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CSF biomarkers cutoffs: the importance of coincident neuropathological diseases
Open accessAbstract
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.
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“As has been shown by Toledo et al., FTD biomarker studies can be confounded by AD co-pathology [91].”
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Bernardi, E., Arranz, J., Rubio‐Guerra, S., Castro, J. G., Maure‐Blesa, L., Rodríguez‐Baz, Í., Peris‐Subiza, J., Selma‐González, J., Vera-Campuzano, E., Vaqué‐Alcázar, L., et al. (2026) · Research Square · doi:10.21203/rs.3.rs-10754560/v1
Metadata
- Authors
- Toledo, J. B., Brettschneider, J., Grossman, M., Arnold, S. E., Hu, W. T., Xie, S. X., Lee, V. M.-Y., Shaw, L. M., & Trojanowski, J. Q.
- Affiliations
- University of Pennsylvania (US)
- Emory University (US)
- Corresponding author
- Trojanowski, John Q.
- ORCID
- Venue
- Acta Neuropathologica
- Published
- 2012-04-22
- Volume
- 124
- Issue
- 1
- Pages
- 23-35
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC3551449
- OpenAlex
- W2022371215
- Cited by
- 182
- References
- 71
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 8 · 2023: 3 · 2022: 14 · 2021: 7 · 2020: 9 · 2019: 15 · 2018: 19 · 2017: 17 · 2016: 11 · 2015: 27 · 2014: 15 · 2013: 22 · 2012: 5
- FWCI
- 15.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Acta Neuropathologica (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Pennsylvania
- National Institutes of Health
- National Institute on Aging (AG15116, AG033101, P30AG010124, R01AG015116, P01AG017586, AG17586, AG-10124, K08AG033101)
- National Institute of Neurological Disorders and Stroke (P01NS044233, NS053488, NS-44266, P50NS053488, R01NS044266)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
- Keywords
- cerebrospinal fluid biomarkers, Alzheimer's disease, frontotemporal lobar degeneration, dementia with Lewy bodies, amyotrophic lateral sclerosis, amyloid-beta 42, phosphorylated tau 181, diagnostic accuracy, neurodegenerative dementia, mild cognitive impairment, biomarker cut-off values
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Amyotrophic Lateral Sclerosis, Analysis of Variance, Enzyme-Linked Immunosorbent Assay, Female, Humans, Male, Middle Aged, Peptide Fragments, Psychiatric Status Rating Scales, Sensitivity and Specificity, Biomarkers, Amyloid beta-Peptides, tau Proteins, Area Under Curve, Frontotemporal Lobar Degeneration, Frontotemporal Dementia
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