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duminică, 5 august 2012

Alzheimer's Found To Be More Aggressive Among Younger Elderly But Slows In Advanced Age

The greatest risk factor for Alzheimer's disease (AD) is advancing age. By age 85, the likelihood of developing the dreaded neurological disorder is roughly 50 percent. But researchers at the University of California, San Diego School of Medicine say AD hits hardest among the "younger elderly" - people in their 60s and 70s - who show faster rates of brain tissue loss and cognitive decline than AD patients 80 years and older.

The findings, reported online in the journal PLOS One, have profound implications for both diagnosing AD - which currently afflicts an estimated 5.6 million Americans, a number projected to triple by 2050 - and efforts to find new treatments. There is no cure for AD and existing therapies do not slow or stop disease progression.

"One of the key features for the clinical determination of AD is its relentless progressive course," said Dominic Holland, PhD, a researcher at the Department of Neurosciences at UC San Diego and the study's first author. "Patients typically show marked deterioration year after year. If older patients are not showing the same deterioration from one year to the next, doctors may be hesitant to diagnose AD, and thus these patients may not receive appropriate care, which can be very important for their quality of life."

Holland and colleagues used imaging and biomarker data from participants in the Alzheimer's Disease Neuroimaging Initiative, a multi-institution effort coordinated at UC San Diego. They examined 723 people, ages 65 to 90 years, who were categorized as either cognitively normal, with mild cognitive impairment (an intermediate stage between normal, age-related cognitive decline and dementia) or suffering from full-blown AD.

"We found that younger elderly show higher rates of cognitive decline and faster rates of tissue loss in brain regions that are vulnerable during the early stages of AD," said Holland. "Additionally cerebrospinal fluid biomarker levels indicate a greater disease burden in younger than in older individuals."

Holland said it's not clear why AD is more aggressive among younger elderly.

"It may be that patients who show onset of dementia at an older age, and are declining slowly, have been declining at that rate for a long time," said co-author Linda McEvoy, PhD, associate professor of radiology. "But because of cognitive reserve or other still-unknown factors that provide 'resistance' against brain damage, clinical symptoms do not manifest till later age."

Another possibility, according to Holland, is that older patients may be suffering from mixed dementia - a combination of AD pathology and other neurological conditions. These patients might withstand the effects of AD until other adverse factors, such as brain lesions caused by cerebrovascular disease, take hold. At the moment, AD can only be diagnosed definitively by an autopsy. "So we do not yet know the underlying neuropathology of participants in this study," Holland said.

Clinical trials to find new treatments for AD may be impacted by the differing rates, researchers said. "Our results show that if clinical trials of candidate therapies predominately enroll older elderly, who show slower rates of change over time, the ability of a therapy to successfully slow disease progression may not be recognized, leading to failure of the clinical trial," said Holland. "Thus, it's critical to take into account age as a factor when enrolling subjects for AD clinical trials."

The obvious downside of the findings is that younger patients with AD lose more of their productive years to the disease, Holland noted. "The good news in all of this is that our results indicate those who survive into the later years before showing symptoms of AD will experience a less aggressive form of the disease."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our alzheimer's / dementia section for the latest news on this subject. Co-authors are Rahul S. Desikan, Department of Radiology, UCSD and Anders M. Dale, Departments of Neurosciences and Radiology, UCSD.
Funding for this research came, in part, from the National Institutes of Health (grants R01AG031224, R01AG22381, U54NS056883, P50NS22343 and P50MH08755); the National Institute on Aging (grant K01AG029218) and the National Institute of Biomedical Imaging and Bioengineering (grant T32EB005970).
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Paralysis In Mice With Multiple Sclerosis Reversed By Alzheimer's Molecule

A molecule widely assailed as the chief culprit in Alzheimer's disease unexpectedly reverses paralysis and inflammation in several distinct animal models of a different disorder - multiple sclerosis, Stanford University School of Medicine researchers have found.

This surprising discovery, which was reported in a study published online as the cover feature in Science Translational Medicine, comes on the heels of the recent failure of a large-scale clinical trial aimed at slowing the progression of Alzheimer's disease by attempting to clear the much-maligned molecule, known as A-beta, from Alzheimer's patients' bloodstreams. While the findings are not necessarily applicable to the study of A-beta's role in the pathology of that disease, they may point to promising new avenues of treatment for multiple sclerosis.

The short protein snippet, or peptide, called A-beta (or beta-amyloid) is quite possibly the single most despised substance in all of brain research. It comes mainly in two versions differing slightly in their length and biochemical properties. A-beta is the chief component of the amyloid plaques that accumulate in the brains of Alzheimer's patients and serve as an identifying hallmark of the neurodegenerative disorder.

A-beta deposits also build up during the normal aging process and after brain injury. Concentrations of the peptide, along with those of the precursor protein from which it is carved, are found in multiple-sclerosis lesions as well, said Lawrence Steinman, MD, the new study's senior author. In a lab dish, A-beta is injurious to many types of cells. And when it is administered directly to the brain, A-beta is highly inflammatory.

Yet little is known about the physiological role A-beta actually plays in Alzheimer's - or in MS, said Steinman, a professor of neurology and neurological sciences and of pediatrics and a noted multiple-sclerosis researcher. He, first author Jacqueline Grant, PhD, and their colleagues set out to determine that role in the latter disease. (Grant was a graduate student in Steinman's group when the work was done.)

Multiple sclerosis, an inflammatory autoimmune disease, occurs when immune cells invade the brain and spinal cord and attack the insulating coatings of nerve cells' long, cable-like extensions called axons. Damage to these coatings, composed largely of a fatty substance called myelin, disrupts the transmission of signals that ordinarily travel long distances down axons to junctions with other nerve cells. This signal disruption can cause blindness, loss of muscle control and difficulties with speech, thought and attention.

Previous research by Steinman, who is also the George A. Zimmerman Professor, and others showed that both A-beta and its precursor protein are found in MS lesions. In fact, the presence of these molecules along an axon's myelinated coating is an excellent marker of damage there.

Given the peptide's nefarious reputation, Steinman and his associates figured that A-beta was probably involved in some foul play with respect to MS. To find out, they relied on a mouse model that mimics several features of multiple sclerosis - including the autoimmune attack on myelinated sections of the brain that causes MS.

Steinman had, some years ago, employed just such a mouse model in research that ultimately led to the development of natalizumab (marketed as Tysabri), a highly potent MS drug. That early work proved that dialing down the activation and proliferation of immune cells located outside the central nervous system (which is what natalizumab does) could prevent those cells from infiltrating and damaging nerve cells in the CNS.

Knowing that immunological events outside the brain can have such an effect within it, the Stanford scientists were keen on seeing what would happen when they administered A-beta by injecting it into a mouse's belly, rather than directly to the brain.

"We figured it would make it worse," Steinman said.

Surprisingly, the opposite happened. In mice whose immune systems had been "trained" to attack myelin, which typically results in paralysis, A-beta injections delivered before the onset of symptoms prevented or delayed the onset of paralysis. Even when the injections were given after the onset of symptoms, they significantly lessened the severity of, and in some cases reversed, the mice's paralysis.

Steinman asked Grant to repeat the experiment. She did, and got the same results.

His team then conducted similar experiments using a different mouse model: As before, they primed the mice's immune cells to attack myelin. But rather than test the effects of A-beta administration, the researchers harvested the immune cells about 10 days later, transferred them by injection to another group of mice that did not receive A-beta and then analyzed this latter group's response. The results mirrored those of the first set of experiments, proving that A-beta's moderating influence on the debilitating symptoms of the MS-like syndrome has nothing to do with A-beta's action within the brain itself, but instead is due to its effect on immune cells before they penetrate the brain.

Sophisticated laboratory tests showed that A-beta countered not only visible symptoms such as paralysis, but also the increase in certain inflammatory molecules that characterizes multiple-sclerosis flare-ups. "This is the first time A-beta has been shown to have anti-inflammatory properties," said Steinman.

Inspection of the central nervous systems of the mice with the MS-resembling syndrome showed fewer MS-like lesions in the brains and spinal cords of treated mice than in those not given A-beta. There was also no sign of increased Alzheimer's-like plaques in the A-beta-treated animals. "We weren't giving the mice Alzheimer's disease" by injecting A-beta into their bellies, said Grant.

In addition, using an advanced cell-sorting method called flow cytometry, the investigators showed A-beta's strong effects on the immune system composition outside the brain. The numbers of immune cells called B cells were significantly diminished, while those of two other immune-cell subsets - myeloid cells and memory T-helper cells - increased.

"At this point we wanted to find out what would happen if we tried pushing A-beta levels down instead of up," Grant said. The researchers conducted a different set of experiments, this time in mice that lacked the gene for A-beta's precursor protein, so that they could produce neither the precursor nor A-beta. These mice, when treated with myelin-sensitized immune cells to induce the MS-like state, developed exacerbated symptoms and died faster and more frequently than normal mice who underwent the same regimen.

Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease in San Francisco and a veteran Alzheimer's researcher, noted that while A-beta's toxicity within the brain has been established beyond reasonable doubt, many substances made in the body can have vastly different functions under different circumstances.

"A-beta is made throughout our bodies all of the time. But even though it's been studied for decades, its normal function remains to be identified," said Mucke, who is familiar with Steinman's study but wasn't involved in it. "Most intriguing, to me, is this peptide's potential role in modulating immune activity outside the brain."

The fact that the protection apparently conferred by A-beta in the mouse model of multiple sclerosis doesn't require its delivery to the brain but, rather, can be attributed to its immune-suppressing effect in the body's peripheral tissues is likewise intriguing, suggested Steinman.

"There probably is a multiple-sclerosis drug in all this somewhere down the line," he said.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our multiple sclerosis section for the latest news on this subject. Additional Stanford co-authors were associate professor of neurology and neurological sciences Katrin Andreasson, MD; professor of genetics Leonore Herzenberg, DSc; emeritus professor of genetics Leonard Herzenberg, PhD; postdoctoral scholars Eliver Ghosn, PhD, Robert Axtell, PhD, Hedwich Kuipers, PhD, and Katja Herges, MD; and graduate student Nathan Woodling.
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joi, 15 decembrie 2011

Biochemical Signature Predicts Progression To Alzheimer's Disease

Main Category: Alzheimer's / Dementia
Also Included In: Biology / Biochemistry
Article Date: 15 Dec 2011 - 1:00 PST

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A study led by Research Professor Matej Oresic from VTT Technical Research Centre of Finland suggests that Alzheimer's disease is preceded by a molecular signature indicative of hypoxia and up-regulated pentose phosphate pathway. This indicator can be analysed as a simple biochemical assay from a serum sample months or even years before the first symptoms of the disease occur. In a healthcare setting, the application of such an assay could therefore complement the neurocognitive assessment by the medical doctor and could be applied to identify the at-risk patients in need of further comprehensive follow-up.

Alzheimer's disease (AD) is a growing challenge to the health care systems and economies of developed countries with millions of patients suffering from this disease and increasing numbers of new cases diagnosed annually with the increasing ageing of populations.

The progression of Alzheimer's disease (AD) is gradual, with the subclinical stage of illness believed to span several decades. The pre-dementia stage, also termed mild cognitive impairment (MCI), is characterised by subtle symptoms that may affect complex daily activities. MCI is considered as a transition phase between normal aging and AD. MCI confers an increased risk of developing AD, although the state is heterogeneous with several possible outcomes, including even improvement back to normal cognition.

What are the molecular changes and processes which define those MCI patients who are at high risk of developing AD? The teams led by Matej Orešic from VTT and Hilkka Soininen from the University of Eastern Finland set out to address this question, and the results were published on 13th Dec. 2011 in Translational Psychiatry.

The team used metabolomics, a high-throughput method for detecting small metabolites, to produce profiles of the serum metabolites associated with progression to AD. Serum samples were collected at baseline when the patients were diagnosed with AD, MCI, or identified as healthy controls. 52 out of 143 MCI patients progressed to AD during the follow-up period of 27 months on average. A molecular signature comprising three metabolites measured at baseline was derived which was predictive of progression to AD. Furthermore, analysis of data in the context of metabolic pathways revealed that pentose phosphate pathway was associated with progression to AD, also implicating the role of hypoxia and oxidative stress as early disease processes.

The unique study setting allowed the researchers to identify the patients diagnosed with MCI at baseline who later progressed to AD and to derive the molecular signature which can identify such patients at baseline.

Though there is no current therapy to prevent AD, early disease detection is vital both for delaying the onset of the disease through pharmacological treatment and/or lifestyle changes and for assessing the efficacy of potential AD therapeutic agents. The elucidation of early metabolic pathways associated with progression to Alzheimer's disease may also help in identifying new therapeutic avenues.

Article adapted by Medical News Today from original press release. Source: Technical Research Centre of Finland
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New Drug That Improves Memory And Prevents Brain Damage In Mice May Prevent Alzheimer's Disease Progression

Main Category: Alzheimer's / Dementia
Also Included In: Parkinson's Disease; Huntingtons Disease; Stroke
Article Date: 15 Dec 2011 - 7:00 PST

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A new drug candidate may be the first capable of halting the devastating mental decline of Alzheimer's disease, based on the findings of a study published in PLoS one.

When given to mice with Alzheimer's, the drug, known as J147, improved memory and prevented brain damage caused by the disease. The new compound, developed by scientists at the Salk Institute for Biological Studies, could be tested for treatment of the disease in humans in the near future.

"J147 enhances memory in both normal and Alzheimer's mice and also protects the brain from the loss of synaptic connections," says David Schubert, the head of Salk's Cellular Neurobiology Laboratory, whose team developed the new drug. "No drugs on the market for Alzheimer's have both of these properties."

Although it is yet unknown whether the compound will prove safe and effective in humans, the Salk researchers' say their results suggest the drug may hold potential for treatment of people with Alzheimer's.

As many as 5.4 million Americans suffer from Alzheimer's, according to the National Institutes of Health. More than 16 million will have the disease by 2050, according to Alzheimer's Association estimates, resulting in medical costs of over $1 trillion per year.

The disease causes a steady, irreversible decline in brain function, erasing a person's memory and ability to think clearly until they are unable to perform simple tasks such as eating and talking, and it is ultimately fatal. Alzheimer's is linked to aging and typically appears after age 60, although a small percentage of families carry a genetic risk for earlier onset. Among the top ten causes of death, Alzheimer's is the only one without a way to prevent, cure or slow disease progression.

Scientists are unclear what causes Alzheimer's, which appears to emerge from a complex mix of genetics, environment and lifestyle factors. So far, the drugs developed to treat the disease, such as Aricept, Razadyne and Exelon, only produce fleeting memory improvements and do nothing to slow the overall course of the disease.

To find a new type of drug, Schubert and his colleagues bucked the trend within the pharmaceutical industry of focusing exclusively on the biological pathways involved in the formation of amyloid plaques, the dense deposits of protein that characterize the disease. To date, Schubert says, all amyloid-based drugs have failed in clinical trials.

Instead, the Salk team developed methods for using living neurons grown in laboratory dishes to test whether or not new synthetic compounds were effective at protecting the brain cells against several pathologies associated with brain aging. Based on the test results from each chemical iteration of the lead compound, which was originally developed for treatment of stroke and traumatic brain injury, they were able to alter its chemical structure to make a much more potent Alzheimer's drug.

"Alzheimer's is a complex disease, but most drug development in the pharmaceutical world has focused on a single aspect of the disease - the amyloid pathway," says Marguerite Prior, a research associate in Schubert's lab, who led the project along with Qi Chen, a former Salk postdoctoral researcher. "In contrast, by testing these compounds in living cell cultures, we can determine what they do against a range of age-related problems and select the best candidate that addresses multiple aspects of the disease, not just one."

With a promising compound in hand, the researchers shifted to testing J147 as an oral medication in mice. Working with Amanda Roberts, a professor of molecular neurosciences at The Scripps Research Institute, they conducted a range of behavioral tests that showed that the drug improved memory in normal rodents.

The Salk researchers went on to show that it prevented cognitive decline in animals with Alzheimer's and that mice and rats treated with the drug produced more of a protein called brain-derived neurotrophic factor (BDNF), a molecule that protects neurons from toxic insults, helps new neurons grow and connect with other brain cells, and is involved in memory formation.

Because of the broad ability of J147 to protect nerve cells, the researchers believe that it may also be effective for treating other neurological disorders, such as Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis (ALS), as well as stroke.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our alzheimer's / dementia section for the latest news on this subject. The research was funded by the Fritz B. Burns Foundation, the National Institutes of Health, the Bundy Foundation and the Alzheimer's Association.
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duminică, 11 decembrie 2011

Researchers Design Alzheimer's Antibodies

Main Category: Alzheimer's / Dementia
Article Date: 10 Dec 2011 - 1:00 PST

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Researchers at Rensselaer Polytechnic Institute have developed a new method to design antibodies aimed at combating disease. The surprisingly simple process was used to make antibodies that neutralize the harmful protein particles that lead to Alzheimer's disease.

The process is reported in the Dec. 5 Early Edition of the journal Proceedings of the National Academy of Sciences (PNAS). The process, outlined in the paper, titled "Structure-based design of conformation- and sequence-specific antibodies against amyloid ß," could be used as a tool to understand complex disease pathology and develop new antibody-based drugs in the future.

Antibodies are large proteins produced by the immune system to combat infection and disease. They are comprised of a large Y-shaped protein topped with small peptide loops. These loops bind to harmful invaders in the body, such as a viruses or bacteria. Once an antibody is bound to its target, the immune system sends cells to destroy the invader. Finding the right antibody can determine the difference between death and recovery.

Scientists have long sought methods for designing antibodies to combat specific ailments. However, the incredible complexity of designing antibodies that only attached to a target molecule of interest has prevented scientists from realizing this ambitious goal.

When trying to design an antibody, the arrangement and sequence of the antibody loops is of utmost importance. Only a very specific combination of antibody loops will bind to and neutralize each target. And with billions of different possible loop arrangements and sequences, it is seemingly impossible to predict which antibody loops will bind to a specific target molecule.

The new antibody design process was used to create antibodies that target a devastating molecule in the body: the Alzheimer's protein. The research, which was led by Assistant Professor of Chemical and Biological Engineering Peter Tessier, uses the same molecular interactions that cause the Alzheimer's proteins to stick together and form the toxic particles that are a hallmark of the disease.

"We are actually exploiting the same protein interactions that cause the disease in the brain to mediate binding of antibodies to toxic Alzheimer's protein particles," Tessier said.

Alzheimer's disease is due to a specific protein the Alzheimer's protein sticking together to form protein particles. These particles then damage the normal, healthy functions of the brain. The formation of similar toxic protein particles is central to diseases such as Parkinson's and mad cow disease.

Importantly, the new Alzheimer's antibodies developed by Tessier and his colleagues only latched on to the harmful clumped proteins and not the harmless monomers or single peptides that are not associated with disease.

Tessier and his colleagues see the potential for their technique being used to target and better understand similar types of protein particles in disorders such as Parkinson's disease.

"By binding to specific portions of the toxic protein, we could test hypotheses about how to prevent or reverse cellular toxicity linked to Alzheimer's disease," Tessier said.

In the long term, as scientists learn more about methods to deliver drugs into the extremely well-protected brain tissue, the new antibody research may also help to develop new drugs to combat disorders such as Alzheimer's disease.

The research was funded by the Alzheimer's Association, the National Science Foundation (NSF), and the Pew Charitable Trust.

Article adapted by Medical News Today from original press release. Source: Rensselaer Polytechnic Institute
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