Fluid biomarkers for Alzheimer’s disease: standardization and recent developments

Abstract

Biomarkers in MedicineVol. 6, No. 4 Theme: Biomarkers in Alzheimer's - ForewordFree AccessFluid biomarkers for Alzheimer’s disease: standardization and recent developmentsHenrik Zetterberg & Pieter Jelle VisserHenrik Zetterberg* Author for correspondenceInstitute of Neuroscience & Physiology, Department of Psychiatry & Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, S-431 80 Mölndal, Sweden and Laboratory of Clinical Chemistry, Sahlgrenska University Hospital, S-413 45 Gothenburg, Sweden and UCL London, Institute of Neurology, Queen Square, London WC1N 3BG, UK. Search for more papers by this authorEmail the corresponding author at henrik.zetterberg@clinchem.gu.se & Pieter Jelle VisserDepartment of Psychiatry & Neuropsychology, Institute of Brain & Behavior, University of Maastricht, Maastricht, The Netherlands and Department of Neurology, VU University Medical Center, Amsterdam, The NetherlandsSearch for more papers by this authorPublished Online:23 Aug 2012https://doi.org/10.2217/bmm.12.40AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Three cerebrospinal fluid (CSF) biomarkers (the 42-amino acid fragment of Aβ, phosphorylated tau and total tau) have been developed, which track the key elements of Alzheimer’s pathology (i.e., plaque and tangle pathology and cortical neurodegeneration) [1]. These biomarkers have opened up for longitudinal studies that help to delineate the sequence of events during Alzheimer’s disease (AD) and test the validity of the amyloid cascade hypothesis in humans. Moreover, they may be used for the diagnosis of AD in nondemented subjects; mounting evidence suggests that amyloid accumulation in the brain is not benign. More specifically, low CSF levels of Aβ42 that reflect amyloid pathology appear already in preclinical disease stages and predict future cognitive decline and neurodegeneration [2–7].Recently, the Alzheimer’s Association and the National Institute of Aging of the NIH published revised diagnostic criteria for AD that incorporate biomarker information as diagnostic adjuncts in predementia stages [101]. In parallel with these developments, there has been increasing awareness in the field that, although relative differences in AD biomarker levels between AD patients and controls most often are similar across studies, the absolute levels may vary [8]. These differences may be due to differences in assay formats, batch-to-batch variation in kit reagents, systematic differences in preanalytical or analytical procedures, or genetic factors. There is also a certain degree of random variation in sample handling and laboratory measurements. Some of these variations have been illustrated in the global Alzheimer’s Association quality control program on CSF biomarkers [9] and also seen in multicenter trials [10,11].This themed issue of Biomarkers in Medicine is dedicated to the clinical use of fluid biomarkers for AD, the need for standardization of sample handling and biomarker measurements, the effect of genetic markers on biomarker levels, the need for new biomarker candidates not only in CSF but also in blood, and ethical issues related to biomarker-assisted diagnosis making. The content reflects current cutting-edge work led by several international networks, including the Alzheimer’s Association Global Consortium for Biomarker Standardization [102], the EU-funded BIOMARKAPD project [103], the International Federation of Clinical Chemistry and Laboratory Medicine Working Group on CSF Proteins [104], the Alzheimer’s Disease Neuroimaging Initiative [105] and AddNeuroMed [106].We hope that this special issue will stimulate further work in our common quest to improve the clinical evaluation of patients with suspected AD or other neurodegenerative diseases and facilitate the design and conductance of clinical trials of novel drugs against the disorder.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.References1 Blennow K, Hampel H, Weiner M, Zetterberg H. Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat. Rev. Neurol.6,131–144 (2010).Crossref, Medline, CAS, Google Scholar2 Fagan AM, Roe CM, Xiong C, Mintun MA, Morris JC, Holtzman DM. Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. Arch. Neurol.64,343–349 (2007).Crossref, Medline, Google Scholar3 Gustafson DR, Skoog I, Rosengren L, Zetterberg H, Blennow K. Cerebrospinal fluid beta-amyloid 1–42 concentration may predict cognitive decline in older women. J. Neurol. Neurosurg. Psychiatry78,461–464 (2007).Crossref, Medline, Google Scholar4 Stomrud E, Hansson O, Blennow K, Minthon L, Londos E. Cerebrospinal fluid biomarkers predict decline in subjective cognitive function over 3 years in healthy elderly. Dement. Geriatr. Cogn. Disord.24,118–124 (2007).Crossref, Medline, CAS, Google Scholar5 Ringman JM, Coppola G, Elashoff D et al. Cerebrospinal fluid biomarkers and proximity to diagnosis in preclinical familial Alzheimer’s disease. Dement. Geriatr. Cogn. Disord.33,1–5 (2012).Crossref, Medline, CAS, Google Scholar6 Ringman JM, Younkin SG, Pratico D et al. Biochemical markers in persons with preclinical familial Alzheimer disease. Neurology71,85–92 (2008).Crossref, Medline, CAS, Google Scholar7 Buchhave P, Minthon L, Zetterberg H, Wallin AK, Blennow K, Hansson O. Cerebrospinal fluid levels of beta-amyloid 1–42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia. Arch. Gen. Psychiatry69,98–106 (2012).Crossref, Medline, CAS, Google Scholar8 Mattsson N, Blennow K, Zetterberg H. Inter-laboratory variation in cerebrospinal fluid biomarkers for Alzheimer’s disease: united we stand, divided we fall. Clin. Chem. Lab. Med.48,603–607 (2010).Crossref, Medline, CAS, Google Scholar9 Mattsson N, Andreasson U, Persson S et al. The Alzheimer’s Association external quality control program for cerebrospinal fluid biomarkers. Alzheimers Dement.7,386–395 e386 (2011).Crossref, Medline, CAS, Google Scholar10 Mattsson N, Zetterberg H, Hansson O et al. SF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA302,385–393 (2009).Crossref, Medline, CAS, Google Scholar11 Visser PJ, Verhey F, Knol DL 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).Crossref, Medline, Google Scholar101 Alzheimer’s and Dementia. New criteria and guidelines for Alzheimer’s disease diagnosis. www.alzheimersanddementia.org/content/ncgGoogle Scholar102 Alz.org Research Center. Global consortium for biomarker standardization. www.alz.org/research/funding/global_biomarker_consortium.aspGoogle Scholar103 JPND Research. BIOMARKAPD. www.neurodegenerationresearch.eu/initiatives/biomarker-transnational-call/results-of-funding-call/biomarkapdGoogle Scholar104 International Federation of Clinical Chemistry and Laboratory Medicine. IFCC – scientific division (SD). www.ifcc.org/ifcc-scientific-divisionGoogle Scholar105 ADNI. Alzheimer’s Disease Neuroimaging Initiative. www.adni-info.orgGoogle Scholar106 The AddNeuroMed Study. Scientific aims and objectives of AddNeuroMed. www.innomed-addneuromed.comGoogle ScholarFiguresReferencesRelatedDetailsCited ByUse of amyloid-PET to determine cutpoints for CSF markers14 October 2015 | Neurology, Vol. 86, No. 1 Vol. 6, No. 4 Follow us on social media for the latest updates Metrics History Published online 23 August 2012 Published in print August 2012 Information© Future Medicine LtdFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download