23 September 2003. The ratio of phosphorylated tau (p-tau) to β-amyloid (Aβ) in the cerebrospinal fluid improves the ability to distinguish clinically defined Alzheimer's patients from normal subjects, according to a study in the September issue of the Archives of Neurology. The same issue contains two other articles looking at the value of tau testing in other tauopathies.
Clinical examination by specialists remains the gold standard in distinguishing Alzheimer's disease from the normal memory loss of aging; from other dementias such as vascular dementia, dementia with Lewy bodies, or frontotemporal dementia; or from other disorders that can produce similar symptoms. "Dementia specialists can diagnose AD with great accuracy, predicting AD lesions at autopsy in about 90 percent of cases," writes Douglas Galasko of the University of California, San Diego, in an accompanying editorial. This number is lower in general practice across the country.
The quest to find a diagnostic marker for AD (see ARF related news story) so far has failed to hand primary care providers a truly useful test that could avoid more time-consuming, expensive examination at specialty centers. Yet there is great hope that biochemical markers or imaging methods will be able to detect AD among patients with mild cognitive impairment (MCI), which researchers believe is predominantly the prodromal stage of Alzheimer's. Biomarkers will also facilitate the assessment of drugs in future clinical trials.
The current study, led by Alssia Maddalena, Andreas Papassotiropoulos, and Christoph Hock of the University of Zurich in Switzerland, is a prospective study of 100 consecutive patients from a dementia clinic. Several features distinguish this study from similar studies, remark the authors. The CSF was not frozen, and patients were studied prospectively in a clinical setting, as opposed to being selected with research criteria. The same population will be followed through postmortem assessment for Alzheimer's disease.
Maddalena and colleagues found that the CSF ratio of tau phosphorylated at threonine 181 to Aβ distinguished AD patients from normal controls with 97 percent sensitivity and 86 percent specificity. The test was less effective at distinguishing AD from other dementias (80 percent sensitivity, 73 percent specificity), or yet other neurological disorders (80 percent sensitivity, 89 percent specificity).
While prior evidence suggests that p-tau may be a better marker for AD than would total tau, the study lacks a direct comparison of these two measures. "As a counterpoint, a recent study of MCI found that an increased CSF level of total tau was a highly sensitive marker for later cognitive decline," writes Galasko, citing a report last year by Riemenschneider and colleagues).
However, Galasko emphasizes that p-tau appears to be more specific, that is, able to distinguish AD from other tauopathies, as well as disorders such as stroke (in which total tau increases temporarily but p-tau 181 does not).
Further study of the accuracy of these tests is clearly necessary, write the authors, especially given that CSF testing requires lumbar punctures, which carry certain risks even in specialized clinics.
In the same issue of the Archives, research by Gomez-Tortosa and colleagues found that measuring total tau achieves 76 percent specificity in distinguishing Alzheimer's from dementia with Lewy bodies. Also, Rosso and colleagues found that patients with frontotemporal dementia caused by tau mutations do not have CSF increases in p-tau 181 relative to controls. Readers interested in CSF markers for incipient Alzheimer’s may also want to watch out for a review on the topic by Kaj Blennow and Harald Hampel in the October Lancet Neurology, at http://neurology.thelancet.com/.-Hakon Heimer.
Maddalena A, Papassotiropoulos A, Muller-Tillmanns B, Jung HH, Hegi T, Nitsch RM, Hock C. Abstract Biochemical diagnosis of Alzheimer disease by measuring the cerebrospinal fluid ratio of phosphorylated tau protein to β-amyloid peptide42. Arch Neurol. 2003 Sep;60(9):1202-6. Abstract
Galasko D. Cerebrospinal fluid biomarkers in Alzheimer disease: a fractional improvement? Arch Neurol. 2003 Sep;60(9):1195-6. Abstract
Rosso SM, van Herpen E, Pijnenburg YA, Schoonenboom NS, Scheltens P, Heutink P, van Swieten JC. Total tau and phosphorylated tau 181 levels in the cerebrospinal fluid of patients with frontotemporal dementia due to P301L and G272V tau mutations. Arch Neurol. 2003 Sep;60(9):1209-13. Abstract
Gomez-Tortosa E, Gonzalo I, Fanjul S, Sainz MJ, Cantarero S, Cemillan C, Yebenes JG, del Ser T. Cerebrospinal fluid markers in dementia with lewy bodies compared with Alzheimer disease. Arch Neurol. 2003 Sep;60(9):1218-22. Abstract