On the trail of the Alzheimer's tragedy.

It is a tragic disease of mysterious cause -- with no known cure and no apparent way to stop its progressive loss of mental acuity. For the estimated 2 million people in the United States who suffer from senile dementia of the Alzheimer type, the brain has inexplicably gone haywire.

Increasing scientific interest in the disease, which is not limited to the aged, has yielded strong evidence indicting abnormalities in the neurotransmitter network in certain areas of the brain (SN: 10/6/84, p. 221). Now, recent research findings offer more etiologic evidence, as well as a new in vivo diagnostic approach and a possible new treatment.

According to a report in the Dec. 6 JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION (JAMA), a group of researchers led by Duke University Medical Center staff members in Durham, N.C., analyzed the concentration of the hormone corticotropin-releasing factor (CRF) in brains from Alzheimer patients. Using radioimmunoassay techniques, they measured CRF in nine brain regions using postmortem brain tissue from 13 patients who had died of Alzheimer's and from 13 age- and sex-matched controls with no evidence of such disease.

Compared with controls, the Alzheimer brains showed a marked reduction of CRF concentrations in three regions: about 50 percent reduction in the frontal and temporal cortex, and 70 percent in the caudate nucleus. The report apparently is the first to point out CRF deficiencies in Alzheimer's, but the significance of the findings remains unclear. Still, the results suggest that CRF-containing neurons degenerate in Alzheimer's disease, joining the previously described somatostatinergic and cholinergic neuronal damage as possible contributors to the disease's pathology.

Signs of neuronal damage found by microscopic evaluation of postmortem brain tissue are needed to confirm the difficult clinical diagnosis, which still depends on physical examination and psychometric testing. Those parameters may be replaced, at least in part, by a new in vivo approach utilizing single-photon emission computed tomography (SPECT), according to another report in the Dec. 6 JAMA by a team from Harvard Medical School and Massachusetts General Hospital in Boston and George Washington University Medical Center in Washington, D.C.

Using radioactive iodine-labeled compounds injected intravenously and a special camera to produce three-dimensional brain images, the researchers studied specific neurotransmitter receptor binding function in a 56-year-old Alzheimer patient. The noninvasive technique revealed a unique and "profound" decrease in blood flow to certain regions of the brain, a phenomenon previously observed using other techniques. Although the SPECT study also corroborates earlier descriptions of specific receptor site distribution based on other methods, the real significance of these findings, despite the very small sample size, may be the eventual introduction of an important diagnostic tool that may provide earlier diagnosis.

Neuronal biochemistry is also the scientific springboard for a search by scientists at Yale Medical School in New Haven, Conn., for drugs to ameliorate cognitive deficits like those associated with Alzheimer's disease, such as memory loss. Attempts to find a drug for age-related cognitive disorders have not produced sudden success stories (SN: 5/7/77, p. 292; 10/27/84, p. 263). Nonetheless, Amy F.T. Arnsten and Patricia S. Goldman-Rakic of Yale report in the Dec. 13 SCIENCE that a different approach may produce results -- one that uses drugs affecting catecholamine transmission in the brain rather than the more commonly utilized acetylcholine transmission. Both neurotransmitter systems deteriorate in the aging brain.

Using five aged rhesus monkeys ranging from 17 to over 30 years of age, the 18-month study tested their performance in memory tests following injection of varying doses of various drugs that affect catecholamine transmission, alternated with doses of a saline placebo. The monkey's performance with the placebo averaged 64 percent correct during the course of the study, with individuals showing a wide range of memory ability.

Specific doses of the drug clonidine, an antihypertensive agent, produced "near-perfect performance" in four of the five animals, with the oldest monkey showing the most marked improvement. Arnsten and Goldman-Rakic found higher doses of clonidine had a sedative effect on the animals, which apparently developed a tolerance to this side effect over a period of time. The researchers caution that clonidine's sedative effects may obscure its beneficial actions and should be considered if the drug is used in human clinical trials.