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No cure

And few—or no—treatments for these devastating brain diseases: Why not?

Dr. Lorne Zinman and Dr. Agessandro Abrahao

Dr. Lorne Zinman (left) and Dr. Agessandro Abrahao say a deeper understanding of ALS is needed to stop it, and for that, biomarkers are needed.

Medical advances have drastically changed the health landscape. Vaccines and antibiotics have wiped from memory once deadly and debilitating diseases like smallpox and polio. Antiretroviral therapies and insulin have transformed AIDS and diabetes from a death sentence to manageable chronic conditions. Despite these leaps, there remain diseases for which a cure—and indeed, effective treatment—remains elusive. Many of these originate in and affect the brain, the body’s most complex and enigmatic organ. Why are we not further ahead? The answers are as complicated as the diseases themselves.

Take amyotrophic lateral sclerosis (ALS), a rapidly progressing neurodegenerative disease in which the nerve cells that control muscles, known as motor neurons, die. “ALS is arguably one of the worst diseases humans have known because you are witness to your body’s decay,” says Dr. Lorne Zinman, a neurologist who directs the ALS clinic at Sunnybrook and is an associate scientist in the Hurvitz Brain Sciences Research Program at Sunnybrook Research Institute (SRI). “You become trapped inside your own body. In most cases, your mind is relatively intact, but you get progressively weaker.” Most patients succumb to the disease two to five years after diagnosis. “Why is this happening?” asks Zinman. “The main gap is an incomplete understanding of the disease pathophysiology. How can you fix a disease if you don’t really understand why it starts and how it progresses?”

Significant progress, including by Zinman, has been made in uncovering the genes responsible for the hereditary type of ALS. Researchers can now identify between 60% and 70% of the genetic alterations that lead to familial ALS. They are studying these mutations in preclinical models to elucidate how they contribute to motor neuron death. The familial variant, however, only accounts for 10% of ALS patients—the remaining 90% develop the condition sporadically, often without any of the previously described genetic aberrations.

“The disease is incredibly heterogeneous,” says Zinman, speaking to its diverse biological origins. This variation represents one of the biggest obstacles to finding an effective treatment. Drug trials tend to lump all patients together—familial cases with sporadic ones. As he notes, it would be simplistic to expect that a single drug would benefit all these patients irrespective of the underlying disease mechanism. The inherent diversity of ALS explains, in part, why human drug trials have failed despite promising results at earlier stages, where testing is typically done in a single, uniform, preclinical model. Without biomarkers of drug activity, however—a characteristic of one’s biology that can be quantified, like the presence of a gene or a protein—it is difficult to pinpoint why a drug was unsuccessful.

In 2014, Zinman and collaborators published the results of a Phase 3 randomized controlled trial examining the safety and efficacy of the antibiotic ceftriaxone for ALS. The drug seemed to slow the progression of symptoms in earlier studies, but had no benefit in the Phase 3 trial. “Over a decade of development, the drug demonstrated safety in Phase 1, showed promise in Phase 2, and sadly, it failed in a large Phase 3 trial.” A trial can fail for many reasons. The medication may not have engaged the target of interest, or perhaps the drug only works in a subset of patients, say, those with a specific mutation; in a mixed-patient population any benefit would be masked. Without a reliable biomarker in ALS, the researchers were unable to determine which of these reasons contributed to their failed study.

It's kind of like playing darts with a blindfold on.

“It’s kind of like playing darts with a blindfold on,” says Zinman, who is also an associate professor of medicine at the University of Toronto. “When you’re playing without a blindfold, you know how far you are from the target and can recalibrate. With a blindfold, you can’t correct your errors. That’s the biggest problem in proceeding without a biomarker in an ALS trial.”

He is partnering with researchers across Canada to look for and validate MRI biomarkers in patients with ALS. These features, which would be visible on an MRI scan, would enable objective and accurate measurements of brain degeneration. A reliable biomarker would also allow researchers like Zinman to observe directly what effects, if any, a treatment has on neurological function in clinical trials. He is leading two such trials to determine whether the herbal remedy ashwagandha and the antipsychotic drug pimozide can slow disease progression as they did in ALS preclinical models. A third study poised to start will examine the safety of using low-intensity focused ultrasound to open the blood-brain barrier of the motor cortex safely—a world first. The motor cortex controls voluntary movements; it is the brain region affected by ALS. The ultimate goal of the study, led by Zinman and his neurology fellow Dr. Agessandro Abrahao, is to deliver stem cells or viral vectors carrying neurotrophic factors to the targeted area where they might protect damaged motor neurons and prevent further deterioration.

As founder and head of the Canadian ALS Research Network, Zinman points out that collaboration is the best hope for progress. “This disease is so complicated, it’s not going to be untangled by one person,” he says.

Dr. Richard Aviv, an affiliate scientist in the Hurvitz Brain Sciences Research Program at SRI and a neuroradiologist at Sunnybrook, feels similarly about his field. He is combining his expertise in MRI and computed tomography (CT) with the knowledge of his neurology colleagues to tackle intracerebral hemorrhage (ICH), a catastrophic event that accounts for 15% of all strokes, but 30% of all stroke deaths. An ICH occurs when a blood vessel ruptures in the brain and blood pools to form a hematoma. If the bleed is not stopped, then the hematoma continues to expand and exert pressure on surrounding tissues, killing brain cells. Roughly one-half of patients who suffer an ICH do not survive. Depending on the location of the hematoma and the extent of the damage, those lucky enough to pull through can face long-lasting consequences, such as paralysis, vision loss and personality changes. “It is the deadliest, most disabling and least treatable type of stroke,” says Dr. David Gladstone, a scientist in the Hurvitz Brain Sciences Research Program at SRI and stroke neurologist at Sunnybrook. “We desperately need to develop effective and safe treatments that can stop bleeding in its tracks and prevent brain hemorrhages from enlarging to a critical, life-threatening size.”

Alzheimer's disease should be recognized as a cause of stroke.

Gladstone and Aviv recently reported the findings of joint research between their Canadian SPOTLIGHT study, of which they are co-principal investigators, and the American STOP-IT study. Both studies tested whether a blood-clotting drug called recombinant activated coagulation factor VII (rVIIa) could reduce hemorrhage expansion and improve outcomes in patients with ICH. “Up to 30% of patients undergo expansion, which is a major determinant of bad outcome,” says Aviv. “We can’t do anything about the initial bleed, but if we can prevent hematoma expansion, that would significantly improve outcomes.”

Dr. Richard Aviv and Dr. David Gladstone

Dr. Richard Aviv (left) and Dr. David Gladstone say time is of the essence when it comes to treating intracerebral hemorrhage, and trials need to figure out how to get treatment to patients sooner.

The initiative involving 26 hospitals, led by Gladstone and Aviv with colleagues in Calgary and Cincinnati, built upon Aviv’s discovery of the spot sign, a bright white spot visible on a CT scan of the blood vessels that predicts hematoma growth. All of the patients enrolled in the SPOTLIGHT and STOP-IT studies had the spot sign, meaning that their hematomas were actively expanding, and were assigned to receive emergency treatment with either rVIIa or a placebo. Despite promising results from earlier studies, the results from this trial were disappointing. Patients in both groups saw their bleeds increase in volume over 24 hours. There was no significant difference in final hematoma size between the groups. Nor did they differ in clinical outcomes at three months. “It underscores how very difficult this condition is to treat,” says Gladstone. More positively, the researchers also tracked a cohort of ICH patients who were spot sign-negative and found that they had a better prognosis than those with the spot sign. “The optimistic side of the results is that they confirmed the spot sign as a potent predictor of hematoma expansion,” says Aviv, who is also a full professor in the department of medical imaging at U of T.

They believe the treatment didn’t work because patients got the drug on average three hours after stroke onset. “By that time, most of the hemorrhage expansion in our patients had occurred,” says Gladstone, who is also an associate professor of medicine at U of T. “This research will push future trials to find ways to deliver this type of treatment to patients earlier,” he says. With emerging technologies, including ambulances equipped with CT scanners, the researchers foresee patients being diagnosed and treated before they get to hospital, for example.

Aviv notes that these studies also helped him to appreciate the spot sign isn’t just a binary indicator of whether or not a bleed will expand; it can also represent different rates of bleeding. He is testing this hypothesis in preclinical models he developed to determine if certain drugs work better against slow- versus fast-growing hematomas. “If you’re gushing blood rapidly, a drug is never going to get in fast enough to work,” he says. “But if you’re bleeding slower, maybe there’s a threshold that we can measure clinically that will determine if you can be treated with these drugs.”

The most common cause of ICH is high blood pressure. “We have made huge progress in [preventing] ICH that are related to hypertension,” says Dr. Sandra Black, director of the Hurvitz Brain Sciences Research Program at SRI. As a neurologist who specializes in cognitive impairment and dementias like Alzheimer’s disease (AD), she studies how amyloid contributes to disease pathology. She is developing better strategies for detecting and targeting amyloid in the brain. Amyloids are protein fragments that clump together to form plaques in the brain. They are most often associated with AD, where they are believed to have a causal role, and can be detected with positron emission tomography (PET).

Less well known is amyloid’s involvement in strokes like ICH. Amyloid angiopathy develops when the toxic protein is deposited along blood vessels in the brain. While this build-up typically increases with age, it is also considered a hallmark of AD, where patients produce too much amyloid or have trouble clearing it from the brain. Unlike hypertension-related ICH, brain bleeds caused by amyloid angiopathy are subtle. They often start out as asymptomatic microbleeds caused when amyloid doesn’t clear properly from the brain but instead accumulates and penetrates the arterial wall, causing tiny breaches and blood cells to leak out into the brain, where they show up as small black spots or streaks on an MRI scan. Sometimes, however, such bleeding can gradually or quickly get larger and cause brain damage.

“Alzheimer’s disease should be recognized as a cause of stroke,” says Black. “Amyloid pathology along the vessels walls can cause hemorrhagic stroke, which can be the first manifestation of AD. That’s totally off the radar, something that people are not aware of.” She is developing strategies to detect and treat amyloid earlier, before devastating consequences—ICH and dementia—occur. In one study, her team is looking at whether amyloid in the retina of the eye or possibly the lens correlates with its presence in the brain and, if so, if it can be observed in the eye before it is detectable in the brain. “If this works out, then you could be checked at your ophthalmologist,” she says. “It would be like having a routine mammogram or colonoscopy.”

Dr. Sandra Black

Dr. Sandra Black says amyloid protein in the brain can cause catastrophic stroke, a mechanism of which many people are unaware. She also notes that such strokes can be the first sign of dementia.

Black is also leading trials to slow the neurodegeneration associated with AD before it begins or reaches an untreatable stage. One trial in AD patients with hypertension is comparing the effectiveness of two anti-hypertensive medications in slowing brain atrophy, where brain cells and tissues waste away. While these drugs are good at lowering blood pressure and protecting the heart, some might have an edge in the brain because they can stimulate uptake of glucose and breakdown of amyloid. Another, the A4 study, is recruiting people from sites across North America and Australia who have no outward signs of AD but detectable deposits of brain amyloid on a PET scan. These people receive either an anti-amyloid antibody or a placebo, with the aim of preventing memory loss.

Given that recent attempts at slowing progression in AD have failed, Black suggests disease stage might be to blame. “It might be too little, too late,” she says. When it comes to ICH, she notes that a history of microbleeds makes it even tougher. “We’ve seen people with over 100 microbleeds. Well, how are you going to deal with that?” One answer is a usual one: more research, especially studies over time to track how the disease progresses. Another is awareness—avoiding drugs or doing things that increase the odds of more bleeding. “It is a terrifying disease, because when you have a brain hemorrhage from amyloid angiopathy, you are at high risk of having another one,” she says. “It’s one of those diseases where there’s a continual worry, and you feel badly for people affected because they know that, and there’s nothing we can do—except to tell them to avoid the things that make you more likely to bleed.”

Against this dark backdrop, seeking out effective therapies for such challenging diseases is not for the fainthearted. “You have to have patience, stamina and determination,” says Black. Critically, even unsuccessful trials are, as Gladstone puts it, “one small step toward future treatment.”

Research Funding

Aviv: Canadian Institutes of Health Research (CIHR). Black: Alzheimer’s Drug Discovery Foundation, Avid Pharmaceutical, Brain Canada, CIHR, GE Healthcare, National Institutes of Health and Ontario Brain Institute. She holds the Deborah Ivy Christian Brill Chair in Neurology at U of T. Gladstone: Heart and Stroke Foundation of Canada. SPOTLIGHT trial (Aviv and Gladstone): CIHR, Ontario Ministry of Research, Innovation and Science, and Ontario Stroke Network. Zinman: ALS Society of Canada, Ontario Brain Institute and Temerty Family Foundation.