The brains of the mice that Bradley Hyman keeps in his sprawling lab at an old naval base in Boston offer a window, literally and figuratively, into the mysterious damage that causes Alzheimer's disease. When each mouse reaches a few months of age, one of the lab workers carefully creates an opening in its skull and places a tiny glass window over the hole. Day after day, week after week, a powerful microscope is trained on the brain, searching for ugly clumps of sticky protein fragments like those that litter the brains of elderly people who have died of Alzheimer's. "It's like time-lapse photography," says Hyman, director of the Massachusetts Alzheimer's Disease Research Center at Harvard Medical School. When the ugly plaques appear—and they always do, as the mice carry genes engineered to produce them—nearby brain cells begin to wither and die, interrupting the flow of information. Next, waves of cells die off.
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Hyman's microscope is one of several new technologies that promise to revolutionize the struggle to understand and beat Alzheimer's, which now afflicts more than 5 million Americans. Worldwide, a staggering 1 percent of all economic output is spent caring for and treating people with it and other types of dementia, according to Alzheimer's Disease International, the umbrella group of Alzheimer's associations around the globe. Meanwhile, just four drugs have been approved by the Food and Drug Administration to battle the disease, and all address symptoms only, not the poorly understood causes. Over the past decade, billions of dollars have been poured into researching drug after initially-promising drug, and nearly all have been disappointing in large clinical trials.
"When you can watch the brain over time, we see now, we didn't have the details right," says Hyman, who holds out great hope that his microscope studies will help correct that. One assumption has been that the plaques themselves, accretions of a protein fragment called beta amyloid, harm the brain. Instead, it appears that the individual sticky strands that eventually form the plaques damage neurons, and that the plaques are a sign of a brain long under siege.
For years, researchers have debated whether the brains of people who develop Alzheimer's produce excess beta amyloid or they're simply bad at clearing it. In December, researchers at Washington University School of Medicine in St. Louis provided strong evidence for the latter theory. They measured radioactively labeled beta amyloid visible in the spinal fluid of healthy older adults and people with Alzheimer's. Both groups appeared to produce the same amount, but the ill individuals cleared the substance from their brains into their spinal fluid at a rate about 30 percent slower. Moreover, since autopsy studies find that some people with no cognitive symptoms of Alzheimer's carry a substantial plaque load, the body may possess a varying capacity to withstand beta amyloid's assault.
Following on the success of periodic cholesterol testing, which has revolutionized heart care, researchers are experimenting with measuring beta amyloid via brain scans, spinal taps, and blood tests. Early results offer hope that, someday, physicians will be able to screen the middle-aged for the hallmarks of pre-Alzheimer's. "It's critical to identify people at risk," says Reisa Sperling, who is using brain PET scans of beta amyloid at Brigham and Women's Hospital in Boston to study the impact in people who are not showing symptoms. She's concerned that right now drug treatment starts five or 10 years too late. An FDA advisory committee recommended in January that the agency approve a PET scan that could be helpful in diagnosing people who already have the plaques.
Of course, without effective drugs, early detection offers little solace. Most of the recently failed drugs aimed to interrupt production of beta amyloid by blocking the enzyme that produces it. However, researchers have opened a new front in the battle, targeting the synapses between neurons, which new research shows may be the first structures to deteriorate. Another approach, based on the theory that the body must have natural defenses if most people don't get Alzheimer's, seeks to train the immune system to attack beta amyloid. But all of the new drugs have been given to patients who already show cognitive symptoms. Adrian Ivinson, director of the Harvard NeuroDiscovery Center, which focuses on degenerative brain diseases, thinks some of the failed drugs should be retested in asymptomatic individuals who show beta amyloid on brain scans or in spinal fluid tests. "The implication of all this work is we have to get [the drugs] into people before they're patients," he says. "They have a silent disease."
What about prevention? There is accumulating evidence that exercise, eating fish or other sources of omega-3 fatty acids, and remaining intellectually and socially engaged throughout life reduce the risk of Alzheimer's. But last year a panel assembled by the National Institutes of Health concluded that the evidence on lifestyle interventions is inconsistent and inconclusive, pretty much across the board. "There are suggestions that some things might be effective, but there isn't strong, high-grade evidence for any of them," says Neil Buckholtz, chief of the dementias of aging branch of the National Institute on Aging. The NIA is now running several large studies to see if exercise, diet, or social or intellectual engagement will reduce risk.
Having had a stroke substantially raises the odds of Alzheimer's, as does having diabetes. But the biggest known risk factor is one people can do nothing about: a family history of the disease. People carrying one copy of variations in a gene called APOE are at about a threefold risk, while those carrying two copies have a whopping 12-fold risk. But it appears possible now that many genes, perhaps even a hundred, may each confer a tiny increased risk of developing Alzheimer's. Still, Rudy Tanzi, an Alzheimer's geneticist at Harvard Medical School, is hopeful that by 2020, a screen of a person's genome will reliably estimate his or her risk of developing the disease. Ideally, the people at highest risk will then have scans or spinal fluid or blood tests regularly to detect accumulating beta amyloid. Once it is seen, they'll begin taking the equivalent of a "statin for the brain" to reduce the load. And Alzheimer's will become as preventable as heart disease is today.
AUTISM: Fighting it in toddlerhood, with play
It was a breakthrough that Lynn Locke of Lodi, Calif., calls "the greatest joy in our lives." After her son Colson, then 3 years old, participated in a year of novel therapy for autism, the brain disorder that inhibits children's ability to communicate and develop relationships, he finally spoke his first word: "Up." A year later, Colson "talks a mile a minute" and is enrolled in a regular preschool class.
Scientists are racing to find autism's causes and the drugs that may help treat the disorder, which now afflicts 1 in every 110 children and 1 in 70 boys, according to the Centers for Disease Control and Prevention. But it's behavior therapies like the one that helped Colson that are giving families immediate hope. His success came as part of research at the University of California, Davis Medical Center testing the Early Start Denver Model. The model holds that children as young as 12 or 18 months can improve significantly with more than two dozen hours a week of intensive therapy emphasizing interactive play; often, interventions don't begin until preschool or kindergarten and are more focused on practicing speech and modifying behavior. The goal is to "reduce autism symptoms or prevent them from ever developing," says Geraldine Dawson, a professor of psychiatry at the University of North Carolina-Chapel Hill School of Medicine who helped develop the model, and lead author of a 2009 study of it. Dawson is also chief science officer for Autism Speaks, a nonprofit that funds research. Her report noted that the IQs of children who received Early Start therapy rose on average by close to 18 points, compared to 7 points in the group receiving traditional autism therapies. The Early Start group's listening and understanding skills rose by about 19 points, almost twice the level of improvement in the control group.
The Early Start therapy is built around activities that require the autistic child to make eye contact, take turns, and communicate. Colson and his therapists, parents, and siblings played board games, sang and danced, and marched around the house. When Colson wanted something, he learned to ask for it by pointing and making the sound of a T (his therapist's first initial). He made an M sound to get his mom's attention. Within a few months, he was addressing people by name. Sally Rogers, the UC-Davis psychologist behind the model, is now launching a study of play therapies aimed at infants.
Meanwhile, the exact causes of autism remain a mystery. In the past three years, researchers at Yale, UCLA, and Johns Hopkins have all concluded that it's a disorder of the brain's synapses; the molecules active in an autistic person's synapse don't function properly. A 2009 study noted that the number of autism diagnoses rose 57 percent between 2002 and 2006, which signals to many experts that new environmental factors may increase the odds of developing these dysfunctional synapses. Research from the California Department of Public Health has indicated that advancing maternal age may play a role. Prematurity has been implicated, as has the timing of pregnancy: A recent study found that a second child conceived within a year of an older sibling's birth was more than three times as likely to be diagnosed with autism as children conceived more than three years after the birth. A child's exposure to pesticides and parents' medical conditions, including type 1 diabetes and rheumatoid arthritis, also are under study as possible factors.
While the 1998 study linking the MMR vaccine to autism has been completely discredited, Dawson does not want to dismiss concerns about vaccines entirely. Autism Speaks earmarks 2 percent of its research budget to vaccine studies. The National Institutes of Health, too, has called for more research, given that certain children appear to be more vulnerable than others to vaccine side effects.
BRAIN CANCER: New and better weapons
Each year, more than 22,000 people nationwide develop brain cancer, and more than half die, usually within 15 months. But researchers say they are now poised to make major breakthroughs. "Our understanding of brain tumors, and the way we think about treating them, has changed dramatically after decades of very little progress," says Susan Fitzpatrick, vice president of the James S. McDonnell Foundation in St. Louis, which funds brain cancer research. "We're starting to make headway against a very difficult type of tumor."
Typically, brain cancer is treated with surgery, radiation, and chemotherapy. All present challenges, says Howard Fine, chief of the National Cancer Institute's neuro-oncology unit, because of the brain's sensitivity. "Most other organ systems have some potentially expendable normal tissue. You can't just remove half the brain," he says. Radiation inflicts toxic side effects, and while certain drugs effectively kill cancer cells, they kill normal cells as well. The brain is protected by a natural defense system called the blood-brain barrier, which keeps toxins out but sometimes prevents drugs from entering, too.
Now, spurred by genomic research, cancer specialists are beginning to understand the physical and chemical properties that predict which drugs will break through the blood-brain barrier. Therapies that home in on specific tumor cells and spare healthy ones are being developed also; one such drug, Avastin, approved by the FDA in 2009, was the first new glioblastoma treatment in more than a decade. Avastin works by curbing the growth of new blood vessels that supply blood to tumors. "This is a tremendous advance," Fine says. "The response rate with most of our drugs is less than 5 percent. With Avastin, we're seeing upwards of 70 percent."
Imaging is improving, too, leading to better monitoring and new surgical techniques. Using functional magnetic resonance imaging to map brain activity in the area surrounding a tumor, for example, surgeons can minimize harm. "We're able to do surgery and remove tumors in areas of the brain that we previously couldn't even think about touching," Fine says. A few institutions, including the University of California, San Francisco Medical Center, are testing a technique that causes even single cancer cells to make their presence known by glowing under fluorescent light.
Research efforts are also targeting stem cells, which have been found in a number of other cancers and are suspected of manufacturing new tumor cells like little factories. Several years ago, researchers discovered that brain tumors contain stemlike cells that can proliferate and self-renew. Coming up with treatments that will defeat these cells might be one key to dramatically improving long-term survival.
CONCUSSION: A heightened respect
Not so long ago, once the confusion, amnesia, dizziness, and nausea from a concussion subsided, the child went back to school, the athlete returned to play, the soldier was sent again into battle. But concussions are no longer being treated quite so lightly, given a growing body of evidence that "mild" traumatic brain injury can result in serious disabilities and fatalities. When the gelatinous brain is subjected to acceleration-deceleration and rotational forces, the metabolism of brain cells is upset and they can no longer function. And it turns out that "second impact syndrome," or a second concussion before the first has had a chance to heal fully, creates a significantly greater risk of dying. Those who survive face long-term consequences.
Indeed, they may eventually suffer from the one form of dementia that's entirely preventable. Ann McKee, an associate professor of neurology and pathology at Boston University who has performed over 50 autopsies on the brains of athletes from age 18 to 83 who played contact sports, has seen evidence of two types of microscopic damage resulting from multiple blows to the head over time. Chronic traumatic encephalopathy, an Alzheimer's-like degenerative disease, strikes the front of the brain, which houses intellect, judgment, learning, and emotions. Affected athletes are in their 30s or 40s before symptoms appear: erratic behavior, staggering gait, amnesia, depression. McKee found a significant indicator of CTE—the buildup of a cell-killing protein called tau—in the brains and spinal cords of deceased athletes and now hopes to identify CTE in the living. Last August, McKee and her colleagues discovered a motor neuron disease similar to amyotrophic lateral sclerosis in three out of 12 deceased athletes, the first evidence that repeated blows to the head might also affect voluntary muscle movements.
How much do parents of athletes need to worry? Researchers at Purdue University outfitted the helmets of 21 high school football players with sensors and found that kids were taking as many as 1,600 hits to the head in a season, registering in many cases some 100 Gs of force (a roller coaster experience equals about 5 Gs). To their surprise, four students who had never actually had a concussion but had taken comparatively more and milder blows to the front and top of their heads showed more cognitive impairment than concussed teammates who took heavy hits mostly to the side of the helmet.
Military wisdom on the topic may soon make it easier to diagnose mild traumatic brain injuries before symptoms appear. About 320,000 troops in Iraq and Afghanistan have suffered concussions from the shock waves generated by roadside bombs and rocket-propelled grenades. So the U.S. Army teamed up with Florida-based Banyan Biomarkers and developed a blood test that accurately diagnosed brain trauma in 34 people with a mild concussion. The test looks for two proteins that enter the bloodstream when the brain is injured. Researchers plan to try it next on 1,200 patients. In addition, the Department of Defense began using eye-tracking goggles last year to measure how well an injured soldier is able to pay attention, the primary cognitive function impaired after a concussion. Someone wearing the goggles watches a circling dot for 30 seconds; ability to focus while tracking the target is measured, and a score is generated to quantify the severity of an injury.
There is optimism, too, about the severe brain traumas that cause a form of coma called persistent vegetative state, in which a person is awake but not aware. Only 3 to 7 percent of people in this state typically recover. But new tactics to jump-start these patients' brains are showing promise as part of the "emerging consciousness" program at the Department of Veterans Affairs. The focus is on combining nursing and rehabilitation services, an individualized therapy program, intensive case management, and psychological support services and education for families and caregivers—a regimen that goes beyond standard care. The program also relies on new approaches such as the use of stimulant drugs like Ritalin, bromocriptine, and modafinil, which appear to galvanize the brain. The VA reports that its multi-pronged program has brought nearly 70 percent of patients back to consciousness.
PARKINSON'S DISEASE: Beyond drugs
Drug treatment for Parkinson's, an incurable neurodegenerative disease, typically targets the characteristic motor disturbances such as tremors, slowed movement, and rigidity by compensating for insufficient dopamine in the brain. As the disease progresses, however, the drugs are less effective and side effects are more evident. The therapy also may not address other significant issues associated with Parkinson's, including depression, anxiety, apathy, thinking and memory problems, and irregular sleep. With the disease now affecting perhaps a million Americans—a number likely to grow as the population ages—complementary strategies are attracting growing interest. Animal studies suggest, for example, that vigorous exercise may have neuroprotective effects, slowing the brain's loss of dopamine.
Gait and balance can also be big problems for Parkinson's patients. At Washington University School of Medicine in St. Louis, researchers tested the impact of tango lessons on two groups with moderate symptoms of the disease. In one group, participants danced alone. In the other, they danced with partners. While both groups showed significant improvement, those who tangoed with partners indicated more interest in continuing—the only way that the benefits could be sustained. The study, published in the May 2010 issue of the journal Neurorehabilitation & Neural Repair, points to the need to get patients involved in physical activities that they can maintain over the long term.
Researchers are also exploring why certain people experience temporary relief from Parkinson's symptoms when they respond to specific cues. For example, some patients can overcome their hobbled movements after hearing familiar rhythms. Others, barely able to walk, can dance when prompted, or can sing effortlessly, even if they have difficulty speaking. For reasons not well understood, auditory cues seem to reawaken, or somehow reconnect, brain circuits that otherwise aren't working as they should.
A team of Italian researchers took this idea a step further, putting people with moderate Parkinson's into a theater group so that they were compelled to take control of their movements and emotions. The three-year pilot study, reported in 2010, found that participants became more confident and motivated. And on a range of measures from mood to mobility, they outperformed a control group given regular physical therapy.
Why such approaches seem to succeed, even if only temporarily, remains largely a mystery. Rigorous studies on them have not been funded to the same extent as efforts to find better drugs, research the feasibility of putting corrected copies of defective genes into the brain, or implant brain-stimulating electrodes, for example. Some experts estimate that the electrodes could help 10 percent of Parkinson's patients. But evidence is mounting that many patients benefit from music and movement therapy, at least in the short term.
SCHIZOPHRENIA: Striving for early detection
This debilitating mental illness has been diagnosed for a century based on symptoms that patients report—the hallucinations, the inability to feel or show emotion, the social withdrawal. That's a major reason there's typically nearly a nine-year gap between the first signs of trouble and the start of treatment. Now, researchers say they are on the verge of developing diagnostic techniques that rely on biomarkers like blood proteins or genes, which could mean much earlier diagnosis and a better outcome. "Our goal is to find something objective," says Stephen Glatt, a psychiatric geneticist at the State University of New York Upstate Medical University in Syracuse. "It holds a lot of potential for people suffering from this condition." Early detection might also identify young people predisposed to schizophrenia in time to head off the worst of its effects.
The news is less good on the treatment front. Standard antipsychotic or neuroleptic drugs, which change the balance of chemicals in the brain and help control symptoms, can lead to sleepiness, weight gain, movement problems, and muscle contractions. While newer drugs called atypical antipsychotics come with fewer side effects, they aren't significantly more effective, Glatt says.
Meanwhile, other ways of managing schizophrenia are growing in popularity. Psycho-education teaches patients and their families about the illness and how to best avoid a relapse. Another approach, problem-oriented personalized psychotherapy, provides guidance on tackling everyday problems. Patients can learn to change their problematic thoughts with cognitive behavior therapy, and cognitive remediation uses computer-assisted training exercises to work on memory, attention, and problem-solving. Combined with medication, these options can make a big difference, experts say.
But with mental health and hospital resources scarce, it doesn't always happen, notes Jeffrey Lieberman, director of the New York State Psychiatric Institute in New York City. "There's a lot more that could be done in this field simply by applying what we already know."
STROKE: Widening the window for treatment
Time is brain, as the saying goes, and the push continues to make the most of those critical first hours after a stroke. The standard treatment for dissolving clots in ischemic strokes is intravenous tPA, or tissue plasminogen activator; administered within three hours, it can greatly increase the odds of recovery. But only one third of candidates make it to the hospital that quickly, and since the treatment isn't appropriate for a hemorrhagic, or bleeding, stroke (it would raise the risk of bleeding), it can't be started in the ambulance.
One promising technique now under study in California is to have emergency medical technicians administer magnesium sulfate (which dilates blood vessels and blocks the calcium buildup responsible for cell death) while en route to the hospital. "The hope is that more brain will be saved with this therapy," says Walter Koroshetz, deputy director of the National Institute of Neurological Disorders and Stroke. Meanwhile, evidence from Europe indicates that tPA can be administered effectively in some people up to four and a half hours after a stroke, and injecting tPA by catheter directly to the clot through an artery in the groin opens the window up to six hours. In some cases, it's possible to remove the clot using tools threaded through blood vessels in the brain; the Merci Retriever System, a coil-shaped device that pulls out clots, and the vacuum-like Penumbra System, which sucks them out, can be used up to eight hours after the first symptoms.
Once the damage is done, how to bring function back? Though many physicians still doubt motor skills can be regained much beyond six months out, the latest research indicates otherwise. One avenue of study suggests that high-intensity repetitive exercise, aided by robots or people, can significantly improve arm functioning even several years later. Transcranial magnetic stimulation also appears to help partially paralyzed patients as much as three years later. And researchers at the Toronto Rehabilitation Institute have reported that just eight sessions of Wii Tennis and Wii Cooking Mama—in which a player simulates peeling, cutting, and slicing—gave motor function a measurable boost.
By using stem cells to stimulate neuron and blood-vessel growth, researchers hope to someday repair stroke-injured areas. Last November, Scottish researchers injected fetal stem cells into the brain of a man in his 60s who had suffered a debilitating stroke 18 months earlier. The man will be monitored over two years to see if he gets better; 12 additional patients will get the therapy this year.