Disease Research Center at the Mount Sinai School of Medicine in New York, says she is encouraged by Sparks's results, but that more work must be done.

"We have been misled before by small studies," Sano says. "This result is very exciting, but it should not lead to using the drug; it should lead to getting a complete answer."

[chubtoad]

http://pub.ucsf.edu/...ases/200404262/

Recent discoveries pave the way toward new treatments for alzheimer's disease

Promising research into the causes of Alzheimer's disease, with an emphasis on the roles of such proteins as amyloid-beta and apolipoprotein E, will be the subject of a plenary session presentation on April 29 at the American Academy of Neurology (AAN) 56th Annual Meeting in San Francisco.

Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease and Joseph B. Martin Distinguished Professor of Neuroscience at the University of California, San Francisco (UCSF), will discuss the latest therapeutic targets and describe molecular markers of cognitive decline that may facilitate the assessment of new treatments for Alzheimer's disease.

"Ongoing studies are beginning to unravel the pathways that lead from the accumulation of toxic proteins in the brain to the biochemical alterations and cognitive decline in patients with Alzheimer's disease," says Mucke.

His talk, "Markers and Mediators of Neuronal Deficits in Dementia," will highlight recent discoveries that shed light on the processes underlying the memory loss and other cognitive deficits associated with Alzheimer's disease. The presentation is part of "Frontiers in Clinical Neurosciences Plenary Session: Beyond the Decade of the Brain," during which several scientists will present recent research findings and discuss their clinical implications.

"Recently, we identified a number of mechanistically informative changes in the brains of transgenic mouse models of Alzheimer's disease, and we have begun to validate the clinical relevance of these findings in human cases," explains Mucke. "For instance, deficits in spatial learning and memory in our mice correlated tightly with the depletion of calcium-dependent proteins in specific brain regions. Similar abnormalities were then found in brains from patients with Alzheimer's disease, and the greatest depletions were seen in the most severely demented people."

Mucke's talk will focus on these and other key findings from studies of transgenic mice and human brain tissues carried out at the Gladstone Institute of Neurological Disease. One study, for example, showed that high levels of amyloid proteins disrupt complex brain circuits in which memories are formed and stored. Mucke's work in this area is contributing to an important paradigm shift in the field. Previously, the most widely held view was that large clumps of amyloid proteins in the brain (referred to as "plaques") cause the neurological decline in Alzheimer's disease. But studies conducted at Gladstone, UCSF, and other centers suggest that much smaller aggregates of these proteins are the real culprits. These findings are helping to resolve the controversy surrounding the role of amyloid proteins in Alzheimer's disease. Other studies he will discuss have identified molecular pathways through which amyloid proteins may impair brain functions and have demonstrated that amyloid proteins can enhance the accumulation and toxicity of other disease-causing proteins. The latter finding may help explain the frequent clinical and pathological overlap between Alzheimer's and Parkinson's disease.

In addition, Mucke will describe findings that explain how apolipoprotein E4 -- the best established genetic risk factor for Alzheimer's disease -- can promote the development of this illness and how its harmful effects might be prevented or reversed with new therapeutic approaches now under development at Gladstone.

Basic research findings are the foundation for developing novel therapeutic strategies and new treatments for diseases such as Alzheimer's. Genetically engineered mouse models are especially useful tools for studying neurodegenerative disease because they allow individual proteins to be studied in the complex environment of the living brain, enabling scientists to determine which of these proteins are the most toxic. Such models are also useful for the preclinical evaluation of new treatments aimed at the toxic proteins themselves or at the disease-causing processes they trigger.

"While the investigation of neurological diseases has promoted basic neuroscientific discoveries for more than a century, there has never been a more promising and exciting convergence of basic and disease-related neuroscience than now," says Mucke.

[chubtoad]

http://www.scienceda...40428062742.htm

Preliminary Results Are Promising In Alzheimer's Gene Therapy Trial

Surgical placement of genetically modified tissue directly into the brains of patients with Alzheimer's disease, an experimental approach to delaying brain cell loss associated with the disease, leads to increased metabolic activity in the brain, with cells apparently responding to the insertion of growth factor-producing grafts, according to preliminary findings reported April 27 at the American Academy of Neurology meeting in San Francisco.

Though the Phase I study conducted at the University of California, San Diego (UCSD) was small and designed to test safety and toxicity, the subjects may also show some early indications of reduction in the advancement of their disease, according to the study's principal investigator Mark Tuszynski, M.D., Ph.D., professor of neurosciences at the UCSD School of Medicine.

"These results are intriguing," said Tuszynski. "If these effects are borne out in larger, controlled trials, this could be a significant advance over existing therapies for Alzheimer's disease."

Eight volunteers diagnosed with early-stage Alzheimer's disease participated in this study, with the first surgery performed in April 2001 at UCSD's John M. and Sally B. Thornton Hospital. Patients' own skin cells were genetically modified in culture to produce Nerve Growth Factor (NGF), a naturally occurring protein that prevents cell death and stimulates cell function. The NGF-producing cells were then surgically implanted into a deep brain region where cholinergic cell degeneration occurs in Alzheimer's disease. The cholinergic system is important in memory and cognitive function. Patients received the implanted grafts in targeted areas on either the left, right or both sides of the brain.

This human trial was undertaken following extensive studies in primates conducted by Tuszynski and colleagues , which showed that grafting NGF-producing tissue into the brains of aged monkeys restored atrophied brain cells to near-normal size and quantity, and also restored axons connecting the brain cells, essential for communication between cells.

With the last human subject now more than a year beyond surgery, no adverse effects from the NGF-producing implants have been detected in the subjects, an indication that the biological therapy is itself safe and well-tolerated.

The procedure initially was performed while patients were awake but lightly sedated. Two patients moved as the cells were being injected, resulting in bleeding in the brain. One of these patients died of acute myocardial infarction (heart attack) five weeks later. Following these events, the protocol was redesigned with patients given general anesthesia during the procedure, and subsequent procedures were performed without complication.

The small-scale study did not include placebo controls, and doctors and patients knew that the procedure was performed (they were not "blinded"). Because of this, Tuszynski is cautious about preliminary findings regarding the cognitive function of the subjects. However, all of the subjects underwent standard cognitive testing before and following surgery, and reductions in rates of cognitive decline compared to their pre-operative function were noted. The six subjects who successfully completed the surgery showed a 50 percent reduction in their annual rate of decline on one of the measured cognitive scales. On another scale, the subjects showed a reduced rate of decline that persisted over the 1.5- to two-year period of the study.

Positron Emission Tomography (PET) imaging of the patients showed increased metabolic activity in the areas of the brains of patients after treatment with NGF, compared with non-treated Alzheimer's disease patients. An autopsy of the patient who died showed active NGF production in the brain, and a growth response of brain cells to the NGF delivery.

Based on these results, Tuszynski concludes that the NGF implants are safe and well-tolerated by patients, and when performed with patients fully anesthetized, the injection procedure is safe.

[chubtoad]

http://www.scienceda...40429054513.htm

Some Cases Of Parkinson's, Alzheimer's Linked To Common Gene

A gene known to have a hand in Alzheimer’s disease may contribute to some cases of Parkinson’s disease as well, according to findings discussed today at the annual meeting of the American Association of Neurology in San Francisco.

University of Rochester scientists and area patients who have Parkinson’s disease played a role in the discovery, which comes through a national Parkinson’s study known as PROGENI – “Parkinson’s Research: The Organized Genetic Initiative.” The study included 600 sibling pairs from 58 sites around North America, including 21 people from 14 families in the Rochester area.

The results were announced by a team from the Indiana University School of Medicine in Indianapolis led by Tatiana Foroud, Ph.D., associate professor of medical and molecular genetics, who heads the PROGENI study nationally.

In the PROGENI study, scientists collect blood samples from brothers and sisters with Parkinson’s disease in an effort to track down genes that play a role in the disease. Doctors have connected a handful of genes to some cases of Parkinson’s, but the causes of most cases are unknown. The PROGENI team has had several previous successes, including identifying a greater role for a gene on chromosome six that had been thought to only cause some cases of early-onset Parkinson’s disease; this gene now appears to also be important in some cases of more typical Parkinson’s disease in other individuals as well. The PROGENI team has also begun work to identify a gene on chromosome two that appears to be key to the disease’s development in some families.

In the latest finding, the team discovered that an area of chromosome 10 previously linked to late-onset Alzheimer’s disease might also play a role in Parkinson’s disease.

“There are several traits that characterize both diseases,” says Roger Kurlan, M.D., the neurologist who led the Rochester portion of the study. “Since there are a limited number of mechanisms by which nerve cells die, it’s not completely unexpected that some genes involved in the process of neurodegeneration are involved in both conditions.”

Alzheimer’s and Parkinson’s diseases are the two most common of a class of diseases known as neurodegenerative diseases, where brain cells sicken and die. There’s more overlap than people realize, doctors say. Foroud says that about one of every four patients with Parkinson’s disease has some dementia, while about one of every five patients with Alzheimer’s disease has some classic symptoms of Parkinson’s. Only a small percentage of Alzheimer’s and Parkinson’s cases have been linked to specific genes thus far.

“The idea that there may be some common pathways for these two diseases is compatible with what we see clinically, and what we actually see happening in the brain,” says Foroud. “If you look at people who have one of these diseases, you will sometimes find evidence of both diseases.”

The scientists are studying brothers and sisters who have been diagnosed with Parkinson’s disease. Since siblings oftentimes do not live near each other, the study is being done at nearly five dozen study sites across North America. The study, funded by the National Institutes of Health, is being coordinated by the Parkinson Study Group, which is based at the University of Rochester. Recently the NIH decided to extend the study for another five years.

In addition to a genetic analysis of people with Parkinson’s disease, scientists are also taking a detailed look at the places where participants live and work, to look at environmental factors that may be related to the disease. For instance, some studies have shown that farmers and others who live in agricultural areas are more prone to developing the disease than others, while basic research has

[chubtoad]

http://www.scienceda...40428061841.htm

OHSU Researchers Uncover Genes Involved In Early Stages Of Alzheimer's Disease

PORTLAND, Ore. – Researchers at Oregon Health & Science University (OHSU) have identified a set of genes that appear to be involved in the development of Alzheimer's disease. They hope this information will help scientists create of methods for early detection of the disease and for the development of therapeutic strategies to delay or even stop its progression. P. Hemachandra Reddy, Ph.D., of the OHSU Neurological Sciences Institute is the first and corresponding author of the paper, which will be published online on April 27, prior to its appearance in the journal Human Molecular Genetics.

"Through studying a mouse model of Alzheimer's, the research team found that a series of genes related to mitochondrial metabolism in brain cells were more active than in normal mice," Reddy said. "Mitochondria are structures located in the cytoplasm of cells that produce energy for the cell. Prior research has linked Alzheimer's to mitochondrial function. However this is the first time genes that are responsible for early cellular change in Alzheimer's disease pathogenesis have been identified."

Currently, there are no early detectable biomarkers for Alzheimer's, and there is a lack of understanding of the functional changes caused by this disease, particularly at its early stages. To intervene before neurons become irreversibly damaged, an understanding of early cellular events in the progression of Alzheimer's is critical. Studies of "pre-symptomatic" human subjects suggest that pathologic changes in the brain occur years before symptoms are evident, suggesting that the brain tissue from patients dying from Alzheimer's exhibits physiologic features indicative of a very late stage in the degenerative process.

To determine early cellular changes connected to Alzheimer's disease, the OHSU scientists studied mice that overexpress human mutated amyloid precursor protein. These genetically-altered mice produce heightened levels of amyloid precursor protein. Over time, higher than normal levels of this protein can result in structures in the brain called beta amyloid plaques, which are thought to be either a cause or an effect of Alzheimer's disease.

By studying 11,283 mouse genes and using a gene chip technology called microarray, OHSU scientists were able to identify a much smaller set of distinct genes that functioned differently in the diseased mice from those in healthy mice. These genes are involved in mitochondrial energy metabolism and programmed cell death.

"We studied gene expression levels at three distinct stages of disease progression in the genetically-altered mice relative to age-matched wild-type normal mice," explained Reddy. "We conducted gene expression analysis long before (2 months of age), immediately before (5 months) and after (18 months) the appearance of beta amyloid plaques. In doing this, we found that these mitochondrial genes were more active at 2 months of age when compared to normal mice, and in some cases their activity heightened as the disease progressed. We believe the abnormal gene expression comes in response to beta amyloid-induced mitochondrial dysfunction, even in its early stages. Based on prior research, it's thought that energy metabolism in mitochondria is impaired by heightened levels of beta amyloid in the brain. We believe the genes identified in our study increase their activity to compensate for this damage, but unfortunately in the end they cannot keep up with the progression of Alzheimer's."

A companion study recently published in the journal NeuroMolecular Medicine also found very similar gene expression differences in Alzheimer's disease patients. Scientists believe this demonstrates the value of the mouse model in gaining new knowledge and developing future human therapies.

"This work likely will sharpen the focus of research on the possible links between mitochondrial gene expression and damage that occurs within and to neurons as Alzheimer's progresses. Understanding these links could lead to the development of novel and effective interventions for this disease," said Stephen Snyder, Ph.D., of the National Institute on Aging's (NIA) Neuroscience and Neuropsychology of Aging Program. The research was partially funded by the NIA, a component of the National Institutes of Health.

[chubtoad]

http://www.scienceda...40518073451.htm

Diabetes Linked To Increased Risk Of Alzheimer's In Long-term Study

Diabetes mellitus was linked to a 65 percent increased risk of developing Alzheimer's disease (AD), appearing to affect some aspects of cognitive function differently than others in a new study supported by the National Institute on Aging (NIA) at the National Institutes of Health. The findings, from the Rush Alzheimer's Disease Center's Religious Orders Study, add to a developing body of research examining a possible link between diabetes and cognitive decline. The results reported today are among the first to examine how certain cognitive "systems" – memory for words and events, the speed of processing information, and the ability to recognize spatial patterns -- may be affected selectively in people with diabetes.

The research, by Zoe Arvanitakis, M.D., David Bennett, M.D., and colleagues at the Rush University Medical Center in Chicago, IL, appears in the May 2004 issue of the Archives of Neurology. The investigators are part of the institution's Rush Alzheimer's Disease Center, headed by Dr. Bennett. The AD Center is one of 30 across the U.S. supported by the NIA to study and care for Alzheimer's patients.

"The research on a possible link between diabetes and increased risk of AD is intriguing, and this study gives us important additional insights," says Neil Buckholtz, Ph.D., head of the Dementias of Aging Branch in the NIA's neurosciences program. "Further research, some currently underway, will tell us whether therapies for diabetes may in fact play a role in lowering risk of AD or cognitive decline."

Some 824 Catholic nuns, priests, and brothers participating in the Religious Orders Study were followed for an average of 5.5 years. They received detailed clinical evaluations annually, including neuropsychological testing of five cognitive "systems" commonly affected by aging, AD, and other dementias – episodic memory (memory of specific life events), semantic memory (general knowledge), working memory (ability to hold and mentally rearrange information), perceptual speed (the speed with which simple perceptual comparisons can be made, such as whether two strings of numbers are the same or different), and visuospatial ability (the ability to recognize spatial patterns). Over the study period, 151 of the participants had a clinical diagnosis of AD, including 31 who had diabetes. The researchers found a 65 percent increase in the risk of developing AD among those with diabetes compared with people who did not have diabetes.

In measures of cognitive function, only in the area of perceptual speed was there an association with an increased rate of decline over time, by about 44%, when comparing the diabetes and non-diabetes groups. Since stroke-related changes in the brain were found in a previous study to be tied to a decline in perceptual speed, the researchers could not say whether the link between cognitive decline and diabetes appeared because of the changes in the brain associated with Alzheimer's disease or those of some other common age-related condition like stroke or other vascular complications. Studies looking at pathological or brain imaging data would be needed to address these possibilities.

In other areas of cognition, the rate of change over the time period of the study was no different in the two groups. However, at the start of the study, the baseline cognitive function scores of people with diabetes were lower than those of people without diabetes.

"We found that diabetes was related to decline in some cognitive systems but not in others," says Dr. Arvanitakis of Rush, the lead author of the report. "Since all participants have agreed to brain donation at their deaths, we will have the opportunity to examine the pathologic basis of the association of diabetes to cognitive decline." The Rush researchers also expressed their indebtedness to the more than 1,000 nuns, priests, and brothers from across the U.S. participating in the Religious Orders Study.

[chubtoad]

http://www.eurekaler...ject/social.php

Alzheimer's pathology reduced, longevity improved in mouse model, Gladstone study shows

Removal of an enzyme that regulates the activity of many proteins can suppress key features of Alzheimer's disease in experimental models, researchers at the Gladstone Institute of Neurological Disease (GIND) recently reported in the Journal of Neuroscience (May 12, 2004).
Using well-established mouse models of Alzheimer's disease, the investigators examined how changing levels of the enzyme Fyn affects key aspects of the disease, including accumulation of large clumps of amyloid proteins in the brain (so-called plaques) and changes in the complex neuronal networks in which memories are formed and stored. Genetic engineering strategies were used to increase or decrease the expression of Fyn, which regulates many other proteins through the attachment of specific groups of atoms known as phosphate groups.

The researchers determined that changing levels of Fyn had no effect on plaque formation or aberrant sprouting (the abnormal growth of nerve terminals, in which neuchemical messages are stored), indicating that these pathologies involve discrete molecular mechanisms. However, they observed that blocking Fyn expression prevented amyloid proteins from damaging synapses, the specialized connections between brain cells, and improved the longevity of mice. (Experimental mice with Alzheimer's-like disease otherwise die prematurely.) In contrast, increasing Fyn in the brain worsened synaptic damage, and also increased the number of premature deaths in the mice.

Loss of synapses and abnormal outgrowth of nerve terminals occur both in people with Alzheimer's disease and in transgenic mice producing human amyloid proteins in the brain (the model used in the study). Humans with the disease, like mice, die prematurely.

"Synaptic degeneration in Alzheimer's disease is like electrical circuits in a computer becoming faulty -- signals can no longer be transmitted through broken connections," says senior author and GIND director Lennart Mucke, MD, who is also Joseph B. Martin Distinguished Professor of Neuroscience at the University of California, San Francisco.

"Our results suggest that Fyn plays a key role in Alzheimer's-related synaptic impairments, and that it can worsen the toxicity of amyloid proteins," says lead author Jeannie Chin, PhD, a GIND postdoctoral fellow. "We are excited about the possibility that pharmacological modulation of Fyn might be of therapeutic benefit in this disease."

Because Fyn is involved in many different processes related to normal neuronal functioning, complete suppression of its activity might have detrimental side effects, says Mucke. Thus, he says, the researchers will be examining whether partial suppression of Fyn is beneficial. They also will be testing the therapeutic potential of manipulating some of the more specific pathways that Fyn regulates.

[chubtoad]

http://www.scienceda...40603064539.htm

Antibody Detection In Alzheimer's May Improve Diagnosis, Treatment

People with Alzheimer’s disease have three to four times more antibodies to two major players in the destructive disease than their healthy counterparts, researchers at the Medical College of Georgia and Veterans Affairs Medical Center in Augusta have found.

The ability to measure these specific antibody levels could lead to a method for early diagnosis of the disease – when treatment has the most potential – and even help identify those at risk, say lead researchers Drs. Shyamala Mruthinti and Jerry J. Buccafusco of work currently published online on ScienceDirect and scheduled for publication in the September issue of Neurobiology of Aging.

The finding may also enable development of a monoclonal antibody that selectively destroys the deadly protein-receptor combination, they say.

The study of plasma samples from 33 patients with Alzheimer’s and 42 healthy people showed a similar effect on leukocytes, white blood cells that are part of the immune response: leukocytes from Alzheimer’s patients had four times the markers for amyloid-â peptide and receptor for advanced glycation end products, or RAGE.

The findings support the theory that autoimmunity and resulting inflammation play a big role in the destructive brain disease.

Previous studies have looked for and found only low levels of these antibodies in Alzheimer’s; Dr. Mruthinti, a neurobiologist at the VA and adjunct instructor of pharmacology/toxicology at MCG, wondered if the experiment design was to blame and designed a more specific approach that yielded results.

"This is one of the most exciting papers I have ever participated in," says Dr. Buccafusco, pharmacologist and director of the MCG Alzheimer’s Research Center. "If it turns out that the assay is a confirmatory assay for Alzheimer’s disease, it would be a very, very useful assay to begin with. But if it has a predictive value as well, it would be more outstanding, obviously." Currently there is no definitive diagnostic test for Alzheimer’s; a definitive diagnosis is made on autopsy.

Amyloid-â peptide is a protein fragment routinely found circulating in the bloodstream that is harmless as long as it stays there. The same can be said for RAGE peptide, another natural human product that actually can help attract cellular garbage in the bloodstream, such as beta amyloid, and remove it from the body. Apart, neither attracts much attention from the immune system. But when RAGE in the brain attracts beta amyloid, they combine to form a complex capable of generating a stronger immune response.

RAGE was discovered by Dr. David M. Stern, dean of the MCG School of Medicine, while he headed the Center for Vascular and Lung Pathobiology and the Juvenile Diabetes Research Center at the College of Physicians & Surgeons of Columbia University in New York. He first found RAGE was a binding receptor for sugar-modified proteins that accumulate in the blood vessels of diabetes; he and colleague Dr. Shi Du Yan published in Nature in 1996 their finding that in the brain, RAGE also binds with amyloid-â peptide in Alzheimer’s. "I am delighted that Drs. Mruthinti and Buccafusco are pushing their work in Alzheimer’s disease forward along a line of inquiry that involves RAGE," Dr. Stern says. "Their findings are both intriguing and unexpected."

"We have shown that advanced glycation end products in the presence of beta amyloid enhance the expression of specific cellular receptors such as RAGE that are known to bind the toxic form of amyloid," Dr. Mruthinti says.

She and Dr. Buccafusco began dissecting the relationship between RAGE and beta amyloid after she immunized laboratory mice with advanced glycation end products in pursuit of a monoclonal antibody that might be a diagnostic marker for Alzheimer’s.

The researchers expected and documented that the mice made antibodies to advanced glycation end products. But in studies published in 2003 in the Journal of Molecular Neuroscience, they were excited to find the mice also made antibodies to RAGE and beta amyloid, which were locked together in a deadly complex that was getting the attention of the immune system.

"It seems that when the mice were immunized, this enhanced the presence of circulating RAGE peptide which, in turn, formed the highly immunogenic complex with beta amyloid protein," Dr. Mruthinti says. "So the antibodies they measured may have been produced in response to the protein complex rather than to the original proteins." The investigators have found evidence of such RAGE-beta amyloid complexes in the blood of Alzheimer’s patients.

"We think the advanced glycation end product causes an increase in cell-surface expression of amyloid-â binding sites, which are RAGE and others, that cause all this amyloid to come and bind to the cell which is not healthy for the cell," Dr. Buccafusco says.

"It stirs up a cyclic, inflammatory event," Dr. Mruthinti says of the deadly cycle set in increasing motion.

Activation of the immune system by the resulting complex has the Augusta researchers believing, as others do, that there is an autoimmune component to the disease. But when she purified out antibodies from the plasma – instead of just looking at intact plasma as other have – and exposed them to specific affinity columns designed to attract antibodies to beta amyloid and RAGE, the researchers were able to count antibodies specific for the two and document the increase in both that occurs in Alzheimer’s. They also found a linear correlation: when amyloid-â antibodies were high, so were RAGE antibodies, probably because they are binding to the same complex, Dr. Buccafusco says.

"What we want to do is find patients who have the propensity of becoming Alzheimer’s patients," he says. "That is where a simple, early diagnostic test would come in handy. If you could tell someone they have a high chance of becoming an Alzheimer’s patient in the next five to 10 years, then you can keep an eye on them and intervene early in the disease when it will do the most good." The researchers’ study already has yielded healthy individuals with relatively high levels of the important antibodies to follow to see if Alzheimer’s develops. They also will work with another group of researchers studying mild cognitive impairment – thought to be a precursor disease – using the new assay to tests its potential as an early diagnostic tool. Meanwhile, Dr. Mruthinti is working toward developing the monoclonal antibody against the destructive complex. “If I can make a human antibody against the complex that can be used a therapy, that would be my dream,” she says.

[chubtoad]

http://www.eurekaler...ct/medicine.php

Study suggests how Alzheimer's patients can be trained

Researchers have discovered that people with early-stage Alzheimer's retain a form of memory capability that could point the way toward training and rehabilitation to help preserve their mental functioning. The findings could also suggest techniques to make life easier for healthy older people.
In an article in the June 10, 2004, issue of Neuron, Cindy Lustig and Randy Buckner reported evidence that older people with symptoms of early-stage Alzheimer's still showed capabilities of "implicit memory" similar to young adults and older adults without symptoms.

Implicit memory -- one type of which is developed by repetition or "priming"-- is a type of memory required to perform tasks. It is distinct from the explicit memory for events and people that is profoundly affected by Alzheimer's. To some extent, even healthy older adults with no Alzheimer's symptoms complain of loss of explicit memory. Each type of memory seems to draw on different regions of the brain, researchers have found.