August 29th, 2012

CSF Markers Aid in Dementia, Parkinson’s Diagnosis

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Action Points
--These researchers found that levels of five proteins in cerebrospinal fluid can distinguish among different types of dementias and also among conditions that resemble Parkinson's disease.
--Note that for the purpose of assisting in the differential diagnosis of dementia and/or parkinsonism, one of the markers, neurofilament light chain, was as accurate when used alone as all five combined.

Levels of five proteins in cerebrospinal fluid can distinguish among different types of dementias and also among conditions that resemble Parkinson's disease, researchers said.

Diagnostic accuracy of the five markers in terms of the area under the receiver-operating characteristic curve was 0.90 for distinguishing Alzheimer's disease from two other common forms of dementia and 0.93 for Parkinson's disease versus other neurodegenerative conditions with similar symptoms, according to Oskar Hansson, MD, PhD, of Skane University Hospital in Malmo, Sweden, and colleagues.

The five proteins are alpha synuclein, the 42-amino acid form of beta amyloid protein (AB42), total tau protein (T-tau), hyperphosphorylated tau protein (P-tau), and neurofilament light chain (NF-L), the researchers explained online in Archives of Neurology.

"Together with earlier published data, our results indicate that these five CSF biomarkers might have clinical value in the differential diagnosis of dementia and/or parkinsonism," they wrote.

In fact, for the latter purpose, one of the markers -- NF-L -- was as accurate when used alone as all five combined. The area under the curve for NF-L in distinguishing Parkinson's disease from "atypical parkinsonian disorders," including progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy, was 0.93.

An accompanying editorial by Richard J. Perrin, MD, PhD, of Washington University in St. Louis, noted that such biomarkers would not only be useful for routine patient care, but also as research tools.

"Useful biomarkers will guide enrollment into trials by ensuring accurate early symptomatic or presymptomatic diagnosis, uniform pathological staging, and selection of individuals at increased risk of a progressive course," Perrin wrote.

"Ideally, trials will also include biomarkers that can assess pharmacological 'target engagement' by the therapeutic agent to verify delivery, efficacy, and appropriate dosage," he added.

For the study, Hansson and colleagues analyzed CSF samples from a total of 346 patients with Parkinson's disease with or without dementia, Alzheimer's disease, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, or dementia with Lewy bodies as well as 107 healthy controls.

Four of the five markers tested in the study (alpha synuclein, AB42, and T- and P-tau) were part of a commercial multiplex assay; NF-L was measured with a separate quantitative diagnostic.

Among the key findings for individual markers:

Alpha synuclein was elevated, relative to controls, in patients with Alzheimer's disease and lower in those with Parkinson's disease (with or without dementia), dementia with Lewy bodies, and multiple system atrophy.
AB42 levels were decreased in dementia with Lewy bodies and extremely decreased in Alzheimer's disease.
Both types of tau protein were elevated in Alzheimer's disease.
NF-L was increased in patients with the atypical parkinsonian disorders.

In dementia patients, according to Hansson and colleagues, T- and P-tau and alpha synuclein were each relatively accurate as standalone markers in distinguishing Alzheimer's disease from the Parkinson's and Lewy body forms, with areas under the receiver-operating characteristic curve of 0.83 to 0.86.

However, using all five markers together boosted the area under the curve to 0.90 -- "high enough to be of clear value in the clinical setting," the researchers wrote.

For the differential diagnosis of Parkinson's disease versus other conditions that may resemble it clinically, on the other hand, the five-marker panel was no more accurate than NF-L by itself.

In his editorial, Perrin cautioned that the markers need testing in more challenging situations -- "clinically ambiguous or seemingly straightforward cases that involve more than one proteinopathy," he wrote, such as patients who have excesses of both tau and alpha synuclein proteins.

"The cases included in this study -- by necessity and by design -- represent relatively ideal clinical examples," he added. "It remains unclear whether the biomarker changes of the entire panel observed at these stages will also be detectable and diagnostic during the early symptomatic or presymptomatic stages that will be targeted in clinical trials."

He noted as well that patients in the sample were diagnosed clinically, with neuropathological confirmation lacking.

Still, Perrin indicated, the work "represents a significant step forward."

The study was supported by Swedish government agencies and private foundations, with no industry funding.

Study authors and Perrin declared they had no relevant financial interests.

Primary source: Archives of Neurology
Source reference:
Hall S, et al "Accuracy of a panel of 5 cerebrospinal fluid biomarkers in the differential diagnosis of patients with dementia and/or parkinsonian disorders" Arch Neurol 2012; DOI: 10.1001/archneurol.2012.1654.

Additional source: Archives of Neurology
Source reference:
Perrin R, "Cerebrospinal fluid biomarkers for clinical trials: why markers for differential diagnosis are important" Arch Neurol 2012; DOI: 10.1001/archneurol.2012