The race to find ‘biomarkers’ that can predict dementia
by Kate Allen for The Star:
In a laboratory on the south side of town one August afternoon, a man names animals as he paces down a walkway; Aardvark. Bear. Camel. Dog. Giraffe. That same afternoon in a lab on the north side of town, a graduate student is poring over data generated by a rare seven-tesla MRI. The brain imaging machine is the most powerful of its kind in Canada, and one of fewer than 60 in the world.
The south-side lab belongs to Manuel Montero Odasso, a geriatrician who studies gait and mobility. The north-side lab belongs to Robert Bartha, a physicist who works with cutting-edge imaging technology. But both researchers — and countless others around the world — are in pursuit of the same thing: dementia “biomarkers,” bodily clues that could predict the existence of the brain disorder years before its worst symptoms take hold.
That two scientists in the same city could be taking such divergent approaches speaks to the sheer challenge involved. Dementia affects nearly 50 million people worldwide, yet there is no single positive-or-negative test for it, only a combination of exams that support a diagnosis.
Biomarker research could provide more certainty for patients. But it could also bring more grief: should doctors tell patients their minds will one day unravel if there is no treatment? Decades of drug trials have failed to cure the disease.
“If tomorrow I could diagnose someone with Alzheimer’s disease five years before they got the symptoms, that would be a huge victory for us in terms of diagnosis. But the bottom line is we don’t have an effective treatment,” says Bartha.
Yet many researchers also believe that the best hope for a dementia drug is to intervene before memory problems become apparent. By the time symptoms are obvious, the brain is already ravaged. To peer inside the brain earlier — figuratively or literally — we need biomarkers.
“Maybe if you give (treatment) before the symptoms are full blown and the brain is already deteriorated, you’ll be able to postpone the disease significantly or change the course altogether,” says Bartha. “So having that biomarker that identifies people early is critical to defining new drugs and evaluating whether or not they’re going to be effective.”
Tim Costello, the 72-year-old man listing animals as he walks, is part of a study led by Montero Odasso that has been running since 2007 at London’s Parkwood Institute, involving 150 participants. The subjects, who have mild cognitive impairment — a diagnosis that sometimes leads to full-blown Alzheimer’s and sometimes doesn’t — return to the lab every six months to repeat the same series of tests.
They walk down a sensor-filled pathway as they undertake a series of cognitively demanding tasks. They count backwards from 100 by ones, and then by sevens. They list as many animals as they can. They balance on a platform. A computer records tiny variances in their gait and balance.
Normal adults slow down if they attempt cognitively demanding tasks while walking. But Montero Odasso has found that patients with cognitive impairment slow down more, and their gait becomes more uneven. If a simple walking test could predict who among the cognitively impaired will advance to more serious dementia, it would have immediate benefits — especially because other targets for biomarker research, such as spinal fluid, are invasive or expensive to obtain.
With gait analysis, “You can do it any time, anyplace,” says Montero Odasso, who is also a clinician-scientist at Western University.
The research also raises fascinating questions about our species, since bipedalism and brain expansion were both crucial adaptations in the evolution of Homo sapiens. In fact, many believe they were linked: that walking upright was necessary to develop bigger, more sophisticated brains. Other mammals, such as cats, can walk in a straight line even without a functioning cortex. But in humans, important aspects of cognition like attention and memory share the same brain circuits that control gait and navigation.
In Bartha’s lab at Western University’s Robarts Research Institute, multiple experiments are underway. But perhaps the most exciting is a collaboration among biophysicists, cell biologists, chemists and others at the multidisciplinary institute: the team is trying to develop injectable chemical tracers that would cling to early imbalances in the dementia-damaged brain and light up under an MRI scan.
“They would kind of hunt out and stick to pathological changes associated with Alzheimer’s disease,” says Bartha. “It’s not something we’re actually doing in people yet — we’re still in the animal phase of testing — but it’s really a neat idea, and I think that’s the big future for imaging.”
Researchers already use a type of imager known as PET to scan for abnormal brain proteins linked to dementia, but in the context of clinical trials and other research — not as a diagnostic tool. PET systems are also rare, requiring long waits.
“In terms of getting this out to people, they wouldn’t have to wait a year or two for a scan. MRI is much more accessible, and it’s much cheaper than PET,” says Bartha. MRI is also a more flexible tool. “We can take really nice pictures, but we can also look at how the brain is functioning; we can do a memory test while someone is in the scanner.”
Montero Odasso and Bartha both see their own approach as the future. But they do not see themselves in competition: in fact, the participants in Montero Odasso’s trial undergo MRIs in Bartha’s lab, and both lead teams in the Canadian Consortium on Neurodegeneration in Aging, a massive research network that aims to promote collaboration among top scientists and lead to transformative results.
Biomarkers: where else are researchers looking?
Saliva: University of Alberta research presented at the Alzheimer’s Association International Conference in July showed that in a small sample of diseased and non-diseased patients, those with dementia had different patterns of certain substances that are the byproducts of metabolism. The evidence is very preliminary, but presents a tantalizing opportunity if it can be validated, because saliva is so easy to obtain.
Cerebrospinal fluid: Research has suggested that those with dementia have different levels of amyloid and tau, two abnormal proteins linked to Alzheimer’s, in their cerebrospinal fluid, the clear fluid that protects the brain and spinal cord. Other proteins indicative of damage to the brain’s synapses, such as one called neurogranin, are also being probed.
Blood: Researchers are also investigating whether abnormal levels of proteins can be detected in blood — a bodily fluid that is much easier to obtain and much more cost-effective, but still more invasive than other techniques.
Eye: Researchers with the Ontario Neurodegenerative Disease Research Initiative are investigating eye movement as a potential biomarker, since some patterns, such as jumping between objects passing by a car window, are linked to the brain’s frontal lobe, where early damage occurs in Alzheimer’s and other neurodegenerative diseases. The researchers are also examining how nerve fibres and blood vessels change over time in the eyes of dementia patients. Research elsewhere has suggested that amyloid and tau can be detected in dementia sufferer’s eye lenses.
Brain: Since dementia is a neurodegenerative disorder, naturally, researchers are investigating many different biomarkers in the brain, including the presence of inflammation, evidence of altered proteins and simple brain size.
Source: http://on.thestar.com/1T83r1P