Research Magazine 2009
Photo from Corbis
There is no known cure for the most common neurodegenerative diseases, including many that produce dementia, and the rapidly escalating number of cases is threatening the shaky financial situation of the U.S. health care system, as baby boomers live into their eighties and nineties. More than 1.5 million Americans currently live with Parkinson’s disease, and another 5 million with Alzheimer’s, both of which primarily affect those 65 and older. Direct and indirect costs for these disorders reached a total of $148 billion in 2005, according to the Alzheimer’s Association, and are expected to rise. The cost in human terms is harder to calculate, as individuals living with dementia endure a progressive loss of cognitive abilities, such as thinking and remembering, and essential motor skills.
Interdisciplinary teams of Boston University researchers are in the vanguard of a new age of discovery for dementing diseases and other disorders that lead to more subtle thinking problems—conducting pioneering research in diagnosing Alzheimer’s earlier and assessing therapies for more effective treatment; investigating the understudied vision disorders associated with Parkinson’s and Alzheimer’s; and identifying a neuropathological disease that leads to dementia in athletes and others who experience repetitive concussions.
The Eyes Have It
Lee E. Goldstein’s lab has developed a noninvasive laser procedure that may help diagnose Alzheimer’s disease years before cognitive symptoms occur.
Lee E. Goldstein is shining a new light on earlier detection of Alzheimer’s disease. If the current clinical trials on his laser technology to identify distinctive Alzheimer’s cataracts are successful, the noninvasive test will move one step closer to becoming a universal screening device, similar to mammography or the prostate specific antigen (PSA) test for cancer, years before patients have Alzheimer’s symptoms.
Amyloid-beta proteins form a sticky plaque substance in the brain and nerve cells of an individual with Alzheimer’s, top. These proteins can also be found outside of the brain in the form of dense bilateral cataracts, above.
Images of amyloid-beta proteins courtesy of Lee E. Goldstein
“Alzheimer’s disease takes 10 to 20 years to develop,” says Goldstein, an associate professor of psychiatry, neurology, ophthalmology, pathology, and laboratory medicine. “By the time the first symptoms appear, it’s not the beginning, but the beginning of the end. The window for maximum therapeutic impact is way past.”
Working with transgenic Alzheimer’s mice, Goldstein and his colleagues discovered the first evidence of beta-amyloid pathology outside the brain in the form of dense bilateral cataracts. These unusual cataracts are easily distinguishable from age-related cataracts because they contain amyloid protein, a sticky plaque substance found in the brains and nerve cells of Alzheimer’s patients.
According to Goldstein, the eye’s lens provides an exquisite map of the biological evolution of the human body. The lens grows as the body ages, adding layers like the rings of a tree to act as a time stamp. As a result, says Goldstein, “we can use the lens as a clock to date when the beta-amyloids first appeared.”
His team, whose research enterprise is housed in both the BioSquare Discovery & Innovation Center on BU’s Medical Campus and the Photonics Center on its Charles River Campus, developed the noninvasive laser procedure and adapted a topical treatment that can identify the cataract in the lens periphery.
“By the time the first symptoms appear, it’s not the beginning, but the beginning of the end. The window for maximum therapeutic impact is way past.”
The Food and Drug Administration (FDA) approved both the laser ophthalmic application and the topical drug for human clinical trials, which are being funded by the NIH’s National Institute on Aging and by Neuroptix, a private company co-founded by Goldstein. In the next research phase, supported by the NIH and the National Science Foundation, he plans to draw on the expertise of the Photonics Center to develop a next-generation laser instrument more powerful than the current prototype.
“I’m blessed to be here,” says Goldstein. “The Photonics Center is the leading center for photonics research. BU is uniquely positioned to be at the forefront of research in this field.”
Connect, Collaborate, Conquer
In the race to discover drugs that delay or prevent the onset of Alzheimer’s or Parkinson’s symptoms, Professor of Pharmacology & Neurology Benjamin Wolozin is one of the front-runners.
His two-pronged approach—basic science that investigates the pathophysiology of neurodegenerative diseases, combined with drug epidemiology studies—has earned him funding from the National Institutes of Health (NIH), Retirement Research Foundation, Alzheimer’s Association, and the Michael J. Fox Foundation for Parkinson’s Research (MJFF), among others.
“Parkinson’s and Alzheimer’s are different neurodegenerative diseases,” says Wolozin, who has been awarded four patents for his work on the two disorders. “But they share a similarity.”
Both diseases have “bad” proteins that interfere with brain function. In Alzheimer’s, a protein termed beta-amyloid builds up in the brain, filling it with small deposits, commonly called neuritic plaques. In Parkinson’s, alpha-synuclein—a protein associated with the loss of dopamine-producing brain cells—depletes the brain of a critical neurotransmitter responsible for communicating with muscles.
Wolozin researches whether medications approved by the FDA for other ailments can be shown to combat Alzheimer’s and Parkinson’s symptoms as well. His most recent study utilized data on more than 5 million patients from the Veterans Administration’s digital database in order to investigate angiotensin-receptor blockers, or ARBs. In a startling discovery, Wolozin found that patients taking ARBs—which are FDA-approved for high blood pressure—showed a 35 to 40 percent lower chance of developing Alzheimer’s disease or dementia.
With their most recent grants from the NIH, Alzheimer’s Association, and MJFF, Wolozin and his team are studying mutations in LRRK2, the most common genetic cause of Parkinson’s disease. They have found that LRRK2 mutations produce similar nerve cell loss in nematodes, or roundworms, and are set to publish preliminary findings showing that resveratrol—an antioxidant found in red wine and dark chocolate—protects nematodes with the mutation against nerve cell degeneration.
In collaboration with biomedical engineer James Collins, they are using these nematodes to screen for the genetic pathways that cause Parkinson’s. Wolozin is also collaborating with another BU faculty member, Jiang-Fan Chen of the Parkinson’s Disease & Movement Disorders Center, on the next stage—an investigation of resveratrol’s effect on the Parkinson’s model in mice.
Rac1, a small protein that stimulates neuronal processes, protects against damage caused by mutations in the LRRK2 gene, which are the most common genetic cause of Parkinson’s disease. Here, neuronal processes are highlighted in red for human neurons engineered to make normal LRRK2 (panel A) or LRRK2 carrying the G2109S mutation (panel B). Producing rac1 along with LRRK2 in the neurons prevents the degeneration caused by G2019S LRRK2 (panel D).
Images of neuronal processes courtesy of Benjamin Wolozin
Both Collins and Chen—along with Lee E. Goldstein, for his work on beta-amyloids—were among the roughly two dozen researchers this year from across the University attending BU’s third annual Parkinson’s Forum, organized by Wolozin. “What I love about BU is that there are so many people doing outstanding research,” he says. “The goal of the forum is to bring together people from different disciplines who are working on Parkinson’s disease directly or indirectly.”
And, of course, to find a cure. The forum’s motto says it all: Connect, collaborate, conquer.
The Memory Game
If you are in your fifties and have the gene associated with Alzheimer’s disease—along with a parent who developed the degenerative brain disorder—chances are you’re more forgetful than your peers.
Sudha Seshadri, an associate professor of neurology, recently discovered that the children of parents with Alzheimer’s disease have more memory problems, compared to other same-aged subjects who have the gene, known as APOE4 (or E4 for short), but whose parents did not develop the disease. Though still within the normal range, the responses of subjects with a parent who has Alzheimer’s are more in line with 70-year-olds than 55-year-olds, says Seshadri.
The findings of the parental-link study—the first to demonstrate memory changes long before Alzheimer’s symptoms are usually diagnosed—were presented at the American Academy of Neurology’s 2009 annual meeting. With funding from the National Institute on Aging, Seshadri next plans to develop risk-prediction scores based on her initial findings.
Using the standard Wechsler Memory Scale, 715 research subjects whose parents’ lifelong dementia status was known and who possess the E4 gene were tested on logical memory and visual spatial memory. They were asked to read aloud a paragraph and then, after a 20-minute interval, to recall the story and the details. They were also shown pictures of geometric shapes and asked to describe the patterns. Half of the participants—all of whom were second-generation offspring of Framingham Heart Study patients—had one or more parents with Alzheimer’s.
Seshadri found that among individuals with an E4 gene, those whose parents had developed dementia performed significantly worse on memory tests, although they were only in their early sixties and Alzheimer’s typically develops in septuagenarians.
“The study results are telling us that something is happening a lot earlier, and we need to look further,” she says. “But I would not suggest that people take a memory test, even if they have the gene.”
Approximately 50 percent of people with the E4 gene will develop the devastating disease, although Seshadri believes that other genes, which have yet to be identified, also play a role. The E4 genetic test is conducted after people show Alzheimer’s symptoms, usually in their mid-seventies. The earlier the diagnosis, before permanent brain damage occurs, the more successful the outcome in relieving symptoms with medication.
Visual and cognitive impairment in Parkinson’s may take a backseat to the loss of motor skills for many in the neurology community, but not for neuropsychologist Alice Cronin-Golomb.
“If you ask Parkinson’s patients what bothers them the most, it won’t always be their deteriorating motor skills,” says Cronin-Golomb, director of the Vision & Cognition Laboratory, and a presenter at the Parkinson’s Forum. “Medicine doesn’t take care of all these other symptoms.”
With grants from the NIH’s National Institute of Neurological Disorders and Stroke, Cronin-Golomb and her team are focusing on object identification in Alzheimer’s disease and the thought processes involving visual and spatial awareness in Parkinson’s disease.
Visual disorders can predict other aspects of Parkinson’s-related dysfunction, says Cronin-Golomb, and those symptoms can be addressed through physical or occupational therapy. Poor contrast sensitivity, for instance, is related to a patient’s “freezing”—an inability to move—and her research suggests it may be caused by a visual trigger such as walking through a doorway. Other findings relate to motion perception, night vision, and visual hallucinations.
“Patients may hallucinate, seeing little animals out of the corner of their eye, for example, and it’s not due to the drugs or a psychotic episode,” she says. “At one Parkinson’s support group, after I had described these sorts of hallucinations, a man stood up and said, ‘I have that.’ And his friend next to him turned and said, ‘You do? So do I.’ If we want to improve their quality of life, we have to discuss these symptoms.”
In 2004, Cronin-Golomb’s so-called red-plate study uncovered visual dysfunction in those with Alzheimer’s, one possible cause of undernourishment and serious weight loss in many patients. Brightly colored plates that differ from the color of the food were found to help people with Alzheimer’s distinguish the food from the plates and cups and to increase their food consumption by approximately 25 percent.
“If you ask Parkinson’s patients what bothers them most, it won’t always be their deteriorating motor skills. If we want to improve their quality of life, we have to discuss these other symptoms.”
Today, with a second NIH grant based on the red-plate study, she is designing tests to maximize Alzheimer’s and Parkinson’s patients’ visual abilities and a computer software program that will customize tests to level the playing field in assessing patients’ abilities. The tests will include words, faces, and geometric figures, and with one keystroke the software will increase the contrast of the objects by exactly the amount needed to compensate for that particular person’s contrast sensitivity deficit. The result is that every person taking the test will be at the same perceptual starting line.
“Most people think they’re seeing things at maximum contrast, but they’re not,” says Cronin-Golomb. “Newspapers are only at 70 percent contrast. Healthy older adults also have an age-related decrease in discerning visual contrast. For people with Alzheimer’s and Parkinson’s, there is even more loss.”
Between 1.6 million and 3.8 million sports-related concussions occur annually in the United States, increasing athletes’ risk of chronic traumatic encephalopathy (CTE), a degenerative brain disease that eventually leads to dementia. Boston University researchers stunned the sports world this year with the discovery that CTE—a condition, often associated with boxers, which gave rise to the term “punch-drunk”—can also be found in football players and other athletes.
That’s the bad news.
The good news is that CTE is the only cause of dementia that is preventable through increased awareness and education about concussions.
Research at BU’s Center for the Study of Traumatic Encephalopathy (CSTE), funded by the University and by grants from the NIH and the National Operating Committee on Standards for Athletic Equipment, is in its infancy. Robert Stern, one of four co-directors, says that CTE is a tau-based disease, only diagnosed after death by examining brain tissue under a microscope. Abnormal accumulations of the tau protein cause neurofibrillary tangles in the brain that are also found in Alzheimer’s disease.
“We want to understand who is likely to develop CTE and to be able to diagnose it during a person’s lifetime,” says Stern, an associate professor of neurology and co-director of the Alzheimer’s Disease Clinical & Research Program.
The center collaborates with the Sports Legacy Institute, founded by Christopher Nowinski, a former football player and professional wrestler, and Robert Cantu, a neurosurgeon at Emerson Hospital as well as a clinical professor of neurosurgery at BU’s School of Medicine, both of whom are also CSTE co-directors. The fourth co-director is Ann McKee, an associate professor of neurology and pathology in the BU School of Medicine, and director of neuropathology for the CSTE, BU Alzheimer’s Disease Center, Framingham Heart Study, and New England Veterans Affairs Medical Centers.
McKee and the research team published their findings on CTE in the Journal of Neuropathology and Experimental Neurology in July 2009. Their article cited 51 neuropathologically confirmed cases, 46 of which involved athletes: 39 boxers, five football players, one professional wrestler, and one soccer player. A third of the athletes profiled experienced symptoms of CTE, including memory loss, cognitive decline, gait abnormalities, and Parkinson’s, at the time of their retirement from the sport. Half developed symptoms within four years of stopping play.
Researchers ultimately found CTE in the brains of six deceased National Football League (NFL) players; the most recent was Tom McHale, a retired lineman for the Tampa Bay Buccaneers who died at the age of 45. More than a dozen high-profile NFL players have agreed to donate their brains to the CSTE brain bank. In May, McKee spoke to the NFL’s Mild Traumatic Brain Injury Committee about their findings.
“Education is our first goal,” she says. “That and convincing people that this disorder does exist. Players, coaches, and parents need to pay a lot of attention to concussions and give players time to recover, sometimes as long as five to six weeks.”
Figures 1 and 2 show varying levels of tau protein deposits in whole brain and microscopic sections taken from three individuals (l–r): a 65-year-old control subject; former NFL linebacker John Grimsley; and a 73-year-old former world-champion boxer. The control subject displays no tau deposition, while the sections taken from Grimsley and the boxer show dense tau-positive neurofibrillary tangles, which can also be found in the brains of patients with Alzheimer’s disease.
Images courtesy of Robert Stern
They were on their own again. The patients—all suffering from Parkinson’s disease—had volunteered for two studies that mixed speech, physical, and occupational therapy to help them achieve a better quality of life than medications alone could deliver. They learned exercises to regain simple pleasures that the disease had taken from them, tips and techniques for getting out of chairs with ease or chatting and socializing with confidence. But once the studies were over, the patients returned to their former reliance on medications.
It felt like a step backward to Terry Ellis, the studies’ author and associate director of clinical care in the BU Center for Neurorehabilitation. She wanted to see her patients keep their forward momentum, so, she says, “based on our results, we developed Community Wellness Programs for people with Parkinson’s disease.”
Community Wellness Programs developed by physical therapist Terry Ellis, right, are helping patients with Parkinson’s disease regain confidence and mobility.
Now in their fifth year, the programs include twice-weekly group sessions providing patients those “elements of exercise and rehabilitation” that the study found to be most important and effective. Thanks to funding from the American Parkinson Disease Association, 13 sites in New England now offer wellness programs following Ellis’s model. She estimates that altogether they have reached more than 300 patients.
“My problem was when I went to bed, wherever I lay, I stayed,” says Jack, a 75-year-old participant in the BU wellness program. “The therapy helped me incredibly—even to get out of bed. When I get in bed, I don’t have movement of the upper part of my body, so they taught us tricks to move around.”
The benefits of outreach also extend to researchers and students in the College of Health & Rehabilitation Sciences: Sargent College. While Ellis’s earlier studies uncovered the broad benefits of certain exercises, much remains to be discovered and refined.
“We’re continuing to look at things like: What are the most important parts of exercise? How much should people be doing? What kind of dose of exercise makes a difference?” she says. “I’m just about to start a longitudinal study following people over time, so we can have a better understanding of the impact we’re making with exercise. Large multi-center clinical trials are currently being proposed to investigate whether exercise is neuro-protective and may have a role in slowing down the progression of the disease.”
That kind of finding could revolutionize the current approach to Parkinson’s, a degenerative disease that many are now living with for 20 or 30 years and for which medications are only effective for a limited time. “I’d like to see exercise be part of the standard care,” says Ellis. “We do that here, but elsewhere it’s rare.”