Arresting Alzheimer's

scientists have developed a new dye that could offer non-invasive early diagnosis of Alzheimer's disease, a discovery that could aid in monitoring the progression of the disease and in studying the efficacy of new treatments to stop it. The work is published in the latest issue of

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Today, doctors can only make a definitive diagnosis of Alzheimer's, currently the fourth-leading cause of death in the United States, through a post-mortem autopsy of the brain. "Before you can cure Alzheimer's, you have to be able to diagnose it and monitor its progress very precisely," said Timothy Swager, leader of the work and a professor in MIT's Department of Chemistry. "Otherwise it's hard to know whether a new treatment is working or not."

To that end, Swager and postdoctoral associate Evgueni Nesterov, also from the MIT Department of Chemistry, worked with researchers at Massachusetts General Hospital and the University of Pittsburgh to develop a contrast agent that would first bind to the protein deposits, or plaques, in the brain that cause Alzheimer's, and then fluoresce when exposed to radiation in the near-infrared range. The new dye could allow direct imaging of Alzheimer's plaques through a patient's skull.

Some of the first non-invasive techniques for diagnosing Alzheimer's involved agents labelled with radioactive elements that could enter the brain and target disease plaque for imaging with positron emission tomography (PET). However, these methods were expensive and limited by the short working lifetime of the labelled agents.

Swager and colleagues developed the new dye, called NIAD-4, through a targeted design process based on a set of specific requirements. These included the ability to enter the brain rapidly upon injection, bind to amyloid plaques, absorb and fluoresce radiation in the right spectral range, and provide sharp contrast between the plaques and the surrounding tissue. The compound provided clear visual images of amyloid brain plaques in living mice with specially prepared cranial windows.

To make the technique truly non-invasive, scientists must further refine the dye so it fluoresces at a slightly longer wavelength, closer to the infrared region. Light in the near-IR range can penetrate living tissue well enough to make brain structures visible. Swager likens the effect to the translucence produced when one holds a red laser pointer against the side of a finger.

"This procedure could be done in a chamber with a photodetector and a bunch of lasers, and it would be painless," he said, adding that infrared fluorescence and other optical techniques will lead to a whole new class of non-invasive medical diagnostics. Swager says fluorescing dyes like NIAD-4 could be ready for clinical trials in the near future.

"What we have is a dye that lights up when it binds to amyloids that form in the brains of people with Alzheimer's. It's a completely new transduction scheme - a way of translating a physical or chemical event that's invisible to the naked eye, into a recognisable signal. Further wavelength adjustments in these dyes will allow us to perform in vivo analysis through human tissue."

The new dye was developed as part of a broader effort in sensing technology at MIT's Institute for Soldier Nanotechnologies. In addition to its applications as a medical diagnostic, Swager says fluorescing dyes like NIAD-4 could work as signals in a wide variety of sensing schemes.