Decreased Cerebrospinal Fluid Amyloid β 38, 40, 42, and 43 Levels in Sporadic and Hereditary Cerebral Amyloid Angiopathy

Abstract

Objective: Vascular amyloid β (Aβ) accumulation is the hallmark of cerebral amyloid angiopathy (CAA). The composition of cerebrospinal fluid (CSF) of CAA patients may serve as a diagnostic biomarker of CAA. We studied the diagnostic potential of the peptides Aβ38, Aβ40, Aβ42, and Aβ43 in patients with sporadic CAA (sCAA), hereditary Dutch-type CAA (D-CAA), and Alzheimer disease (AD). Methods: Aβ peptides were quantified by immunoassays in a discovery group (26 patients with sCAA and 40 controls), a validation group (40 patients with sCAA, 40 patients with AD, and 37 controls), and a group of 22 patients with D-CAA and 54 controls. To determine the diagnostic accuracy, the area under the curve (AUC) was calculated using a receiver operating characteristic curve with 95% confidence interval (CI). Results: We found decreased levels of all Aβ peptides in sCAA patients and D-CAA patients compared to controls. The difference was most prominent for Aβ42 (AUC of sCAA vs controls for discovery: 0.90, 95% CI = 0.82-0.99; for validation: 0.94, 95% CI = 0.89-0.99) and Aβ43 (AUC of sCAA vs controls for discovery: 0.95, 95% CI = 0.88-1.00; for validation: 0.91, 95% CI = 0.83-1.0). All Aβ peptides except Aβ43 were also decreased in sCAA compared to AD

Aβ38 and Aβ43 do not differentiate between Alzheimer's disease and cerebral amyloid angiopathy

“…al who achieved excellent separation between AD and CAA by adding Ab38 and Ab43 to standard CSF biomarkers for AD. 5,8 As expected, we found an excellent separation between controls and AD. The diagnostic metrics, for example, AUC, sensitivity and specificity using the standard AD biomarkers and the Ab42/Ab40 ratio are similar to the ones reported in the literature, 9 arguing that we analyzed "typical" AD and control samples.…”

“…Figure 1A,B and Tables S1 and S2 show data from the ROC analysis for discriminating CAA from controls and AD from controls. To achieve comparable quantifications, we used the same ratios and combinations as de Kort et al 5,8 It is apparent that the separation between AD and controls is excellent for most biomarkers including the parameters Ab42/Ab40 and p-tau, which are most commonly used in clinical practice (Fig. 1A, Table S1).…”

“…4 Recently, de Kort and colleagues reported that the addition of Ab38 and Aßb43 to the biomarker panel significantly improves the differentiation. 5 We tested this hypothesis in a cohort of well-characterized CAA and AD patients and healthy controls.…”

Iatrogenic cerebral amyloid angiopathy: A multinational case series and individual patient data analysis of the literature

“…Reduced CSF Aβ-42 and Aβ-40 form a component of the broader iCAA criteria as one of the pieces of evidence of Aβ accumulation in the central nervous system (CNS). Based on what has been established in sporadic and hereditary CAA disease, 8 CSF analysis may provide an opportunity to assess the severity or even recognize iCAA at an earlier stage. Therefore, we examined the relationship between CSF biomarker levels, latency, and age at the onset of symptoms.…”

Correction: Decreased Cerebrospinal Fluid Amyloid β 38, 40, 42, and 43 Levels in Sporadic and Hereditary Cerebral Amyloid Angiopathy

“…Following the publication of our article, 1 we noticed that there was an error. The combinations of amyloid β (Aβ) peptides that result in the highest areas under the curve (AUCs) to discriminate patients with sporadic cerebral amyloid angiopathy (sCAA) from patients with Alzheimer disease (AD) are different than stated in the original article.…”