Key Points
- Dr. Black is a world-renowned neurologist who is investigating Alzheimer’s and dementia treatment from multiple angles.
- She is an expert on the relationship between the brain’s microvasculature and dementia.
- Dr. Black explains why some neurologists are hesitant about opening the blood-brain barrier.
In the Foundation’s September 2022 Alzheimer’s Webinar, the featured speaker was Sandra Black, OC, O.Ont., MD, FRSC, a renowned neurologist, senior scientist, and the director of the Dr. Sandra Black Centre for Brain Resilience & Recovery at Sunnybrook Research Institute in Toronto.
Dr. Black is a world expert in dementia who is investigating Alzheimer’s and dementia treatment from multiple angles by investigating the molecular biology of the brain, brain cell imaging, drug and biological therapies, and interventional strategies like focused ultrasound. She has spent much of her career uncovering the relationship between the brain’s microvasculature and dementia. Dr. Black has been an enrollment site investigator for numerous clinical trials for Alzheimer’s Disease, including several current trials involving antiamyloid antibodies. She has also led many investigator-driven trials and observational trials in Alzheimer’s and other dementias, including amyloid PET in large amyloid imaging clinical trials in Alzheimer’s and Parkinson’s-Lewy Body Spectrum disorders and in people with moderate to severe cerebral white matter disease.
Beyond her clinical practice, Dr. Black has given countless hours to organizations such as the Toronto Dementia Research Alliance, the Ontario Neurodegenerative Research Initiative, the Canadian Consortium for Neurodegeneration and Aging, the Alzheimer’s Association International Society to Advance Alzheimer Research, the International Society for Vascular Behavioural and Cognitive Disorders, the Alzheimer’s Disease Neuroimaging Initiative, and the Ontario Stroke Network.
We interviewed Dr. Black to learn about her work as a member of Sunnybrook’s focused ultrasound team that treats patients with essential tremor, Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and more.
How did you first learn about focused ultrasound?
I was lucky to have had this bright young neurosurgeon, Nir Lipsman, arrive at our institution. Not only brilliant, but he also has tremendous integrity, ambition, and discipline. It has been a pleasure to work with Dr. Lipsman at Sunnybrook’s Harquail Centre for Neuromodulation. The center is doing many types of ablation interventions and opening the blood-brain barrier (BBB).
How did you get involved with the focused ultrasound group?
My involvement came when Nir approached me and asked me to be a co-principal investigator (PI) for a BBB opening trial for Alzheimer’s Disease. I did so with some trepidation, because most of my neurology colleagues think opening the BBB is absolutely crazy – and likely dangerous. I have always been open to new ideas and innovation and had trust in Nir’s acumen and integrity. In Canada, we do not get reimbursement for research, so the department must decide if a project is worthy enough for protected time. Neurology is within the Department of Medicine, which has resources to protect time for research, so I got involved. We assess the focused ultrasound patients and support the neurosurgery department’s efforts to use focused ultrasound for multiple BBB openings. Our offices are in the same hospital building where the neurosurgery team performs essential tremor treatments, so our whole team is all in the same place.
Why are some neurologists hesitant about BBB opening?
In my opinion, we neurologists tend to be on the conservative side. Some neurologists think that disrupting the BBB lets bad proteins (like fibrinogen) into the brain – like a funnel leaking into the brain. They are especially concerned about this leakage for vulnerable people with Alzheimer’s disease and brain tumors. They think that opening the BBB has the potential to cause problems. But at Sunnybrook, we are focusing on diseases with the greatest vulnerability because they are worthy of investigation despite the risk. I think that the BBB is already leaking. It is already happening slowly, and some people just develop the disease earlier. We need to collect more evidence to convince the neurologists about the benefits of using focused ultrasound to disrupt the BBB.
What is the outlook for treating people with Alzheimer’s disease?
People with Alzheimer’s disease are generally treated by cognitive neurologists or geriatric specialists. The numbers are frightening. Right now, people over 65 are starting to outnumber the people who are under 15 in Canada, creating a real top heavy future problem for the next generation. Focused ultrasound provides a little beacon of hope that there will be new approaches for removing amyloid and providing neural modulation to restore some connectivity.
How has the diagnosis of Alzheimer’s disease advanced over the years?
In the 1990s, when we started to have MRI more available, the radiologists came up with a quantitative protocol to image cerebrospinal fluid and white matter disease. We adopted these new sequences for the Sunnybrook dementia study. I have had the pleasure of seeing the evolution of the diagnosis of neurodegenerative diseases with imaging. Now there is more awareness of the anatomy and the pathology of diseases like Alzheimer’s, other white matter disease, and stroke. We were fortunate to have neurophysiologists to collect data and neuropathology studies to allow us to unlock the mysteries of white matter disease. We have learned a lot about amyloid removal with antibodies and the complications of these new antibodies.
How has your research on white matter disease advanced the field?
My research has been focused on the connection between blood supply and white matter disease. We learned that most people over the age of 65 have some degree of white matter spots. With improvements in treatment and prevention of heart disease and stroke, that percentage has been coming down. This fact is important to consider when trying to decide whether a patient is suitable for one of the Alzheimer’s clinical trials. Some patients have a disease blood supply in the deep parts of the brain; others accumulate amyloid from birth. Sleep processes are extremely important for brain health, as are physical activity and proper diet. People with white matter disease also have hardening of the arteries and arterioles.
What have you learned about Alzheimer’s disease over the years?
It is unclear whether people with Alzheimer’s disease have only Alzheimer’s disease, because of other white matter pathologies. About 10% of people in their 80s and 90s have some type of neurodegenerative disease, many of which affect short-term memory. The largest contributing factor is vascular problems, which cause ischemic injury. Vascular problems also probably drive Alzheimer’s disease. It is thought that amyloid and tau may be the brain’s responding to vascular injury. For example, people with head injury or stroke get a buildup of amyloid around the area of injury. In the history of human evolution, this buildup may be the reason that people could survive infections before the invention of antibiotics. One theory is that Alzheimer’s disease is a chronic immune response syndrome that is trying to protect that brain but becomes injurious (like rheumatoid arthritis). I think that white matter disease is not only about the myelination; it is also a vascular pathology.
How is the Alzheimer’s disease clinical trial going?
We have had some interesting preliminary findings. The technique has been effective in removing some amyloid. The amyloid reduction did not happen in all participants, but it hinted that there might be something going on. When we gave the contrast agent, we could see the perivascular spaces and the contrast going where it should have been going. We were seeing BBB opening in man for the first time. These are exciting observations!
When you are screening patients for participation in focused ultrasound clinical trials, it is much more complicated than most people realize?
Yes, patient selection is so important because amyloid can become incredibly injurious. We try to make sure that each participant is appropriate. These clinical trials usually have a long list of enrollment inclusion and exclusion criteria.
How has focused ultrasound evolved since you began doing clinical trials?
The technique is improving. The first sessions had a team around the table, and the person had pins in their temples (a stereotactic frame). We were following the same model with BBB opening as for essential tremor, which requires millimeter precision. BBB opening does not require that same level of precision. We are now amending the protocols so that we do not have to use the pins. The BBB procedure is better tolerated, and the participants do not need to be observed overnight.
What are the goals for creating new treatments for Alzheimer’s disease?
It will be interesting to see whether treatments can slow the spread of the disease in symptomatic patients who are diagnosed early. Can we remove the networks that have been gummed up? Can we reverse progression or at least prevent decline? We hope to show improvement in cognitive abilities and even neurogenesis. Sunnybrook researchers are looking at the entire family of cells. It’s not just the neuron that we have to care about. There’s a whole family, including endothelial cells, astrocytes, the microbial cells (the guard cells), and neurons. We must protect the whole family. If you just think it’s all about neurons, you’re missing the boat. Many researchers undervalue the importance of the endothelial cells and the family of cells that protects the brain.
Do you use liquid biopsy in your practice?
It is amazing that there is a blood test for measuring tau. It is approved in the United States but not yet in Canada. The phospho tau measure detects amyloid in the brain through a complicated path. Other tests can measure microglial activation. Liquid biopsies will transform our understanding and treatment of neurodegenerative disease. Right now, we are opening very small areas of the BBB, but the whole brain is leaking out on a regular basis. One theory is that amyloid is trafficking out of the brain along the perivascular spaces. Your brain is pumping out the garbage when you’re in deep sleep. Sleep is essential for brain health.
Do you think that focused ultrasound can increase the yield on liquid biopsies?
I don’t know. We need to accumulate evidence. Liquid biopsies as blood tests may not be as good as testing the cerebrospinal fluid (CSF), because CSF has higher concentrations of biomarkers. We need to continue to study the correlations and make sure that the correct diagnosis has been made with the patients (e.g., that the liquid biopsy from a patient with “Alzheimer’s disease” truly has Alzheimer’s). We are trying to help with collecting blood tests before and after focused ultrasound, and we are amending Health Canada protocols to try to obtain biomarkers from blood and CSF (which still gives the most accurate reflection).
Tell us about the participants who enroll in clinical trials.
The people who are coming in to do these studies are pioneering patients who don’t call themselves “participants.” They are prepared to contribute even if they don’t benefit. It is amazing. It is nicer when they can benefit, and we can show that there is a bit of hope in our results. Of course, we don’t know if it improves anything, or how long it will last.
Do you have any interesting patient anecdotes to share?
Just before the onset of the pandemic, a piece of artwork arrived in a Christmas card from one of my patients. The painting is called ‘Peace.’ Interestingly, the next year this patient sent a new card that also used blocks of colors, but the colors were dark purple and mauve and much more somber and befitting a world in crisis. This patient is an example of someone with a neurodegenerative condition who still has creative spirit and skills. He is still doing his artwork and has exhibits in the north part of Toronto. I even use his art for my Zoom background because it keeps me grounded and optimistic.
What are your funding sources?
I have received research funding from the Alzheimer’s Drug Discovery Foundation, Brain Canada, Canadian Institutes of Health Research (CIHR), Heart and Stroke Foundation of Canada, the National Institutes of Aging, and Weston Brain Institute.
Tell us about your extensive mentoring experience.
My experience includes the mentoring of many young faculty and trainees, including 36 postdoctoral fellows, 18 PhD students, and 15 master’s students. I am honored to have earned outstanding mentorship awards from the University of Toronto’s Institute of Medical Sciences and department of medicine.
Recent Publications
(Dr. Black has more than 500 publications.)
1. Meng Y, Goubran M, Rabin JS, et al. Blood-brain barrier opening of the default mode network in Alzheimer’s disease with magnetic resonance-guided focused ultrasound. Brain J Neurol. Published online January 25, 2023:awac459. doi:10.1093/brain/awac459
2. Abrahao A, Meng Y, Llinas M, et al. First-in-human trial of blood–brain barrier opening in amyotrophic lateral sclerosis using MR-guided focused ultrasound. Nat Commun. 2019;10(1):4373. doi:10.1038/s41467-019-12426-9
3. Meng Y, Abrahao A, Heyn CC, et al. Glymphatics Visualization after Focused Ultrasound-Induced Blood-Brain Barrier Opening in Humans. Ann Neurol. 2019;86(6):975-980. doi:10.1002/ana.25604
4. Meng Y, MacIntosh BJ, Shirzadi Z, et al. Resting state functional connectivity changes after MR-guided focused ultrasound mediated blood-brain barrier opening in patients with Alzheimer’s disease. NeuroImage. 2019;200:275-280. doi:10.1016/j.neuroimage.2019.06.060
5. Lipsman N, Meng Y, Bethune AJ, et al. Blood–brain barrier opening in Alzheimer’s disease using MR-guided focused ultrasound. Nat Commun. 2018;9(1):2336. doi:10.1038/s41467-018-04529-6
6. Meng Y, Volpini M, Black S, Lozano AM, Hynynen K, Lipsman N. Focused ultrasound as a novel strategy for Alzheimer disease therapeutics. Ann Neurol. 2017;81(5):611-617. doi:10.1002/ana.24933
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