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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.
JAMA Neurol. 2014 Oct; 71(10):1282-9.JN

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.

Authors+Show Affiliations

Clinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden2Department of Neurology, Skåne University Hospital, Malmö, Sweden.Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg and Mölndal, Sweden.Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg and Mölndal, Sweden.Geriatric Psychiatry Unit, Department of Clinical Sciences, Lund University, Lund, Sweden5Department of Psychology, Lund University, Lund, Sweden.Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg and Mölndal, Sweden.Department of Medicine, Imperial College London, London, England7Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.GE Healthcare, Life Sciences, Uppsala, Sweden.Department of Clinical Neurophysiology, Skåne University Hospital, Lund, Sweden.Clinical Physiology and Nuclear Medicine Unit, Department of Clinical Sciences, Lund University, Lund, Sweden.Clinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden.Clinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Validation Study

Language

eng

PubMed ID

25155658

Citation

Palmqvist, Sebastian, et al. "Accuracy of Brain Amyloid Detection in Clinical Practice Using Cerebrospinal Fluid Β-amyloid 42: a Cross-validation Study Against Amyloid Positron Emission Tomography." JAMA Neurology, vol. 71, no. 10, 2014, pp. 1282-9.
Palmqvist S, Zetterberg H, Blennow K, et al. Accuracy of brain amyloid detection in clinical practice using cerebrospinal fluid β-amyloid 42: a cross-validation study against amyloid positron emission tomography. JAMA Neurol. 2014;71(10):1282-9.
Palmqvist, S., Zetterberg, H., Blennow, K., Vestberg, S., Andreasson, U., Brooks, D. J., Owenius, R., Hägerström, D., Wollmer, P., Minthon, L., & Hansson, O. (2014). Accuracy of brain amyloid detection in clinical practice using cerebrospinal fluid β-amyloid 42: a cross-validation study against amyloid positron emission tomography. JAMA Neurology, 71(10), 1282-9. https://doi.org/10.1001/jamaneurol.2014.1358
Palmqvist S, et al. Accuracy of Brain Amyloid Detection in Clinical Practice Using Cerebrospinal Fluid Β-amyloid 42: a Cross-validation Study Against Amyloid Positron Emission Tomography. JAMA Neurol. 2014;71(10):1282-9. PubMed PMID: 25155658.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Accuracy of brain amyloid detection in clinical practice using cerebrospinal fluid β-amyloid 42: a cross-validation study against amyloid positron emission tomography. AU - Palmqvist,Sebastian, AU - Zetterberg,Henrik, AU - Blennow,Kaj, AU - Vestberg,Susanna, AU - Andreasson,Ulf, AU - Brooks,David J, AU - Owenius,Rikard, AU - Hägerström,Douglas, AU - Wollmer,Per, AU - Minthon,Lennart, AU - Hansson,Oskar, PY - 2014/8/27/entrez PY - 2014/8/27/pubmed PY - 2015/2/3/medline SP - 1282 EP - 9 JF - JAMA neurology JO - JAMA Neurol VL - 71 IS - 10 N2 - 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. SN - 2168-6157 UR - https://www.unboundmedicine.com/medline/citation/25155658/Accuracy_of_brain_amyloid_detection_in_clinical_practice_using_cerebrospinal_fluid_β_amyloid_42:_a_cross_validation_study_against_amyloid_positron_emission_tomography_ L2 - https://jamanetwork.com/journals/jamaneurology/fullarticle/10.1001/jamaneurol.2014.1358 DB - PRIME DP - Unbound Medicine ER -