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Accuracy of Brain Amyloid Detection in Clinical Practice Using Cerebrospinal Fluid β-Amyloid 42: A Cross-Validation Study Against Amyloid Positron Emission Tomography
Abstract
IMPORTANCE: Before adding cerebrospinal fluid (CSF) biomarkers to the diagnostic workup of Alzheimer disease, it needs to be determined whether CSF biomarkers analyzed in routine clinical practice can reliably predict cortical β-amyloid (Aβ) deposition. OBJECTIVES: To study whether CSF biomarkers, analyzed consecutively in routine clinical practice during 2 years, can predict cortical Aβ deposition and to establish a threshold for Aβ42 abnormality. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study (The Swedish BioFINDER [Biomarkers For Identifying Neurodegenerative Disorders Early and Reliably] Study) was conducted at 3 memory clinics. It involved consecutively referred, nondemented patients with mild cognitive symptoms (original cohort, n = 118; validation cohort, n = 38). EXPOSURES: Amyloid positron emission tomography imaging with 18F-flutemetamol. MAIN OUTCOMES AND MEASURES: Analyses of CSF Aβ42, total tau, and phosphorylated tau using an enzyme-linked immunosorbent assay (INNOTEST) in clinical samples. RESULTS: The agreement between Aβ classification with CSF Aβ42 and 18F-flutemetamol positron emission tomography was very high (κ = 0.85). Of all the cases, 92% were classified identically using an Aβ42 cutoff of 647 pg/mL or less. Cerebrospinal fluid Aβ42 predicted abnormal cortical Aβ deposition accurately (odds ratio, 165; 95% CI, 39-693; area under the receiver operating characteristic curve, 0.94; 95% CI, 0.88-0.97). The association was independent of age, sex, APOE (apolipoprotein E) genotype, hippocampal volume, memory, and global cognition (adjusted odds ratio, 169; 95% CI, 25-1143). Using ratios of CSF Aβ42:tau or Aβ42:phosphorylated tau did not improve the prediction of Aβ deposition. Cerebrospinal fluid Aβ42 correlated significantly with Aβ deposition in all cortical regions. The highest correlations were in regions with high 18F-flutemetamol retention (eg, posterior cingulum and precuneus, r = -0.72). 18F-flutemetamol retention, but not CSF Aβ42, correlated significantly with global cognition (r = -0.32), memory function (r = -0.28), and hippocampal volume (r = -0.36) among those with abnormal Aβ deposition. Finally, the CSF Aβ42 cutoff derived from the original cohort (≤647 pg/mL) had an equally high agreement (95%; κ = 0.89) with 18F-flutemetamol positron emission tomography in the validation cohort. CONCLUSIONS AND RELEVANCE: Cerebrospinal fluid Aβ42 analyzed consecutively in routine clinical practice at an accredited laboratory can be used with high accuracy to determine whether a patient has normal or increased cortical Aβ deposition and so can be valuable for the early diagnosis of Alzheimer disease. Abnormal 18F-flutemetamol retention levels correlate with disease stage in patients with mild cognitive symptoms, but this is not the case for CSF Aβ42 measurements.
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“Mixture modeling statistics provide an unbiased threshold for abnormality (i.e., the diagnosis or status is not used in analysis) and it is a well-established method for defining Aβ PET cut-offs12, 17, 60, 61.”
From Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity (2017) · cites this paper as [60]
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Metadata
- Authors
- Palmqvist, S., Zetterberg, H., Blennow, K., Vestberg, S., Andreasson, U., Brooks, D. J., Owenius, R., Hägerström, D., Wollmer, P., Minthon, L., & Hansson, O.
- Affiliations
- Lund University (SE)
- University of Gothenburg (SE)
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg and Mölndal, Sweden
- Aarhus University (DK)
- GE Healthcare, Life Sciences, Uppsala, Sweden
- Skåne University Hospital (SE)
- Corresponding author
- Hansson, Oskar
- ORCID
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2014-10-01
- Volume
- 71
- Issue
- 10
- Pages
- 1282
- ISSN
- 2168-6149 (ISSN-L)
- OpenAlex
- W1992165389
- Cited by
- 368
- References
- 48
- Citations by year
- 2026: 5 · 2025: 25 · 2024: 21 · 2023: 16 · 2022: 27 · 2021: 38 · 2020: 48 · 2019: 46 · 2018: 31 · 2017: 34 · 2016: 33 · 2015: 39 · 2014: 3
- FWCI
- 27.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- JAMA Neurology (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- 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
- Alzheimer's disease, cerebrospinal fluid biomarkers, amyloid-beta 42, cortical amyloid deposition, 18F-flutemetamol PET, total tau, phosphorylated tau, diagnostic accuracy, mild cognitive impairment, APOE genotype, hippocampal volume, memory clinics, early detection of neurodegeneration
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Aniline Compounds, Brain, Cerebral Cortex, Cross-Sectional Studies, Female, Gyrus Cinguli, Humans, Male, Middle Aged, Peptide Fragments, Reproducibility of Results, Cohort Studies, Amyloid beta-Peptides, Radiopharmaceuticals, Early Diagnosis, Positron-Emission Tomography, Benzothiazoles, Cognitive Dysfunction
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