Biomarkers in Cerebrospinal Fluid Discriminate Between Dementias

Allison Gandey

September 24, 2010

September 24, 2010 (San Francisco, California) — Combining biomarkers from cerebrospinal fluid is helping researchers identify and distinguish between dementia with Lewy bodies and Alzheimer's disease.

Presenting here at the American Neurological Association 135th Annual Meeting, investigators showed that patterns of β-amyloid 42 and α-synuclein in cerebrospinal fluid appeared to differ between these conditions.

"Our study supports the hypothesis that combining biomarkers — one for Alzheimer's disease and one for dementia with Lewy bodies — improves our ability to discriminate between disorders," presenter James Galvin, MD, from New York University in New York City, said at the meeting.

Investigators found that combining markers worked best.

Dr. Galvin's research team studied 33 patients who underwent cognitive testing and lumbar puncture procedures. Of these, 11 had dementia with Lewy bodies, 11 had Alzheimer's disease, and 11 served as controls.

Dr. Galvin was working at WashingtonUniversity in St. Louis, Missouri, at the time of the study. His team classified patients with symptomatic Alzheimer's according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria. These patients did not have symptoms suggestive of other dementing illnesses and had cerebrospinal biomarkers β-amyloid 42 and tau.

Investigators studied cerebrospinal samples for all participants and analyzed them for total tau, p-tau at threonine 181, and β-amyloid 42. They used a commercial enzyme-linked immunosorbent assay (ELISA) (Innotest, Innogenetics NV). They measured α-synuclein using another ELISA, this one from Invitrogen Corporation.

"We found that α-synuclein was lowest in the dementia with Lewy bodies group," Dr. Galvin said at the meeting, "while the β-amyloid 42 was lowest in the Alzheimer's group."

Both tau and p-tau were not sufficient to discriminate between dementia with Lewy bodies and Alzheimer's disease, he reported.

Dr. James Galvin

"We propose cutoffs for α-synuclein that were 73% sensitive and 73% specific. Using cutoffs, it may be possible to identify individuals who are free of dementia pathology or, if dementia pathology is present, to classify them as dementia with Lewy body only, Alzheimer only, or mixed pathology," Dr. Galvin explained.

As expected, patients with both dementia with Lewy bodies and Alzheimer's biomarkers performed more poorly on memory tests than people with single biomarkers. "This is consistent with previous reports of mixed pathologies having poorer cognitive performance," Dr. Galvin noted.

His team was also able to distinguish the biomarker profile in 3 preclinical dementia with Lewy bodies cases. The patients had no symptoms at the time of lumbar puncture but had low α-synuclein levels.

"These individuals later manifested the clinical phenotype of possible or probable dementia with Lewy bodies," Dr. Galvin said. He suggests that preclinical dementia with Lewy bodies may be predicted by declining α-synuclein years before clinical symptoms emerge.

During an interview with Medscape Medical News earlier this year, William Thies, PhD, a spokesperson for the Alzheimer's Association in Chicago, Illinois, acknowledged that being able to intervene at an earlier disease stage to prevent progression would be ideal. "We will eventually be able to identify and treat people before they're symptomatic in order to prevent dementia from arising and even prevent these very early signs of cognitive decline," Dr. Thies said.

"This is in line," Dr. Galvin added, "with current thinking about Alzheimer biomarkers."

Making Headlines

Biomarkers started making headlines this summer when researchers reporting in the Archives of Neurology suggested lumbar punctures should be part of the clinical diagnosis and care of patients with mild cognitive impairment (2010;67:949-956).

Investigators detected a signature of low cerebrospinal fluid levels of β-amyloid 1-42, high total tau protein, and elevated phosphorylated tau181P that appeared to help predict progression to mild cognitive impairment and Alzheimer's disease. Overall, the diagnostic sensitivity was 90% for Alzheimer's disease, with a specificity of 64%. These results were consistent in 3 independent data sets.

The researchers, led by Geert De Meyer, PhD, from Ghent University in Belgium, point out that the unexpected presence of these biomarkers in more than a third of cognitively normal subjects suggests that Alzheimer's disease is "active and detectable" earlier than has ever before been envisioned.

It is a claim that was backed by editorialists Zara Herskovits, MD, from Brigham and Women's Hospital and John Growdon, MD, from Massachusetts General Hospital in Boston. The results of this study, they note, and the scientific evidence accumulated during the past decade confirm the importance of analyzing biomarkers in cerebrospinal fluid.

"There is now ample evidence that these measurements have value; physicians need to formulate when and how to incorporate cerebrospinal fluid measurements into their practice," they noted.

At the meeting, Dr. Galvin did not advocate physicians start using the biomarkers described here in clinical practice yet. But with the team's hypothesis now confirmed, investigators have important clues to guide further research.

This study was funded by the National Institute on Aging. Dr. Galvin has disclosed no relevant financial relationships.

American Neurological Association (ANA) 135th Annual Meeting: Derek Denny-Brown New Member Symposium. Presented September 14, 2010.

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