Breaching the blood-brain barrier

A simple 9’ by 11’’ sheet of white paper containing a description of his mother’s story hangs by the door of Dr. Alon Friedman’s office at Dalhousie’s Faculty of Medicine. Beneath it, the neurovascular researcher has pinned a black-and-white photograph of his paternal grandparents and his uncle Miklosh.

The picture is the last one taken before Nazis transported his grandparents and uncle to Auschwitz. They never returned.

His mother and maternal grandmother did survive the Second World War – thanks to their own bravery and the help of a stranger.

“The Holocaust was legal. Slavery was legal. Segregation was legal. The brave woman who cared for and hid my mother and grandmother in an attic in Hungary was a criminal. She broke the law by sheltering Jews.”

“Legality is not a guide for morality,” the paper in Dr. Friedman’s office reads.

The photograph and his mother’s survival story form the genesis of why Dr. Friedman studies brain-based diseases, and specifically, leaks in the blood-brain barrier.

“The reason I started to work on the blood-brain barrier almost 30 years ago is the effect of stress on the brain,” he says. “Stress actually affects the vasculature system.”

Penetrating the barrier

The blood-brain barrier consists of a network of small blood vessels and tissue, tightly packed with cells, which keeps harmful substances from passing into the brain from the blood circulatory system. Dr. Friedman is investigating how factors as varied as stress, traumatic injuries, infections, high blood pressure or strokes can penetrate that barrier, allowing proteins to seep in.

Given the sustained stress his surviving family members endured during the Holocaust, Friedman’s interest in the physiological changes stress can produce in the brain arose from observing that intergenerational trauma.

As a child in Israel in the 1960s, Dr. Friedman did not have a name for the post-traumatic stress his parents were experiencing.

“I remember (my mother’s) nightmares, that I was awake in the night,” he says.

His parents never talked about what happened to them, or how their trauma affected them. He could see that the stress they had endured altered their perceptions, however. Their experiences, as well as what he observed in young soldiers when he served as a doctor with the Israeli Defence Forces, fuelled his decision to train as a neurosurgeon and then focus his talents as a researcher.

The blood-barrier leaks, Friedman says, can trigger a biological cascade that includes in inflammation and results in dementia, epilepsy, bipolar disorder, and a range of other illnesses medical researchers have long sought to decipher.

“In all of these conditions, we can identify a subgroup of patients with openings in the blood/brain barrier,” Dr. Friedman says.

The type of illness that results from the leak depends upon its size, duration, and location in the brain, he theorizes.

“The idea is the different neurological disorders have different symptoms not because it’s a different mechanism of disease, but because it’s a different area of the brain – the leaks affect different networks in the brain,” he says.

The hopeful implication of Dr. Friedman’s research is that there may be ways to repair the blood-brain barrier.

Establishing the status of an individual’s blood-brain barrier and pinpointing where in the brain any leaks are occurring, is a critical milestone in his research.

Pinpointing leaks

So far, he and his colleagues at four other universities around the globe have used Magnetic Resonance Imaging (MRI) to scan the brains of 800 patients. Working with the Biomedical Translational Imaging Centre in Halifax, they’ve found and pinpointed leaks in the small blood vessels in the blood-brain barrier and mapped the affected areas in participants.

That new technique has effectively created a diagnostic biomarker, Friedman says.

Now that he can use imaging to see what areas in the brain these leaks affect, he and his colleagues can also test potential drug candidates to see how well they seal leaks in the blood-brain barrier, and even reverse cognitive damage.

“We are looking for existing drugs that target this mechanism – we have a few,” he says.

He is hoping to secure enough funding to begin a clinical trial of one of the drugs, to see if it can repair the blood-brain barrier.

In the meantime, he is collaborating with colleagues to see if they can detect blood brain-barrier leakage by examining the retina. Using Artificial Intelligence to examine images of the retina, “we teach the machine what a leakage should look like, and then tell us if there is leakage and decrease in blood flow,” Friedman says.

In people diagnosed with dementia, they will also see if they can correlate the signs of blood-brain barrier leakage in the eyes and what shows up on brain scans conducted with Magnetic Resonance Imaging.

Being able to scan the eyes rather than the brain holds promise as a much more accessible, affordable technology, Friedman says.

“If they have the leakage and it’s visible in the eye, it’s probably there in the brain. It’s another biomarker,” he adds.

Not everyone with these illnesses has a leak in the blood-brain barrier, and the extent and duration of openings if the barrier also vary. That fact has led Dr. Friedman and his team to also study the way resilience affects the progression of many of these illnesses.

“We’re looking at mechanisms of susceptibility and resilience,” he says.

When he thinks of resilience, he often thinks of his mother, Eva. After the Second World War ended, she emigrated to Israel, changed her name to Rachel, met and married his father, and became a social worker. She died in 2023, at the age of 96.

“She was a very tough woman,” he says.

Dr. Friedman is a member of the Brain Repair Centre, a research Centre of Excellence that Dalhousie University, the Nova Scotia Health Authority and the IWK Health Centre founded to reverse illness and injuries to the brain and nervous system.