Friday, February 08, 2008

A Window into Alzheimer's

Advances in imaging shed light on how the disease develops.

By Jocelyn Rice

Instant plaques: Because Alzheimer's disease develops over the course of decades, many scientists assumed that its hallmark brain lesions, called amyloid plaques, were slow to appear. A new imaging technique called multiphoton confocal microscopy reveals that on the contrary, plaques can form in a single day. This image of a mouse's cortex shows a mature plaque (large blue splotch) with a brand-new "microplaque" (small blue dot within the white square) developing beside it. Reimaging the same brain area over several subsequent days showed the plaque growing. Credit: Melanie Meyer-Luehmann et al., courtesy of Nature Publishing Group

An innovative imaging technique has revealed that the plaques that develop throughout the brains of Alzheimer's patients can form overnight, and they are likely a cause rather than a symptom of the disease.

Plaques, a defining hallmark of Alzheimer's disease, are brain lesions that result from the abnormal accumulation of a protein called amyloid-beta. Since the symptoms of the disease progress over the course of decades, plaques were generally thought to appear and accumulate slowly.

"The notion was that since the disease plays out over a long period of time, individual lesions in the disease process would also have that same tempo," says Bradley Hyman, director of the Alzheimer's unit at Massachusetts General Hospital's MassGeneral Institute for Neurodegenerative Disease. But his study's results, which appear in this week's Nature, suggest that plaques can develop in a single day.

Hyman's team harnessed a fledgling imaging technique called multiphoton confocal microscopy to peer into the brains of living mice. The technique generates images using rapidly pulsed lasers that penetrate deep into living tissue without damaging it. By cutting out tiny sections of skull and replacing them with glass, the researchers created windows into the brains of mice that were genetically engineered to develop amyloid plaques. They could then repeatedly observe the same area of brain, and thus follow plaque formation over time.

"This gives us an opportunity to apply a time stamp to the events that are occurring," says Hyman. "So rather than simply having an individual snapshot of a pathophysiologic event, we can watch the process evolve."

While groups have applied multiphoton confocal microscopy to living brains before, Hyman's group is the first to apply the technique to the study of a neurodegenerative disorder. "It really pushes the technology forwards," says Steven Finkbeiner, associate director of the Gladstone Institute of Neurological Disease at the University of California, San Francisco, who was not involved with the study.

Besides revealing the surprisingly fast pace of plaque formation, the study addresses a long-standing debate over the role of amyloid plaques in the development of Alzheimer's disease.

A long-established hypothesis posits that amyloid plaques themselves bring about damage to neural tissue, causing the disease's symptoms--most notably behavioral changes, memory loss, and dementia. But some scientists counter that plaques are not correlated strongly enough with the disease to be a convincing culprit for its symptoms. Rather than causing the symptoms of Alzheimer's, plaques could themselves be symptoms--stemming from some other, yet unknown mechanism.

"There's always been a lot of debate," says Juan Troncoso, codirector of the Alzheimer's Disease Research Center at Johns Hopkins School of Medicine, who was not involved with the study. "What happens first, and what's responsible for what? Is the damage to the nerve cells first, and then the plaque, or vice versa?"