Congestion and chaos on the brain’s highways: this is neurodegeneration
The human brain is magnificently elaborate. It is thought to contain 86 billion neurons interconnected by several trillions of synapses that process and transmit information about pleasure, pain, emotion and movement, and form memories. When neurons fail, as they do in neurodegenerative diseases like Alzheimer’s disease and amyotrophic lateral sclerosis (ALS), those connections collapse and information-processing stops. For the most part, these diseases progress slowly and remain hidden for years. By diagnosis, they have taken hold of the neurons and begun dismantling them.
Clinicians would prefer to diagnose neurodegenerative diseases before they wreak havoc, but much of their neurobiological basis remains unknown. To that end, scientists at Sunnybrook Research Institute (SRI) are pulling at the threads of neurodegenerative diseases to understand their origins and progression, and uncover ways of changing their course.
The signature of many neurodegenerative diseases is the accumulation of abnormal proteins in the brain. Healthy neurons produce lots of beta-amyloid, but clearing this toxic protein becomes troublesome with age. In the early stages of Alzheimer’s disease these proteins form clumps, contributing to the demise of nearby neurons. In ALS, which has beset notable figures including the physicist Stephen Hawking and New York Yankees Hall of Famer Lou Gehrig, misfolded proteins accumulate in the brain and spinal cord.
Dementia comes in several forms; Alzheimer’s disease is the most common. Short-term memory loss is frequent in its earliest stages. As it advances, people become disoriented and experience mood changes. They have trouble planning and organizing, and may struggle to find words. The World Alzheimer Report 2010 predicts the number of people with dementia will double every 20 years, rising to 65.7 million in 2030.
Plaques and tangled neurons are the hallmarks of Alzheimer’s disease, but there are also almost always flaws in the brain’s blood vessels. These failings occur in the small vessels in the cortex, the brain’s outermost layer, also called the grey matter, and in those vessels that plunge from the surface into the white matter to nourish the deepest areas of the brain. The blood vessels feed the brain with oxygen, glucose and other nutrients; channels along the vessel walls gather up and dispose of waste and debris. The brain’s vasculature has thus become a priority for scientists interested in the origins and progression of Alzheimer’s disease.
Dr. Bojana Stefanovic, a biomedical engineer in the Brain Sciences Research Program at SRI, wanted to understand the relationship between beta-amyloid accumulation and the brain’s blood vessels in Alzheimer’s disease. In collaboration with Dr. JoAnne McLaurin at the University of Toronto, she used a preclinical model of the disease, a genetically engineered mouse with an aggressive and early onset of amyloid deposition in the cortex. Working with a microscope that uses a laser to illuminate fluorescent dyes injected into the mouse, they were able to watch the changes in the individual blood vessels as they failed.
The more beta-amyloid on a vessel, the more tortuous and narrow it becomes.
In 2012, Stefanovic and her colleagues published the results of their study in the journal Brain. They found that as the beta-amyloid accumulates around the neurons and blood vessels, the arterioles traversing the cortex become misshapen—twisting and coiling within the tissue. The more beta-amyloid on a vessel, the more tortuous and narrow it becomes. Stefanovic also found that these changes to the arterioles undermined their function. They didn’t react to carbon dioxide, a potent vasodilator, as normal arterioles do by widening and increasing blood flow to the tissue.
“You used to have this straight highway through the brain, and now you’re left with a curvy country road,” says Stefanovic. “The delivery of nutrients and the dumping of debris, or metabolic waste, becomes less efficient.” The findings offer evidence of the disease’s early stages and how vascular changes might prime the brain for neurodegeneration.
Beneath the cortex lies white matter, containing glial cells that provide support and protection for the brain’s neurons, and myelinated axons that transmit signals from one part of the brain to another. Dr. Sandra Black, director of the Brain Sciences Research Program at SRI, and Dr. Brad MacIntosh, a medical biophysicist in the program, have been using imaging technologies to probe the brain’s white matter for clues about the early signs of dementia.
Bright spots and patches sometimes show up within the white matter on certain types of magnetic resonance imaging (MRI) brain scans called T2-weighted MRI images. The spots, called white matter hyperintensities (WMH), can be little holes in the brain resulting from blockage due to twisting or hardening of artery walls. The patches develop from leakage of blood plasma into the brain due to hardening of the deep veins. They are seen in normal aging brains, but can also be associated with a higher risk of stroke, dementia and death. They are like dry patches in a lawn that doesn’t get enough water. “It’s not a specific sign, but it’s telling of an overarching problem and a sign of future risk,” MacIntosh says.
In 2013, he and Black, along with Ilia Makedonov, a graduate student at U of T, published a study in the European Journal of Neurology comparing the blood flow near WMH in older adults with and without Alzheimer’s disease. They found that blood didn’t flow through these regions as readily as it did in the normal-appearing white matter, and that adults with Alzheimer’s disease were more likely to have WMH in the tissue near the ventricles, the large cavities deep in the brain that produce cerebrospinal fluid.
Blood pulses through the brain in synch with the heartbeat. As it does, it sends vibrations through the brain tissue like the ripples that radiate outward after a stone is dropped into water. “Your brain is like Jell-O—every heartbeat, it jiggles around a little bit, but not a lot. Too much is not a good thing,” says MacIntosh.
Recently, scientists have found that changes in the brain’s pulsatility can be a useful marker for some diseases. In a study published in PLOS One, Black, MacIntosh and Makedonov used a brain imaging technique called BOLD functional MRI that measures blood flow and oxygen uptake by brain tissue to show that the pulsatility of normal-looking white matter was dramatically higher in people with damaged cerebral blood vessels (a condition called small vessel disease) compared with age-matched healthy controls. They think the brain’s deep veins may harden in response to lower oxygen levels, causing plasma leakage and difficulty clearing amyloid from the brain.
“The work we’re doing is opening the world’s eyes to the venous side of the brain’s circulation, and how changes that go on with aging can contribute to the acceleration of Alzheimer’s disease,” says Black. A brain with scarred blood vessels or clogged spaces around the vessels can have trouble clearing debris and waste, including accumulated proteins. “There’s an important system in the brain to get rid of garbage, but this has only come to light recently,” says Black. “The garbage truck can’t go into a neighbourhood if a whole lot of streets are blocked.”
The research shows there are strong links between cerebrovascular disease and Alzheimer’s disease. The risk factors associated with white matter disease include hypertension, high cholesterol, smoking, unhealthy diet and lack of exercise, so intervention may be possible. For MacIntosh the next step is to see if exercise can benefit people at risk of developing WMH. “Exercise may not impact directly the hypoxic zone, but it may help everything else around it and buy people time,” he says.
Amyotrophic lateral sclerosis is another age-related neurodegenerative disease. It is marked by the death of motor neurons in the central nervous system. The first signs are often muscle weakness and atrophy, usually in the legs and arms. People with it may suddenly feel awkward when they run or walk, or trip or stumble. They might find buttoning a shirt or turning a key in lock challenging.
“It’s a devastating disease. People have total insight and just watch themselves become weaker and weaker,” says Dr. Lorne Zinman, a neurologist and the director of the ALS Clinic at Sunnybrook. On average, two new cases are diagnosed for every 100,000 people per year. About 3,000 Canadians live with the disease. With no cure, most people with ALS survive two to five years after they begin to show symptoms.
Sometimes to decipher a disease you need to start from scratch. When Zinman began his academic career about a decade ago, he was disappointed by the lack of clinical trials to test promising therapies available to Canadians with ALS. “I used to tell my patients that they would have to go to New York or Boston to get into a clinical trial,” he says.
In 2008, he founded the Canadian ALS Research Network to link the 15 academic ALS clinics across Canada. The network promotes multicentre ALS studies in Canada with the help of a patient registry, established in late 2010. The registry allows researchers to identify Canadian ALS trends and Canadian ALS patients to participate in clinical trials, by logging information about people’s genetics, symptoms, risk factors and medications. “A principal barrier to doing a trial is recruitment,” says Zinman. When the registry launched, researchers submitted the details of more than 1,700 individuals, 25% more cases than expected.
The registry will help researchers share blood and tissue samples from people with ALS so that they can better understand the disease and find genetic mutations associated with its inherited form. About 10% of ALS cases have a familial link. Recently, an international group of researchers, including Zinman, published a study in Nature Neuroscience detailing the discovery of mutations in a newly identified gene called Matrin 3 that causes an inherited form of ALS. In 2011, Zinman’s research team had helped identify a mutation on chromosome 9 that is found in one-third of people with familial ALS. Mapping these genes gives scientists a better understanding of the biological pathways that cause ALS and provide novel targets for intervention. “This is information we need to have so that we can start designing treatments to test in patients,” says Zinman.
The registry has already helped Canadian ALS patients enrol in large, international clinical trials. Two additional industry trials are underway in Canada, and the network will lead a Phase 2 trial in late 2014 to test a plant extract compound that has slowed ALS progression in preclinical studies. “We’re aiming to enroll 100 patients across Canada to determine if this compound can also slow disease progression in our patients,” says Zinman. “It’s something we’re really excited about.”
Research Funding & Other Information
Black: Alzheimer Society of Canada, Canada Foundation for Innovation (CFI), Canadian Institutes of Health Research (CIHR), Heart and Stroke Foundation Canadian Partnership for Stroke Recovery (CPSR), LC Campbell Foundation, and the Ontario Ministry of Research and Innovation (MRI). MacIntosh: CIHR, CPSR, and Natural Sciences and Engineering Research Council. Stefanovic: CFI, CIHR and MRI. Zinman: ALS Society of Canada, CIHR and Temerty Family Foundation. Black and Zinman are faculty within the department of medicine (neurology) at the University of Toronto; MacIntosh and Stefanovic, the department of medical biophysics.