MARKERS IN CSF PREDICTS ALZHEIMER DISEASE

August 11, 2010 — Cerebrospinal fluid contains important information that should be part of the clinical diagnosis and care of patients with mild cognitive impairment, report researchers. Using lumbar punctures, investigators identified 3 biomarkers that predict who is most likely to develop Alzheimer's disease.

Researchers detected a signature of low cerebrospinal fluid levels of β-amyloid 1-42, high total tau protein, and elevated phosphorylated tau181P. 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 investigators, 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 heretofore been envisioned."

The work was just published in the August issue of the Archives of Neurology and is already generating media attention.

Editorialists Zara Herskovits, MD, from Brigham and Women's Hospital and John Growdon, MD, from Massachusetts General Hospital in Boston, say the results of this study and the scientific evidence accumulated during the past decade confirm the importance of cerebrospinal fluid.

"To date, cerebrospinal fluid analyses have not been a routine component of assessment and care for patients with cognitive impairments and suspected Alzheimer's disease in the United States," the editorialists note. "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."

In the current analysis, investigators used data from the Alzheimer's Disease Neuroimaging Initiative, which is examining the use of biomarkers and imaging to aid in measuring progression of mild cognitive impairment and Alzheimer's. The analysis showed that these 3 biomarkers were more prominent in patients who were declining.

Table. Biomarkers in Cerebrospinal Fluid
Group Patients, %
Alzheimer's disease (n = 102) 90
Mild cognitive impairment (n = 200) 72
Cognitively normal (n = 114) 36



The researchers report the cognitively normal group with the Alzheimer's disease signature was enriched in apolipoprotein E ε4 allele carriers.

These results were validated on other data sets. In a study consisting of 68 autopsy-confirmed Alzheimer's cases, 64 patients were correctly classified (94% sensitivity). Another data set with 57 patients with mild cognitive impairment followed up for 5 years showed a sensitivity of 100% in patients progressing to Alzheimer's disease.

"We strongly recommend cerebrospinal analyses of β-amyloid 1-42, high total tau protein, and elevated phosphorylated tau181P in circumstances where having a definitive diagnosis of Alzheimer's disease is important for counseling patients about such concerns as work, driving, and making other lifestyle changes," note Dr. Herskovits and Dr. Growdon.

The editorialists point out that most family physicians and internists are not skilled or experienced in performing a lumbar puncture and may not embrace cerebrospinal fluid analyses unless they could refer patients to a central facility.

"Neurologists are trained to perform lumbar punctures," they add, "but those in busy practice and on the senior staff at teaching hospitals may have done very few since their residency. They too might welcome the idea of establishing or expanding a lumbar puncture clinical unit in their outpatient practice or hospital setting and devoting a morning every week or month, according to the need."

Expense is a relative measure and should be viewed in a cost-benefit context, Dr. Herskovits and Dr. Growdon add. In most centers, the consulting physician's bill, the charge for neuropsychological testing, and the cost of a magnetic resonance brain scan are all greater than obtaining cerebrospinal fluid values.

The editorialists suggest the adverse effect profile is favorable, with virtually no mortality, and the risk of morbidities such as infection and post–lumbar puncture headache is well under 5%.

This study was funded by the Alzheimer's Disease Neuroimaging Initiative. Coauthors Dr. Vanderstichele, Dr. Vanmechelen, and Dr. Coart are employees of Innogenetics (now part of Solvay-Pharma). Dr. De Meyer is a former employee of Innogenetics. The editorialists have disclosed no relevant financial relationships.

Arch Neurol. 2010;67:949-956.