October 2008
Feature Story

Karen Lusky

Could a serum antibody targeting brain microglia provide a heads up that a person has Alzheimer’s-type dementia?

Early study results point in that direction, according to information presented in July at the American Association for Clinical Chemistry annual meeting.

What makes this antibody attractive is that you don’t have to compare levels of substances over time, says Amanda McRae, PhD, who along with Gershwin Davis, MD, PhD, of the University of the West Indies at St. Augustine, Trinidad, and Tobago, presented their research findings. “The fact that the antibody is either there or not makes it very internationally attractive,” Dr. McRae says.

The study conducted in Trinidad by these investigators and their colleague, psychiatrist Nelleen Baboolal, MBBS, DM, involved 46 controls and 29 people clinically diagnosed for dementia. Dr. Baboolal diagnosed dementia based on the standard DSM-IV TR (regular diagnosis criteria for psychiatric illness), blood investigations, and neuroimaging studies of the brain. According to her diagnosis, a higher frequency of microglial antibodies was found in the serum of 42.1 percent of the AD patients compared with 4.3 percent of the controls.

Dr. Davis says researchers have shown the antibody can be present up to two years before clinical signs of AD. “So those who show the antibody [in the control group] could have neuropathology that’s not detected clinically,” he says. He and his colleagues are, in fact, performing followup studies with any control patient who displays the antibody.

The study also included homocysteine measurements and found that elevated levels of homocysteine differentiated between controls and vascular dementia patients (Davis GK, et al. Neurosci Lett. 2007;424: 27–30). Subjects with the microglial antibody had AD, and those with elevated homocysteine had vascular dementia, he says (www.ncbi.nlm.nih.gov/pubmed/17703882?dopt=Abstract).

A previous study performed in Europe by Dr. McRae and Judith Miklossy, MD, a neuropathologist, found that even people with a moderate amount of neuropathology of the AD-type at autopsy showed the microglial antibody in their cerebrospinal fluid. Yet none of the controls (those without AD-type neuropathology at autopsy) showed the microglial antibodies. The study involved 38 subjects postmortem. These results showed that CSF antimicroglial antibodies are present in a high percentage 71.5 percent of neuropathologically confirmed AD cases. Most important, the researchers say, is that the frequency of CSF antimicroglial antibodies was comparable (80 percent) in the group of cases with moderate AD-type cortical changes.

What role might the microglial cells play in AD? As Dr. McRae explains, “The microglial cells are shown to play a very early role in inflammation going on as amyloid is deposited in the brain.” The microglial cells may add to the neuronal damage “by secreting dangerous cytokines, interleukins—mainly interleukin 1 and 6 and tumor necrosis factor alpha.”

As a next step, the University of the West Indies researchers are trying to identify the antigen recognized by the microglial antibody to develop an ELISA test for blood that would be “more clinically attractive,” Dr. Baboolal says. “Presently, the antibody is determined immunocytochemically using perinatal rat brain as the substrate for the antibody,” a test method that would not be suitable for clinical use.

Dr. McRae surmises that the test used in the study measuring serum microglial antibodies might not be sensitive enough to detect low antibody titers in serum. This might help explain why only 42.1 percent of the subjects with AD tested positive, she adds.

“The fact that the vascular dementia patients did not display the antibody is in itself a good indication that the antibody shows specificity for AD pathology.” Drs. Baboolal and Davis concur.

Finding the antigen could also provide essential information about the type of microglia involved in the inflammatory process in AD. “We don’t know whether or not microglia are transformed during the pathological process,” Dr. McRae says. Thus, identifying the antigen may be vital for the future development of therapies, she says, to target the harmful microglia while leaving alone the microglia defending the central nervous system.

The researchers also plan to use the antibody as a marker for treatment efficacy, Dr. Baboolal says.

• Ageless quest—hunt for AD biomarkers