A new study, published this week, from Sunnybrook senior scientist Dr. Donald Redelmeier explores how an available simple diagnosis can skew complex medical decision making.

“Occam’s razor is the traditional idea that simple explanations should be preferred over more convoluted theories,” says Dr. Redelmeier, who is also a Sunnybrook staff physician and Canada Research Chair in Medical Decision Making. “Yet this idea has rarely been subjected to experimental testing for evidence-based medicine.”

Dr. Redelmeier and his co-author Dr. Eldar Shafir from Princeton University were interested in testing the concept in the context of the COVID-19 pandemic. “We hypothesized that an available alternative explanation might lead individuals to underestimate the likelihood of a COVID-19 diagnosis,” says Dr. Redelmeier.

The study asked community members and health-care professionals to judge the chances of COVID-19 in a hypothetical patient through a set of different surveys. Each survey provided a succinct description of a hypothetical patient scenario, suggestive of COVID-19. Each scenario was formulated in two versions randomized to participants, differing only in whether an alternative diagnosis was present or absent.

“Through scenarios involving a spectrum of risk, we found that respondents judged the probability of COVID to be much lower in the presence of another diagnosis, such as influenza or strep throat, compared with when an alternative diagnosis was absent,” says Dr. Redelmeier. This contradicts available microbiological evidence.

“The bias can lead individuals to mistakenly lower their judged likelihood of COVID or another disease when an alternate diagnosis is present. In turn, underestimating the risk of COVID infection might reduce a patient’s willingness to seek care and a clinician’s willingness to investigate a medical diagnosis.”

Dr. Redelmeier adds that the results suggest an available simple diagnosis can lead to premature closure and a failure to fully consider additional serious diseases.

“This bias occurs because risk factors such as crowded living spaces, lapses in hand hygiene, and poverty are risk factors for COVID infection, as well as for other diseases such tuberculosis. After diagnosing a patient with COVID, for example, a clinician might pause and check — is that really everything?”

He adds that as patients are living longer with multiple diagnoses occurring together, an over-reliance on Occam’s razor can contribute to misplaced complacency and discourages the search for additional contributing factors.

“The bias may be important to recognize for the COVID-19 pandemic, other diseases, and for the next disease outbreak.”

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Dr. Rikke Kofoed and Dr. Isabelle Aubert

In a new study, postdoctoral researcher Dr. Rikke Kofoed and senior scientist Dr. Isabelle Aubert and their team at Sunnybrook Research Institute determined the feasibility and safety of two noninvasive methods for delivering gene therapy to the brain in a preclinical model of Alzheimer’s disease.

The study has been published in Molecular Therapy – Methods & Clinical Development.

Alzheimer’s disease is the most common form of dementia, which impacts more than 430,000 Canadians aged 65 years and older. Hallmarks of the neurodegenerative disease include “plaques” and “tangles” composed of toxic protein that develop in the brain and eventually prevent the production of nutrients and the transmission of signals that are necessary for the health of brain cells. Over time, this causes deficits in cell-to-cell communication and functions, leading to memory loss, confusion and difficulty reasoning. There is currently no effective treatment for the disease.

Researchers at Sunnybrook are interested in gene therapy as a potential treatment for Alzheimer’s disease and other disorders of the brain. Gene therapy can replace a gene that is missing or defective. Specific genes can also be added to allow brain cells to stay healthy, produce therapeutics, or generate new cells to curb the disease.

Although gene therapy shows promise in Alzheimer’s disease, the blood-brain barrier poses a challenge for delivering it to the brain. In this study, the research team evaluated two innovative methods to non-invasively deliver gene therapy across the blood-brain barrier: a) focused ultrasound combined with intravenous microbubbles, which increase the permeability of the blood-brain barrier at targeted sites, and b) modified gene carriers, which are capable of crossing the blood-brain barrier and delivering genes to brain cells.

Dr. Kofoed and Dr. Aubert share thoughts on their research.

Dr. Rikke Kofoed in the lab

What did your study find?

Dr. Kofoed: In this preclinical study, we found that depending on which delivery method is used (focused ultrasound or modified gene carriers), a unique distribution of genes is seen in the brain. These findings tell us that in the future, gene therapy can likely be tailored to achieve personalized deliveries of genes depending on disease stage and the type of therapeutic gene.

We also determined that these non-invasive delivery methods have a good safety profile and that the immune response triggered is similar to what is seen after gene delivery using brain surgery. Our findings suggest that the immune response to non-invasive gene delivery can be controlled, as it is currently done in the clinic for other gene therapy approaches.

What could these results mean for patients in the future?

Dr. Aubert: In the past, the delivery of therapeutic genes required invasive surgeries for patients with Alzheimer’s disease. ​Non-invasive and personalized gene delivery to the brain has the potential to increase beneficial clinical effects for the treatment of Alzheimer’s disease. Our preclinical study confirms that focused ultrasound and modified gene carriers are feasible strategies for gene delivery to the brain, and that their immunological effects can be controlled.

What’s next in this research?

Dr. Kofoed: In this study, we used an easily visible “reporter” gene to explore the potency of gene delivery. The next stage of our research will look to deliver a therapeutic gene to target Alzheimer-related pathology in a preclinical model. These studies will help us determine the therapeutic potential of our delivery strategy.

Dr. Aubert: Gene therapy has tremendous potential for the treatments of brain disorders. The current study and the next stage of our research are required steps to evaluate the safety and efficacy of gene therapy approaches. With colleagues and collaborators at Sunnybrook and other institutions, these approaches could one day be brought to patients to halt degeneration and promote brain health for conditions such as Alzheimer’s disease.

Key drivers of Sunnybrook’s research are funding agencies and philanthropic investment. This study was funded with support from the Alzheimer Society Research Program, the Carlsberg Internationalisation Fellowship, the Canada Research Chairs Program, Canadian Institutes for Health Research (CIHR), the Weston Brain Institute, the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health and Temerty Chair in Focused Ultrasound Research. Additional funding was received from the FDC Foundation, the WB Family Foundation and Gerald and Carla Connor.

The post Behind the research: Study explores delivery of gene therapy to treat Alzheimer’s appeared first on Your Health Matters.

This year, a generous local company, D + H, has supported the program.

The D + H Summer Student Research Program started last week with an orientation session where Dr. Michael Julius, vice-president of research at Sunnybrook and SRI, welcomed students.

“It’s a great pleasure to have you here,” said Julius, to a packed audience in Sunnybrook’s Harrison Hall lecture theatre. “Some of the people you’re working with are the best on the planet. I would encourage you to interact with them and with each other.”

Read more about the program here.

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