action error Dr. Michael Mullan | Alzheimer Mullan Research Notes

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Dr. Michael Mullan

Vitamin E May Aid in Slowing down Alzheimer’s disease

A new study published in the January 1st online edition of the Journal of the American Medical Association discussed findings conducted at the Icahn School of Medicine at Mount Sinai. In this study, the school’s faculty worked with the Veterans Administration Medical Centers and found that alpha tocepherol, otherwise known as Vitamin E with antioxidants, could help slow functional decline of patients with mild-to-moderate Alzheimer’s disease. Problems of functional decline include issues with daily activities; shopping, preparing meals, planning, and traveling. This study could bring much welcomed aid from the estimated 5.4 million families and caregivers of 5.1 million patients suffering with mild to moderate Alzheimer’s disease.

Mary Sano, PhD, trial co-investigator, professor within the Icahn School of Medicine’s department of psychiatry, and director of research at the James J, Peters Veteran’s Administration Medical Center at the Bronx, New York headed up this study. She stated that since the days of cholesterase inhibitors, such as galantamine, donepezil, and rivastigmine, there were few options for patients with mild-to-moderate dementia. However, with the results of the current study run, the use of vitamin E could delay the progression of functional decline within mild-to-moderate Alzheimer’s disease patients by 19 percent per year, which would translate into 6.2 months benefit over the placebo. Vitamin E is nowadays easily purchasable and non-expensive, and it could be an effective treatment strategy for Alzheimer’s patients.

Team AD, the Veteran’s Administration Cooperative Randomized Trial of Vitamin E and mimantine in Alzheimer’s disease, examined the effects of vitamin E 2,000 IU/d, and 20 mg/d of memenatine, the placebo used. For the study, testing was conducted at 14 different Veteran’s Affairs Medical Centers, 613 patients with mild to moderate Alzheimer’s disease were followed from August 2007 until September 2012. Dr. Sano reported that in previous studies she conducted with moderately severe Alzheimer’s, vitamin E also slowed the disease’s progression.
1) Maurice W. Dysken, Mary Sano, Sanjay Asthana, Julia E. Vertrees, Muralidhar Pallaki, Maria Llorente, Susan Love, Gerard D. Schellenberg, J. Riley McCarten, Julie Malphurs, Susana Prieto, Peijun Chen, David J. Loreck, George Trapp, Rajbir S. Bakshi, Jacobo E. Mintzer, Judith L. Heidebrink, Ana Vidal-Cardona, Lillian M. Arroyo, Angel R. Cruz, Sally Zachariah, Neil W. Kowall, Mohit P. Chopra, Suzanne Craft, Stephen Thielke, Carolyn L. Turvey, Catherine Woodman, Kimberly A. Monnell, Kimberly Gordon, Julie Tomaska, Yoav Segal, Peter N. Peduzzi, Peter D. Guarino. Effect of Vitamin E and Memantine on Functional Decline in Alzheimer Disease. JAMA, 2014; 311 (1): 33 DOI: 10.1001/jama.2013.282834
2) Mount Sinai Medical Center (2013, December 31). Vitamin E may delay decline in mild-to-moderate Alzheimer’s disease. ScienceDaily. Retrieved January 2, 2014, from¬ /releases/2013/12/131231163755.htm

By: Lauren Horne

The Roskamp Institute is a 501(c)3 research facility dedicated to translating the efforts of its qualified research staff into real-world results for those suffering from neurological diseases. To learn more about our programs and to get information about donating, visit

ACE Inhibitors and Alzheimer’s Prevention

Cedars-Sinai scientists published a study in Journal of Clinical Investigation that suggests ACE inhibitors, in the right context and at the right time, can be a good thing.

Many people with high blood pressure take ACE inhibitors, medication meant to widen blood vessels by limiting activity of ACE (angiotensin-converting enzyme), a naturally occurring protein. However, in new research using a rodent model of Alzheimer's Disease, it is shown that genetically targeting certain immune blood cells to overproduce the ACE enzyme can systematically break down defective proteins in the brain associated with Alzheimer’s disease and cognitive decline. The results demonstrate that ACE, not known for central nervous system involvement, can actually induce a protective immune response in the brain to ultimately affect cognition. In addition, ACE could possibly have a novel role in the clearance of excessive beta-amyloid plaques from brain blood vessels.

Kenneth Bernstein, MD, designed a rodent model to study the effects of an over-expression of ACE in macrophages, microglia, and similar cells of the immune system. The study shows the value of a strategy that delivers an enzyme to attack and destroy beta-amyloid to eschew resultant inflammation. Scientists are yet to determine if the deposits result from overproduction of beta-amyloid or an inability of mechanisms, like the immune system, to clear the plaques. Either way, a common view supports any strategy that reduces the amount of beta-amyloid protein in the brain as a way to delay progression of Alzheimer's.

Ultimately, rodents in this model with Alzheimer’s-like symptoms and those engineered to over-express ACE in immune cells produced offspring with greatly reduced beta-amyloid protein levels, inflammation, and increased performance on learning and memory tests.

The research contemplates ACE as a natural enzyme that can be harmful or helpful, depending on how and where it is active. Though it contributes to angiotensin II production, a hormone that causes high blood pressure, it can also quickly and efficiently lead an immune system response to beta-amyloid protein.

1) Kenneth E. Bernstein, Yosef Koronyo, Brenda C. Salumbides, Julia Sheyn, Lindsey Pelissier, Dahabada H.J. Lopes, Kandarp H. Shah, Ellen A. Bernstein, Dieu-Trang Fuchs, Jeff J.-Y. Yu, Michael Pham, Keith L. Black, Xiao Z. Shen, Sebastien Fuchs, Maya Koronyo-Hamaoui. Angiotensin-converting enzyme overexpression in myelomonocytes prevents Alzheimer’s-like cognitive decline. Journal of Clinical Investigation, 2014; DOI: 10.1172/JCI66541
2) Cedars-Sinai Medical Center. (2014, February 3). Can a protein controlling blood pressure enhance immune responses and prevent Alzheimer's?. ScienceDaily. Retrieved February 6, 2014 from

Written by Emma Henson
Edited by Patrizio Murdocca

Flavonoids lower Alzheimer's Aβ production via an NFκB dependent mechanism.

Alzheimer’s disease (AD) is characterized by the brain accumulation of Aβ peptides and by the presence of neurofibrillary tangles. Aβ is believed to play an important role in AD and it has been shown that certain flavonoids can affect Aβ production. Recently, it was suggested that the Aβ lowering properties of flavonoids are mediated by a direct inhibition the β-secretase (BACE-1) activity, the rate limiting enzyme responsible for the production of Aβ peptides. Westernblots and ELISAs were employed to monitor the impact of flavonoids on amyloid precursor protein processing and Aβ production. A cell free chemoluminescent assay using human recombinant BACE-1 was used to assess the effect of flavonoids on BACE-1 activity. The effect of flavonoids on NFκB activation was determined by using a stable NFκB luciferase reporter cell line. Molecular docking simulations were performed to predict the binding of flavonoids to the BACE-1 catalytic site. Real time quantitative PCR was used to determine the effect of flavonoids on BACE-1 transcription. We show in a cell free assay that flavonoids are only weak inhibitors of BACE-1 activity. Docking simulation studies with different BACE-1 structures also suggest that flavonoids are poor BACE-1 inhibitors as they appear to adopt various docking poses in the active site pocket and have weak docking scores that differ as a function of the BACE-1 structures studied. Moreover, a weak correlation was observed between the effect of flavonoids on Aβ production in vitro and their ability to lower BACE-1 activity suggesting that the Aβ lowering properties of flavonoids in whole cells are not mediated via direct inhibition of BACE-1 activity. We found however a strong correlation between the inhibition of NFκB activation by flavonoids and their Aβ lowering properties suggesting that flavonoids inhibit Aβ production in whole cells via NFκB related mechanisms. As NFκB has been shown to regulate BACE-1 expression, we show that NFκB lowering flavonoids inhibit BACE-1 transcription in human neuronal SH-SY5Y cells. Altogether, our data suggest that flavonoids inhibit Aβ and sAPPβ production by regulating BACE-1 expression and not by directly inhibiting BACE-1 activity.

for more information on the Roskamp Institute and Alzheimer’s please visit:

Identification of Plasma Biomarkers of TBI Outcome Using Proteomic Approaches in an APOE Mouse Model.

Abstract The current lack of diagnostic and prognostic biomarkers for traumatic brain injury (TBI) confounds treatment and management of patients and is of increasing concern as the TBI population grows. We have generated plasma proteomic profiles from mice receiving TBI by controlled cortical impact at either 1.3 mm or 1.8 mm depth, comparing these against those of sham injured-animals to identify plasma biomarkers specific to mild or severe TBI at 24 hours, 1 month, or 3 months post-injury. To identify possible prognostic biomarkers, we used apolipoprotein E (APOE)3 and APOE4 transgenic mice, which demonstrate relatively favorable and unfavorable outcomes respectively, following TBI. Using a quantitative proteomics approach (isobaric tagging for relative and absolute quantitation - iTRAQ) we have identified proteins that are significantly modulated as a function of TBI and also in response to the TBI*APOE genotype interaction, the latter representing potential prognostic biomarkers. These preliminary data clearly demonstrate plasma protein changes that are not only injury dependent but also interaction dependent. Importantly, these results demonstrate the presence of TBI-dependent and interaction-dependent plasma proteins at a 3-month time point, which is a considerable time post-injury in the mouse model, and will potentially be of significance for combat veterans receiving assessment at extended periods post-injury. Furthermore, our identification of clusters of functionally related proteins indicates disturbance of particular biological modules, which potentially increases their value beyond that of solitary biomarkers.

for more information on the Roskamp Institute and Alzheimer’s please visit:

Anatabine lowers Alzheimer's Aβ production in vitro and in vivo

Brain Aβ accumulation represents a key pathological hallmark in Alzheimer’s disease. In this study, we investigated the impact of anatabine, a minor alkaloid present in plants of the Solanacea family on Aβ production in vitro using a cell line overexpressing the human amyloid precursor protein (APP) and in vivo using a transgenic mouse model of Alzheimer’s disease. In vitro, anatabine lowers Aβ₁₋₄₀ and Aβ₁₋₄₂ levels in a dose dependent manner and reduces sAPPβ production without impacting sAPPα levels suggesting that anatabine lowers Aβ production by mainly impacting the β-cleavage of APP. Additionally, we show that anatabine lowers NFκB activation at doses that inhibit Aβ production in vitro. Since NFκB is known to regulate BACE-1 expression (the rate limiting enzyme responsible for Aβ production), we determined the impact of anatabine on BACE-1 transcription. We show that anatabine inhibits BACE-1 transcription and reduces BACE-1 protein levels in human neuronal like SHSY-5Y cells suggesting that the Aβ lowering properties of anatabine are mediated via a regulation of BACE-1 expression. In vivo, we show that an acute treatment with anatabine for four days significantly lowers brain soluble Aβ₁₋₄₀ and Aβ₁₋₄₂ levels in a transgenic mouse model of Alzheimer’s disease. Altogether our data suggest that anatabine may represent an interesting compound for regulating brain Aβ accumulation.

for more information on the Roskamp Institute and Alzheimer’s please visit:

Elevated CSF levels of TACE activity and soluble TNF receptors in subjects with mild cognitive impairment and patients with Alzheimer's disease.

Expression levels of tumor necrosis factor (TNF) receptors, TNFR1 and TNFR2, are significantly changed in the brains and cerebrospinal fluid (CSF) with Alzheimer’s disease (AD). Moreover, we also found that, in an Alzheimer’s mouse model, genetic deletion of TNF receptor (TNFR1) reduces amyloid plaques and amyloid beta peptides (Aβ) production through β-secretase (BACE1) regulation. TNF-α converting enzyme (TACE/ADAM-17) does not only cleave pro- TNF-α but also TNF receptors, however, whether the TACE activity was changed in the CSF was not clear. In this study, we examined TACE in the CSF in 32 AD patients and 27 age-matched healthy controls (HCs). Interestingly, we found that TACE activity was significantly elevated in the CSF from AD patients compared with HCs. Furthermore, we also assayed the CSF levels of TACE cleaved soluble forms of TNFR1 and TNFR2 in the same patients. We found that AD patients had higher levels of both TACE cleaved soluble TNFR1 (sTNFR1) and TNFR2 (sTNFR2) in the CSF compared to age- and gender-matched healthy controls. Levels of sTNFR1 correlated strongly with the levels of sTNFR2 (rs = 0.567-0.663, p < 0.01). The levels of both sTNFR1 and sTNFR2 significantly correlated with the TACE activity (rs = 0.491-0.557, p < 0.05). To examine if changes in TACE activity and in levels of cleaved soluble TNFRs are an early event in the course of AD, we measured these molecules in the CSF from 47 subjects with mild cognitive impairment (MCI), which is considered as a preclinical stage of AD. Unexpectedly, we found significantly higher levels of TACE activity and soluble TNFRs in the MCI group than that in AD patients. These results suggest that TACE activity and soluble TNF receptors may be potential diagnostic candidate biomarkers in AD and MCI.

for more information on the Roskamp Institute and Alzheimer’s please visit:

Genetic deletion of TNF receptor suppresses excitatory synaptic transmission via reducing AMPA receptor synaptic localization in cortical neurons.

The distribution of postsynaptic glutamate receptors has been shown to be regulated by proimmunocytokine tumor necrosis factor α (TNF-α) signaling. The role of TNF-α receptor subtypes in mediating glutamate receptor expression, trafficking, and function still remains unclear. Here, we report that TNF receptor subtypes (TNFR1 and TNFR2) differentially modulate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) clustering and function in cultured cortical neurons. We find that genetic deletion of TNFR1 decreases surface expression and synaptic localization of the AMPAR GluA1 subunit, reduces the frequency of miniature excitatory postsynaptic current (mEPSC), and reduces AMPA-induced maximal whole-cell current. In addition, these results are not observed in TNFR2-deleted neurons. The decreased AMPAR expression and function in TNFR1-deleted cells are not significantly restored by short (2 h) or long (24 h) term exposure to TNF-α. In TNFR2-deleted cells, TNF-α promotes AMPAR trafficking to the synapse and increases mEPSC frequency. In the present study, we find no significant change in the GluN1 subunit of NMDAR clusters, location, and mEPSC. This includes applying or withholding the TNF-α treatment in both TNFR1- and TNFR2-deleted neurons. Our results indicate that TNF receptor subtype 1 but not 2 plays a critical role in modulating AMPAR clustering, suggesting that targeting TNFR1 gene might be a novel approach to preventing neuronal AMPAR-mediated excitotoxicity.-He, P., Liu, Q., Wu, J., Shen, Y. Genetic deletion of TNF receptor suppresses excitatory synaptic transmission via reducing AMPA receptor synaptic localization in cortical neurons.

for more information on the Roskamp Institute and Alzheimer’s please visit:

Institute targets in on Alzheimer's

May 7, 2007 - At St. James Hospital in Dublin, Ireland, a nurse is checking the blood pressure of a 62-year-old man. Later, a tech will use a hand-held scanner to measure blood flow in his middle cerebral artery.

The patient has never met Michael Mullan, nor Fiona Crawford. But some 4,150 miles away, they could hardly be happier about his test results.

They show that the man, whose identity is confidential, is showing no adverse reactions to a drug that might be a promising treatment for Alzheimer's disease.

That is good news for Mullan and Crawford. Directors of the Roskamp Institute, on Whitfield Avenue in southern Manatee County, they are running a clinical trial of Nilvadipine, a drug widely used abroad but not approved in the United States.

The drug is intended to lower blood pressure. But in studies on mice, Roskamp researchers found it also reduced the level of a protein in the brain believed to be at the heart of Alzheimer's.

The Ireland trial just completed its second phase, a safety study, and the 20 patients taking the drug showed almost no ill effects, paving the way for a broader study.

The clinical trial is the institute's highest-profile project, but its two dozen scientists also work in fields including drug addiction and head injury.

With even more promising treatments deep in its labs, the little nonprofit academic center is becoming more and more a biotechnology start-up.

Birth of the institute

The institute was born in 1997, but its origins date back another 40 years.

Bob Roskamp was a high school physics teacher. His older brother, diagnosed with schizophrenia, killed himself.

Roskamp tells the story with understatement: "Obviously, it catches your attention in a big way."

The loss of his brother prompted him to give up teaching and work on opening homes for developmentally disabled adults. He later moved into developing housing communities for seniors.

He began selling his companies -- including his Freedom Group to American Retirement Group for $23 million in cash and $14.9 million in stock -- leaving him with a question: "What do we do with these surplus dollars?"

The answer is in the logo of the institute bearing his name: "Curing Diseases of the Mind."

Roskamp and his wife, Diane, are among the pioneers of a style of philanthropy, now more widely followed, of carefully aiming resources at one target and tracking performance.

"Instead of spreading it thinly throughout the world, we would 'rifle-shot' it, and have a lot more fun with it," he said.

Roskamp historically has given the institute about one-third of its operating budget, the rest coming through grants and contracts.

But as federal money has been diverted elsewhere, and the institute's work has grown more complex, Roskamp has had to pick up more of the tab. He gave just over $1 million in 2005, but $4.6 million this year, he said.

His involvement began with funding a lab at the University of South Florida, then a teaching position eventually filled by Mullan.

In 2003, the institute left the university amid personnel and bureaucratic disputes and moved into the former Bausch & Lomb building in southern Manatee County. Roskamp said university overhead was too expensive, and that scientists can work faster in the independent setting.

"You bring your entrepreneurial hat to this kind of research," he said. "We're results-oriented people."

The scientists appreciate not having to wait for grants and approvals.

"We have the funding from Bob and Diane that allow us to move forward very quickly when we make a new discovery," Crawford said. "We are really free to focus on the research."

Paddling mice

Most Alzheimer's researchers now focus on a protein known as beta-amyloid that forms when a chemical process goes awry. The protein clumps together outside neurons, eventually killing those memory cells.

Mullan and Crawford were part of a team that in 1991 published papers establishing a link between a human gene, on chromosome 21, and early onset of the disease in patients in their 40s and 50s.

A year later, after they came to the United States, they published a paper looking at another genetic link to early-onset Alzheimer's.

The research made beta-amyloid a prime suspect in Alzheimer's, and stopping its buildup a potential cure.

Roskamp researchers look for existing drugs and new compounds with that effect. Nilvadipine showed enough promise to test it on lab mice engineered to have Alzheimer's.

At 10 months, with the disease in full bloom, some mice got the drug while others got a placebo. Later, they scanned the mice's brains for blood flow.

In the color-coded pictures, the brighter the image, the better the blood flow. The mice getting Nilvadipine scan largely red and orange.

The control animals scan mostly blue-green.

Mullan points to a chart with results of a more traditional test, tracking a mouse's effort to paddle its way out of a mouse-sized swimming pool.

The mice repeat the test, day after day. Normal mice figure it out and eventually swim a shorter route to the exit.

Mice with Alzheimer's disease never figure it out, actually taking longer and longer routes.

"But if you give them Nivaldipine, they go from here to here; they do better," Mullan said, pointing at the figures. "And if you give Nilvadipine to a normal mouse, they do best of all."

The drug appears to slow or stop the production of beta-amyloid, Mullan said.

As the brain grudgingly yields the mysteries of its architecture, Roskamp's scientists are exploring how those diseases of the mind may be related by more than just words.

'Blocking that burst'

In 2002 the institute teamed with the Department of Veterans Affairs to look at memory skills in people who had received traumatic brain injuries.

They found that people who had a gene linked to Alzheimer's disease recovered less memory function than those without it, even when they had comparable injuries and demographics.

Further research has shown that when the brain suffers such an injury, there is a burst of amyloid production. One theory is that the brain produces the protein as a defense mechanism, but it sometimes overreacts and makes matters worse.

"Blocking that burst appears to be at least one way to try and improve outcomes after head injury," said Crawford, lead author of the 2002 article.

Last year the Department of Defense approved a $1.5 million grant to the institute to expand that research. It is a particularly urgent matter for the military: Improved body armor is helping soldiers survive explosions -- but with little-understood head injuries.

"People can have brain injury even if they didn't suffer any loss of consciousness, weeks and months of being in the vicinity of an explosive attack," Crawford said.

For now, that grant is hung up in final reviews.

"We have yet to see dime one," Roskamp said -- but even that $1.5 million pales in comparison with the costs of the Nilvadipine study.

That cuts to the heart of the dilemma scientists face. They might get a moderately effective drug to market quickly, or try to discover the "silver bullet," which could take many years and exponentially more money.

Roskamp is preparing the foundation to do both.

Just a question of when

To Mullan, the question is not whether there will be treatments for Alzheimer's.

"It's the question of when we're going to get them there," he said.

It is a question of how effective they will be. Mullan cited three drugs far along in the pipeline, all targeted at reducing amyloid. "They're not going to be block-busting, perfect drugs by any means, but I think at least two of them will be approved for Alzheimer's this year."

Nilvadipine most likely would be like them -- useful but not the cure-all. But it offers some advantages.

Developing a new drug from scratch is a much worse bet, Mullan said. Count on 10 to 12 years for development, testing and approvals, with a high failure rate.

"Sometimes they fail spectacularly," he said, citing Vioxx, a promising drug with unforeseen and deadly side effects.

Nilvadipine, in use for more than a decade, already has a track record for safety. It could help patients while allowing the institute time to find the silver bullet.

By mid-year, the institute hopes to continue the Ireland trial with a double-blind study, meaning neither patients nor doctors know who gets Nilvadipine and who gets a placebo until they conclude. That study, which would involve about 200 people, could cost $20 million, Roskamp said.

Should the drug prove effective, Nilvadipine's manufacturer could profit -- but so would the institute. Because it holds rights to the drug's newly indicated use, the institute would receive royalty payments, Roskamp said.

The institute has set up a for-profit subsidiary, Roskamp Research LLC, which holds its patents. Roskamp structured it to allow outside backers to support studies, provide the subsidiary with a return on its investment, and guarantee most of the revenue goes to his institute.

"We don't want to give it to a pharma company, and say here, go make a lot of money off of it," Roskamp said.

Compounds back in the institute's labs could provide better returns -- and better treatments.

for more information on the Roskamp Institute please visit:

Sarasota’s Roskamp Institute Releases Study Defining a Mechanism for Development of Obesity and the Metabolic Syndrome, Forerunners of Type 2 Diabetes

Sarasota, Fla. – August 1, 2007 The Roskamp Institute released a study defining a mechanism for the development of obesity and the metabolic syndrome, which are the forerunners of type 2 diabetes. The study, led by Roskamp’s Dr. Robert Farese, is detailed in the August issue of The Journal of Clinical Investigation, a highly prestigious medical research journal.

While the Roskamp Institute’s primary focus is on Alzheimer’s disease, Roskamp researchers have a significant interest in diabetes due to studies that suggest those who have diabetes are more likely to develop Alzheimer’s disease.

The study found that a deficiency in an enzyme, atypical protein kinase C, impairs the ability of insulin to stimulate glucose uptake into the muscle, which produces a state of resistance to circulating insulin. Once this occurs, the liver begins to produce excessive quantities of fat, causing abdominal obesity and alterations in blood lipids. According to the study, this can then lead to obesity and the metabolic syndrome, the precursors of type 2 diabetes.

“Although this gene-knockout study was done on mice, it is particularly relevant to type 2 diabetic humans, who are known to have deficiencies of this enzyme in their muscles,” said Dr. Farese. “The findings showed that in the mice a simple loss of one or more genes that are responsible for the production of this enzyme could eventually cause obesity and the metabolic syndrome which then could lead to type 2 diabetes.”

Further research must be done to determine how human diabetics acquire a deficiency of this enzyme in their muscles; however, this mouse model should be especially helpful to further study and devise treatments for obesity and the metabolic syndrome.

“We are particularly excited about this study and the potential to develop treatments for obesity and the metabolic syndrome, which are both global health problems,” said Dr. Michael Mullan, director of the Roskamp Institute. “This study will also be helpful in further determining how obesity, the metabolic syndrome and type 2 diabetes are linked to Alzheimer’s disease.”

The study was co-authored by Dr. Farese, who led the team of Mini P. Sajan, Hong Yang, and Sonali Nimal at the Roskamp Institute; and others at the James A. Haley Veterans Administration Medical Center in Tampa; the University of South Florida College of Medicine; the Joslin Research Foundation and Harvard University School of Medicine; Yale University School of Medicine, and Research Center at Oslo, Norway.

For more information regarding this study or the Roskamp Institute please visit:

The Roskamp Institute

The Roskamp Institute, a not-for-profit research Institute, is dedicated to finding cures for neuropsychiatric disorders, with the emphasis on Alzheimer’s disease (AD). Current research at the Roskamp Institute is focused on dissecting the molecular biological pathways implicated in AD pathogenesis in order to develop therapeutic targets specific to AD etiology. Dr. Michael Mullan (Director of the Roskamp Institute) and Fiona Crawford (Associate director of the Roskamp Institute) were part of the original team that discovered a genetic error called the “Swedish mutation” which results in overproduction of -amyloid (A) by aberrant proteolytic processing of the amyloid precursor protein (APP). This mutation now forms the bases of most mouse model of Alzheimer’s disease. Previously, the Roskamp Institute published an article in a prestigious scientific journal, Nature, showing that A plays a normal role in vasoactive mechanisms but also plays a role in vascular abnormalities and neurodegeneration mediated by free radical. Subsequently, Dr. Daniel Paris, a senior scientist at the Roskamp Institute, discovered that the vasoactive effects of A are partly mediated via a pro-inflammatory pathway and showed that this effect of A on the vasculature can be blocked by inhibiting specific target molecules. In order to further understand the role of A in the vasculature, Dr. Paris investigated the long term effect of A on vascular homeostasis. He then discovered that at low doses, A promotes angiogenesis, while at high doses, certain forms of A peptides are anti-angiogenic. Collectively, these novel findings resulted in new therapeutic prospects for the treatment of Alzheimer’s disease as well as Cancer.
Researchers at the Roskamp Institute also showed that the presence of functional CD40/CD40L signaling is essential for the full development of AD like pathology in transgenic mouse models of AD. In particular, it was demonstrated that accumulation of cerebral A is reduced in transgenic mouse models of AD by genetically or pharmacologically reducing the availability of CD40L to CD40. The Roskamp Institute investigators subsequently revealed that loss of functional CD40L diminishes both APP processing to A and microglial activation in the brain (Original findings published in journals Science and Nature Neuroscience). CD40L activated pathways in the presence of A appear to mediate both of these effects as well as the hyperphosphorylation of murine tau in vivo at epitopes analogous to those which precede tangle formation of human tau. More recently, Dr. Ghania Ait-Ghezala of the Roskamp Institute showed that CD40/CD40L interaction also affects APP via the NF-B pathway. Using NF-B inhibitors and SiRNAs to silence diverse elements of the NF-B pathway, she demonstrated that reduction in levels of both pathological forms of A. These results showed that CD40L stimulation may be a key component in AD pathology and that NF-B pathway may be suitable targets for therapeutic approaches against AD.
Another major focus of research at the Roskamp Institute includes Traumatic Brain Injury (TBI) Program headed by the Associate Director of the Roskamp Institute. Dr. Crawford and her Roskamp Institute team demonstrated an important relationship between apolipoprotein E (APOE) and memory following TBI. She demonstrated that in Veteran’s with TBI, memory performance was significantly worse in individuals who had at least one copy of APOE ε4 allele than those who did not. She had subsequently been funded through the Veteran’s Administration to further study the relationship between different forms of APOE in TBI with the emphasis on finding treatments for this devastating condition.
Drs. Michael Mullan and Fiona Crawford also received funding by the Counterdrug Technology Assessment Center (CTAC) to evaluate the newly emerged genomics and proteomics technology and find biological markers of substance abuse. Recently, Dr. Crawford’s team showed that cocaine treatment of human progenitor neuronal cells results in increased oxidative stress (possibly mediated by inflammatory responses) which precedes cell death. Thus, these findings may have implications for the consequences of cocaine abuse in situations where antioxidant capacity is compromised, as in the aging brain.
As evident here, the Roskamp Institute team has been a pioneer in many area of research in neuropsychiatric diseases and will continue to do so to find novel therapies for these disorders. Currently, a new clinical trial based on the discoveries made at the Roskamp Institute is underway to assess safety and efficacy of nilvadipine in treatment of Alzheimer’s disease. Through the generous support of Diane and Robert Roskamp, the Veteran’s Administration, the National Institutes of Health, CTAC and the Department of Defense, the Roskamp Institute will continue to provide potential avenues for novel therapeutic interventions for neuropsychiatric disorders.

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Roskamp Institute on Gulf War Illness

The Roskamp Institute located in Sarasota, Florida is the leading research center in the area. The research focuses on neurological diseases that affect young and elderly men and women of this world. Some of the main focuses are Alzheimer's disease, addiction, post-traumatic stress disorder (PTSD), multiple scoliosis, Gulf War syndrome and many more. The Director Dr. Michael Mullan leads his team of researchers to exciting findings. Recently the Institute has been given a grant from the VA for their research involving Gulf War Illness. This Illness that inflicts the soldiers that fought during the Gulf War affects their motor skills, memory, stability and other problematic symptoms. How the Illness commenced was through the combination of the neurotoxins and pesticides given to the soldiers. The research done in the Institute led to the finding that shows the toxic mixture affects the long fatty acid chains within the brain. Research continues within the walls of the 42,000 sq. ft research facility hopefully terminating the life altering Illness for our Veterans.

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Roskamp Institute Scientists Discover Genetic and Biological Consequences of Substance Abuse

A 2004 National Survey on Drug Use and Health reported that about 34 million Americans have had some exposure to cocaine at least once in their lifetime. The addictive properties of this drug is well recognized and results in an increased direct cost in medical care as well as indirect cost due to increased societal burden. The Roskamp Institute, located in Sarasota Florida is currently engaged in research into discovery of biological biomarkers and novel treatments for substance abuse. Michael Mullan MD PhD (Director of the Roskamp Institute), during his medical training in London, worked on addiction and determined that certain addictive disorders had a significant genetic component. It is now well-established that substance dependency has a prominent genetic component and approximately 40-60% of the vulnerability to substances can be sufficiently attributed to these genetic factors. Previously, the Roskamp Institute scientists demonstrated that a polymorphism in gene for mu-opioid receptor (OPRM1 +118A) is a risk for alcohol dependency. This Roskamp Institute team then examined the frequency of OPRM1 +118A carrying genotypes and alleles in several groups of substance-dependent cases compared to individuals with no history of reported substance abuse. These Roskamp Institute scientists found that the OPRM1 +118 polymorphism is a genetic risk factor for substance dependence but not specific to a particular substance (findings published in the journal Molecular Psychiatry).

Dr. Fiona Crawford (Associate director, Roskamp Institute) and Dr. Michael Mullan (Director, Roskamp Institute) received an award from the Counterdrug Technology Assessment Center (CTAC) to evaluate the newly emerged genomics and proteomics technologies and determine their usefulness in finding potential biomarkers and treatments for substance abuse. Dr. Fiona Crawford along with her Roskamp Institute team using this genomic technology investigated the fundamental transcriptional responses occurring in neurons as a consequence of acute cocaine exposure over a time period. These Roskamp Institute scientists used GeneChip Operating Software from Affymetrix to compare the genomic response in neuronal cells exposed to cocaine compared to cells that were not exposed and showed a time-dependent increase of genes associated with pro-inflammatory and immune responses. These findings suggest that the inflammatory and immune systems maybe involved in modulating response to an acute cocaine exposure (originally published in the Journal of Neurochemistry).

Next, this Roskamp Institute team determined a role of oxidative stress in cocaine exposure in human progenitor neuronal cells. Although, it is evident that cocaine induces oxidative stress in the central nervous system, little is known whether such increase in oxidative stress is also relevant to cell death in cocaine-exposed models. To gain further insight into the role of cocaine-induced oxidative stress, the Roskamp Institute scientists hypothesized that oxidative stress precedes cell death upon cocaine exposure and demonstrated that oxidative stress was significantly increased in neuronal cells treated with cocaine and this phenomenon preceded cell death. Therefore, these findings have implications for cocaine abuse in circumstances where antioxidant system is compromised, as in the aging brain (original findings in the Journal of Neurochemistry International).

The addictive properties of these psychoactive substances is well recognized and results in enormous burden of direct and indirect costs to the US economy. The Roskamp Institute is dedicated to understanding the factors that predispose individuals to substance abuse as well as discover additional molecular targets for therapeutic intervention.

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The Roskamp Institute funded by the Veterans Administration to find cellular mechanism implicated in the Gulf War Illnesses

The Veterans Administration announced that by November 2004, veterans who served in the Gulf War between 1990 and 1991 experienced illnesses of unknown etiology which were subsequently categorized as “Gulf War Illnesses”. The Veterans Administration acknowledges a need for systematic scientific identification of the specific molecular mechanisms underlying this disease, from which development of treatments may emerge. The Veterans Administration is particularly dedicated to improving healthcare for veterans who served in the Gulf War.

Michael Mullan MD, PhD (Director of the Roskamp Institute) and Fiona Crawford PhD (Associate Director of the Roskamp Institute) received a three-year grant from this esteemed agency to fund the research on genomics and proteomics analysis of cellular responses to Gulf War agents. Drs. Michael Mullan and Fiona Crawford were previously funded through the Counterdrug Technology Assessment Center (CTAC) to evaluate these advance genomics and proteomics technologies for potential use in identification of biological pathways implicated in neuropsychiatric diseases. Thus, this is a great collaborative union between US government agencies to help find treatments for illnesses that affect our beloved veterans.

This funded proposal will utilize genomics and proteomics technologies among other state-of-the-art resources available at the Roskamp Institute and its affiliated laboratories at the James A. Haley VA Hospital to characterize the cellular responses to biological warfare agents. At the Roskamp Institute, these technologies will be applied to investigate and characterize the in vitro responses to agents such as acetylcholinesterase inhibitors (i.e. pyridostigmine bromide, organophosphate pesticides) and anthrax vaccination. By identifying biological and cellular mechanisms modulated in response to these exposures in the simple in vitro models, the Roskamp Institute scientists will identify initial responses to these agents and then determine if they become pathological with disease progression. This research by the Roskamp Institute will increase our understanding of the underlying mechanisms of these illnesses as well as present targets for potential therapeutic intervention.

The Roskamp Institute is dedicated to exposing the causes of and finding novel treatments for neuropsychiatric, neurodegenerative and addictive disorders. The Roskamp Institute was founded in 1998 by the philanthropic visions of Robert and Diane Roskamp of Sarasota, Florida. In 2003, under the directorship of Dr. Michael Mullan and through the generous support of Mr. and Mrs. Roskamp, the Roskamp Institute was relocated to Sarasota, Florida. The Roskamp Institute, at present, is funded by various US government agencies, such as the National Institute of Aging, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), CTAC, the US Department of Defense and the Veterans Administration. Currently, the Roskamp Institute occupies approximately 41,000 sq ft of facility with over 50 brilliant scientists engaged in creative research endeavors to find treatments for neuropsychiatric disorders and clinicians who are dedicated to helping patients and their family members cope with these devastating disorders.

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The Roskamp Institute Battles Drug Abuse

A National Survey on drug abuse in America reported in 2004 that about 34 million Americans are currently using or have been exposed to cocaine at some point in their lifetime. Cocaine is highly addictive and affects individuals along with their families. The cost of health care services has risen due to the increasing use of cocaine. Currently, the Roskamp Institute is involved in research to discover a treatment for substance abuse. Dr. Michael Mullan MD, PhD is the director of the Roskamp Institute and has worked vigorously on addiction and has found that addictive disorders have a significant genetic component. These genetic components play a key role in drug abuse.
The Roskamp Institute scientists have previously shown that a genetic change called polymorphism in a gene for an opioid receptor in the brain is a risk factor for alcohol dependency. With this information, the Roskamp Institute researchers then examined the frequencies of this polymorphism carrying genotypes and alleles in numerous groups of individuals addicted to the substance versus individuals with no history of addiction to the substance. These Roskamp Institute scientists found that the mu-opioid receptor’s polymorphism is a genetic risk factor for substance dependence but not to any particular type of drug. Meaning, an individual with this polymorphism is more likely to become addicted to a substance than an individual without it. The Roskamp Institute previously published these findings in the journal Molecular Psychiatry.
Dr. Mullan and Dr. Crawford along with the other researchers at the Roskamp Institute received an award from the Counter drug Technology Assessment Center (CTAC), to continue their work on drug addiction.
Affymetrix is a name of the company which provides the Roskamp Institute with the genetic software that is used by scientists who study genetics (genomics). The Roskamp Institute used genomics technology in order to find the cocaine’s affects on the brain cells known as neuronal cells. The Roskamp Institute scientists continue to research projects which are focused on the inflammatory and immune responses to cocaine. The Roskamp Institute scientists showed that these responses also results from the exposure of the neuronal cells to cocaine and these responses are also time dependant. These findings, originally published in the Journal of Neurochemistry, illustrate that there are biological and physical consequences of cocaine addiction.
The Roskamp Institute researchers are currently working on studies involving oxidative stress in the brain. This oxidative stress can also be caused by excessive use of cocaine and is hypothesized to result in permanent brain damage. With such experiments in progress, the Roskamp Institute is a good candidate for additional government funding and these discoveries will be useful towards the battle against drug abuse in form of treatments.

The Traumatic Brain Injury Program at the Roskamp Institute

Among the soldiers who survive conflicts in Iraq and Afghanistan, the traumatic brain injuries account for a larger proportion of their casualties than in any other US war in recent history. According to the Joint Theater Trauma Registry, established by the U.S. Army Institute of Surgical Research, approximately 22 percent of the injured US soldiers received injuries to the head, face, or neck. A major reason for this high ratio of these injuries is Kevlar body armor and helmets. Although, it successfully protects these soldiers from bullets and shrapnel exposure,Kevlar helmets cannot fully protect theface, head, and neck areas. Additionally, it is also unsuccessful in preventing the closedbrain injuries produced by blasts. Furthermore, among patients evaluated at Walter Reed hospital, closed head injuries outnumber other penetrating injuries (originally published in New England Journal of Medicine).

Most individuals with a mild traumatic brain injury improve entirely within a year,but moderate and severe brain injuries are more complex and have long-term consequences. The Center of disease Control and Prevention estimated that 5.3 million Americans are living with disabilities resulting from traumatic brain injury. Dr. Michael Mullan (Director of the Roskamp Institute) Dr. Fiona Crawford (Associate Director of the Roskamp Institute) and their team of scientists previously demonstrated that apolipoprotein E (APOE) influences traumatic brain injury outcomes. These Roskamp Institute scientists examined 110 participants from the Defense and Veterans’ Head Injury Program to determine a relationship between APOE genotype and memory performance on certain cognitive tests administered to these head injured soldiers. The memory performance was much worse in soldiers who had at least had one APOE epsilon 4 allele compared to those who did not. This Roskamp Institute team also determined that these findings were limited to memory and not other cognitive performances such as executive functioning. Therefore, these data support a specific role for the APOE protein in memory outcome following TBI, and suggest an APOE isoform-specific effect on neuronal repair processes (originally published in the journal Neurology).

Dr. Fiona Crawford received a Merit award from the Veteran’s Administration to further study, using genomics technology, the role of APOE in Traumatic Brain Injury. Dr. Fiona Crawford and her Roskamp Institute team have now completed the experiments showing differences in genomics response among the different mouse models after traumatic brain injury. Recently, Drs. Michael Mullan and Fiona Crawford received a prestigious award of $1.5 million from the Department of Defense which will allow the Roskamp Institute to investigate ApoE and other proteins to find potential peripheral biological markers and novel therapeutic treatments for traumatic brain injury. Florida Senator Bill Nelson recently toured the Roskamp Institute to observe its traumatic brain injury program in support of the soldiers affected by this devastating condition.

The Roskamp Institute is a world-renowned state-of-the-art research and clinical facility located in Sarasota Florida dedicating to finding novel therapeutics for treatment of neuropsychiatric disorder, especially Alzheimer’s disease, traumatic brain injury and substance abuse. The Roskamp Institute is supported by the funding from government agencies such the National Institutes of Health, the Veteran’s Administration and the Department of Defense as well as private donations from the Robert and Diane Roskamp Foundation.

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Roskamp Institute finds one of the genetic causes for Tourettes syndrome

Tourette syndrome (TS) is a heterogeneous childhood disorder and occurs with a frequency of approximately four to ten per 10,000 in the general population (Mason et al. 1998). The symptoms for Tourette syndrome include multiple motor and one or more vocal tics. These symptoms appear to overlap with other neurobehavioral disorders such as obsessive-compulsive disorder, attention deficit/hyperactivity disorder, mood disorders and learning disorders. The origin of Tourette syndrome is not clearly understood at this time. However, there appears to be presence of a genetic component, evidence for which comes from both family and twin studies. Furthermore, a complex mode of inheritance has been suggested which probably involves several genes with different effect size. Additionally, environmental factors such as prenatal and birth complications may also influence the disease manifestation.
The Roskamp Institute scientists Drs. Michael Mullan (Director of the Roskamp Institute), Fiona Crawford (Associate Director of the Roskamp Institute) and Ghania Ait-ghezala (a senior scientist at the Roskamp Institute) have previously shown that among patients diagnosed with Tourettes syndrome in two unrelated families, there appears to be a breakage and translocation on chromosome 8 (original findings published in the journal Human Genetics). Drs. Fiona Crawford and Ghania Ait-ghezala subsequently received funding from the Tourettes syndrome association to further characterize this chromosomal breakage.
Currently, there is no treatment available for Tourettes syndrome. Although, the symptoms in most individuals improve by the late teens and early 20s, this disorder is generally lifelong and chronic. Studies have also shown that although symptoms such as tics may disappear after the childhood period, it is possible that other psychiatric disorders such as depression, panic attacks, mood swings, and antisocial behaviors persist and cause lifelong impairment in adults. Therefore, a treatment for this disorder is much needed so that a child can actually be disease free throughout his/her life and has a decent chance of living a normal life. The Roskamp Institute is currently engaged in molecular biological research aimed at determining the genes that are disturbed when this chromosomal breakage and translocation occur. Through this novel finding, the scientists at the Roskamp Institute hope to discover a treatment for Tourettes syndrome.
The Roskamp Institute is located in Sarasota Florida and is a not-for-profit stand alone research institute dedicated to finding cures for neuropsychiatric disorders. The Roskamp Institute is currently conducting a clinical trial evaluating safely and efficacy of nilvadipine for the treatment for Alzheimer’s disease (clinical trial being performed in Dublin, Ireland). Furthermore, the Roskamp Institute is conducting various molecular biological studies to find treatment for chronic diseases such as cancer, diabetes, and other neuropsychiatric disorders such as traumatic brain injury, gulf war syndrome, and substance abuse. The Roskamp Institute operates two memory disorder clinics located in Sarasota and Tampa, Florida. These clinics conduct diagnostic assessments for memory disorders and conduct industry and government funded clinical trials in several neurological and neuropsychiatric disorders. The Roskamp institute is currently funded by the National Institutes of Health, the Veteran’s Administration, the Department of Defense and the private donation by the Robert and Diane Roskamp foundation. For more information or the research or clinical trials, please contact us at 94-752-2949.

Sarasota’s Roskamp Institute Welcomes U.S. Senator Bill Nelson

August 21, 2007

Sarasota, Fla. – The Roskamp Institute today welcomed U.S. Senator Bill Nelson to its research facility in Sarasota, Florida, where the Senator toured the laboratories and discussed the various types of research currently being conducted at the Institute.

“We thank Senator Nelson for his interest in our research and for coming to the Institute to tour our lab and view our good work first hand,” said Dr. Michael Mullan, director of the Roskamp Institute. “We are proud of the research our Institute has done and look forward to continuing in our quest to better understand and ultimately cure debilitating diseases of the mind.”

While Senator Nelson’s visit was mainly to discuss with the researchers the current and future research being done in relations to Traumatic Brain Injury, the Roskamp Institute is devoted to understanding the causes of and finding cures for various neuropsychiatric and neurodegenerative disorders and addictions. Specifically, the Institute utilizes a broad range of scientific approaches to understand the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease.

“We currently have 45 scientists and 10 clinicians with eight active clinical trials in the field with several more on the horizon,” Dr. Mullan continued. “It is vital that we are persistent in our pursuit to help Florida’s sufferers and their families and we are glad Senator Nelson is here to share in our goal.”

The Roskamp Institute has built its esteemed reputation amongst the research community and has been heralded for its achievements including:

• Being the first Florida-based Alzheimer’s Research Institute (and one of only a handful of Institutes worldwide) to conduct a human clinical trial with a drug discovered by its own research.
• Discovering a new class of drugs that lower the production of the main pathological protein that causes Alzheimer’s disease.
• Applying state of the art technologies (proteomics and genomics) to find early diagnostic markers for Alzheimer’s disease.
• Extensive participation from Florida residents in the Institute’s leading edge Alzheimer’s research program.

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Dr. Mullan’s Alzheimer Research Offers Invaluable Insights On The Disease

Millions of people across the globe suffer from Alzheimer’s disease. It is estimated (Alzheimer’s Association, 2008) that in every 71 seconds someone from the US develops Alzheimer’s disease, and estimations by mid-century shows that the probability of someone developing Alzheimer’s disease is every 33 seconds. At present, there are approximately 5.2 million Americans in all age groups who suffer from Alzheimer’s disease; and 13% of these patients fall in the age category of 65 years and older. It is calculated that by 2050 the number of Alzheimer’s patients falling in the age category of 65 years and older will increase to a range of over 11 million to 16 million alone (Alzheimer’s Association, 2008). The facts and figures are alarming and bring our focus to the unmet demand for effective therapeutics and new researches for treatments related to Alzheimer’s disease.
Dr. Michael Mullan is an accredited professional from biomedical field. He has extensively researched on the causes and prospective cures of Alzheimer’s disease and other neurodegenerative disorders conditions. Based in Sarasota, Florida, he is reputed Director of Roskamp Institute. He is a highly qualified professional and has dedicated his time to finding cures for neuropsychiatric and neurodegenerative disorders and addictions. Dr. Mullan’s Alzheimer research work has provided invaluable insights on the disease with which many potential cures have been developed and tested. Dr. Mullan’s Alzheimer research indicates that one of the causes directly related to the disease is the excess accumulation of beta-amyloid, a type of protein, present in the brain. It was estimated that the protein is produced in every human but its excess accumulation can result in Alzheimer’s. Besides, Dr. Mullan’s Alzheimer research continuously tests medications and therapeutic treatments to help slow down the accumulation of beta-amyloid and related inflammation in patients.
About Dr Michael Mullan
Dr Michael Mullan has been working in the biomedical field for many years. He is a leading researcher with special expertise in assessment of the earliest cognitive symptoms and stages of Alzheimer’s disease. Mullan’s Alzheimer research works are also published in various articles which help students and researchers for making new discoveries. Find out more about his Alzheimer research works, by browsing through or or

Dr. Mullan’s Alzheimer Research Identified Various Genetic Variations

Based in Sarasota, Florida, The Roskamp Institute is a not-for-profit organization. It has dedicated time to finding cures for several neuropsychiatric disorders with a special emphasis on Alzheimer’s disease (AD). In order to develop therapeutic targets which are specific to Alzheimer’s disease etiology, the scientists engaged in current research at Roskamp Institute focus on dissecting the molecular biological pathways which are associated in Alzheimer’s disease pathogenesis.
Dr. Michael Mullan is the Director of the Roskamp Institute, and along with his team, he discovered the concept of ‘Swedish mutation’, a genetic error which results in overproduction of beta-amyloid by aberrant proteolytic processing of amyloid precursor protein (APP). The concept of Swedish mutation now forms the bases of most mouse model of Alzheimer’s disease. Many tests and findings by the Roskamp Institute resulted in several therapeutic prospects for the treatment of Alzheimer’s disease as well as Cancer.
The Roskamp Institute has contributed greatly by providing research on the treatments of several neuropsychiatric disorders like traumatic brain injury, substance abuse, and Alzheimer, etc. With the guidance and knowledge provided by Dr. Mullan, the institute tested many causes and correlations between Alzheimer’s disease and proteins present in human brain. With Dr. Mullan’s Alzheimer research, several types of genetic variations, which can be the cause of Alzheimer’s, have been identified. It was discovered that the central reason to the disease process is a small protein identified as the ß (beta)-amyloid. Although, this protein is present normally in the human brain, but at times excess or abnormal accumulation can result in Alzheimer’s disease. With Dr. Mullan’s Alzheimer research, the institute tests cutting edge cures, therapeutic treatments and medications to slow down the process of toxic ß-amyloid accumulation.
Dr Mullan’s Alzheimer research proves that Aβ peptide prevents blood vessel growth and eventually inhibits tumor growth in brain. To identify if Aβ has the same effect with short derivatives, he studied various sequences within the Alzheimer’s Aβ peptide which have potential therapeutic relevance in preventing tumor growth. Dr. Mullan’s Alzheimer research work has contributed exceptionally to the field to help understand the disease and find its cures. Find out more about his Alzheimer research works, by browsing through or or

Family History of Alzheimer's disease - what does it mean?

Frequently in the Roskamp institute Memory Clinic we are asked what a family history of Alzheimer’s disease means for the children and other blood relatives of sufferers. Although this question is always handled on an individual basis there are some general guidelines that can be offered to access risk for the disease to children and other family members related to a sufferer. Naturally, family members who perceive they are at risk for developing the disease themselves may suffer from a great degree of anxiety it is therefore important to ask the staff at the Roskamp Institute what the individual risk is for developing the disease. In general the genetic risk for Alzheimer’s disease can be divided into two categories; early onset familial disease which is highly genetic and occurs in families which may have onsets of the disease in the 40s,50s or 60s; late onset disease which is frequently familial but where the disease onsets in the seventh decade onwards. We shall consider these two scenarios separately.

Early onset Alzheimer’s disease.

The term “early onset Alzheimer’s” is frequently misunderstood or used in a confusing way. What we generally mean by early onset Alzheimer’s is Alzheimer’s that onsets before the age to 60 years. This is in contrast to the term early onset as referencing the early stage of the disease. This is a confusing way to use the term and is discouraged. Early stage disease is a better term to describe the early phases of the disease. Early onset familial disease occurs in families that are affected in multiple generations by mutations in genes that can trigger the disease. Families of early onset disease thankfully are very rare but they have provided great insight into the disease process probably in all cases of the disease (early and late onset). Sadly, frequently in these families the disease is inherited in what is known as an autosomal dominant fashion. Autosomal dominant inheritance means that 50% of the offspring of each generation on average are impacted by the disease. Some generations may be very fortunate and although they may be at risk for inheriting the diseased gene from one or the other parent none of the siblings in a sibship may be affected. On the contrary sibships can be very unlucky in which case more than 50% are impacted with the disease. For each child of an affected parent there is a 50% chance of inheriting the disease and this chance is not influenced by whether other siblings have already inherited the disease or not.

Unfortunately the inheritance of these rare genetic variance means that individuals at risk are highly likely to develop the disease if they live long enough. One of the important characteristics of these familial mutations is that the disease tends to onset around approximately the same time of life. Thus if a family has a mean (average) age of onset of 52 and one inherits one of these rare generic errors then one is unlikely to live to 60 without developing signs or symptoms of the disease. By contrast if one does not carry the mutation then there is no more risk for the disease than the general population.

Again it is most important to emphasize that such families are extremely rare and early onset Alzheimer’s is not the most likely reason for patients or their families to visit the Roskamp Institute Clinic. In fact, approximately 1% or less of cases of Alzheimer’s Disease have what can be described as early onset disease. In the past, individuals who come from such families have sought genetic counseling including genetic testing for these genetic errors. It is relatively straightforward to detect such errors but clearly the genetic information is highly sensitive. Family members should therefore think very carefully before seeking such information however initially finding out more about early onset disease is a recommended step.

Clinicians at the Roskamp Institute are happy to discuss early onset disease with patients and their families as they wish. Finally it should be noted that many cases of early onset disease occur without a family history. Thus individuals can manifest the disease before the age of 60 but have no other known family members either in the prior generations or in subsequent generations that develop the disease the cause of early onset Alzheimer’s that is not familial is not well understood but importantly there is no risk to subsequent family members for development of the disease.

Late onset (common) Alzheimer’s disease. Much more commonly patients and their families come to the clinic at the Roskamp Institute and seek advice on the inheritance of Alzheimer’s when one or more members of the family has late onset disease. This is defined as disease which onsets over the age of 60 and this is by far in a way the most common cause of the disease. It is estimated that approximately 4 million Americans presently either have the disease or are in the early or pre clinical stages - most of these cases are late onset Alzheimer’s Disease. The predicted numbers for future disease prevalence are very high. For instance it is estimated that by mid century there could be as many as two hundred million individuals afflicted with the disease.

Most late onset Alzheimer’s disease does not exhibit a clear autosomal dominant pattern meaning that the risk to offspring of individuals suffering with the disease is usually considerably less than 50%. Certain genetic risk factors for late onset disease have been identified - the most important of which is apolipoprotein E (APOE). There are 3 common forms of APOE: E2, E3 and E4. The discovery by Allen Roses and his colleagues at Duke University showed that Alzheimer’s disease sufferers were much more likely to carry one or two copies of the E4 allele (genetic form) of APOE than the normal population. Carrying one copy of APOE 4 increases ones risk for the disease by approximately three times and carrying two copies can increase the risk for the disease by up to fifteen times compared to individuals who do not carry an APOE 4 allele.

Many family members express interest in being genetically tested for their risk for the disease. Such tests are commercially available but most centers discourage the use of testing prior to symptoms because many individuals who carry an APOE 4 allele do not necessarily develop the disease at least until late old age. Conversely it’s very possible to develop Alzheimer’s disease without carrying an APOE 4 allele. Therefore on an individual basis the test is not overly helpful in specifying who may or may not develop the disease. However on a group basis APOE genetic testing is very helpful to give an average estimate of the numbers of individuals who will subsequently develop Alzheimer’s.

It is anticipated that as better treatments are available for Alzheimer’s disease there will be greater interest in genetic testing. For instance it is expected that as treatments are used earlier and earlier in the stages of the disease that individuals in the very early stage or maybe with no symptoms at all might seek medical treatment once such treatment has been established as effective in stopping the rate of progression or disease onset.

Despite the fact that genetic testing is not used frequently in clinical practice it is a tremendous tool in assisting researchers in understanding when and why the diseases develops and in planning clinical trials to take into account who is most likely to develop the disease. Already there is evidence from several clinical trials that individuals that carry the APOE 4 allele may be more refractory to certain treatments. As drug development progresses it will be important to develop medications that are able to tackle the severest form of the disease i.e. those patients who are carrying and APOE 4 allele.

Summary: The two types of familial Alzheimer’s disease differ in the risk for offspring of developing the disease. The early onset cases as noted have children that are highly at risk for developing the disease if there is a family history. By contrast late onset disease or low clustering in families is much less genetically predisposed. In both cases genetic tests are available but are generally discouraged particularly for late onset disease. Roskamp Institute researchers and clinicians are well versed in the genetic aspects of the disease and can advise on an individual or family basis as required.

The Roskamp Institute is a not-for-profit research Institute located in Sarasota and Tampa, 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 Institute’s Memory Clinics 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

By Dr. Michael Mullan, Director of Alzheimer Research Institute, The Roskamp Institute

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ß-amyloid exchage in the blood-brain barrier

Why work with Alzheimer's disease patients?

Walking into the Memory Disorder Clinic at the Roskamp Institute one might ask “Why work with Alzheimer’s patients and their families?” The answers are manyfold. One of the most rewarding aspects of working with Alzheimer’s patients is that they are most commonly our oldest citizens who have 60, 70 or 80 years of life experience behind them many of them have served their country in one form or another - frequently in the military but often times in businesses working for others or their own companies. Many of those serving in the armed forces have captivating stories. One visitor to the clinic had parachuted into three war zones Normandy, the “boot” of Italy, and Germany. Remembering this tale this gentleman was most afraid of being shot by the Russians! Of course being able to recall these old memories is not unusual for Alzheimer disease suffers. In fact the tendency to reminisce sometimes becomes a prominent feature of the disorder. Most caregivers are initially concerned by another aspect of the disorder namely the forgetfulness for recently acquired or presented information. Such things as recent visits recent phone calls or recent conversations and events may not be remembered either in part or in full. This distressing symptom interferes with social activities and is a progressive aspect of the disease. Therefore one of the most rewarding aspect of working with Alzheimer’s sufferers and their families is being able to convey to them the several treatment options that are available. This includes, as well as those drugs approved by the FDA, new and experimental treatments including those that are being developed by the Roskamp Institute itself.

Providing hope for patients and their families is a critical part of interfacing with them. In addition helping families to come to terms with a disorder that can impact many aspects of their love ones’ lives (including social interactions, pastimes and sports, financial transactions and medical legal issues) enables families to make the necessary adjustments to deal with the condition. Naturally a particularly satisfying interaction can occur when certain elements of a patient’s health can be altered to improve the outcome once a diagnosis of Alzheimer’s has been made. For instance we know that cardio-vascular health interacts critically with Alzheimer’s disease and aversion of cerebrovascular events (such as small strokes or transient ischemic attacks) has a highly beneficial effect on the outcome of Alzheimer’s patients. In addition other conditions such as diabetes or thyroid disease can interact negatively with the disease. These and many other treatable causes of cognitive dysfunction appear at the Roskamp Memory Clinic and are regularly amenable to intervention. Sometimes previous diagnoses are found to be incorrect and memory loss may be completely reversible. For instance people suffering from normal pressure hydrocephalus have a condition that is completely amenable to surgical correction.

Another gratifying aspect of working with Alzheimer’s patients is being able to give their families and loved ones a clear indication of what the treatment options are and what the outcomes are likely to be. In addition family members are often concerned about their own risk for developing the disease it now being common knowledge that the disease has a familial aspect.

All in all there is much to recommend a profession working and caring for Alzheimer’s patients. Our elderly are frequently amongst our most valued citizens who have contributed to the prosperity and safety of subsequent generations. Continuing to work for their immediate care and finding new treatments to improve their long term prognosis are the premier interests of the Roskamp Institute’s researchers, physicians and clinicians.

Alzheimer's disease drug developed at Roskamp Institute approved for key clinical trial funding in Europe

Nilvadipine, an Alzheimer’s drug developed at the Roskamp Institute in Sarasota announced earlier this year was selected for funding or a large-scale European clinical trial. An international research consortium led by Trinity College Dublin (Ireland) announced more than 500 patients will participate in the multicenter Phase III clinical trial designed to study the effectiveness of Nilvadipine.
Michael Mullan, M.D., Ph.D., Roskamp Institute director who, with associate director Fiona Crawford, Ph.D and lead scientist Daniel Paris, Ph.D., led the research team that developed the drug. Mullan said, “We need many more medicines to move forward into advanced clinical trials in the fight against Alzheimer’s Disease and we are pleased the Roskamp institute has played such a major role in the development of this drug.” Before a drug can move into clinical practice, Phase III is usually the last step in the regulatory process.
The clinical trials will take place in Europe, where Brian Lawlor, M.D., Connolly Norman Professor of Old Age Psychiatry at Trinity College Dublin, Ireland, will be principal investigator and coordinator. The study will be funded by the European Commission Seventh Framework Programme and more than 20 European clinical sites will participate. Nilvadipine is already approved for the use in mild cases of hypertension (high blood pressure) and Mullan says, “The process can move more quickly in Europe, and the study findings may help accelerate the process with the U.S food and Drug Administration (FDA).
Mullan and Crawford have been studying Alzheimer’s disease for more than 20 years, moving from the UK to Florida in 1991 and to Sarasota in 2003 to establish the Roskamp Institute. “Some of our recent studies have involved Sarasota area residents, who have contributed to our understanding of Alzheimer’s disease and helped move the development process forward,” said Crawford. Now, the Roskamp Institute will provide research support for the Phase III clinical trial, such as assessing genetic and other markers for Alzheimer’s disease in study participants.
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Roskamp institute studies may lead to better diagnosis

Researchers at the Roskamp Institute have new studies that could lead to better diagnosis and eventual treatment for U.S. military personnel as well as other patients with TBI, commonly known as traumatic brain injuries.
Fiona Crawford, Ph.D., associate director of the Institute, a leading research facility for Alzheimer’s disease and other neurological disorders says, “We have found that there are changes in blood proteins that occur after a head injury, and that these are dependent on the severity of the injury, the time since the injury and genetic factors influencing outcomes after head injury.” Crawford’s research indicates that TBI can affect cellular mechanisms in the brain long after the original trauma, and that blood biomarkers reflect these ongoing processes. She also stated, “Translating these finding from the laboratory to human patients may help clinicians determine the extent of the brain injury, how long ago the injury occurred and the patient’s prognosis for a favorable or a poor outcome.”
Traumatic brain injury has multiple consequences at the cellular level and so molecular changes can persist for weeks and months after the initial brain swelling and other immediate issues have resolved. Crawford says, “Identifying blood biomarkers of mild TBI would improve medical management by enabling us to identify patients who need treatment or intervention, even if they do not have obvious signs of a brain injury.” The U.S. Department of Defense, and the Veterans Administration supports all of Crawford’s work because it could lead to better diagnosis of military personnel with mild brain injuries and better long-term care of our veterans.
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Dr. Mullan’s Alzheimer Research Involved Studying Brain Proteins

The Roskamp Institute has surfaced as a leading and reputable non-for-profit biomedical research organization. It has successfully experimented to find cures for several neurodegenerative disorders and conditions like Alzheimer’s disease. Through the clinical trials division and outpatient clinic, at the institute, thousands of Alzheimer’s patients get superior services and therapeutic treatments. Dr. Michael Mullan is the Director of Roskamp Institute. Dr. Mullan is an experienced and a competent individual. His research efforts led to the identification of Swiss Mutation.
Along with Dr. Mullan, the institute has helped in contributing to provide insights on the treatments of neuropsychiatric disorders such as Alzheimer, traumatic brain injury, substance abuse, etc. through unparalleled research. Under the supervision and guidance of Dr. Michael Mullan, several causes and cures related to Alzheimer’s disease have been found. Dr. Mullan’s Alzheimer research identified various types of genetic variations which may be the cause of predispose humans to this disease. His research and study identified that the central reason to the disease process is a small protein known as ß (beta)-amyloid. The excess and abnormal accumulation of ß-amyloid in the brain results in Alzheimer’s disease. With Dr. Mullan’s Alzheimer research, cutting edge cures, medications, and therapeutic treatments are tested and developed to help slow down the process of ß-amyloid’s toxic accumulation.
As per the research on Dr Mullan’s Alzheimer, Aβ peptide is responsible for preventing blood vessel growth and inhibiting tumor growth. He studied several particular sequences within the Alzheimer’s Aβ peptide to identify if Aβ can have the same effect with short derivatives as well. The research proved that the peptide has potential therapeutic relevance to prevent the growth of tumor. The research involved conducting clinical trials which are specifically conducted to developing superior treatments for neurodegenerative diseases. In order to understand the diseases and finding its causes and prevention, Dr. Mullan’s Alzheimer research work has contributed extraordinarily in the field. Furthermore, with his constant efforts and guidance, the Roskamp Institute was also able to carry out research in neuropsychiatric disorders such as Traumatic Brain Research, Gulf War Illness, and Alzheimer’s. Find out more about his Alzheimer research works, by browsing through or or


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