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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In Rat Model Of Lou Gehrig's, Disease Progression Halted

Main Category: Neurology / Neuroscience
Also Included In: Genetics
Article Date: 13 Dec 2011 - 1:00 PST

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Amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig's disease) is an incurable adult neurodegenerative disorder that progresses to paralysis and death. Genetic mutations are the cause of disease in 5% of patients with ALS.

Of immense interest, Hongxia Zhou, Xu-Gang Xia, and colleagues, at Thomas Jefferson University, Philadelphia, now show that progressive neuron degeneration can be halted in a rat model of familial ALS linked to mutations in the gene that carries the instructions for making the protein TDP-43.

Progressive motor neuron degeneration was stopped when expression of the ALS-associated mutant human TDP-43 was switched off. If expression of the mutant protein was switched off before many motor neurons had degenerated, the rats recovered function. Conversely, if expression was switched off after most motor neurons had degenerated, functional recovery was minimal. These data indicate that mutant TDP-43 in motor neurons is sufficient to promote the onset and progression of ALS and that progression of motor neuron degeneration (and thereby progression of disease) is partially reversible in the rat model.

TITLE: Mutant TDP-43 in motor neurons promotes the onset and progression of ALS in rats

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
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Biopsies Reveal Nature Of Brain Lesions Early In MS Progression, Countering Conventional Wisdom

Main Category: Multiple Sclerosis
Also Included In: Neurology / Neuroscience
Article Date: 09 Dec 2011 - 1:00 PST

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Working together, researchers at Cleveland Clinic and Mayo Clinic have for the first time examined early multiple sclerosis (MS) brain lesions in the cerebral cortex. These lesions are thought to be critical to MS progression and the researchers found that the lesions are distinctly different than previously speculated, giving clues to better disease management.

The long-accepted theory has been that MS begins in the myelin on the inner layers of the brain, also known as white matter. However, the findings of this collaborative study show the opposite -- that the disease likely can move from the outer (cortical) layers of the brain toward the white matter, offering new insight into the progression of MS.

"For patients, the key idea of this research is that we have discovered an entirely new concept of how MS may start," said Richard Ransohoff, M.D., Director of the Neuroinflammation Research Center of the Department of Neurosciences at Cleveland Clinic's Lerner Research Institute, who co-led the study. "This research shows that a non-inflammatory form of MS is much less likely, and the prevailing research path has been going in the right direction."

While the causes of MS remain undetermined, it is thought to be a disease in which the body's immune system attacks and destroys its own myelin, a fatty insulator of the crucial nerve fibers that are responsible for communication between different sections of the brain.

However, in autopsy tissues of MS patients, lesions in the cerebral cortex show demyelination without inflammation, raising a challenging issue: if cortical lesions form entirely without inflammation, then cortical demyelination would not be explainable by current theories of MS nor treatable by current MS therapies.

The present study, published in the New England Journal of Medicine, was a collaborative effort by Dr. Ransohoff, also a staff neurologist at the Mellen Center for Multiple Sclerosis Treatment and Research at Cleveland Clinic's Neurological Institute, and by Claudia Lucchinetti, M.D., of the Mayo Clinic's Department of Neurology.

The study involved examination of 563 brain biopsies resulting in the diagnosis of inflammatory demyelinating disease of the central nervous system, with 138 being determined to have sufficient cortex for study. Of these, 77 cases provided long-term follow-up data, with 58 cases (75 percent) going on to develop verified MS. The vast majority of biopsies were performed at community hospitals with the brain tissue being sent to the Mayo Clinic for neuropathological consultation services. Dr. Lucchinetti leads the National MS Society's MS Lesion project housed at the Mayo Clinic. This study was funded in part by that project as well as the National Institutes of Health.

MRI neuroimaging studies in early multiple sclerosis can't detect cortical lesions but have revealed cortical abnormalities, suggesting that the cortex may be damaged near the time of disease onset. The current research shows that the cortex harbors inflammatory lesions accounting for MRI indicators of damage.

"The next step in this research is to study the lesions to uncover new molecular targets for treatment. We also need to push forward to develop imaging techniques to view these cortical lesions," said Dr. Lucchinetti. "In that way, effects of treatment can more easily be measured."

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. Other authors on this study include: Natalia Moll, M.D., Ph.D., from the Neuroinflammation Research Center and Department of Neurosciences of Lerner Research Institute, Cleveland Clinic; Bogdan Popescu, M.D., Reem Bunyan, M.D., Shanu Roemer, M.D., Joseph Parisi, M.D., Bernd Scheithauer, M.D., Caterina Giannini, M.D., Stephen Weigand, M.S., Jay Mandrekar, Ph.D., all from Mayo Clinic; Hans Lassmann, M.D., from the Center for Brain Research, Medical University of Vienna, Austria; and Wolfgang Bruck, M.D., from the Department of Neuropathology, University Medical Center and Institute for MS Research in Gottingen, Germany.
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