Criteria for an ideal diagnostic marker / Current status for CSF biomarkers
Detect a fundamental feature of the molecular pathogenesis or neuropathology of AD / Autopsy and PIB-PET studies have shown that CSF Ab1–42 is a marker of fibrillar amyloid pathology in the brain1–4
Several lines of evidence show that CSF t-tau reflects the intensity of axonal degeneration and damage,5–11 although the release of tau from tangle-bearing neurons might contribute2
Autopsy studies show that CSF p-tau reflects tangle pathology in the brain2,12
Validated in neuropathologically confirmed AD cases / Several studies based on patient series with autopsy-confirmed diagnoses have verified the high sensitivity and specificity of CSF biomarkers in differentiating patients with AD from cognitively normal elderly individuals and patients with other forms of dementia13–17
Have a sensitivity >80% for detecting AD and a specificity >80% for differentiating AD from other dementias / Numerous studies have shown that CSF biomarkers have sensitivity and specificity values in the context of AD in the range of 80–90%;18,19 such value have been shown in large prospective studies20
Be able to detect AD in its early stages (i.e. during MCI) / Several large multicenter studies have shown that CSF biomarkers have a high predictive value for identifying prodromal AD in cases of MCI14,21,22
Be reliable / Data on analytical methods is available for both ELISA and xMAPâ methods (Luminex, Austin, TX, USA), with both approaches showing excellent antibody specificity and assay performance23–25
Within-assay and within-laboratory variation for the biomarker assays are low, but between-laboratory variation is high, which highlights a need for standardization26
Be noninvasive / LP can be regarded as a moderately invasive procedure,27 but large prospective studies show that there are no serious complications of this approach, and that the risk of post-LP headache in patients admitted for evaluation of cognitive symptoms is very low28–30
Be simple to perform, inexpensive and, thus, adaptable in routine clinical practice / ELISAs are part of the standard analytical techniques used in clinical laboratories; CSF biomarkers are increasingly used in clinical practice31,32
These criteria were outlined by the Ronald and Nancy Reagan Research Institute–National Institute on Aging Working Group on Biomarkers for AD.27 Abbreviations: AD, Alzheimer disease; CSF, cerebrospinal fluid; ELISA, enzyme-linked immunosorbent assay; LP, lumbar puncture; MCI, mild cognitive impairment; PIB, Pittsburgh compound B; p-tau, phosphorylated tau; t-tau, total tau.
1. Strozyk, D., Blennow, K., White, L. R. & Launer, L. J. CSF Ab 42 levels correlate with amyloid-neuropathology in a population-based autopsy study. Neurology 60, 652–656 (2003).
2. Tapiola, T. et al. Cerebrospinal fluid b-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain. Arch. Neurol. 66, 382–389 (2009).
3. Fagan, A. M. et al. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Ab42 in humans. Ann. Neurol. 59, 512-519 (2006).
4. Forsberg, A. et al. PET imaging of amyloid deposition in patients with mild cognitive impairment. Neurobiol. Aging 29, 1456–1465 (2008).
5. Hesse, C. et al. Transient increase in total tau but not phospho-tau in human cerebrospinal fluid after acute stroke. Neurosci. Lett. 297, 187–190 (2001).
6. Ost, M. et al. Initial CSF total tau correlates with 1-year outcome in patients with traumatic brain injury. Neurology 67, 1600–1604 (2006).
7. Zetterberg, H. et al. Neurochemical aftermath of amateur boxing. Arch. Neurol. 63, 1277–1280 (2006).
8. Blom, E. S. et al. Rapid progression from mild cognitive impairment to Alzheimer's disease in subjects with elevated levels of tau in cerebrospinal fluid and the APOE e4/e4 genotype. Dement. Geriatr. Cogn. Disord. 27, 458–464 (2009).
9. Samgard, K. et al. Cerebrospinal fluid total tau as a marker of Alzheimer's disease intensity. Int. J. Geriatr. Psychiatry (2009).
10. Wallin, A. K., Hansson, O., Blennow, K., Londos, E. & Minthon, L. Can CSF biomarkers or pre-treatment progression rate predict response to cholinesterase inhibitor treatment in Alzheimer's disease? Int. J. Geriatr. Psychiatry 24, 638–647 (2009).
11. Otto, M. et al. Elevated levels of tau-protein in cerebrospinal fluid of patients with Creutzfeldt–Jakob disease. Neurosci. Lett. 225, 210–212 (1997).
12. Buerger, K. et al. CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer's disease. Brain 129, 3035–3041 (2006).
13. Koopman, K. et al. Improved discrimination of autopsy-confirmed Alzheimer's disease (AD) from non-AD dementias using CSF P-tau181P. Neurochem. Int. 55, 214–218 (2009).
14. Shaw, L. M. et al. Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects. Ann. Neurol. 65, 403–413 (2009).
15. Clark, C. M. et al. Cerebrospinal fluid tau and b-amyloid: how well do these biomarkers reflect autopsy-confirmed dementia diagnoses? Arch. Neurol. 60, 1696–1702 (2003).
16. Bian, H. et al. CSF biomarkers in frontotemporal lobar degeneration with known pathology. Neurology 70, 1827–1835 (2008).
17. Sunderland, T. et al. Decreased b-amyloid1–42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer disease. JAMA 289, 2094–2103 (2003).
18. Blennow, K. Cerebrospinal fluid protein biomarkers for Alzheimer's disease. NeuroRx 1, 213–225 (2004).
19. Blennow, K. & Hampel, H. CSF markers for incipient Alzheimer's disease. Lancet Neurol. 2, 605–613 (2003).
20. Blennow, K. CSF biomarkers for Alzheimer's disease: use in early diagnosis and evaluation of drug treatment. Expert Rev. Mol. Diagn. 5, 661–672 (2005).
21. Mattsson, N. et al. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA 302, 385–393 (2009).
22. Visser, P. J. et al. Prevalence and prognostic value of CSF markers of Alzheimer's disease pathology in patients with subjective cognitive impairment or mild cognitive impairment in the DESCRIPA study: a prospective cohort study. Lancet Neurol. 8, 619–627 (2009).
23. Olsson, A. et al. Simultaneous measurement of beta-amyloid(1–42), total tau, and phosphorylated tau (Thr181) in cerebrospinal fluid by the xMAP technology. Clin. Chem. 51, 336–345 (2005).
24. Vanderstichele, H. et al. Standardization of measurement of b-amyloid1–42 in cerebrospinal fluid and plasma. Amyloid 7, 245–258 (2000).
25. Vanderstichele, H. et al. Analytical performance and clinical utility of the INNOTEST PHOSPHO-TAU181P assay for discrimination between Alzheimer's disease and dementia with Lewy bodies. Clin. Chem. Lab. Med. 44, 1472–1480 (2006).
26. Verwey, N. A. et al. A worldwide multicentre comparison of assays for cerebrospinal fluid biomarkers in Alzheimer's disease. Ann. Clin. Biochem. 46, 235–240 (2009).
27. [No authors listed] Consensus report of the Working Group on: "Molecular and Biochemical Markers of Alzheimer's Disease". The Ronald and Nancy Reagan Research Institute of the Alzheimer's Association and the National Institute on Aging Working Group. Neurobiol. Aging 19, 109–116 (1998).
28. Andreasen, N. et al. Evaluation of CSF-tau and CSF-Ab42 as diagnostic markers for Alzheimer disease in clinical practice. Arch. Neurol. 58, 373–379 (2001).
29. Blennow, K., Wallin, A. & Hager, O. Low frequency of post-lumbar puncture headache in demented patients. Acta Neurol. Scand. 88, 221–223 (1993).
30. Hansson, O. et al. Combined rCBF and CSF biomarkers predict progression from mild cognitive impairment to Alzheimer's disease. Neurobiol. Aging 30, 165–173 (2007).
31. Frisoni, G. B. et al. Markers of Alzheimer's disease in a population attending a memory clinic. Alzheimers Dement. 5, 307–317 (2009).
32. Parnetti, L., Lanari, A., Silvestrelli, G., Saggese, E. & Reboldi, P. Diagnosing prodromal Alzheimer's disease: role of CSF biochemical markers. Mech. Ageing Dev. 127, 129–132 (2006).