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ABSTRACT: Immuno-assays are increasingly used for quantification of protein biomarkers for neurodegeneration. It has been proposed to use such cerebrospinal fluid (CSF) protein biomarkers as diagnostic tests for Alzheimer's disease. In two recent world-wide validation studies we found the analytical accuracy to be poor (inter-laboratory coefficient of variation, CV>10%) for CSF tau protein, CSF phospho-tau protein, CSF amyloid beta protein and the CSF neurofilament light chain protein. Retrospectively we suspected that the lack of preparation of accurate and consistent protein standards may have been one reason for the poor inter-laboratory CV. Here we confirm this hypothesis prospectively under standardised and optimised conditions. The CVs for CSF tau, CSF phospho-tau and CSF amyloid beta of individually prepared standards are 8%, 12% and 12% compared to significantly lower CVs for batch prepared standards (5%, 8%, 7%, respectively, p<0.05). This issue will need to be solved in order to ensure that the attempts to include these CSF protein biomarkers either as a diagnostic tool or a secondary outcome measure for treatment trials will be successful.
Journal of neuroscience methods 11/2010; 193(2):296-9. · 2.30 Impact Factor
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A Petzold,
M D Chapman,
S Schraen,
N A Verwey,
F Pasquier,
S Bombois,
J Brettschneider,
N C Fox,
C A F von Arnim, C Teunissen,
Y Pijnenburg,
M W Riepe,
M Otto,
H Tumani,
P Scheltens,
L Buee,
M N Rossor
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ABSTRACT: Newly proposed diagnostic criteria for Alzheimer's disease include cerebrospinal fluid (CSF) tau levels as one core supportive criterion. The published high sensitivity and specificity figures for CSF tau levels in Alzheimer's disease are offset by the large range of proposed cutoff values (9.6 pg/mL to 1140 pg/mL). This study aimed to provide guidance on how to establish, validate and audit CSF tau cutoff values using an unbiased, two-stage multicentre strategy. Both receiver operator characteristics (ROC) optimised and population-based cutoff values were calculated on a pilot dataset (n=99), validated in a large dataset (n=560) and then compared to the literature. The data suggest using an ROC optimised cutoff level of 323+/-51.7 pg/mL allowing for the published inter-laboratory coefficient of variation of 16%. This cutoff level was confirmed in a prospective audit (n=100). As demand for CSF tau levels will increase globally, the accuracy of local CSF hTau cutoff levels can be compared against this benchmark.
Experimental Neurology 12/2009; 223(2):432-8. · 4.70 Impact Factor
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ABSTRACT: We reviewed the literature for disease-specific markers in cerebrospinal fluid (CSF) and evaluated their diagnostic and prognostic relevance in neurological diseases. High tau protein in combination with low amyloid beta levels has a high sensitivity (80%) and specificity (90%) for Alzheimer's disease (AD) against normal aging and can predict conversion of mild cognitive impairment to AD. The detection of 14-3-3 has a high sensitivity (80-90%) and specificity (90%) for the diagnosis of CJD. Low or undetectable CSF hypocretin-1 (orexin-1) levels constitute a diagnostic biomarker for narcolepsy with cataplexy. Detection of beta-2-transferrin indicates CSF contamination in oto- and rhinorrhoe with a sensitivity of > 79% at a specificity of 95% similar to the beta-trace protein (sensitivity > 90%, specificity 100%). However, beta-trace protein is faster and cheaper to perform. Possible future biomarkers are: elevated levels of vascular endothelial growth factor are relatively sensitive (51-100%) and specific (73-100%) for leptomeningeal metastases from solid tumors and are associated with a poor prognosis in this condition. Elevated CSF neurofilament (Nf) levels probably reflect acute neuronal degeneration. The prognostic value of CSF Nf levels is highest in acute conditions such as subarachnoid hemorrhage, acute optic neuritis and neuromyelitis optica.
European Journal of Neurology 06/2009; 16(6):760-70. · 3.69 Impact Factor
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Bulletin of Environmental Contamination and Toxicology 03/1988; 40(2):204-11. · 1.02 Impact Factor
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A. Petzold,
M. D. Chapman,
S. Schraen,
N. A. Verwey,
F. Pasquier,
S. Bombois,
J. Brettschneider,
N. C. Fox,
C. A. von Arnim, C. Teunissen,
Y. Pijnenburg,
M. W. Riepe,
M. Otto,
H. Tumani,
P. Scheltens,
L. Buee,
M. N. Rossor
[show abstract]
[hide abstract]
ABSTRACT: Newly proposed diagnostic criteria for Alzheimer's disease include cerebrospinal fluid (CSF) tau levels as one core supportive criterion. The published high sensitivity and specificity figures for CSF tau levels in Alzheimer's disease are offset by the large range of proposed cutoff values (9.6 pg/mL to 1140 pg/mL). This study aimed to provide guidance on how to establish, validate and audit CSF tau cutoff values using an unbiased, two-stage multicentre strategy. Both receiver operator characteristics (ROC) optimised and population-based cutoff values were calculated on a pilot dataset (n=99), validated in a large dataset (n=560) and then compared to the literature. The data suggest using an ROC optimised cutoff level of 323+/-51.7 pg/mL allowing for the published inter-laboratory coefficient of variation of 16%. This cutoff level was confirmed in a prospective audit (n=100). As demand for CSF tau levels will increase globally, the accuracy of local CSF hTau cutoff levels can be compared against this benchmark.
Exp Neurol. 223(2):432-8.
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A. Petzold,
M.D. Chapman,
S. Schraen,
N.A. Verwey,
F. Pasquier,
S. Bombois,
J. Brettschneider,
N.C. Fox,
C.A.F. von Arnim, C. Teunissen,
Y. Pijnenburg,
M.W. Riepe,
M. Otto,
H. Tumani,
P. Scheltens,
L. Buee,
M.N. Rossor
[show abstract]
[hide abstract]
ABSTRACT: Newly proposed diagnostic criteria for Alzheimer's disease include cerebrospinal fluid (CSF) tau levels as one core supportive criterion. The published high sensitivity and specificity figures for CSF tau levels in Alzheimer's disease are offset by the large range of proposed cutoff values (9.6 pg/mL to 1140 pg/mL). This study aimed to provide guidance on how to establish, validate and audit CSF tau cutoff values using an unbiased, two-stage multicentre strategy. Both receiver operator characteristics (ROC) optimised and population-based cutoff values were calculated on a pilot dataset (n = 99), validated in a large dataset (n = 560) and then compared to the literature. The data suggest using an ROC optimised cutoff level of 323 ± 51.7 pg/mL allowing for the published inter-laboratory coefficient of variation of 16%. This cutoff level was confirmed in a prospective audit (n = 100). As demand for CSF tau levels will increase globally, the accuracy of local CSF hTau cutoff levels can be compared against this benchmark.
Experimental Neurology.
