Pittsburgh compound B imaging and cerebrospinal fluid amyloid-β in a multicentre European memory clinic study

Abstract

The aim of this study was to assess the agreement between data on cerebral amyloidosis, derived using Pittsburgh compound B positron emission tomography and (i) multi-laboratory INNOTEST enzyme linked immunosorbent assay derived cerebrospinal fluid concentrations of amyloid-β42; (ii) centrally measured cerebrospinal fluid amyloid-β42 using a Meso Scale Discovery enzyme linked immunosorbent assay; and (iii) cerebrospinal fluid amyloid-β42 centrally measured using an antibody-independent mass spectrometry-based reference method. Moreover, we examined the hypothesis that discordance between amyloid biomarker measurements may be due to interindividual differences in total amyloid-β production, by using the ratio of amyloid-β42 to amyloid-β40 Our study population consisted of 243 subjects from seven centres belonging to the Biomarkers for Alzheimer's and Parkinson's Disease Initiative, and included subjects with normal cognition and patients with mild cognitive impairment, Alzheimer's disease dementia, frontotemporal dementia, and vascular dementia. All had Pittsburgh compound B positron emission tomography data, cerebrospinal fluid INNOTEST amyloid-β42 values, and cerebrospinal fluid samples available for reanalysis. Cerebrospinal fluid samples were reanalysed (amyloid-β42 and amyloid-β40) using Meso Scale Discovery electrochemiluminescence enzyme linked immunosorbent assay technology, and a novel, antibody-independent, mass spectrometry reference method. Pittsburgh compound B standardized uptake value ratio results were scaled using the Centiloid method. Concordance between Meso Scale Discovery/mass spectrometry reference measurement procedure findings and Pittsburgh compound B was high in subjects with mild cognitive impairment and Alzheimer's disease, while more variable results were observed for cognitively normal and non-Alzheimer's disease groups. Agreement between Pittsburgh compound B classification and Meso Scale Discovery/mass spectrometry reference measurement procedure findings was further improved when using amyloid-β42/40 Agreement between Pittsburgh compound B visual ratings and Centiloids was near complete. Despite improved agreement between Pittsburgh compound B and centrally analysed cerebrospinal fluid, a minority of subjects showed discordant findings. While future studies are needed, our results suggest that amyloid biomarker results may not be interchangeable in some individuals.

Keywords: Alzheimer’s disease; CSF Aβ42; CSF Aβ42/40; Centiloids; PiB PET.

PET and CSF biomarkers of amyloid-β are considered interchangeable in defining ‘amyloid positivity’. However, Leuzy et al. report discordance between these measures in a multicentre memory clinic population. This suggests that in a minority of individuals these metrics may not be interchangeable, and may instead reflect distinct but interrelated processes.

Figure 1

Linear correlation plot showing the relationship between original/recalculated PiB Centiloids. Original (Pittsburgh) and recalculated (Stockholm) PiB Centiloids are shown on the ordinate and abscissa, respectively (YC-0, n = 34; AD-100, n = 45).

Figure 2

Linear correlation plots showing the relationship between locally and centrally measured CSF amyloid-β. (A) INNOTEST and MSD amyloid-β₄₂; (B) INNOTEST and MS-RMP amyloid-β₄₂; (C) MSD and MS-RMP amyloid-β₄₂; and (D) MSD and MS-RMP amyloid-β_42/40.

Figure 3

Scatterplot showing concordance between INNOTEST amyloid-β₄₂ and PiB Centiloids. Circles indicate cognitively normal subjects, triangles MCI, squares Alzheimer’s disease, crosses FTD, and crossed squares VaD. The vertical line reflects the Centiloid cut-off of 34; the horizontal line the cut-off of 557 pg/ml for INNOTEST amyloid-β₄₂. Blue indicates PiB scans were visually rated as negative, red as positive. The grey quadrants indicate concordance between amyloid-β biomarkers (top left, concordant negative: PiB−/CSF−; bottom right, concordant positive: PiB+/CSF+). The white quadrants indicate discordance between amyloid-β biomarkers (bottom left, discordant with isolated CSF positivity: PiB−/CSF+; top right, discordant with isolated PiB positivity: a PiB+/CSF−).

Figure 4

Scatterplots reflecting concordance between PiB Centiloids and reanalysed CSF. (A) MSD amyloid-β₄₂ (cut-off < 515 pg/ml). (B) MSD amyloid-β_42/40 (cut-off < 0.72); (C) MS-RMP amyloid-β₄₂ (cut-off < 896 pg/ml), and (D) MS-RMP amyloid-β₄₂/amyloid-β₄₀ (cut-off < 0.76). Grey circles indicate cognitively normal healthy control subjects, triangles indicate MCI, squares indicate Alzheimer’s disease, crosses FTD, and crossed squares VaD. The vertical lines reflects the Centiloid cut-off of 34; the horizontal lines the cut-offs of < 515 pg/ml, <0.72, <896 pg/ml, and <0.76 for MSD (amyloid-β₄₂, amyloid-β_42/40) and MS-RMP (amyloid-β₄₂, amyloid-β_42/40), respectively. Blue indicates PiB scans visually rated as negative, red as positive. The grey quadrants indicate concordance between amyloid-β biomarkers (top left, concordant negative: PiB−/CSF−; bottom right, concordant positive: PiB+/CSF+). The white quadrants indicate discordance between amyloid-β biomarkers (bottom left, discordant with isolated CSF positivity: PiB−/CSF+; top right, discordant with isolated PiB positivity: a PiB+/CSF−). Aβ = amyloid-β.

Figure 5

Frequency plots showing different agreement profiles between PiB PET and CSF. Values of <557 pg/ml (INNOTEST amyloid-β₄₂), <515 pg/ml (MSD amyloid-β₄₂), <0.72 (MSD amyloid-β_42/40), <896 pg/ml (MS-RMP amyloid-β₄₂), <0.76 (MS-RMP amyloid-β_42/40), and global Centiloid value > 34 were used to classify subjects as concordant positive (PiB+/CSF+), concordant negative (PiB−/CSF−), discordant with CSF positivity (PiB−/CSF+), and discordant with PiB positivity (PiB+/CSF−). Aβ = amyloid-β.