title: CSF biomarkers cutoffs: the importance of coincident neuropathological diseases.
abstract: The effects of applying clinical versus neuropathological diagnosis and the inclusion of cases with coincident neuropathological diagnoses have not been assessed specifically when studying cerebrospinal fluid (CSF) biomarker classification cutoffs for patients with neurodegenerative diseases that cause dementia. Thus, 142 neuropathologically diagnosed neurodegenerative dementia patients [71 Alzheimer's disease (AD), 29 frontotemporal lobar degeneration (FTLD), 3 amyotrophic lateral sclerosis, 7 dementia with Lewy bodies, 32 of which cases also had coincident diagnoses] were studied. 96 % had enzyme-linked immunosorbant assay (ELISA) CSF data and 77 % had Luminex CSF data, with 43 and 46 controls for comparison, respectively. Aβ(42), total, and phosphorylated tau(181) were measured. Clinical and neuropathological diagnoses showed an 81.4 % overall agreement. Both assays showed high sensitivity and specificity to classify AD subjects against FTLD subjects and controls, and moderate sensitivity and specificity for classifying FTLD subjects against controls. However, among the cases with neuropathological diagnoses of AD plus another pathology (26.8 % of the sample), 69.4 % (ELISA) and 96.4 % (Luminex) were classified as AD according to their biomarker profiles. Use of clinical diagnosis instead of neuropathological diagnosis led to a 14-17 % underestimation of the biomarker accuracy. These results show that while CSF Aβ and tau assays are useful for diagnosis of AD and neurodegenerative diseases even at MCI stages, CSF diagnostic analyte panels that establish a positive diagnosis of Lewy body disease and FTLD are also needed, and must be established based on neuropathological rather than clinical diagnoses.
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, CNDR, University of Pennsylvania School of Medicine, 3rd Floor Maloney Building, 3600 Spruce Street, Philadelphia, PA 19104, USA.
authors.forename: Jon B
authors.initials: JB
authors.lastname: Toledo
authors.forename: Johannes
authors.initials: J
authors.lastname: Brettschneider
authors.forename: Murray
authors.initials: M
authors.lastname: Grossman
authors.forename: Steven E
authors.initials: SE
authors.lastname: Arnold
authors.forename: William T
authors.initials: WT
authors.lastname: Hu
authors.forename: Sharon X
authors.initials: SX
authors.lastname: Xie
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Shaw
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D000690:Amyotrophic Lateral Sclerosis / Q000134:cerebrospinal fluid*; D000704:Analysis of Variance; D019540:Area Under Curve; D015415:Biomarkers / Q000134:cerebrospinal fluid*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D057180:Frontotemporal Dementia / Q000134:cerebrospinal fluid* / Q000473:pathology; D057174:Frontotemporal Lobar Degeneration / Q000134:cerebrospinal fluid* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D011569:Psychiatric Status Rating Scales; D012680:Sensitivity and Specificity; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins