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Alzheimer's Biomarkers Found in Persons with Mild Cognitive Deficits

The same biomarker signature found in advanced Alzheimer disease (AD) has been detected in the CSF of patients with mild cognitive impairment (MCI), and could be used one day to identify AD in its earliest stages and differentiate it from other forms of dementia, a new study indicates.

The ratio of amyloid-beta (Abeta) and tau proteins in the CSF of persons with mild cognitive impairment paralleled the ratio in more advanced AD, and correlated with the presence of amyloid deposits in the brain, according to researchers at Washington University School of Medicine in St. Louis, MO.

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Dr. Anne M. Fagan: ”We dont know how early [these biomarkers] can be seen, but in our subjects its at a very early stage, one that wouldnt be detected by most clinicians. In fact, most doctors wouldnt even consider many of the symptoms as signs of dementia.”

The findings were reported in a Jan. 8 advance online version of Archives of Neurology.

Lead investigator Anne M. Fagan, PhD, research associate professor in the school's department of neurology, told Neurology Today in a telephone interview that the biomarker phenotype is identical in patients with cognitive problems that would be overlooked by all but the most astute physician.

“We don't know how early [these biomarkers] can be seen, but in our subjects it's at a very early stage, one that wouldn't be detected by most clinicians,” she said. “In fact, most doctors wouldn't even consider many of the symptoms as signs of dementia,” she said.

STUDY PROTOCOLS

The researchers examined CSF and plasma for several biomarkers associated with Alzheimer disease — Abeta40, Abeta42, tau, phosphorylated tau181, and plasma Abeta40 and Abeta42. They compared ratios with clinical follow-up (up to eight years) in 139 volunteers between the ages of 60 to 91 years. Clinical Dementia Rating (CDR) scores indicated either “normal” (CRD 0), very mild (CDR 0.5), or mild (CDR 1.0) AD dementia.

As in more advanced AD, subjects with mild AD had reduced mean levels of CSF Abeta42 and increased levels of CSF tau and phosphorylated tau181. Lower CSF Abeta42 levels corresponded closely with the presence or absence of brain amyloid, the researchers discovered when subjects were examined with the Pittsburgh Imaging Compound (PIB), which binds to amyloid and can be detected by PET.

The CSF tau to Abeta42 ratio (95 percent confidence interval, 1.58–17.22) and phosphorylated tau181 to ABeta42 ratio (95 percent confidence interval, 1.62–11.86), accurately predicted conversion from a CDR of 0 to a CDR greater than 1 indicating dementia, the team found.

“The biomarker phenotype can detect early AD and the signature correlates positively with both clinical diagnosis and the presence of amyloid in the brain,” said Dr. Fagan.

“In seemingly normal subjects and those with mild cognitive symptoms, that's exactly what we saw. A group of subjects who tested positive for brain amyloid using PIB imaging also had low Abeta42 levels, corroborating the hypothesis that levels drop as amyloid is deposited in the brain,” she explained. “This could have practical utility. A patient could have low Abeta42 levels and a negative PIB, which would indicate that something other than AD is going on, for example frontal dementia or stroke, so the technique can provide a differential diagnosis,” she said.

COMPLEMENTARY CORROBORATION

Co-author John Morris, MD, the Harvey and Dorismae Hacker Friedman Distinguished Professor of Neurology and director of the Alzheimer Disease Research Center at Washington University School of Medicine, told Neurology Today in a telephone interview that the findings are three-fold.

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Dr. John Morris: “Clinically diagnosing AD can be done accurately at a much earlier stage than can be done today, using the Abeta42-to-phosphorylated tau ratio. Its the same pathological process as in advanced Alzheimer disease, only much earlier.”

“Clinically diagnosing AD can be done accurately at a much earlier stage than can be done today, using the Abeta42-to-phosphorylated tau ratio. It's the same pathological process as in advanced Alzheimer disease, only much earlier.”

Second, the biomarkers “complement each other,” he noted. “Everyone with a positive PIB PET scan for amyloid in the brain had low Abeta42 levels. The two indicators corresponded perfectly.”

The third important finding is that the test appears to work in people who show no clinical signs of dementia. “This is perhaps the most portentious finding,” he said. “That people who are not demented also show the phenotype could mean we've identified a new pre-clinical stage of the disease. We have to continue monitoring these patients, but our hypothesis is that they will develop cognitive symptoms over time. Until then, we can't know for sure. We have a long way to go.”

OTHER MARKERS POSSIBLE

At the Silberstein Institute at New York University School of Medicine's Center for Brain Health in New York City, Kenneth E. Rich, MD, coordinates clinical studies exploring potential biomarkers in the progression of mild cognitive impairment in Alzheimer disease.

“One of our goals is to determine whether brain imaging (through MRI or PET) can help predict and monitor the onset and progression of Alzheimer disease. In addition to neuroimaging, our trial collects and tests blood and CSF to determine if biomarkers can predict and monitor the disease. This study looks promising,” he told Neurology Today in a telephone interview.

It will be very helpful to be able to predict which patients with mild cognitive impairment will develop Alzheimer disease, and how soon, not only in terms of monitoring these patients but also for developing and testing new medications, he added.

“If we have a better idea which patients to target, we'll know whom to treat in early stages. Being able to differentiate Alzheimer dementia from other types of dementia at an early stage is equally important.”

Dr. Rich said it is impossible to predict a timeline for when such screening might become available for physicians and patients. Resistance to spinal taps is a barrier that must be overcome if such testing is ever to become part of a standard diagnostic AD workup, he noted.

“It would be nice to have a blood test, but I think that may not happen soon,” he said. “Spinal taps are very easy to tolerate, if done properly, but recruitment is always challenging in CSF trials. There's a degree of spinal tap phobia among the public. But lumbar punctures at our center are done under fluoroscopy, or x-ray guidance. Therefore, they are quick, safe, and almost always without complications.”

With a growing awareness of the potential benefits, and especially if doctors can diagnose and provide treatment for something as serious as Alzheimer disease early on, he said, spinal taps may yet become a state-of-the-art diagnostic procedure. “In Europe people seem to already understand this.”

ARTICLE IN BRIEF

The ratio of amyloid-beta and tau proteins in CSF of persons with mild cognitive impairment paralleled the ratio in more advanced AD, according to a new study.

REFERENCE

Fagan AM, Roe CM, Holtzman DM, et al. Cerebrospinal fluid tau/&b.beta; amyloid42 ratio as a prediction of cognitive decline in nondemented older adults. Arch Neuro l 2007;64: E-Pub 7 Jan 2007.