Roskamp Institute Articles

By S. FERGUSON,a* B. MOUZON,a G. KAYIHAN, a M. WOOD, a F. POON, a S. DOORE, a V. MATHURA, a

J. HUMPHREY, a B. O’STEEN, b R. HAYES, c A. ROSES, d M. MULLANa AND F. CRAWFORDa

aThe Roskamp Institute, 2040 Whitfield Avenue, 34243, Sarasota, FL,

USA

bCenter for Traumatic Brain Injury Studies, McKnight Brain Institute of

the University of Florida, 100 Newell Drive, Gainesville, FL, USA

cBanyan Biomarkers, 12085 Research Drive, 32615, Alachua, FL,

USA dR. David Thomas Executive Training Center, Duke University, One

Science Drive, Suite 342, Durham, NC, USA

Abstract—Traumatic Brain Injury (TBI) is known to result in oxidative stress, which is an increase or imbalance in the amount of cytotoxic oxidants and free radicals beyond what the cell can normally handle.  The Apolipoprotein E (APOE) gene has different variations called alleles, with two of the most common known as APOE3 and APOE4.  The different APOE alleles have been shown to influence outcome following TBI in different ways, with the APOE4 allele being associated with poor outcome, but through as yet unclear mechanisms, so we used transgenic APOE mouse models to examine the relationship between APOE genotype and oxidative stress following TBI.  Mice transgenic for either human APOE3 or APOE4 on a murine APOE-deficient background were examined in an approved model of TBI. RNA was prepared from the ipsilateral hippocampi and cortices retrieved at 24 h and 1 month post-TBI. Microarray (“gene chip”) analysis was performed on individual samples from three mice per group to determine the way different genes are turned on or off in response to TBI and to specifically investigate the response of genes involved in oxidative stress mechanisms. Our data demonstrated TBI-induced expression of many more anti-oxidant related genes in the APOE3 mice, suggesting a potential anti-oxidative role for the ApoE3 compared to ApoE4. However, in an additional cohort of mice we isolated the ipsilateral hippocampi, cortices, and cerebella at 1 month after TBI for immunohistochemical analysis of markers of oxidative stress: the formation and presence of carbonyls (indication of general oxidative modification), 3-nitrotyrosine (3NT; specific to protein modification), or 4-hydroxyl-2-nonenal (HNE; specific to lipid peroxidation). Although we observed significant increases in all three markers of oxidative stress in response to injury, and genotype was a significant factor for carbonyl and 3NT, we found no significant interaction between genotype and injury. This may be due to the overwhelming effect  injury has on the oxidative stress level compared to genotype in our ANOVA, but nonetheless suggests that an influence on oxidative stress response is not the primary mechanism behind the APOE-genotype specific differences of outcome following TBI.

To reach the article that was published in Neuroscience Volume 168, Issue 3, 14 July 2010, Pages 811-819, please follow the link.

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949

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A methodology is described for use of a 16-hole circular platform task to test spatial memory in mice. Both bright light and a fan were used to motivate mice to escape the platform surface through a single hole containing an attached escape box. For each daily trial, three correlated measures (escape latency, number of errors, and error rating) comprehensively evaluated cognitive performance. In an initial study, the ‘spatial’ nature of this task was demonstrated by the much poorer performance of non-transgenic mice when visual cues are removed. Behavioral sensitivity of the circular platform task was then shown through its ability to discern cognitive impairment in 7-month-old transgenic mice, carrying the mutant APPSW gene for early-onset Alzheimer’s disease in humans, from non-transgenic litter-mates. Since there are currently only a few tasks available to definitively test cognitive performance in mice, the circular platform task offers a versatile, multiple-measure option with numerous advantages. Particularly in view of the increasing number of genetically manipulated mouse models being produced, the circular platform task should be most useful in providing a sensitive evaluation of cognition in mice.

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Sarasota, Fla. Dr. Daniel Paris, a senior scientist of the Roskamp Institute, was awarded an Investigator Initiated Research Grant Award from the Alzheimer’s Association to investigate the preclinical efficacy of a natural compound (celastrol) in a genetically engineered mouse model of Alzheimer’s disease.

The brain of Alzheimer’s disease patients is characterized by the accumulation of a small protein called beta-amyloid or Abeta and by the presence of intraneuronal tangle of a protein called tau. Abeta appears to be a key player in the pathology of Alzheimer’s disease and has been shown to trigger memory impairment, neuronal loss, abnormal tau protein accumulation, as well as cerebrovascular damages in various animal models of the disease. Abeta is produced by the cleavage of a larger protein precursor by two different enzymes called beta and gamma-secretase. Beta-secretase is the rate limiting enzyme in the production of Abeta and is viewed as a golden target for the treatment of Alzheimer’s disease. However despite intensive work, direct inhibitors of beta-secretase or Gamma-secretase with good drug-like properties have been extremely difficult to make. Given the difficulties being encountered by pharmaceutical industries for developing direct secretase inhibitors, Dr. Paris hypothesized that drugs which indirectly target the beta-secretase by affecting the production of the enzyme rather than by inhibiting it would be beneficial. Following the development of a screening method for identifying such drugs, Dr. Paris’ research team identified that a small molecule called celastrol is an indirect beta-secretase inhibitor that can potently oppose the production of Abeta. Celastrol is a natural compound extracted from a perennial creeping plant indigenous to a large area in southern China and known as the “Thunder of god vine”. Extracts containing celastrol have been given to Chinese patients for many years and are known to be efficient against inflammatory conditions. In the present research, Dr. Paris will determine whether celastrol holds promise as a therapeutic agent for the treatment of Alzheimer’s disease. He will further investigate whether this compound can prevent or reverse cognitive deficits, Abeta accumulation and tau pathology that affect a transgenic mouse model of Alzheimer’s disease.

Roskamp is a not-for-profit research Institute located in Sarasota, Fla., that is dedicated to understanding the causes of, and finding cures for, neuropsychiatric and neurodegenerative disorders with an emphasis on Alzheimer’s disease. The Institute’s Memory Clinic also offers comprehensive cognitive and medical assessment toward differential diagnosis of Alzheimer’s disease and offers treatments and disease management options once the diagnostic evaluation is complete.

For more information, please contact the Institute at (941) 752-2949, Roskamp’s Clinical Trials Division in Sarasota at (941) 256-8018 or visit www.RoskampInstitute.com.

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Sarasota, FL The Roskamp Institute today announced that its researchers have uncovered a new link between inflammation and Alzheimer’s disease and have identified a potential target for developing novel therapeutics for intervention in this disease. The study, led by Roskamp Institute’s Pancham Bakshi, Ph.D., is detailed in the American Chemical Society’s Chemical Biology Journal, a leading online publisher of peer-reviewed research.

It has long been known that Alzheimer’s disease is accompanied by inflammation, which both exacerbates and is caused by the underlying disease. In addition, it has long been suggested that abnormal deposits of a small protein, known as amyloid, which accumulate in the brain of those afflicted by Alzheimer’s disease, also trigger an inflammatory response. This inflammatory response is thought to be detrimental to nerve cells, eventually causing their destruction.

Recent research at the Roskamp Institute has revealed that inflammation can lead to the production of more amyloid, and researchers have found that a specific receptor on the nerve cell surface, known as CXCR2, is an interface between inflammation and new amyloid production. As specific inflammatory molecules contact CXCR2, a signal is generated which results in increased amyloid production. The presence of the abnormally occurring amyloid; therefore, contributes to its own reproduction through the inflammatory response it triggers.

“I found that by genetically knocking out CXCR2, we can reduce the amount of amyloid in various laboratory models and, by using drugs that specifically block the CXCR2 receptor, we are able to show that a decrease in production of amyloid can be achieved,” said Dr. Bakshi. “This study, which for the first time shows the early role of inflammation in AD, opens a new door for therapeutic intervention, potentially leading to the use of CXCR2 blocking agents as a way to treat both the inflammation and the amyloid production in Alzheimer’s disease.”

“Finding new classes of medications for Alzheimer’s disease is a world-wide priority,” said Michael Mullan, M.B.B.S., Ph.D., director of the Roskamp Institute. “Dr. Bakshi’s work highlights a new class of drugs that should have the benefit of both stopping inflammation and, importantly, stopping the accumulation of the pathologic amyloid. In addition to the drug Dr. Bakshi has already tested, she is making her own drugs to attack this potentially important target.”

Dr. Bakshi is currently a scientist II in the Roskamp Institute and leads the Laboratory of Chemical Biology and Drug Discovery in Neurology. Prior to the Roskamp Institute, Dr. Bakshi was a postdoctoral researcher with Dr. Michael Wolfe at Harvard Medical School, Center for Neurology from 2001-2004 and a sabbatical postdoctoral fellow at Harvard Medical School, Laboratory of Drug Discovery in Neurology with Dr. Michael Wolfe and Dr. Ross Stein from 2002-2003. Dr. Bakshi has a Ph.D. in Bioorganic Chemistry from the Center for Biochemical Technology, New Delhi, and a Master of Science in Organic Chemistry and Bachelor of Science in Chemistry from the University of Delhi, New Delhi.

The Roskamp Institute is a not-for-profit research Institute located in Manatee County and Hillsborough County, Florida, that is dedicated to understanding the causes of, and finding cures for, neuropsychiatric and neurodegenerative disorders and addictions with an emphasis on Alzheimer’s disease. The Roskamp Institute’s Memory Centers also offer comprehensive cognitive and medical assessment toward differential diagnosis of Alzheimer’s disease and offers treatments and disease management options once the diagnostic evaluation is complete.

For more information, please contact the Institute at (941) 752-2949, Roskamp’s Clinical Trials Division in Sarasota at (941) 256-8018 or visit www.RoskampInstitute.com.

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Sarasota, FL Roskamp Institute was the focus of Southeast High Technology Student Association (TSA) team project in the Medical Technology category which was awarded fifth place in the Nation at the 31ST Annual TSA National Conference in Denver, Colorado June 28 – July 2 after wining first place in the State of Florida competition held in Orlando on March 3rd 2009 . The team fromSoutheast attended the National finals representing the State of Florida and holds the distinction of being Florida’s Most Outstanding TSA High School.

The Team’s project highlighted some of the cutting edge research being carried out at the Roskamp Institute. The TSA team members from Southeast High are Maya Meredith, Andres Romero, Rachel Metras, Lor Gregor, Diego Corzo, John Nguyen, Marissa Bressi. As well, the team won first place in Florida for another Roskamp-assisted project in the Scientific Visualization category. Southeast High School is located in Bradenton, Florida and is an International Baccalaureate Diploma School.

Please click here to see video of this award wining work by the Team from Southeast High.

Roskamp is a not-for-profit research Institute located in Sarasota, Fla., that is dedicated to understanding the causes of, and finding cures for, neuropsychiatric and neurodegenerative disorders with an emphasis on Alzheimer’s disease. The Institute’s Memory Clinic also offers comprehensive cognitive and medical assessment toward differential diagnosis of Alzheimer’s disease and offers treatments and disease management options once the diagnostic evaluation is complete.

For more information, please contact the Institute at (941) 752-2949, Roskamp’s Clinical Trials Division in Sarasota at (941) 256-8018 or visit www.RoskampInstitute.com.
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This summer, researchers from Roskamp Institute in Sarasota, FL, will begin testing an investigational approach to slowing down the progression of Alzheimer’s disease (AD) using Intravenous Immune Globulin (IGIV), also known as gammaglobulin. IGIV is currently used to treat primary immunodeficiency disorders but is not currently approved for treating AD, which is one of the leading causes of dementia in the elderly.

Initial research in experimental models and patients suggests that immunotherapy targeting beta amyloid (the protein that forms the core of plaques in the brain) may provide an effective way to treat AD. Antibodies that bind to beta amyloid are present in IGIV, which is made from the blood of several thousand healthy adults. This effort seeks the public’s participation in testing IGIV in a major clinical trial that is jointly funded by the National Institute on Aging and Baxter International Inc.

One of the hallmarks of AD pathology is an abundance of beta-amyloid deposits in the brain. While it is not yet known if beta amyloid plaques cause AD or are a byproduct of the disease, scientists are interested in finding ways to reduce the toxic effects of beta amyloid on the brain. Antibodies against beta amyloid may do so by binding to toxic forms of beta amyloid, thereby neutralizing them and/or promoting their elimination.

“We are investigating whether IGIV, which contains naturally occurring human anti-amyloid antibodies, will defend the brain of AD patients against the damaging effects of beta amyloid. If it does, giving IGIV to patients with mild to moderate Alzheimer’s may potentially slow the rate of progression of the disease,” says Dr. Andrew Keegan, the principal investigator for the study at Roskamp Institute.

“In our initial studies in AD patients, IGIV provided cognitive benefits, improved brain metabolism and reduced beta amyloid levels in the spinal fluid,” says Norman Relkin, M.D., Project Director and Director of the Weill Cornell Alzheimer’s Disease and Memory Disorders Program. In a Phase II trial at Weill Cornell, Dr. Relkin reported that participants undergoing several months of continuous IGIV therapy also demonstrated improvement in their activities of daily living. He added, “These findings, as well as IGIV’s established record of use for treating other diseases, provide a strong rationale for further study in AD patients on a larger scale.”

The GAP (Gammaglobulin Alzheimer’s Partnership) Study will examine the safety, effectiveness and tolerability of IGIV in patients with mild to moderate AD. GAP is recruiting 360 participants at 36 sites nationwide. This large Phase III clinical trial expands on earlier testing, is one of two Phase III trials, and is part of the final phase in studying IGIV as a potential treatment for AD before seeking regulatory approval.

The GAP trial is a double-blind, placebo-controlled study in which two-thirds of participants will receive IGIV and one-third will receive placebo. It will last up to 82 weeks. Sites are looking for study volunteers who fit the following criteria:

* Male or female, 50-89 years old
* Have been diagnosed with probable mild to moderate Alzheimer’s disease
* Have a study partner (spouse, child, sibling or friend) in contact with the participant 10 hours/week or more

The trial is being conducted by the Alzheimer’s Disease Cooperative Study (ADCS), a nationwide consortium of research centers and clinics coordinated by the University of California at San Diego and directed by Paul Aisen, M.D.

“As many as five million Americans may be afflicted now and with the numbers growing rapidly, ADCS clinical trials such as the GAP study are essential to finding new and more effective treatments for Alzheimer’s disease,” Aisen commented.

The ADCS is primarily supported by the National Institute on Aging (NIA), part of the National Institutes of Health. The GAP study is jointly funded by Baxter International Inc. and the NIA. For further information on the trial, please go to: http://www.adcs.org/Studies/IGIV.aspx

For more information on this study and Alzheimer’s disease, please visit the Alzheimer’s Disease Education and Referral Center website: http://www.alzheimers.org/clinicaltrials/fullrec.asp?PrimaryKey=282

Roskamp is a not-for-profit research Institute located in Sarasota, Fla., that is dedicated to understanding the causes of, and finding cures for, neuropsychiatric and neurodegenerative disorders with an emphasis on Alzheimer’s disease. The Institute’s Memory Clinic also offers comprehensive cognitive and medical assessment toward differential diagnosis of Alzheimer’s disease and offers treatments and disease management options once the diagnostic evaluation is complete.

Contact:
Dr. Andrew Keegan Jeffree Itrich
Roskamp Institute Alzheimer’s Disease Cooperative Study
email: rclinic @ rfdn.org email:jitrich @ ucsd.edu
Phone: (941)256-8018 Phone:(858)622-5827
www.RoskampInstitute.com www.adcs.org

For more information, please contact the Institute at (941) 752-2949, Roskamp’s Clinical Trials Division in Sarasota at (941) 256-8018 or visit www.RoskampInstitute.com.

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The relationship between blood pressure and Alzheimer’s disease is complex. However, we do know that blood pressure raised in mid-life (hypertension) is a risk for the development of Alzheimer’s disease later on. Uncontrolled hypertension is a risk for dementia in general. In fact, stroke related dementias are primarily caused by either clotting or small bleeds in the brain. Hypertension can lead to bleeding, primarily in the brain, but can also damage the heart triggering the release of small clots that lodge in the brain, thus depriving the nerve cells (neurons) of oxygen supply.

It remains unclear to scientists why hypertension is a risk for Alzheimer’s disease, but we do know that in spontaneously hypertensive rats, there is a tendency to accumulate some of the pathology of Alzheimer’s disease.

In 1996, researchers at the Roskamp Institute discovered that the causative protein in Alzheimer’s (the amyloid protein) has a drastic effect on blood vessels. The effect is to increase the propensity of blood vessels to constrict. Subsequently, others show that after a small stroke (when blood vessels close down temporarily) the presence of amyloid tends to keep the blood vessels closed. It is assumed that the consequence of reduced blood flow to the brain, secondary to closed blood vessels, causes deprivation of oxygen and glucose to the neurons, thus causing more damage in a brain with high amyloid levels than one with not.

Translated into clinical terms, this means that the effect of a small stroke on somebody who is in the early stages of Alzheimer’s can be more devastating than somebody who is not. In fact, a study of nuns who were asked to complete mental state questionnaires in life and who subsequently died has revealed an important interaction between small strokes and the clinical signs of Alzheimer’s. Even though some nuns had amyloid deposits in their brain, they did not exhibit the symptoms of amyloid in life. Those nuns that had amyloid deposits but did exhibit the clinical symptoms of Alzheimer’s in life also had multiple small strokes.

Thus, damage to the blood vessels in the presence of amyloid is more devastating than if amyloid is absent. Hypertension tends to damage blood vessels throughout the body, but it is only in the brain that amyloid accumulates and can contribute to poor recovery after vascular injury.

What does this mean for patients treated at the Roskamp Institute? Patients are advised to take particular care to have their blood pressure and cardiovascular status monitored. High lipid or triglyceride levels can contribute to cerebrovascular (brain/blood vessel) damage and uncontrolled or poorly monitored high hypertension can also be highly detrimental. In addition, we know that other cardiac problems, such as arrhythmias can contribute to cerebrovascular damage, as mentioned, by throwing off small clots.

As we await effective treatments to combat Alzheimer’s directly, we need to ensure that we control other disorders which can contribute significantly to rapid declines in mental status. Interestingly, some antihypertensives seem to be able to control the risk for Alzheimer’s disease as well as controlling blood pressure.

Researchers at the Roskamp Institute have clearly shown that this does not apply to all antihypertensives and they are investigating why some are able to regulate both blood pressure and can reduce the incidence of Alzheimer’s disease while others cannot. This is an important area of research and clearly one that holds out hope for Alzheimer’s sufferers as the search for new treatments continues.

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Alzheimer’s disease is a neurodegenerative disorder (i.e., one which attacks neurons in the brain) which robs us of our memories, language, reasoning and thought. However, the clinical picture of Alzheimer’s has a very distinctive pattern which distinguishes it from other forms of dementia (dementia is a general term which simply means the loss of memory, some other mental function, and the loss of normal social functioning). In Alzheimer’s disease, the early signs are almost invariably the same and include loss of memory for recently presented information.

What does this mean practically? It means that someone in the early stages of Alzheimer’s will not remember information presented to them a short time ago. For instance, if somebody receives a phone call, a few minutes later they may not remember who it was who called. Similarly, if they set out for the grocery store, once they arrive there they may not remember what it is they set out for.

Today, we are so used to receiving news all the time from our computers, our televisions, radios, and mobile phones that we don’t realize that we are being presented with new information all the time. The Alzheimer’s sufferer is at a particularly grave disadvantage in this situation. Current events may escape their memory stores and a good test of whether someone may be suffering from the disorder or not is whether they can remember information that appears as news on television or other ways. So, for instance, knowing the big events in the campaign for the US presidential election will be registered by most of us and remembered. The Alzheimer’s sufferer may not know that Hillary Clinton has dropped out of the race nor that Barack Obama has been nominated. Knowledge of these events, which most of us take for granted are lost to the Alzheimer’s sufferer and thus monitoring our loved ones and friends for signs that they are not aware of current events may help us to detect early signs of the disease. Concern that somebody may not be acquiring new information should be a trigger to have them evaluated in a memory disorder clinic.

The Roskamp Institute has two such clinics – one in Tampa and one in Sarasota, Florida and they offer full evaluations for Alzheimer’s and other causes of memory loss.

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A recent paper (June 22nd from scientists from Harvard University and Trinity College, Dublin) has shown that the amyloid protein is most toxic to memory when it appears in a double form. The researchers extracted the amyloid protein (the small protein that has long thought to be the cause of Alzheimer’s) from the brains of Alzheimer’s disease victims and when the proteins were injected into rats, they noted that, depending on the specific form of amyloid, memory impairment occurred.

Alzheimer, himself, saw the accumulation of amyloid protein in what are now know as plaques, but these accumulations of amyloid represent many, many single amyloid molecules aggregated together.

The researchers found that this highly aggregated form of amyloid was not injurious to memory. However, when the amyloid protein occurred in just a doublet, (i.e., two molecules of amyloid stuck together) then it was in its most toxic form. Single amyloid (which we all produce for much of the time) was harmless to memory. These findings are important because the doublet form of amyloid is soluble and therefore can travel freely throughout the brain. These findings also suggest that the aggregated form that is visible to the eye under the microscope is not the most important form for researchers to prevent.

These findings are of particular interest to researchers at the Roskamp Institute, who showed in 1996 that soluble forms of amyloid could be toxic to blood vessels, increasing the likelihood that they would constrict. This is a particularly bad thing, especially after stroke, and it raised the possibility at that time that the soluble forms of Aß of amyloid might be more important than the aggregated forms.

These new findings also suggest that treatments aimed at lowering the amount of the amyloid doublet, might be those that are most effective in the disease. The new vaccine treatment, for instance, aimed at lowering the amount of amyloid by soaking up the amyloid with an antibody, might be effective at lowering these amyloid doublets. Other drugs that are coming on-line for the treatment of Alzheimer’s also targeted at the amyloid protein will now, no doubt, be examined to see whether they can lower the amount of the amyloid doublet.

Researchers at the Roskamp Institute are dedicated to finding new treatments and cures for Alzheimer’s disease. They were among the first in the world to show that the amyloid protein was most likely central to the disease process. This theory is now being tested in clinical studies throughout the world with exciting recent results suggesting that, indeed, the removal of amyloid might be an effective treatment for the disease (see recent reports on Elan Pharmaceuticals).

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In 1991, researchers currently at the Roskamp Institute published a paper in the highly prestigious Nature journal entitled “Early Onset Alzheimer’s Disease Caused by Mutations of the Amyloid Gene”. This and related findings were historic milestones in the understanding of the causes of Alzheimer’s disease. Today, seventeen years later, Roskamp Institute researchers are delighted to hear that Elan, one of the largest pharmaceutical companies, is having success with an approach which targets the amyloid protein.

The early findings by Roskamp researchers placed amyloid at center stage as the cause of the disease. Now Elan’s vaccine, which is targeted to soak up the amyloid protein, may be a verification that reducing amyloid accumulation is a way to tackle the disease. Although some researchers remain skeptical of the validity of this approach, the early results from Elan’s Phase II study, published this week (June 17) indicate that reducing amyloid levels with the anti-amyloid vaccine has slowed the rate of progression of the disease in some patients. Interestingly, the vaccine approach has been helpful in cases of the disease that do not have a high genetic risk loading. Although there was a hint that all cases of Alzheimer’s (even those with high genetic loading might benefit from the vaccine), there was not a statistically significant difference between placebo group and those individuals that carry an APOE4 gene. This gene is known to increase the likelihood of developing Alzheimer’s early in life and may represent a particularly aggressive form of the disorder. Nevertheless, the fact that there were trends in a treatment improvement in the high risk group and statistically significant improvement in income in the low genetic risk group, strongly suggest that targeting amyloid will be a therapeutically useful strategy.

For Roskamp Institute researchers the new data from Elan is very important as Roskamp Institute researchers have developed drugs that do the same thing as the vaccine, i.e., lower the accumulation of amyloid levels. One of those drugs is in clinical trials already in Europe and trials are set to begin in the US pending FDA approval.

For Alzheimer’s sufferers and Alzhiemer’s researchers alike, the news from Elan is very hopeful.

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The Roskamp Institute has a commitment to bring state-of-the-art new therapies to our patients at both the Sarasota and Tampa sites. For Alzheimer’s disease, for instance, the Institute is taking part in the Elan Wyeth clinical trials of a vaccine for Alzheimer’s disease. Important results for the Elan Wyeth vaccine were released on June 17, 2008.

The study of the vaccine called bapineuzumab (AAB-001) in a Phase II clinical trial was conducted in mild to moderate Alzheimer’s disease. The clinical trial lasted eighteen months and overall the bapineuzumab appeared to have clinical activity in treating the disease.

The company found that although the study did not attain statistical significance on the primary efficacy endpoints in the total study population, it was shown that in Alzheimer’s patients who do not carry the APO lipo protein E4 (APOE4) version of the APOE gene there were statistically significant and clinically meaningful benefits associated with the vaccine. The endpoints used included the Alzheimer’s disease assessment scale (ADAScog), the neuropsychological test battery (NTB), the mini-mental state examination (MMSE) and the clinical dementia rating scale (CDR). Interestingly too, when the company looked at brain scans of Alzheimer’s patients in the trial, they found that the MRI indication of loss of brain substance was decreased in those patients that were treated versus the placebo group.

The Roskamp Institute (Institute) is engaged in a Phase III study of the vaccine for Elan Wyeth and these encouraging results suggest that the larger clinical trial may also be beneficial. The vaccine targets are a small protein called amyloid, which researchers at the Institute believe is associated and triggers the disease pathology.

In fact, researchers at the Institute were among the first in the world to show that an accumulation of amyloid could cause Alzheimer’s disease. This they did by working with early-onset families (where the disease occurs in the 40, 50, or 60 year age groups) and showing that genetic errors in the amyloid gene were all that was responsible for the early build-up of the amyloid protein in the brain.

The Elan Wyeth vaccine is engineered to identify amyloid and remove it from the body and as such, holds potential for halting the disease progression. It is expected that the vaccine would be given every few weeks throughout the life of the Alzheimer’s sufferer.

This and other innovative treatments are available to our clinic population at the Roskamp Institute.

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An article in the Wall Street Journal on the 18th of June 2008, encapsulates the current expectation, hope and knowledge in the field of Alzheimer’s disease research. Researchers at the Roskamp Institute (Institute) have been part of the history of the discovery of new possibilities for stopping this devastating disease.

The article importantly discusses the recent work of Elan and Wyeth and their vaccine approach to Alzheimer’s disease. The reason this is central to the work of the Institute is that the same target of the vaccine is the protein that was highlighted by Institute researchers in the early 1990s as being causal in the disease process. The protein called amyloid accumulates in the brains of those with Alzhiemer’s disease and early genetic studies by members of the Institute team showed that amyloid definitely could cause the disease in certain individuals. Articles published in Nature in the early 1990s verified the causal relationship between the buildup of amyloid and the development of Alzheimer’s disease.

Now, almost twenty years later, Elan and Wyeth have developed a vaccine called bapineuzumab, which targets amyloid and reduces its accumulation in the brain. Although the exact mechanism of the antibody vaccine is not known, it is believed to act as a sponge in the blood supply, sucking amyloid from the brain and disposing of it harmlessly around the body.

Interestingly, the Wall Street Journal article points out that although the vaccine Phase II study failed on some of its clinical endpoints, there was enough of a positive signal in the data to enthuse not only Wall Street but researchers world-wide that the lowering of amyloid may be an effective approach to stopping this devastating disease. Many drug companies world-wide are pursuing treatments for Alzheimer’s which lower amyloid. The Institute is one such not-for-profit group which has developed drugs which lower amyloid levels and which are now in clinical trials around the world.

It is estimated that the pharmaceutical industry and biotech companies will spend more than a billion dollars this year researching into new treatments for Alzheimer’s. A Phase III study for the vaccine is underway and is being conducted at clinical sites around the country, including the Roskamp Institute site in Sarasota, Florida. The Institute researchers and clinicians are gratified, not only that they contributed to the early understanding of the causes of Alzheimer’s disease, but that drugs now are coming into clinical trials that target amyloid and look as if they may well be effective in stopping this dreadful disorder.

Another very interesting aspect of the Phase II results from Elan and Wyeth, is that the vaccine seemed to have more benefit in some genetically non-predisposed individuals than others. A gene known as the APOE gene dictates our risk for Alzheimer’s disease, particularly regarding whether we are likely to get the disease when we are 65, 75, or 85. Two copies of the E4 version of APOE, for instance, increase the risk of getting the disease earlier in life. The Elan and Wyeth vaccine looks as if it wasn’t particularly effective in that group, although the numbers treated that were E4 carriers was quite small, as it is in the general population. However, for those not at high genetic risk, the results were significant in that, after eighteen months, there was statistically valuable reduction in the rate of decline of cognitive processes. Integrating genetic tests into clinical trials for Alzheimer’s disease has now become a standard and is one of the adjunct research tests conducted at the Institute.

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Clinicians at the Roskamp Institute are conducting a clinical trial for Elan Pharmaceuticals, Inc. of San Francisco and Transition Therapeutics, Inc. of Toronto, Canada.

The drug is designated ELND005 and the study is a phase two study in mild to moderate Alzheimer’s disease. ELND005 is an orally available drug that is designed to prevent the aggregation of the amyloid peptide. The amyloid peptide is thought to be central to the disease process in Alzheimer’s disease.

As the amyloid peptide accumulates in the brain in Alzheimer’s disease patients, it forms aggregates which are toxic to neurons. ELND005, which was formally known as AZD103, was developed in collaboration with transition therapeutics and has been shown to be able to reduce the amount of amyloid that accumulates in the brains of transgenic mouse models of the disease. This reduction in accumulation correlates with improved memory testing in such animals.

Phase I studies have already been completed in healthy volunteers with ELND005. The drug is shown to be well tolerated and crosses the blood/brain barrier. Importantly, ELND005 has been shown to reach CSF concentrations in humans that are equivalent to the effective mouse concentrations that can reduce the burden of amyloid in mice.

The Phase II study design includes three treatment arms and one placebo group. The treatment arms receive twice a day oral dosing of ELND005. The dose is either 250 mg, 1000 mg, or 2000 mg. The treatment phase will last for 78 weeks.

The endpoints of the study will include cognitive and functional testing of mild to moderate Alzheimer’s disease patients and MRI imaging of brain volumes. Quality of life measures will also be included. As in all Phase II studies, safety will be a primary measure throughout the clinical trial.

Clinical researchers at the Roskamp Institute are committed to bringing new drug treatments like ELND005 to our Alzheimer’s population. It is hoped that either this drug or others like it will play a significant role in the control of Alzheimer’s disease in the near future.

The Roskamp Institute is developing its own drug therapies for Alzheimer’s disease. One of which, nilvadipine, is currently under clinical trials in Ireland. This drug is shortly to be brought into clinical trials in the United States pending FDA approval.

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The Roskamp Institute (Institute) is engaged in the study of drug addiction from a genomic and proteomic perspective.

The genomic analysis, which covers the examination of all the genes in the human genetic make-up allows research at the Institute to determine which genes respond in relation to exposure to certain drugs of addiction.

The proteomic analysis allows researchers at the Institute to determine which drugs of addiction trigger particular protein responses. The proteomic approach that the Institute adopts allows the researchers there to look at all the proteins in the human body in one go.

Changes in genomic and proteomic (gene and protein) profiles, enables the researchers to examine which particular profiles are associated with particular drugs. Moreover, by examining which genes and proteins are changed in response to drugs of addiction, it is expected that new methods to fight drug addiction will be developed. In particular, by knowing which proteins are switched on by particular drugs such as cocaine, heroin, or morphine, the researchers are able to determine whether there may be ways of blocking the addictive effects of these drugs.

Drug addiction impacts a very large part of American society and addiction to cocaine, heroin, morphine, and other drugs, including prescription drugs, is a persistent part of our culture. Developing new ways to combat addiction, both in the early stages and when it becomes chronic, is critical to help manage the devastating effect that addiction can have on the individuals concerned, their families, and their work colleagues.

The original funding to develop new insights into drug addiction and potentially new therapies came from the offices of National Drug Control Policy, which is in an executive branch of the federal government.

Currently, funding for drug addiction research at the Institute is provided by the Roskamp Foundation.

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An article in the New England Journal of Medicine entitled “Traumatic Brain Injury in the War Zone” details the experiences of a supply officer with a US Army Stryker Brigade after suffering a head injury in Northern Iraq in a convoy transporting Iraqi volunteers to Mosul for military training.

The officer reported remembering that the streets were unusually quiet, and he remembered making a radio call to others in the convoy warning them that something might happen. After the vehicle he was traveling in was struck by an improvised explosive device (IED), he remembers having thoughts of why he couldn’t see or hear and remembers wondering where he was. The blast had thrown him from his vehicle, causing a fractured skull and severe contusion of the left fronto-temporal area of his brain.

As one of the most damaging and dangerous consequences of Traumatic Brain Injury (TBI) is brain edema causing swelling of the brain, neurosurgeons performed a craniectomy removing a large piece of skull from the left temporal region, allowing the brain room to swell without being constrained. The compression of the brain in a confined space after a head injury can lead to severe complications, including death.

The next the officer remembers was waking up ten days later at the Walter Reed Hospital. Following treatment, including cognitive and speech therapy, this particular officer made a good recovery, but the article points out that others with similar head injuries do not do as well.

Researchers at the Roskamp Institute (Institute) have previously shown the recovery after TBI is partly controlled by a gene called the APOE gene. Variations in the APOE gene determine whether one will make a good or slow recovery after TBI. It is of interest to note that the same gene determines the risk of developing Alzheimer’s disease in older age groups. APOE may therefore be a general repair gene and current research at the Institute is examining the role of APOE and how it can influence recovery after head injury.

The Institute researchers hope to understand how APOE can, on the one hand increase rates of repair, or on the other hand, encourage degeneration after head injury. Such understanding may lead to the development of new treatments after TBI and may assist young officers, such as the one mentioned here, who suffer the effects of TBI while doing their duty.

This program is funded by the Department of Defense (DoD) as part of the DoD’s general strategy to find new treatments for soldiers who suffer from TBI. TBI is a common occurrence in the civilian population too and treatments developed for military personnel are likely to be extended very quickly for use in civilian population if shown to be successful.

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A recent article in the New England Journal of Medicine emphasizes the important medical consequences of Traumatic Brain Injury (TBI) in US soldiers returning from Iraq. Although the exact number of combat related TBIs is not known, in a survey of over 2500 soldiers returning from Iraq, almost five percent reported injuries with loss of consciousness. A further ten percent reported injuries with altered mental status and seventeen percent reported other injuries during deployment. Importantly, of those reporting loss of consciousness, nearly forty-four percent met criteria for Post Traumatic Stress Disorder (PTSD) and over twenty-seven percent of those reporting altered mental status, also met criteria for PTSD.

The authors conclude that mild TBI, i.e. concussion, occurring among soldiers deployed in Iraq is strongly associated with PTSD and physical health problems three to four months after the soldiers return home. The authors point out that PTSD and depression are important mediators of the relationship between mild TBI and physical health problems.

Researchers at the Roskamp Institute (Institute) are seeking to find new treatments for TBI. In order to do this, they are examining the pathways which are disrupted after TBI to determine which genes and proteins are implicated in pathways of repair or of degeneration. Institute researchers are particularly interested in finding new medications that can intercept the degenerative pathways which occur after TBI. The Institute is devoted to finding new treatments and cures for Alzheimer’s disease (AD) and Institute researchers have a particular interest in the link between AD and TBI.

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Roskamp Institute has previously worked extensively on the ability of amyloid (the main protein that causes Alzheimer’s disease) to stop the growth of blood vessels. Although this is bad news in Alzheimer’s and probably contributes to the decline in cognitive function the effect has been turned to good use in other areas. The Roskamp Institute researchers have shown that amyloid or small fragments of it can stop the growth of blood vessels that supply cancers. It has been known for many years that stopping the growth of blood vessels to cancers can literally starve them of nutrients and arrest their growth or even cause them to shrink. The Roskamp Institute researchers have shown that many cancers are susceptible to having their blood supply cut off. For instance they have shown that amyloid or fragments of it can stop the growth of melanoma, lung cancer and brain tumors. Most recently they have received funding to continue their work with amyloid on lung cancers. They are interested to know whether in addition to stopping the growth of lung cancers amyloid can stop the spread of metastases which so commonly accompany this type of cancer.
Funding from the James & Esther King Biomedical Research Program grant for your project titled will help fund the work for a year and specifically will help to find smaller versions of amyloid that might be suitable for use in humans. One of the challenges that the researchers face is stopping the quick breakdown of amyloid which happens with so many proteins in the blood stream. They plan to alter the basic chemical structure of amyloid to stop it degrading.
The researchers say there is no chance that injecting amyloid can cause Alzheimer’s as it is known in fact that injecting amyloid can be used as a treatment for Alzheimer’s rather than a cause of it.
The award was based on the scientific merit assigned to the proposal by qualified peer reviewers and other factors considered by the Biomedical Research Advisory Council of the State of Florida.

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In September of 2004, the research advisory committee on Gulf War veteran’s illnesses produced a report and recommendation on the scientific progress and understanding the complex condition known as Gulf War Syndrome.

This report suggested that important contributors to Gulf War Syndrome included the nerve agent prophylaxis pill, pyridostigmine bromide, pesticide exposure and potentially anthrax vaccination. One of the recommendations that came out of this committee’s work was that new state-of-the-art technology should be applied to Gulf War Syndrome to try to understand the causes and potential cures of this disorder.

The Roskamp Institute, in collaboration with the Veteran’s Administration (VA), won a grant to pursue this end. The particular approach taken by the Roskamp Institute is to analyze Gulf War Syndrome at the cellular level. To do this, new technology known as proteomics is being used. Proteomic analysis basically allows researchers at the Roskamp Institute to visualize all the proteins which change in a cell after exposure to these potentially toxic agents. In partnership with the Tampa VA, the Roskamp Institute researchers and VA researchers are identifying which proteins characterize exposure to pyridostigmine bromide, organophosphate pesticides and anthrax vaccination.

It will of particular interest to understand which of the proteins that are observed to change after exposure to these agents are specific to the central nervous system. The long-term goal of this project is to understand why Gulf War veterans may be impacted by Gulf War Syndrome and what the underlying biochemical disturbance may be. This in turn, may allow avoidance of Gulf War-type syndromes in the future and may allow VA/Roskamp Institute researchers to consider protection against such syndromes in the event of exposure to nerve agent prophylaxis or pesticides or anthrax vaccination.

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The Roskamp Institute is one of many sites nationally that has been chosen to conduct a clinical trial in Alzheimer’s disease using a vaccine approach. Although the mechanism of action of vaccine is unknown, the original idea was that antibodies would circulate in the body and find the amyloid protein in the brain. There are two basic ways to make antibodies appear in the body. One is to give a stimulus protein: in this case the amyloid peptide, which is known as active vaccination or antibodies can be prepared somewhere else and delivered intravenously which is known as passive vaccination.

Original studies conducted by Elan focused on the former approach. Studies carried out in Europe, using an active approach, appeared encouraging in terms of the reduction of pathology of the disease and improved cognition. Unfortunately, however, several patients taking part in the clinical trials with the active vaccine died, most probably due to the vaccination.

At autopsy, it was clear that individuals had suffered a large inflammatory response in their brains. However, importantly, the amyloid deposits, which characterize Alzheimer’s disease, were diminished. This suggested that although the active vaccination was clearly dangerous, it was able to reduce the amyloid load in the brain, which is potentially a cure for Alzheimer’s disease.

A much more controllable way to deliver antibodies for amyloid is by passive vaccination. In this approach, antibodies are prepared outside of the human body and delivered intravenously every few weeks. This approach constitutes the new clinical trial being conducted by Elan Pharmaceuticals, including at the Roskamp Institute site. Although experimental, this approach is likely to be much safer than the active vaccine approach and offers real hope that this amyloid lowering therapy may be able to reduce the cognitive impairment (memory loss, disorientation, etc.) that invariably accompany the disease.

The Roskamp Institute is committed to delivering state-of-the-art therapies for Alzheimer’s disease as they appear on the market or in experimental clinical trials.

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The Roskamp Institute has received an award from the James & Esther King Biomedical Research Program grant for your project titled “Treatment of Lung Adenocarcinoma and Metastasis by Anti-angiogenic Fragments of Abeta.” The award was based on the scientific merit assigned to the proposal by qualified peer reviewers and other factors considered by the Biomedical Research Advisory Council. The official award letter came from the State Surgeon General Ana M. Viamonte Ros. Roskamp Institute researchers have previously shown that the Abeta peptide (also known as amyloid and which causes Alzheimer’s when it accumulates in the brain) is particularly good at stopping blood vessel growth to tumors. The Roskamp Institute researchers have shown that lung cancer growth is severely inhibited by the Abeta peptide. The funding from the state which was awarded after a peer review of the proposal will allow the development of the original findings towards clinical trials with the peptides. The research team are not concerned that if Abeta is used as a treatment for lung cancer it will cause Alzheimer’s because the small protein has in fact been given in human clinical trials as a vaccine prevention of Alzheimer’s.

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Mainly two cerebral lesions characterized Alzheimer’s disease (AD): an extracellular deposition of the beta-amyloid peptide (Abeta) in senile plaques and an intracellular accumulation of neurofibrillary tangles (principally composed of protein tau). Besides these lesions, a continuous inflammatory state exists in the brain of AD patients.
In AD brains, the tau protein becomes hyper-phosphorylated and acquires a new three-dimensional conformation that results into its aggregation in neuronal cells to form neurofibrillary tangles (NFT). It is generally accepted that the accumulation of Abeta in senile plaques promotes the formation of NFT in AD.
The impact of cerebral inflammation on the aggregation of Abeta has been widely studied. At the Roskamp Institute, it has been previously shown that the binding of CD40 ligand (CD40L) to its receptor CD40, two protein mediating inflammation, is deleterious for AD. Indeed, in the transgenic mouse model for AD Tg2576, disruption of CD40-CD40L binding — by genetic deletion of either CD40 or CD40L, or by a pharmacological treatment — mitigates the amyloid deposition and the associated neuro-inflammation.
In a recent study to be published in Brain Research, the Roskamp Institute reports that the same genetic manipulation (CD40 or CD40L deficiency) in the Tg2576 mouse model for AD reduces the hyper-phosphorylation of the tau protein as well. Interestingly, these data suggest that this decrease is independent than that of Abeta deposition implying that CD40-CD40L pathway has a direct effect on the phosphorylation of tau. Because it would act on the two main pathological features of AD, the therapeutic interest of targeting this pathway is greatly increased by this discovery.

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Alzheimer disease is the most common cause of dementia, afflicting 24 million people worldwide. Over time, Alzheimer’s disease gradually destroys a person’s memory and ability to learn and carry out daily activities. In addition; individuals may also experience changes in personality and behavior. Alzheimer disease is accompanied by the presence of amyloid plaques and neurofibrillary tangles in the brain of Alzheimer’s patients with increases in pro-inflammatory cytokines. Beta-amyloid is a key protein shown to play a central role in Alzheimer’s disease etiology. Unfortunately, there is currently no known cure, finding a way to stop Beta-amyloid production and/or increase it degradation will lead to a potentially drug target that can be used to stop the disease. Researchers at the Roskamp Institute showed that inhibition of a Pro-inflammatory cytokine; the granulocyte macrophage colony stimulating factor (GM-CSF) a category of signaling proteins used extensively in cellular communication. GM-CSF has been suggested to induce programmed cell death in the brain tissue of patients with dementia once secreted. Scientist at the Roskamp institute showed that blocking this protein reduce the production of the main pathological protein that causes Alzheimer’s disease (beta-Amyloid) below basal level. In addition the Roskamp Institute scientists examined the mechanism underlying Beta-amyloid reduction after silencing of the receptor protein of G-CSF. Their result show that these effect is due to the fact that blocking the GM-CSF receptor reduce APP (Beta-amyloid protein precursor) trafficking from the cell membrane to the inside of the cell were the preotein in cleaved to generate the beta-Amyloid fragment. The discovery is detailed in an article appears in the journal Cytokine.

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Roskamp Institute study entitled “Potent anti-angiogenic motifs within the Alzheimer’s β-amyloid peptide” was published in the January 2008 issue of the scientific journal Amyloid. Work by Dr. Michael Mullan and Dr. Daniel Paris showed that a protein central to Alzheimer’s disease pathology is also able to prevent blood vessel growth and stop tumors. In our current study, we investigated whether shorter versions of this same protein could have the same effect. By stopping the blood supply to a tumor, we can effectively starve it and stop cancer. In this study, we have identified a small protein that is able to halt blood vessel growth. Therefore, this short protein has great potential as a novel treatment for cancer.

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