Alzheimer's disease, a devastating neurodegenerative disorder, is a challenge to treat effectively. Often, as quickly as within a year, individuals who were once spry and engaged become husks of their former selves, unable to remember, reason or perform even the most basic tasks. Unfortunately, once behavioral symptoms are present-when the disorder is most diagnosable-irreversible damage to the brain has already occurred. Today, scientists and clinicians are looking to the pre-clinical stages of the disease for potential prevention and treatment opportunities. This year, at the Nantz National Alzheimer Center's Third Annual Alzheimer Symposium at the Houston Methodist Neurological Institute, Alzheimer experts from around the world convened to discuss the important role that neuroimaging will play in discovering those opportunities.
Understanding the pre-clinical stage
It was not all that long ago that an Alzheimer's disease diagnosis could only be confirmed by autopsy. In his welcoming statements at the symposium, moderator Joseph Masdeu, head of Integrative Neuroimaging at the National Institutes of Health, said that neuropathology has given us a lot of information about the long-term effects of the disease but it's way too late to help the patient. The advent of neuroimaging techniques has given doctors a window into the brain-the ability to view not only the disease's neuropathology at advanced stages but also the various biomarkers that precede it by decades. For many years, amyloid beta, a protein that forms the disease's tell-tale plaques, was thought to be the sole culprit behind the disease's neural devastation. But Gaël Chetélat, an Alzheimer's researcher from France's Université de Caen/Basse-Normandie who presented her research at the symposium, reports that the scientific community is learning that there are many factors involved.
"Alzheimer's pathology is not just amyloid. And amyloid is probably not the only thing causing cognitive impairment. We see many other factors," says Chetélat. "We need to understand the biological sequence of events and all the biological targets we need to engage with in order to stop the progression of the damage. Neuroimaging can help us do that."
Researchers presented evidence that, besides increased amyloid beta load, the pre-clinical stage of Alzheimer's disease includes increased tau protein, changes to metabolic activity, changes to synaptic connections, and even changes to serotonin receptor densities across various brain areas. Kejal Katarci, a presenter from the Mayo Clinic, says that advanced neuroimaging techniques can help researchers determine how all these factors may be related and which may have causal relationships. Taken together, this can help researchers identify opportunities to intervene early.
"The pathology starts very early, decades before you see any cognitive impairment. Our study showed there was a period of 15 years between us seeing some of these markers and the onset of Alzheimer's disease," she says. "That presents a very large therapeutic window."
Not your Mama's neuroimaging techniques
Masdeu says that when many people hear the term neuroimaging, they think of old-fashioned anatomical or structural scans. He says that today's neuroimaging techniques are more sophisticated, and can build a bridge between the bench and the bedside.
"We now have molecular neuroimaging which can help us go back and forth between the data obtained in animal models and the experimental data observed in humans. It allows us to really qualify the questions we are asking about how and when Alzheimer's changes the brain," he says. "For instance, a technique called positron emission tomography-fludeoxyglucose (PET-FDG) lets us look at metabolic activity in the brain. We have imaging tools that can target proteins implicated in amyloid beta and tau, two proteins that are abnormal in Alzheimer's disease. The techniques are evolving."
For example, John Detre, director of the Center for Functional Neuroimaging at the University of Pennsylvania, presented data on a new magnetic resonance imaging (MRI) technique called arterial spin labeling (ASL). ASL uses magnetically labeled water as a diffusible tracer, measuring cerebral blood flow like the more common MRI blood oxygen level dependent (BOLD) technique. It is less invasive than PET techniques, shows less noise in the signal than traditional MRI, and is versatile enough to measure changes in metabolism, neuronal loss, and protein levels-all of which are affected in Alzheimer's disease.
"It's a very exciting time in neuroimaging," says Masdeu. "These techniques can help us learn more about the pre-symptomatic stage of the disease, to look closely at what is happening with the neurobiology, not just in the hippocampus but across the whole brain."
Another benefit of neuroimaging is the ability to look at the brains of patients over time. Masdeu says neuroimaging is the ideal technique to follow many of these biomarkers longitudinally.
"Previously, we could only look at something like amyloid beta by doing a biopsy. This was not only very invasive but it only gave us information on a very small part of the brain. It precluded any kind of longitudinal study," he says. "But now we can use imaging to look at the brain when a patient is 45 and again at 50 and then again at 60 and see what is happening with any of these biomarkers at each point."
Chetélat adds that longitudinal studies also will help researchers better understand the relationships between markers. "There seem to be many different pathologies happening in parallel. So if we see, over time, that amyloid deposition is there before neural degeneration, then we can act against that amyloid maybe in very early stages and stop that. If we see that there are partly independent processes occurring, then it may not make sense to act on just one. And we may see different contributions of these pathologies, perhaps additive, perhaps linear, over different points in time."
Masdeu's goal for the symposium was simple: to raise awareness of the presymptomatic stage of Alzheimer's and how neuroimaging can help better illuminate what is going awry before the damage is too far along to treat. He is very enthusiastic about what the next few years will bring to our understanding of the disorder's etiology. "Our goal is to one day cure Alzheimer's disease. We know now that once the nerve cells have been killed, it's too late," he says. "If we can prevent it, however, we can make a difference. And more and more, through the use of these kinds of novel imaging studies, it seems that prevention is close at hand."