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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FTD biomarker studies can be confounded by AD co-pathology.
“As has been shown by Toledo et al., FTD biomarker studies can be confounded by AD co-pathology [91].”
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Self-citationFrontotemporal lobar degeneration: defining phenotypic diversity through personalized medicine
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Self-citationAdvances in the development of new biomarkers for Alzheimer’s disease
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Self-citationCerebrospinal fluid tau and amyloid-β1-42in patients with dementia
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Imaging and fluid biomarkers in frontotemporal dementia
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Elevated CSF GAP‐43 is Alzheimer's disease specific and associated with tau and amyloid pathology
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Self-citationLongitudinal change in CSF Tau and Aβ biomarkers for up to 48 months in ADNI
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Clinical and multimodal biomarker correlates of ADNI neuropathological findings
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Cerebrospinal fluid biomarkers in trials for Alzheimer and Parkinson diseases
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Alzheimer's disease cerebrospinal fluid biomarker in cognitively normal subjects
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Self-citationPlasma amyloid beta measurements - a desired but elusive Alzheimer's disease biomarker
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Pathological Influences on Clinical Heterogeneity in Lewy Body Diseases
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Extracellular Vesicle as a Source of Alzheimer’s Biomarkers: Opportunities and Challenges
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Amyloid Beta and Tau as Alzheimer’s Disease Blood Biomarkers: Promise From New Technologies
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Self-citationNeuropathology and emerging biomarkers in corticobasal syndrome
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Self-citationDementia with Lewy bodies: Impact of co‐pathologies and implications for clinical trial design
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Self-citationThe Alzheimer's Disease Neuroimaging Initiative 2 Biomarker Core: A review of progress and plans
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Self-citationWhite matter imaging helps dissociate tau from TDP-43 in frontotemporal lobar degeneration
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Self-citationPhosphorylated Tau as a Candidate Biomarker for Amyotrophic Lateral Sclerosis
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CSF tau and β-amyloid predict cerebral synucleinopathy in autopsied Lewy body disorders
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Self-citationNeuronal injury biomarkers and prognosis in ADNI subjects with normal cognition
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TDP-43 suppresses tau expression via promoting its mRNA instability
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Self-citationA 2-Step Cerebrospinal Algorithm for the Selection of Frontotemporal Lobar Degeneration Subtypes
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The Global Alzheimer's Association Interactive Network
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Self-citationClinical and diagnostic implications of Alzheimer's disease copathology in Lewy body disease
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Self-citationMemory, executive, and multidomain subtle cognitive impairment
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Self-citationDefining and predicting transdiagnostic categories of neurodegenerative disease
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Proteomic Analysis of Cerebrospinal Fluid in Alzheimer's Disease: Wanted Dead or Alive
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Cerebrospinal fluid α‐synuclein contributes to the differential diagnosis of Alzheimer's disease
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CSF P-Tau181 and Other Biomarkers in Patients With Neuronal Intranuclear Inclusion Disease
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- 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
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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