A New Biomarker of Cognitive Decline in Alzheimer’s

Megan Brooks

March 09, 2012

March 8, 2012 — In a study of patients with very mild Alzheimer's disease (AD), baseline levels of visininlike protein 1 (VILIP-1) in cerebrospinal fluid (CSF) strongly predicted the rate of cognitive decline over roughly 3 years, report researchers at Washington University School of Medicine in St. Louis.

Memory and other cognitive abilities declined faster in patients with the highest levels of VILIP-1, a neuronal calcium-sensor protein that is a sign of neuronal injury.

"VILIP-1 appears to be a strong indicator of ongoing injury to brain cells as a result of Alzheimer's disease," lead author Rawan Tarawneh, MD, now an assistant professor of neurology at the University of Jordan, in Amman, said in a statement. "That could be very useful in predicting the course of the disease and in evaluating new treatments in clinical trials."

Dr. Rawan Tarawneh

David M. Holtzman, MD, professor and chairman of the department of neurology at Washington University, who worked on the study, told Medscape Medical News, "The levels of VILIP-1 were generally better than other established biomarkers such as tau, p-tau, and amyloid beta 1-42 (Aβ-42) in predicting rate of decline."

The study was published March 6 in Neurology.

Study Builds on Prior Work

In an earlier study, the researchers found that VILIP-1 alone and together with Aβ-42 predicted future cognitive impairment in cognitively normal older adults over 2 to 3 years, at least as well as tau/Aβ-42 and p-tau181/Aβ-42.

In their latest study, they investigated the usefulness of VILIP-1 and VILIP-1/Aβ-42 in predicting rates of cognitive decline in early AD. Sixty individuals with a clinical diagnosis of very mild AD (Clinical Dementia Rating [CDR] 0.5) or mild AD (CDR 1) and baseline CSF measures of VILIP-1, tau, p-tau181, and Aβ-42 were followed for an average of 2.6 years. Annual assessments included the CDR, CDR-sum of boxes (CDR-SB), and global composite scores.

The researchers report that baseline VILIP-1 and VILIP-1/Aβ-42 levels in CSF were significantly higher in patients with very mild and mild AD than in a control cohort of 211 cognitively normal individuals from the previous study.

Table. Baseline CSF Biomarker Levels in Controls and AD Patients

Baseline Controls (CDR 0) CDR 0.5 and 1 P
VILIP-1 (pg/mL) 396 536 < .0001
VILIP-1/Aβ-42 0.74 1.62 < .0001

AD = Alzheimer’s disease; CDR = Clinical Dementia Rating; CSF = cerebrospinal fluid

Consistent with their earlier findings, baseline CSF VILIP-1 and VILIP-1/Aβ-42 predicted annual change in CDR-SB and global scores during follow-up in this cohort with very mild AD.

Individuals with baseline CSF VILIP-1 levels of 560 pg/mL or greater (corresponding to the upper tercile) progressed much more rapidly in CDR-SB (1.61 boxes/year; P = .0077) and global composite scores (− 0.53 points/year; P = .0002) than individuals with lower values (0.85 boxes/year and − 0.15 points/year, respectively).

Moreover, "our results suggest trends for a potentially superior predictive performance for VILIP-1 to tau or Aβ-42 in the AD cohort over a 2- to 3-year follow-up period," the investigators say. "However, while VILIP-1 is similar to tau in its prognostic ability, we cannot say for sure at this time whether VILIP-1 is better than tau in this regard from our current data."

Observations 'Interesting'

In a telephone interview with Medscape Medical News, Eugene C. Lai, MD, PhD, director of the Neurodegenerative Disease Clinic, Methodist Neurological Institute in Houston, Texas, who was not involved in the study, said: "There have been several articles about this biomarker (VILIP-1) because it was found that this protein seems to be involved in Alzheimer's disease."

"The findings are interesting," he said, "because we are desperately needing biomarkers for Alzheimer's disease for several reasons: for a more accurate diagnosis, especially in the preclinical stage and for a better gauge of disease severity. According to this paper, it seems that VILIP-1 can predict the rate of cognitive decline, which could be very helpful in the future in terms of determining whether or not a treatment is beneficial or not."

Dr. Lai said "larger studies and more experience is needed, also by other groups of researchers, to see how reproducible the findings are. Right now, we have tau and (Aβ-42) and they are pretty good and pretty well established. Any additional biomarkers that would increase the accuracy or reliable would be great."

Echoing this sentiment, Dr. Tarawneh said in a statement: "These results are intriguing, but we need a larger study to fully understand how the insights provided by VILIP-1 compare to those we can gain from other markers." The researchers are now working to standardize the VILIP-1 immunoassay for expanded use in research.

The study was supported by the National Institutes of Health, Siemens Health Care Diagnostics, and the Charles and Joanne Knight Alzheimer Research Initiative. Dr. Tarawneh and Dr. Lai have disclosed no relevant financial relationships. Dr. Holtzman serves on scientific advisory boards for Satori Pharmaceuticals, C2N Diagnostics, and EnVivo Pharmaceuticals. A complete list of author disclosures is listed with the original article.

Neurology. 2012;78:709-719. Abstract

Ann Neurol. 2011;70:274-285. Abstract

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