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ARTICLES: M. Riemenschneider, S. Wagenpfeil, J. Diehl, N. Lautenschlager, T. Theml, B. Heldmann, A. Drzezga, T. Jahn, H. Förstl, and A. Kurz Tau and Aß42 protein in CSF of patients with frontotemporal degeneration Neurology 2002; 58: 1622-1628 [Abstract] [Full text] [PDF]

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Reply to Letter to the Editor

M Riemenschneider, S Wagenpfeil, A Kurz, and H Forstl   (23 October 2002)

Tau and Aß42 protein in CSF of patients with frontotemporal degeneration

Yolande AL Pijnenburg, Niki SNM Schoonenboom and Philip Scheltens   (23 October 2002)

Reply to Letter to the Editor 23 October 2002
M Riemenschneider Technische Universitat Munchen Munich Germany, S Wagenpfeil, A Kurz, and H Forstl Send Correspondence to journal: Re: Reply to Letter to the Editor m.riemenschneider{at}lrz.tu-muenchen.de M Riemenschneider, et al.	We appreciate Pijnenburg et al. [3] comments that markers of a pathological condition should improve the diagnostic algorithm. This is rarely the case. In our explorative study [1] we noted slightly elevated levels of tau and moderately decreased Ab42 concentrations in the CSF of patients with FTD. Although, this pattern may not be specific for FTD, [2] the discrimination of FTD from AD, probably the most common issue for a clinician----had sensitivity and specificity values of 85%. As mentioned before, due to the low prevalence rate of FTD (e.g. 5-15%) in a demented population the combination of both markers results in a low positive predictive value (PPV; 23-50%), which is accompanied by a high negative predictive value (NPV; 97-99%). Using this setting the marker combination would be better suited to exclude the presence of FTD. [1] Pijnenburg et al. [3] argue that in a young onset dementia population, the prevalence of FTD equals that of AD and the a priori chance of FTD may be as high as 50% leading to a decline of the NPV to 85%, which in our view still is remarkably high. However, they noted the PPV increases up to 85% and thus the marker combination approaches an ideal biomarker. [4] As mentioned by Pijnnenburg et al., [3] the value of both markers remains limitless by the overlap between FTD and AD. For the future an improvement of the diagnostic accuracy based on relatively inexpensive biomarkers will be mandatory. In particular, two approaches will be followed. One is based on the identification of factors (e.g. genetic factors), which cause low tau protein concentrations in patients with AD, (e.g. cathepsin D polymorphism). [5] The second approach to increase diagnostic accuracy will aim at the development and application of more specific markers such as measurement of phosphorylated tau proteins, which may be more specific for AD. [6] Concerning the suggested combination of markers, we agree that a combination of clinical, demographic, neuroimaging, and biochemical markers will bring us closer to the neuropathological gold standard. References: 1. Riemenschneider M, Wagenpfeil S, Diehl J, et al. Tau and Ab42 protein in CSF of patients with frontotemporal degeneration. Neurology 2002;58:1622-1628. 2. Vanmechelen E, Vanderstichele H, Hulstaert F, et al. Cerebrospinal fluid tau and beta-amyloid(1-42) in dementia disorders. Mech Ageing Dev 2001;122:2005-2011. 3. Pijnenburg Y, Schoonenboom N, Scheltens P. Measurement of tau and Ab42 proteins in CSF of patients with frontotemporal lobar degeneration: What’s the use?. Neurology.... 4. Consensus report of the working group on "Molecular and biochemical markers of Alzheimer‘s disease, Neurobiol Aging 1998;19:109- 116. 5. Riemenschneider M, Diehl J, Wagenpfeil S, Förstl H, Kurz A. The cathepsin exon 2 polymorphism: functional effects on cerebrospinal fluid concentrations of beta-amyloid (1-42), tau, and cystatin C in patients with Alzheimer’s disease. Neurobiol Aging 2002;23:S375. 6. Riemenschneider M, Wagenpfeil S, Vanderstichele H, et al. The phosph-tau/total tau ratio in cerebrospinal fluid discriminates Creutzfeldt-Jacob disease from other dementias. Neurobiol Aging 2002;23:S274.
Tau and Aß42 protein in CSF of patients with frontotemporal degeneration 23 October 2002
Yolande AL Pijnenburg VU Medical Center Amsterdam The Netherlands, Niki SNM Schoonenboom and Philip Scheltens Send Correspondence to journal: Re: Tau and Aß42 protein in CSF of patients with frontotemporal degeneration y.pijnenburg{at}vumc.nl Yolande AL Pijnenburg, et al.	Riemenschneider et al. describe CSF tau and Aâ42 in patients with frontotemporal degeneration. [1] They included patients with all three prototypical variants of frontotemporal lobar degeneration (FTLD): frontotemporal dementia, semantic dementia and progressive nonfluent aphasia. [2] They found intermediate high levels of tau and slightly decreased levels of Aâ42 in the FTLD-group, compared with AD and cognitively healthy controls that underwent myelography. Combined measurement of these markers yielded reasonable diagnostic accuracy, discriminating FTLD and AD with sensitivity and specificity of 85% on the one hand, and FTLD and controls with a sensitivity of 90% and specificity of 77% on the other hand. Despite these positive results one must ask what the clinical relevance is. In clinical practice, differential diagnosis is usually not based on the choice between two predefined conditions, such as FTLD and AD. Especially intermediate levels of CSF tau, but also of Aâ42 can be found in a number of other neurodegenerative conditions. [3] Highly variable and contradictory CSF-findings in FTLD have been demonstrated and can be explained by both the lack of uniform intracerebral tau-pathology in FTLD as well as the spatial variation within FTLD. In addition, what does measurement of these CSF biomarkers add to the diagnosis of FTLD based on the already highly accurate clinical-diagnostic criteria? [4] The authors argue that the high negative predictive value (99-97%) is most valuable in this respect, but this is mainly determined by the relative low prevalence of FTLD (5-15%). In a young onset dementia population however, the prevalence of FTLD equals that of AD [5] and the a priori chance of FTLD may be as high as 50% yielding a lower negative predictive value of 85%. In this respect, since FTLD is a presenile dementia, in trying to mimic the memory clinic setting it would have been more appropriate to compare the FTLD patients with age-matched subjects, consisting of both AD patients and subjects with subjective memory complaints. Based on these arguments we do agree with the authors that the accuracy of these markers is reasonable, at best, but the clinical utility is still hampered by the considerable overlap with both other types of dementia and subjects without dementia. When studying CSF-biomarkers in dementia, the additional value over clinical diagnostic criteria should be investigated. The challenge is to look for (a combination of) more disease -specific markers. In this respect the combination of CSF and imaging markers may be more promising. References 1.Riemenschneider M, Wagenpfeil S, Diehl J, et al. Tau and Abeta42 protein in CSF of patients with frontotemporal degeneration. Neurology 2002;58:1622-1628. 2.Neary D, Gustafson L, Passant U, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998;51:1546-1554. 3.Vanmechelen E, Vanderstichele H, Hulstaert F, et al. Cerebrospinal fluid tau and beta-amyloid (1-42) in dementia disorders. Mech Ageing Dev 2001;122:2005-2011. 4.Rosen HJ, Hartikainen KM, Jagust W, et al. Utility of clinical criteria in differentiating frontotemporal lobar degeneration (FTLD) from AD. Neurology 2002;58:1608-1615. 5.Ratnavalli E, Brayne C, Dawson K, Hodges JR. The prevalence of frontotemporal dementia. Neurology 2002;58:1615-1621.