Cerebrospinal Fluid Biomarkers in Cerebral Amyloid Angiopathy: New Data and Quantitative Meta-Analysis

Nils G Margraf; Ulf Jensen-Kondering; Caroline Weiler; Frank Leypoldt; Walter Maetzler; Sarah Philippen; Thorsten Bartsch; Charlotte Flüh; Christoph Röcken; Bettina Möller; Georg Royl; Alexander Neumann; Norbert Brüggemann; Benjamin Roeben; Claudia Schulte; Benjamin Bender; Daniela Berg; Gregor Kuhlenbäumer

doi:10.3389/fnagi.2022.783996

Cerebrospinal Fluid Biomarkers in Cerebral Amyloid Angiopathy: New Data and Quantitative Meta-Analysis

Front Aging Neurosci. 2022 Feb 14:14:783996. doi: 10.3389/fnagi.2022.783996. eCollection 2022.

Authors

Nils G Margraf¹, Ulf Jensen-Kondering^{2

3}, Caroline Weiler¹, Frank Leypoldt^{1

4}, Walter Maetzler¹, Sarah Philippen¹, Thorsten Bartsch¹, Charlotte Flüh⁵, Christoph Röcken⁶, Bettina Möller¹, Georg Royl⁷, Alexander Neumann³, Norbert Brüggemann^{7

8}, Benjamin Roeben^{9

10}, Claudia Schulte^{9

10}, Benjamin Bender¹¹, Daniela Berg^{1

9}, Gregor Kuhlenbäumer¹

Affiliations

¹ Department of Neurology, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel University, Kiel, Germany.
² Department of Radiology and Neuroradiology, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel University, Kiel, Germany.
³ Department of Neuroradiology, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
⁴ Institute of Clinical Chemistry, University Medical Center Schleswig-Holstein, Kiel/Lübeck, Germany.
⁵ Department of Neurosurgery, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel University, Kiel, Germany.
⁶ Department of Pathology, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel University, Kiel, Germany.
⁷ Department of Neurology, University Medical Center Schleswig Holstein, Campus Lübeck, Lübeck, Germany.
⁸ Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
⁹ Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
¹⁰ German Center for Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany.
¹¹ Department of Neuroradiology, Diagnostical and Interventional Neuroradiology, University Hospital of Tübingen, Tübingen, Germany.

Abstract

Background: To evaluate the diagnostic accuracy of cerebrospinal fluid (CSF) biomarkers in patients with probable cerebral amyloid angiopathy (CAA) according to the modified Boston criteria in a retrospective multicentric cohort.

Methods: Beta-amyloid 1-40 (Aβ40), beta-amyloid 1-42 (Aβ42), total tau (t-tau), and phosphorylated tau 181 (p-tau¹⁸¹) were measured in 31 patients with probable CAA, 28 patients with Alzheimer's disease (AD), and 30 controls. Receiver-operating characteristics (ROC) analyses were performed for the measured parameters as well as the Aβ42/40 ratio to estimate diagnostic parameters. A meta-analysis of all amenable published studies was conducted.

Results: In our data Aβ42/40 (AUC 0.88) discriminated best between CAA and controls while Aβ40 did not perform well (AUC 0.63). Differentiating between CAA and AD, p-tau¹⁸¹ (AUC 0.75) discriminated best in this study while Aβ40 (AUC 0.58) and Aβ42 (AUC 0.54) provided no discrimination. In the meta-analysis, Aβ42/40 (AUC 0.90) showed the best discrimination between CAA and controls followed by t-tau (AUC 0.79), Aβ40 (AUC 0.76), and p-tau¹⁸¹ (AUC 0.71). P-tau¹⁸¹ (AUC 0.76), Aβ40 (AUC 0.73), and t-tau (AUC 0.71) differentiated comparably between AD and CAA while Aβ42 (AUC 0.54) did not. In agreement with studies examining AD biomarkers, Aβ42/40 discriminated excellently between AD and controls (AUC 0.92-0.96) in this study as well as the meta-analysis.

Conclusion: The analyzed parameters differentiate between controls and CAA with clinically useful accuracy (AUC > ∼0.85) but not between CAA and AD. Since there is a neuropathological, clinical and diagnostic continuum between CAA and AD, other diagnostic markers, e.g., novel CSF biomarkers or other parameters might be more successful.

Keywords: Alzheimer’s dementia (AD); Boston criteria; cerebral amyloid angiopathy (CAA); cerebrospinal fluid (CSF); high-precision electro-chemiluminescence immunoassay (ECLIA).