‘These findings represent real hope that we can stop, and even reverse, the deterioration that until now we considered an inevitable part of aging.’

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Israeli researchers have taken the first step toward developing a revolutionary new treatment to slow or reverse age-related cognitive decline.

The treatment combines a new diagnostic technique to detect a leaking blood-brain barrier (BBB) with an anti-inflammatory drug based on a small molecule called IPW.

While the study, led by research teams at Ben-Gurion University of the Negev (BGU) and the University of California-Berkeley, has only been tried so far in rodent models, it has the power to make senile rodents nearly as cognitively adept as those half their age.

“These findings represent real hope that we can stop, and even reverse, the deterioration that until now we considered an inevitable part of aging,” said senior study author BGU Prof. Alon Friedman and his Israeli research partner, Prof. Daniela Kaufer of UC Berkeley’s department of integrative biology.

Clearing brain fog

If in the past the story was about aging leading to loss of function and dead cells, the new data suggests that age-related cognitive decline is in fact a result of increased inflammation that leads to a kind of mental “fog” causing tiny seizure-like events.

An accompanying paper by the two researchers and Dan Milikovsky of BGU shows that after clearing up the inflammatory fog, “within days the aged brain acts like a young brain,” Kaufer says. This indicates “that we can reverse brain aging.”

The key to the researchers’ insight was looking at the BBB – a semi-permeable interface that separates circulating blood from the brain. When the BBB is breached, brain diseases and neurodegeneration become more frequent – and more destructive.

Previous MRI scans led by Friedman at BGU have found that the BBB breaks down in nearly 60% of people by the age of 70.

In particular, the researchers found that albumin, a protein made in the liver, can cross the BBB into the brain. Albumin is associated with increased inflammation.

Friedman and Kaufer demonstrated that if you introduce albumin into the brain, within just one week, the brains of young mice look like those of old mice in terms of neuronal functions and their susceptibility to seizures. The albumin-treated rodents also navigated a maze as poorly as senile mice.

Infusing the anti-inflammatory medicine IPW, however, alleviates the effects of a leaky BBB and seems also to heal the barrier itself.

Images by Alon Friedman and Daniela Kaufer: Dynamic contrast-enhanced MRI scans show that with age, the blood-brain barrier becomes leakier. This dysfunction in shown in both humans and mice. A leaky BBB triggers a cascade of cell death that may be the cause of age-related cognitive decline.

New biology

The drug is only part of the equation. Equally important was the development of an MRI imaging protocol and mathematical algorithms that quantify leakage in the BBB, allowing physicians to flag people who may develop (or already have developed) dementia.

Friedman’s group in the BGU Brain Imaging Center developed the scanning protocol.

“The evidence points to a dysfunction in the brain’s vasculature as one of the earliest triggers of neurological aging,” Friedman explains. “This combination of two biomarkers and a drug gives us the innovative ability to diagnose and treat patients with blood-brain barrier leakiness and cease treatment once the BBB closes and danger decreases.”

Put another way, “when the blood barrier is healed, you no longer need the drug,” Kaufer says. “This is new biology, a completely new angle on why neurological function deteriorates as the brain ages.”

Road to commercialization

So, when will an actual treatment protocol be available to reverse cognitive decline in humans, not just mice?

That’s still in the future. The researchers have taken a step toward commercialization by forming a company to develop IPW and other therapeutics with the goal of reducing brain inflammation and the permanent damage that results after strokes, concussions and traumatic brain injuries.

Ultimately, the researchers hope that their work may eventually help older adults suffering from early dementia or Alzheimer’s disease. Today there are only drugs that treat the symptoms, not the cause.

The study was supported by the US National Institutes of Health, the Bakar and Archer Foundations, the European Union’s Seventh Framework Program, the Israel Science Foundation, and the Binational Israel-USA Science Foundation.


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