Alzheimer`s disease, a degenerative condition of the brain, is an affliction surrounded by uncertainty. Its sufferers experience memory loss and unpredictable shifts in mood and personality. The disease itself progresses in fits and starts, and its physical effects on the brain are currently identifiable only by autopsy. A procedure for noninvasive diagnosis would be of great benefit to medical researchers as well as to patients and family members.
For the first time, this sort of test may be close to reality. Researchers at the Geriatric Research Education Clinical Center (Bedford Veteran`s Administration Medical; Bedford, MA), has announced that they can detect Alzheimer`s-induced changes to the brain by using nothing but red light as a probe. Taking advantage of the fact that skin, blood, and bone transmit relatively well between wavelengths of 600 and 1300 nm, the researchers send light at a wavelength of 647 nm through the skull and into the brain, where it causes tissue to fluoresce in the near infrared. The fluorescence spectrum, transmitted back out through the skull and collected for analysis, carries a shape characteristic either of healthy or diseased tissue. The technique, called near-infrared fluorescence spectroscopy, is completely noninvasive (see figure).
The best spot to probe for evidence of Alzheimer`s is the temporal bone above the ear, explains Dr. Neil Kowall, the center`s director. This is where the skull is thinnest and where the temporal lobe--the portion of the brain`s cortex most affected by the disease--is located. Here, the brain lies at a distance of only 1 cm from the outside of the skull. Kowall notes that all tests so far have been done on autopsy specimens, where brain tissue can be quickly analyzed in conventional ways for signs of Alzheimer`s.
Differences in the shapes of the fluorescence spectra are not obvious to the eye but become apparent when the spectra are subjected to a procedure called principal component analysis. "The result," says Kowall, "is a clear segregation between Alzheimer`s tissue and normal tissue." Out of 22 cases of Alzheimer`s disease, only one was not detected in the center`s proof-of-principle study. The research, funded by the Alzheimer`s Association (Chicago, IL), will be summarized in a paper to be published shortly.
The source of the red light is an optical parametric oscillator pumped by a frequency-tripled Nd:YAG laser emitting at 355 nm. A fiberoptic probe pipes the 647-nm light to the skull, and six fiber bundles surrounding the probe bring the fluorescence light to a spectrograph, where the spectrum is captured by a charge-coupled-device array cooled with liquid nitrogen. A holographic notch filter at the entrance slit of the spectrograph filters out the 647-nm probe light, allowing collection of spectral data to within a few nanometers of the probe wavelength over a 640-1000-nm range. Finally, three 2.5-s exposures are averaged to obtain the spectrum. The equipment was developed in collaboration with the Laser Biomedical Research Center, George R. Harrison Spectroscopy Laboratory, Massachusetts Institute of Technology (Cambridge, MA).
Alzheimer`s disease harms the brain in two ways, one termed neurofibrillary tangle and the other amyloid plaque. "We don`t yet know which of these influences the fluorescence spectra more," says Kowall. He and his colleagues have yet to figure out what specific biochemical changes are reshaping the spectra, and whether the altered spectra are unique to Alzheimer`s or whether they may also show themselves in other diseases. They have determined, however, that the skull bone through which the light passes does not interfere with the spectra. The researchers are doing Raman spectroscopy on tissue samples to better understand the physical changes to the brain and correlate them to the fluorescence spectra. The procedure has not been tested on living patients.
The next phase, says Kowall, will be an extensive analysis of hospital patients just after death. The Geriatric Research Education Clinical Center has 100 beds, he notes, and 20 to 30 people die there every year. After that will come perhaps the most exciting step--the move to living patients. Researchers will be monitoring spectral changes to see how early the disease can be detected and how well the changes correlate with the progression of the disease. An ultimate large-scale trial could encompass thousands of patients at many research centers.
Experimental treatments for Alzheimer`s disease now include Vitamin E, ibuprofen and other anti-inflammatory drugs, and estrogen. But lack of a diagnostic technique short of autopsy leaves the accuracy of drug trials wanting. Dr. Kowall would like to see that change. "Might we be able to measure differences in the rate of change of Alzheimer`s between patients taking treatments and those who aren`t?" he asks. If so, then spectroscopy will have become a primary weapon in the fight against Alzheimer`s disease.
