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Dementia diagnostics 2.0--transfer from research studies into routine clinical practice.

Neurodegenerative disorders are a major health and quality-of-life problem in our aging society. Associated disease groups include Alzheimer disease (AD), [2] Parkinson disease, Parkinson disease dementia, and frontotemporal lobar degeneration. A common feature of these diseases is the protein aggregates that can be found in the brain. Strategies to stop or delay the accumulation of these protein aggregates have been proposed, but essentially no cure exists to reverse the damage that has already occurred in the brain and neuronal tissue.

Until the early 1990s, the laboratory diagnosis of neurodegenerative disorders mainly concentrated on the exclusion of other nonneurodegenerative diseases. For example, cerebrospinal fluid analysis was performed primarily to exclude the presence of encephalitis. Because neurodegenerative processes start long before clinical symptoms become obvious and proceed for years in a slow but irreversible way, it is of paramount importance to diagnose these processes as early as possible and to be able to distinguish between the different disorders, because their treatments differ. Therefore, researchers have concentrated within the last decade on finding biomarkers to support a diagnosis. With such biomarkers, the answers to specific questions are being sought. What kind of dementia is it (e.g., AD vs frontotemporal lobar degeneration)? Does the patient indeed suffer from a dementia or not (e.g., dementia vs depression)? Will the patient develop a dementia or not (e.g., progression from minimal cognitive complaints to AD)? Will the patient with Parkinson disease develop a dementia (1, 2)?

Unfortunately, lumbar puncture is an invasive method that cannot be used for screening and is restricted to patients with clinically important symptoms. Thus, it is particularly important to develop minimally invasive, analytically sensitive, and low-cost tools to detect relevant biomarkers in a more easily obtainable body fluid, such as blood. Several potential blood biomarkers have been suggested for AD (3), with additional markers being proposed each year. Until now, however, none of these biomarkers, individually or in combination, has reached the level of reproducibility and reliability needed for use in routine clinical practice. For this reason, cerebrospinal fluid is still the body fluid of choice.

A cornerstone of the neuropathologic diagnosis of AD is the presence of senile plaques, which consist largely of amyloid [beta] (A[beta]) peptides (4) and intracellularly located Alzheimer fibrils (neurofibrillary tangles) of hyperphosphorylated [tau]-protein monomers (5) that have formed double-helix filament pairs. Therefore, it seems logical to measure A[beta] peptides and r protein as "pathologic hallmarks."

Several studies have convincingly shown with the demonstration of the combination of a decreased A[beta]1-42 concentration and an increased [tau]-protein concentration that AD patients can be differentiated from nondemented control individuals (6, 7). Additionally, this differentiation between AD and nondemented controls has been shown to be slightly improved by the use of phospho-[tau] protein (8). The use of ratios (e.g., A[beta]1-42/phospho-[tau]) further improved this differentiation, and, more recently, patients with a mild cognitive disorder were also shown to have much higher probability of converting to AD if they present with a typical biomarker constellation (9, 10). These findings have led to the inclusion of these biomarkers in the new research criteria for AD (11).

There are some drawbacks to these biomarkers, however. They are rarely measured in routine clinical settings (12), cutoff values and ratios for their interpretation can be applied only to the investigated cohort, their differential diagnostic values depend highly on the patient's stage of dementia, and, finally, there is large variation in their measurement among different medical centers (13) that makes the introduction of ratios questionable.

In this issue of Clinical Chemistry, Mulder and coworkers, who are experts in the neurochemical diagnosis field, provide data on the performance of these biomarkers in a routine setting over a 7-year period (14). They confirmed the high diagnostic value of the use of increased [tau] protein and decreased A[beta]1-42 concentrations for AD; however, their data did not support the improved diagnostic accuracy of the use of phosphorylated [tau] protein. This finding is inconsistent with earlier studies but possibly reflects the true performance of the test in a routine setting. In addition, these investigators have demonstrated that cutoff values vary over time, possibly from assay problems or lot-to-lot variation, and that the stability of these cutoff values must be monitored.

The data of Mulder and coworkers suggest that tests for the diagnosis of dementia suffer from the same limitations and problems as other tests, such as lot-to-lot variation and high imprecision. Now is the time to overcome these issues by initiating standardization and interlaboratory comparison programs (15) so that study results can be extrapolated into clinical practice. Dementia diagnostics 2.0 should start then.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition ofdata, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures of Potential Conflicts of Interest: No authors declared any potential conflicts of interest.

Role of Sponsor: The funding organizations played no role in the design of study, choice of enrolled patients, review and interpretation of data, or preparation or approval of manuscript.


(1.) Otto M, Lewczuk P, Wiltfang J. Neurochemical approaches of cerebrospinal fluid diagnostics in neurodegenerative diseases. Methods 2008;44:289-98.

(2.) Jesse S, Steinacker P, Lehnert S, Gillardon F, Hengerer B, Otto M. Neurochemical approaches in the laboratory diagnosis of Parkinson and Parkinson dementia syndromes: a review. CNS Neurosci Ther 2009;15:157-82.

(3.) Ray S, Britschgi M, Herbert C, Takeda-Uchimura Y, Boxer A, Blennow K, et al. Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins. Nat Med 2007;13:1359-62.

(4.) Masters CL, Multhaup G, Simms G, Pottgiesser J, Martins RN, Beyreuther K. Neuronal origin of a cerebral amyloid: neurofibrillary tangles of Alzheimer's disease contain the same protein as the amyloid of plaque cores and blood vessels. EMBO J 1985;4:2757-63.

(5.) Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A 1986;83:4913-7.

(6.) Blennow K, Hampel H. CSF markers for incipient Alzheimer's disease. Lancet Neurol 2003;2:605-13.

(7.) Galasko D. Biomarkers for Alzheimer's disease--clinical needs and application. J Alzheimers Dis 2005;8:339-46.

(8.) Hampel H, Buerger K, Zinkowski R, Teipel SJ, Goernitz A, Andreasen N, et al. Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study. Arch Gen Psychiatry 2004;61:95-102.

(9.) Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L. Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 2006;5:228-34.

(10.) de Leon MJ, DeSanti S, Zinkowski R, Mehta PD, Pratico D, Segal S, et al. Longitudinal CSF and MRI biomarkers improve the diagnosis of mild cognitive impairment. Neurobiol Aging 2006;27:394-401.

(11.) Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, et al. Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 2007;6:734-46.

(12.) Ibach B, Binder H, Dragon M, Poljansky S, Haen E, Schmitz E, et al. Cerebrospinal fluid tau and beta-amyloid in Alzheimer patients, disease controls and an age-matched random sample. Neurobiol Aging 2006;27: 1202-11.

(13.) Lewczuk P, Beck G, Ganslandt O, Esselmann H, Deisenhammer F, Regeniter A, et al. International quality control survey of neurochemical dementia diagnostics. Neurosci Lett 2006;409:1-4.

(14.) Mulder C, Verwey NA, van der Flier WM, Bouwman FH, Kok A, van Elk EJ, et al. Amyloid/3(1-42), total tau, and phosphorylated tau as cerebrospinal fluid biomarkers for the diagnosis of Alzheimer disease. Clin Chem 2010; 56:248-53.

(15.) Verwey NA, van der Flier WM, Blennow K, Clark C, Sokolow S, De Deyn PP, et al. A worldwide multicentre comparison of assays for cerebrospinal fluid biomarkers in Alzheimer's disease. Ann Clin Biochem 2009;46:235-40.

Markus Otto [1] *

[1] Department of Neurology, University of Ulm, Ulm, Germany.

[2] Nonstandard abbreviations: AD, Alzheimer disease; A[beta] amyloid [beta].

* Address correspondence to the author at: Department of Neurology, University of Ulm, Steinhovelstr. 1, 89075 Ulm, Germany. Fax +49-731-500-63012; e-mail

Received September 14, 2009; accepted September 21, 2009.

Previously published online at DOI: 10.1373/clinchem.2009.136051
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Title Annotation:Editorial
Author:Otto, Markus
Publication:Clinical Chemistry
Date:Feb 1, 2010
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