The dream of curing serious neurologic diseases has been frustrated by the fact that the diseases always seem to be several steps ahead of researchers. By the time a condition is detected, it may have progressed too far to do anything other than alleviate symptoms.
Researchers are hoping to change that trajectory as a new wave of clinical trials emerges that focuses on people who are genetically predisposed to developing a neurologic condition or are in very early stages of disease. The trend comes from the belief that the seeds of disorders such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease, epilepsy, Huntington's disease, multiple sclerosis, or Parkinson's disease may be sown very early, perhaps even at conception, showing up in obscure cell changes or in biomarkers (molecules that are signs of a normal or abnormal process, or of a condition or disease) found in saliva, blood, or spinal fluid, or in tiny changes visible on a brain scan. If those early signs can be identified, it may set the stage for early treatment—or even prevention.
These sorts of trials are critical, says Michael G. Benatar, MD, PhD, FAAN, chief of the neuromuscular division at the University of Miami. "Increasingly, scientists recognize that it's easier to preserve a living or sick motor neuron than to restore a dead one," he says.
Early Clues
The goal of these trials is to find biomarkers or gene triggers that will identify the disease before symptoms appear, says David B. Clifford, MD, FAAN, professor of neurology and medicine at Washington University in St. Louis.
For those in the beginning phases of a slowly progressing condition such as Parkinson's disease, the impact of such trials may be significant, Dr. Clifford says. To date, most of the therapies for Parkinson's have been directed at reducing symptoms.
Prevention strategies might also apply to conditions such as epilepsy or multiple sclerosis, says James Hendrix, PhD, director of global science initiatives for the Alzheimer's Association. "Catching any disease with a neurodegenerative component early could be useful."
It is now thought that Alzheimer's disease causes measurable changes in the brain decades before thinking and memory problems surface. New diagnostic guidelines released by the National Institute on Aging and the Alzheimer's Association describe two newly delineated phases of the disease: pre-symptomatic and mildly symptomatic but pre-dementia.
Two clinical trials that represent this approach to understanding early signs include the A4 and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies. The A4 trial is considered the "ultimate test, to date, of the notion of early intervention in treatment of late-onset Alzheimer's disease," says Maria Carrillo, PhD, chief science officer of the Alzheimer's Association. The LEARN study is a companion to the A4 trial and involves long-term monitoring of people who do not yet have evidence of amyloid-beta plaque or memory and thinking problems. The goal is to identify other biological changes related to cognitive decline and to learn whether treatments that block amyloid-beta protein buildup in the brain can slow or prevent Alzheimer's disease. Read more about these trials.
ALS Biomarkers
When Dr. Benatar first conceived of a trial aimed at identifying early signs of ALS, he was concerned that people wouldn't want to participate. But the response was enthusiastic. "There's huge interest among people who are potentially at genetic risk," he says. Called Pre-Symptomatic Familial ALS (Pre-fALS), the longitudinal study is designed for people with a biological parent, sibling, or child with ALS, or who have certain associated gene mutations, but no symptoms.
Participants, who must be 18 or older, get genetic testing—with the option of not being told the results—and visit either the University of Miami or the University of California, San Diego, every 12 to 18 months to undergo testing, which includes magnetic resonance imaging (MRI) scans, neurologic examinations, assessments of thinking skills, blood and urine analyses, and a survey of exposure to environmental risks. Follow-up phone calls occur about three months after a study visit. The goal of the trial is to improve understanding of the pre-symptomatic phase of familial ALS, says Dr. Benatar. Findings are likely to have profound implications for understanding the biology of ALS, discovering potential environmental risk factors, developing effective therapies, and even preventing the disease, he explains.
In another study, called Pre-Symptomatic Studies in ALS (PRESS-ALS), Dr. Benatar will be looking for early signs of disease in areas of the body not yet affected in people with recently diagnosed familial or sporadic ALS. PRESS-ALS also involves healthy controls—people with no known signs of ALS and no family links to the disease—for comparison.
Participants go for five study visits, three months apart, at the University of Miami. At each visit, they may undergo various procedures, including an MRI, physiological and cognitive tests, and a neurologic examination. In PRESS-ALS, Dr. Benatar hopes to identify biomarkers of pre-symptomatic ALS.
Huntington's Disease Brain Imaging
In the Kids-HD study, which involves children and young adults with a parent or a grandparent who has Huntington's disease, a genetic degenerative brain condition, researchers use MRIs to detect and chart early signs of the disease, such as changes in size or shape of the striatum, the area of the brain below the cortex known for its role in facilitating voluntary movement.
Symptoms of the disease typically develop between the ages of 30 and 40, but some people have mild problems for many years before they are diagnosed. The study, led by Peg Nopoulos, MD, professor of psychiatry, pediatrics, and neurology at the University of Iowa Carver College of Medicine, in Iowa City, includes brain imaging, genetic testing, and tests of thinking, memory, movement, and balance. Its subjects range in age from 6 to 18 years of age.
Because Huntington's disease is a "single gene disorder," Dr. Nopoulos says she can predict with 100 percent accuracy who will develop it. That makes it relatively easy to look for very early signs of the disease in a child who tests positive for the gene, she explains. The goal of the research is to recognize signs sooner, potentially leading to earlier interventions and treatment, she says.
Parkinson's Disease Markers
The Parkinson's Progression Markers Initiative (PPMI) is a large observational study that uses samples of urine, blood, cerebrospinal fluid, data from MRI and positron emission tomography (PET) scans, and clinical and behavioral assessments to identify biomarkers of Parkinson's disease progression. Data and samples from nearly 800 participants in the study will help develop a database and bio-repository.
"Parkinson's starts with mild symptoms, and diagnosis may take a long time, so symptoms are harder to identify," says Christopher Coffey, PhD, professor of biostatistics and director of the Clinical Trials Statistical and Data Management Center at the University of Iowa, in Iowa City. Dr. Coffey is a consultant to the study.
In March, the Michael J. Fox Foundation released some of the findings thus far, including information about how Parkinson's evolves over time and changes that occur in certain proteins in spinal fluid, as well as clues toward understanding genetic risk for the disease.
Changes at Conception
As evidence accumulates that many of these diseases start long before symptoms appear, some researchers such as Dr. Nopoulos are looking as far back as conception. In Huntington's, for example, it looks like the gene responsible for the disease and its protein affect the circuitry in the brain's striatum, Dr. Nopoulos says. "When the gene is expressed, the responsible protein has been developing from the time the egg and sperm combined," she says. Later in life, either through the eventual accumulation of the abnormal protein or through some other process involved in pruning nerve cells and their connections, more signs of the disease appear.
An early paper linking neural stem cells during embryonic and postnatal development to problems in the mature and aging brain was written by Mark F. Mehler, MD, FAAN, professor of neurology, neurosciences, and psychiatry and behavioral sciences at Albert Einstein College of Medicine in the Bronx, NY. His team is attempting to apply lessons learned from studies that focus on embryonic development to design gene and stem cell-based regenerative therapies. But first, researchers studying the impact of fetal and early development have to understand the dynamic roles of factors such as environment and cell signaling pathways. Even now, these researchers are able to reprogram some stem cells and progenitor cells (which are considered early descendants of stem cells) to develop abilities that are lost in some neurologic diseases.
If what is suspected in Huntington's disease is true for other neurologic diseases, then the underlying genes are involved in brain development, says Dr. Nopoulos. That's fascinating but challenging. "It would be scary to the community [to hear that] a mutated gene causes abnormal brain development," she says.
Research Challenges
Studies looking at the early expression of disease have enormous potential, but inherent challenges exist in designing and conducting them. For instance, studies are often long-term, looking for changes that may—or may not—appear over time. This can be expensive, notes Dr. Coffey.
Additionally, it can be difficult to recruit people for observational studies since they are designed to collect data, not test a new drug or treatment, says Dr. Coffey. "Most people who participate in a clinical trial typically do it because they're hoping to get the treatment," he says.
And yet, large numbers of people are needed to help ensure early detection. With ALS, for example, the broad range of subtypes of the disease complicates things, says Dr. Benatar. "We have to cast a very wide net. In ALS, you don't know where to look. The motor cortex? Peripheral nerves? Muscle? Cognition? The disease could potentially be distributed in so many places."
One of the challenges of the PRESS-ALS study, which is recruiting people recently diagnosed with the disease, is the time it takes to get a diagnosis. By the time participants are chosen, most already are one to two years into the disease, says Lucie Bruijn, PhD, chief scientist at the ALS Association in Washington, DC. That could make detecting the earliest clues less likely, she explains.
The studies can also be logistically difficult. "If the study lasts a long time, there will be concerns about cost, identifying the disorders, and retaining volunteers over time," says Robin Conwit, MD, program director in the division of extramural research at the National Institute of Neurological Disorders and Stroke in Bethesda, MD. "The rarer the disease, the more challenging it is." It can be difficult to know what is most important to track or what blood or body fluid tests will end up being most relevant, she says. "We find it helpful to collect blood and bank it," she adds, so that tests can be performed later if new biomarkers are identified.
Ethical Considerations
The Kids-HD study is controversial because it involves collecting children's genetic material for research purposes. "The biggest concern is that [the research] now suggests that in order to cure Huntington's we would have to treat it in babies," says Dr. Nopoulos.
The prospect of finding a gene early in life that might be responsible for a neurologic condition raises another important question. Given that brain development continues up to about age 26, could there be an unknown downside to shutting down prematurely a gene that affects brain development? Bad genes may have a positive job to do, too, says Dr. Nopoulos. "Do we want to treat the pre-symptomatic at age 25? Would that have adverse effects?"
The Kids-HD study also involves "a higher level of diligence, as children are considered to be a vulnerable population with the potential to be coerced," says Dr. Nopoulos. To complicate things further, many parents with the disease haven't told their younger children about it, nor have they told them that they, too, may develop it. "We can only study children who understand that they are at risk."
Another dilemma is whether to inform people who are participating in a study that they have a disease that isn't currently a problem for them, says Dr. Clifford. This is particularly true for people who know they may have a genetic predisposition to the disease.
With Alzheimer's disease, Dr. Clifford says, "the issue is charged because many of these families [with genetic risk factors] don't want to know their own status, and they have a 50-50 chance [of getting it]. As long as you don't know you've got it, you can hold on to the hope." Studies typically allow participants to decide beforehand whether they want to know the results. For those who do, genetic testing and related counseling is provided, he explains.
The confidentiality and security of genetic information are also important to ensure that genetic knowledge does not negatively affect participants' ability to get health or life insurance, or to remain employed, says Dr. Benatar.
Future Benefits
Because these studies typically don't offer access to a potentially promising drug, and because they go on for a long time, participating is truly altruistic, says Dr. Conwit. "People who join these trials are helping society, helping other people, and helping to get answers."
Dr. Conwit says the studies are absolutely crucial. "Researchers may find potential targets for future biomarkers, and [they may] find a new treatment or understand the natural history of the disease."
The benefits definitely outweigh the downsides, says Dr. Nopoulos, who is developing a possible gene therapy for Huntington's. Clinical trials may reveal treatments that could be used before children mature to the age at which commonly known signs of Huntington's disease develop. "Do you give them an opportunity for a normal life-even before their disease starts—the opportunity to get in the trial and [potentially] not get that disease? The potential prize is so huge, it minimizes the risk."
And then there's a practical side. "For diseases that involve neurodegeneration, early-stage clinical trials are the way to go," says Dr. Hendrix of the Alzheimer's Association. While there is no assurance that those who participate in these early-stage trials will ever benefit, there is a possibility that they or their family members, or others, will. As Dr. Hendrix notes, "Prevention is easier than repair."
