Brain trust: Florida research groups target Alzheimer's

Thinking back t o what inspired her path into brain research, Fiona Crawford remembers her childhood in Belfast and a Jack-o-Lantern poster that her mother hung on her bedroom wall, bearing the message, "The greatest unexplored area lies under your hat." Her mother also gave her a National Geographic issue with a story about DNA technology.

"Blew me away. I looked at this and thought genetics, DNA, this is fantastic. My mom has a lot to answer for." Her mother's choice of inspirational materials was substantiated as Crawford pursued a research career in molecular biology that's taken her from Northern Ireland to London to Florida.

Additional validation may come this month. Somewhere in Europe, researchers will sign up the last recruit needed for a 500-patient, phase three clinical trial to see whether an obscure blood pressure medication called Nilvadipine can slow the devastating progression of Alzheimer's disease. The application of the drug to Alzheimer's is the collective brainchild of the Roskamp Institute in Sarasota, where Crawford works as president and CEO alongside Daniel Paris, head of research and development, and 50 other scientists in an old contact lens manufacturing building.

The results won't be in for 18 months — the end of 2016 — but success at even slowing the disease with a readily available medication would be hailed globally by millions who have, or are destined to get, the incurable, progressive, fatal affliction.

A caveat must come early: Hopeful stories of potential Alzheimer's breakthroughs are a dime a dozen, and so far the disease has proved as fatal to drug development hopes and budgets as it is to people. A study of 244 compounds in trials from 2002 to 2012 for Alzheimer's found only one approved. That amounts to one of the highest failure rates for any targeted treatment — 99.6% for potential Alzheimer's drugs compared to 81% for cancer-related compounds, Scientific American reported last year.

And Roskamp isn't the only rider at the rodeo. The institute is just one of many institutions, universities and research centers in Florida, the United States and around the world that are pursuing hypotheses about Alzheimer's.

The federal government has set a goal of finding an Alzheimer's cure or prevention by 2025. Aside from the personal toll it takes on sufferers, their caregivers and loved ones, Alzheimer's devours family savings and government health care budgets. Policy group Florida TaxWatch, usually not a voice for more government spending, last year called for Florida to spend more on research in the face of "Florida's looming Alzheimer's crisis." In 2025, the state will be second only to California nationally in the number of people over 65 with Alzheimer's.

The institute's work traces to the early 1990s in London. There, Crawford, then a doctoral candidate, and institute co-founder Michael Mullan were on the team that first discovered a genetic influence among the causes of Alzheimer's. The University of South Florida recruited Mullan, as part of a "wider push by institutions in the (then) fourth-mostpopulous U. S. state to punch their weight in biomedical research," reported Nature magazine.

In science, recruiting star researchers often means recruiting a team; Crawford moved to USF as well. In 2003, during the dawn of the bioresearch industry in Florida, Mullan, Crawford, Paris and others, along with their financial supporter, senior living facilities developer Robert Roskamp, left USF to found the Sarasota institute. That same year, Florida recruited research organization Scripps, later joined by Sanford-Burnham in Orlando, Torrey Pines and VGTI in Port St. Lucie and Max Planck in Jupiter.

The new institute set up in a modest building in an industrial section where Manatee and Sarasota counties meet and stated its immodest ambition to do leadingedge research on neurological disorders. Crawford became CEO in 2014 when Mullan left to head Rock Creek Pharmaceuticals. That for-profit Sarasota company shares Roskamp's address. Mullan remains a consultant to the institute.

As privately funded scientists must when a single chip for testing genes costs $800, Crawford spends a good bit of her time trying to raise money for the institute. Compared to some academic settings where researchers shield their work from colleagues, Roskamp, she says, prides itself on openness and flexibility. "It's very open. Everybody talks to each other," she says.

It's also nimble and flexible as results challenge hypothesis. There's lots of cross talk among researchers. Because the institute has only about 60 people, a bioinformatics researcher has no trouble getting face time with, say, a chemist, nor does it take long to get lab results. Perspective ^ "I get access to animal tech. I get access to genomics. I get access to the chemist. It just takes one week to set up a project," says bioinformatics researcher Venkat Mathura.

Roskamp is a lab-coated melting pot. Mathura is a Texas-educated Indian, Crawford is Irish, pathologist Benoit Mouzon is French — a Florida Tech grad who came here for the beach. Mass spectrometry chief Jon Reed is a native Floridian who spends his days in a room maintained at a constant 70 degrees to protect equipment such as a $600,000 mass spectrometer that looks, as he says, like a college dorm fridge.

The institute runs on a $6-million budget, with donations from Robert Roskamp, among others, and with financial support from the National Institutes of Health, Alzheimer's Association, Veterans Administration and Defense Department. (It does a lot of work on brain injuries.)

The institute has a clinic that offers free memory screening for about 2,000 people a year. It also sees another 4,800 patients as part of clinical trials it conducts on behalf of pharma and nutraceutical companies.

The headliner for Roskamp at present, though, is the drug that's the subject of the European trial — Nilvadipine, a medication for hypertension originally developed by Fujisawa Pharmaceutical. That company is now part of Astrellas, which no longer maintains intellectual property rights to the drug.

Examining the way Alzheimer's affects blood flow in the brain, and the buildup of proteins and inflammation, a Roskamp team led by Paris decided to look at Nilvadipine as an answer. That led to successful trials on mice. The European Union in 2011 put out a call for Alzheimer's projects, and the trial using Roskamp's idea won more than $8 million in funding. The nine-country trial is being coordinated by clinician Brian Lawlor at Trinity College in Dublin.

In favor of Nilvadipine's prospects, aside from Roskamp's work, is a tiny study in Japan of 15 people with "mild cognitive impairment" who were given two different medications over 18 months. Only one of seven who received Nilvadipine progressed to a diagnosis of Alzheimer's, compared to all but one on the other drug. Also, anecdotally, when Roskamp was in safety tests in Europe with Nilvadipine as a precursor to the phase three trial, family members reported their Alzheimer's sufferers seemed to do better — more aware, more conversant — on it. A widespread European study of a drug in the same chemical family showed a lower incidence of Alzheimer's.

Roskamp researchers, according to an article in October in the Journal of Biological Chemistry, fingered a particular enzyme, spleen tyrosine kinase, that propagates the three hallmarks of Alzheimer's disease that damage the brain: A buildup of amyloid plaque, tangled tau proteins and inflammation. Nilvadipine attacks that particular enzyme, Crawford says. Additionally, the drug has been on the market in Europe and Japan for 20 years and is safe for humans. (U.S. FDA approval was never sought.) Nilvadipine also doesn't lower the blood pressure of people who already have low blood pressure, which some people with Alzheimer's have.

The trial under way in Europe will be what's called a double blind, with neither patients nor their doctors knowing which 250 people with mild to moderate Alzheimer's get a placebo and which get the drug.

If it works, the medication may change the slope of deterioration but won't cure the illness or reverse it.

But just slowing Alzheimer's would save millions in health care spending and relieve caregivers and patient suffering. "If it does a fraction of what it does on the animal models, we're on to something," Crawford says.

Depending on the trial results, Archer Pharmaceuticals, a for-profit company spun off from the institute in 2008, will commercialize Nilvadipine for use against Alzheimer's.

Crawford often says scientists shouldn't get married to their hypotheses. The dose in the trial might prove to be wrong or the intervention too late. She would like to see what happens when people with mild cognitive impairment, a precursor to Alzheimer's, get Nilvadipine.

She also says Roskamp has other Alzheimer's drugs in the pipeline. Meanwhile, it awaits the 2016 results. "That's when we'll know," Crawford says. 

Perspective

Marco Pahor, M.D. 

Director / Institute on Aging, University of Florida, Gainesville 

“One component of cognitive decline is the vascular component. Avoid smoking. Moderate alcohol consumption is positive. Control blood pressure, high cholesterol. Maintaining body weight is effective. Maintenance of blood sugar. Not only engaging in physical activity, but avoiding the sedentary lifestyle. Sitting for a long time has a negative effect. That’s a reason we have walking desks at our offices here. The other aspect is maintaining a cognitive active life, engaging in cognitive Perspective exercises Of course, having a job is important, having socialization is important. Computer games, Sudoku games, chess games are mental training activities. I do everything I’m preaching. I have a half a glass of wine in the evening. I exercise. I try to avoid prolonged sitting. Try to maintain my weight and also my cardiovascular risk profile at the lowest possible risk profile.” 

Research Efforts Statewide 

From Florida State University in the north to the University of Miami in the south, researchers are working on understanding and beating Alzheimer's.

> The University of South Florida, home to the USF Health Byrd Alzheimer's Institute, has a lengthy list of trials under way tied to work by its own scientists, the community and pharma companies.

> Research institutes, doctors, hospitals and centers are at work as well. Mayo Clinic in Jacksonville is the only U. S.-designated Alzheimer's Disease Research Center in Florida (California has six). Cleveland Clinic Florida in Weston is in a trial of whether a currently approved diabetes drug delays Alzheimer's.

> At researcher Max Planck Florida Institute for Neuroscience in Jupiter last year, scientists found a particular protein in the brain, called CentA1, that increased in Alzheimer's and appeared to cause the symptoms. When they blocked the protein's effects, brain dysfunction returned to normal.

> Last year, the Legislature implemented some of the recommendations of its Purple Ribbon Task Force, created in 2012 to come up with a state plan on Alzheimer's. The Legislature gave $3 million to establish the Ed and Ethel Moore Alzheimer's Disease Research Program to fund Florida research. In December, the first grants went to researchers at USF, UM, UF and Mayo. 

The Numbers

480,000 — Floridians with Alzheimer’s in 2014

5. 2 million — Americans with Alzheimer’s in 2014 

720,000 — Floridians over 65 with Alzheimer’s by 2025. The Alzheimer’s Association projects only California will have more.

17. 7 billion — Number of hours that unpaid caregivers spent on care in 2013. Out-of-pocket care expenses are so large that Alzheimer’s sufferers eventually fall back on Medicaid. It’s the most costly disease to Medicare and Medicaid.

11. 1% — Strikes one in nine over age 65.

16. 6% — One in six over age 80 will get Alzheimer’s. It’s the sixth-leading cause of death in the U.S. 

Florida TaxWatch; Alzheimer’s Association 

Perspective

Courtney Miller, Ph.D. 

Associate professor, neuroscience / Scripps, Jupiter 

“I wish there was a triedand- true way to fight off Alzheimer’s disease. It is what we hear over and over again: Eat healthy and stay active. The thing that’s becoming clear is your health heavily influences your brain health later in life. There’s a higher rate of Alzheimer’s in people with diabetes, for example.” 

Perspective

Neill Graff-Radford, M.D. 
Professor, neurology / Mayo Clinic, Jacksonville

“Perhaps the most compelling evidence is in aerobic exercise — keeping one’s mind active and busy. There are a whole bunch of dietary things that may be helpful. The Mediterranean diet is helpful to the brain, antioxidants, eating fish, a handful of almonds and tree nuts, taking a B-complex vitamin and vitamin C. The one thing that’s been shown helpful to slow dementia down is to treat cardiovascular risk factors. There are good studies to show treating sleep apnea can improve memory. Socialization and keeping contact with families and friends is important as well.”

Alzheimer’s 

What happens: The loss of brain cells shrinks the brain. Most scientists point to a buildup of what’s called amyloid plaque and the twisting of tau proteins into tangles. Inflammation occurs, connections between brain cells are disrupted, neurons die and symptoms appear.

There are correlations with obesity, hypertension and other conditions that could be altered by lifestyle. Genetics and injury also play a role. It’s the most common cause of dementia.

Prognosis: Fatal, at present incurable. The disease’s hallmarks include memory loss, an inability to dress or take care of oneself, mood and personality changes, social withdrawal, loss of bodily control.

Treatment: Some drugs, caregiver and therapy interventions can improve quality of life but can’t halt progress of the disease.

Alzheimer’s Association

Perspective

David Morgan 

CEO / Byrd Alzheimer’s Institute, University of South Florida College of Medicine, Tampa 

“The best evidence suggest those same healthy lifestyle activities that reduce risk for heart disease, stroke, cancer and diabetes will also reduce your risk for dementia. These are weight maintenance, exercise, control of cardiovascular risk factors — blood pressure, cholesterol, etc. — control of blood sugar levels, a varied and rational diet, all are associated with decreased risk for dementia. The reason is probably that these lifestyle activities and appropriate medical care are slowing the rate of aging. Aging is the greatest risk factor for dementia. There is no evidence that supplements of any kind can reduce your risk of dementia. It is not what you eat but how much you eat that is critical. Moderate alcohol intake is probably a reasonable activity as well. There is no panacea agent that you can take that will reduce the need for a healthy lifestyle. Anyone who makes such a claim is trying to sell you something you probably don’t need. The data strongly suggest attaining higher levels of education reduces risk. On the other hand, boxing, football and other activities that increase head injury increase risk of dementia, and these should be avoided.” 

Leave Time Law

Taking unpaid time off to care for a parent with Alzheimer’s is protected under the 1994 federal Family and Medical Leave Act. The act, however, only covers businesses with 50 or more employees. Employees have the right to take unpaid time off — without affecting health insurance and other benefits — for up to 12 weeks in a 12-month period to care for a parent, step-parent, foster parent or anyone who raised the employee, such as an aunt or grandparent, who has a persistent or long-term condition for which treatment isn’t effective, says attorney Keith Sonderling, of Gunster’s labor employment practices group in West Palm Beach. Medical certification of the need is usually required but easy to obtain with a standard government form filled out by a health care provider.

The employee is guaranteed to get his or her job back or an equivalent job. Particularly important for workers with an elderly parent in need of care: The leave can be taken intermittently — a couple hours here or there, for example, or every Wednesday afternoon to take the parent to therapy, or three weeks while a sibling who’s the primary caregiver takes a break.

There are conditions: Has the employee been there for 12 months and worked a certain number of hours? Florida, unlike some other states, has no leave act of its own extending the federal protections. For businesses with fewer than 50 employees, the law doesn’t apply. Sonderling notes that some smaller businesses offer leave as a human resources benefit or to help a valued employee. “There are some companies with 30, 40 employees or 10 to 15. A lot don’t because they simply can’t afford it,” he says.

Tags: Healthcare, Research & Development