By David N. Leff
Quick - what physical traits set human beings apart from subhuman primates? Anthropologists cite three: a skeleton designed for walking upright; sharp eyes that can see color and three dimensions; hands with a strong grip and delicate dexterity.
Over-arching (literally) these obvious abilities is the brain's cerebral cortex - a six-layered, 1- to 4-centimeter-thick sandwich of neurons, which endows Homo sapiens with rational thought and speech. ("Sapiens" means savvy.)
A 600-pound gorilla has a brain smaller than a man's. Humans need a larger skull to make room for their cerebral cortex, which not only is bigger, but more deeply folded. It interprets the sensory world, also memory, introspection and association. (The convolutions add more surface area per unit of interior skull volume.)
In far-advanced Alzheimer's disease (AD), as many as half of the neurons that deal with memory and cognition in the cortex have died off. Neurologists intuitively link their demise to the proliferation of senile neuritic plaques, which surround these key nerve cells, and fibrillary tangles that choke their interior. But smoking-gun evidence of this guilt is still speculative.
Now a novel imaging technology, based on statistical physics, is adding a new dimension (again, literally) to visualize the billions of cerebral neurons that densely populate the two-dimensional layers of the cortex - for starters, those implicated in senile dementias. It introduces microcolumns - vertically aligned neurons that cut across the cortical layers, or laminae.
A research paper in the current Proceedings of the National Academy of Sciences (PNAS), released April 18, 2000, reports: "Description of microcolumnar ensembles in association cortex and their disruption in Alzheimer and Lewy body dementias." Its co-senior authors are polymer physicist H. Eugene Stanley at Boston University and clinical neurologist Brad Hyman, who directs the Alzheimer's Research Unit at Massachusetts General Hospital in Boston. (See BioWorld Today, July 9, 1997, p. 1.)
Eleven Little Nerve Cells, All In A Row
"What our paper shows," Stanley told BioWorld Today, "is that the microcolumns that are present in the normal brain go away with disease. One such microcolumn," he added, "resembles a row of 11 neurons, arranged like segments of a worm or snake, or a necklace of pop-it beads, perpendicular to the laminae."
The PNAS paper's lead author, statistical physicist Sergei Buldyrev, told BioWorld Today how the team's new density matrix system works:
"Prof. Bradley Hyman," he recounted, "supplied us with confocal microscope images of various cortex tissue samples from 22 people with Alzheimer's disease, five with Lewy body dementia (LBD), plus 11 control individuals. We analyzed these samples by the methods we developed in the field of statistical physics for the study of liquids and crystals. And we discovered that there is a significant difference between the samples taken from healthy control people and patients with AD and LBD.
"It was not very easy to see this with the naked eye," Buldyrev continued, "because what we study is a statistical vicinity of each neuron. Suppose you fix on one neuron," he explained, "and you see some neighboring neurons. At first glance this neighborhood looks quite random. On the other hand, if you average over many different neurons, you can see some pattern, and that there is a high probability of finding another neuron in a vertical direction from the one where you are sitting. In LBD," Buldyrev recalled, "we saw practically no such microcolumns, and in AD the columns were much smaller and less pronounced than in controls."
Statistical physicist Brigita Urbanc, a co-author of the paper, picked up the story:
"We were applying our density matrix method on the normal control brain, from simply elderly people with no AD, no symptoms. And we found that these microcolumns exist - something that is not entirely obvious by just observing the entire mass of neurons in the brain. But this image-interpretation method allowed us to magnify such neuronal architectural features as microcolumns.
"It had already been speculated," Urbanc went on, "that these microcolumns exist, and that they have some kind of function in the brain. However, nobody up until now was able to quantify it. And then when we applied the same method on these two dementias - one with LBDs and the other with AD - we found that this feature is very diminished, that these microcolumns are almost gone - in direct proportion to the number of tangles, but not to plaques. Those findings led us to two conclusions:
"First," she enumerated, "that in a healthy brain the organization of neurons is such that in these microcolumns they may have a functional property. And our second conclusion is that in AD and LBD disease, these microcolumns are strongly impaired - correlating with cognitive impairment.
"Now, in AD," she pointed out, "this may not be such a big surprise, because in that disease roughly half of the neurons are lost. So it is very likely that any structure of the brain would be lost as well. However, in LBD, there is no dramatic neuronal loss. Maybe it's around or below 10 percent, and still the microcolumns are gone. So it's this disruption of microcolumnar organization that is surprising. And it led us to hypothesize that this microcolumnar organization would be a strong functional property of the brain, that it is connected to the cognitive loss in AD and LBD diseases."
Working The Averages On Neuron Density
Urbanc went on to describe the statistical physics technology she and her co-authors employed:
"The method is in a way analogous to X-ray pictures, which are usually performed to describe the structure of solid- or liquid-state matter. So we basically jumped from one neuron to the other in the tissue image, and for each neuron drew a centered density map. Then, we calculated a statistically average environment of a typical neuron in the brain.
"There are other neurological diseases," she observed, "such as schizophrenia, where this method could be applied to see whether that disease causes some change in this microcolumnar organization. But for now, we are sticking to studying the brains of patients with dementia. For this," she concluded, "we depend on the neuroscience researchers who are actually dealing with the tissue, for whatever kind of images they have at a particular time."