Comparison of amyloid PET measured in Centiloid units with neuropathological findings in Alzheimer’s disease

Abstract

Background: The Centiloid scale was developed to standardise the results of beta-amyloid (Aβ) PET. We aimed to determine the Centiloid unit (CL) thresholds for CERAD sparse and moderate-density neuritic plaques, Alzheimer's disease neuropathologic change (ADNC) score of intermediate or high probability of Alzheimer's Disease (AD), final clinicopathological diagnosis of AD, and expert visual read of a positive Aβ PET scan. Methods: Aβ PET results in CL for 49 subjects were compared with post-mortem findings, visual read, and final clinicopathological diagnosis. The Youden Index was used to determine the optimal CL thresholds from receiver operator characteristic (ROC) curves. Results: A threshold of 20.1 CL (21.3 CL when corrected for time to death, AUC 0.97) yielded highest accuracy in detecting moderate or frequent plaque density while < 10 CL was optimal for excluding neuritic plaque. The threshold for ADNC intermediate or high likelihood AD was 49.4 CL (AUC 0.98). Those cases with a final clinicopathological diagnosis of AD yielded a median CL result of 87.7 (IQR ± 42.2) with 94% > 45 CL. Positive visual read agreed highly with results > 26 CL. Conclusions: Centiloid values < 10 accurately reflected the absence of any neuritic plaque and > 20 CL indicated the presence of at least moderate plaque density, but approximately 50 CL or more best confirmed both neuropathological and clinicopathological diagnosis of Alzheimer's disease.

Novel tau biomarkers phosphorylated at T181, T217 or T231 rise in the initial stages of the preclinical Alzheimer’s continuum when only subtle changes in Aβ pathology are detected

“…The 12 CL cut‐off was previously proposed to detect subtle Aβ pathology in a comparison against CSF Aβ42 and neuropathological assessment of Aβ plaques (La Joie et al , 2019; Salvadó et al , 2019). In contrast, 30 CL is a cut‐off that is in the range of agreement with the visual read method in clinical populations (24–35 CL) and therefore reflects established Aβ pathology (Leuzy et al , 2016; Rowe et al , 2017; La Joie et al , 2019; Salvadó et al , 2019; Amadoru et al , 2020). We observed that all CSF and plasma p‐tau biomarkers were increased in the group of participants with CL > 30 with respect to the negative group (CL ≤ 12; Fig 3K–O).…”

“…To note, the cut‐off used here for CSF Aβ42/40 has been optimized to detect preclinical Alzheimer and is higher (and thus more sensitive) than cut‐offs with high specificity usually used for diagnostic purposes in symptomatic AD (Milà‐Alomà et al , 2020). Likewise, we used the cut‐off of CL > 12 (Salvadó et al , 2019), which reflects very mild Aβ changes, and it is considerably lower than the CL values found when Aβ pathology is well‐established in symptomatic AD (Leuzy et al , 2016; Rowe et al , 2017; La Joie et al , 2019; Salvadó et al , 2019; Amadoru et al , 2020). Even with these very early cut‐offs, we were able to detect significant changes in these novel CSF p‐tau biomarkers.…”

Defining a Centiloid scale threshold predicting long-term progression to dementia in patients attending the memory clinic: an [18F] flutemetamol amyloid PET study

“…Interestingly, in this same PET autopsy study [ 18 ] as well as in a previous report [ 26 ], a higher threshold (Centiloid = 24) was observed against intermediate to high levels of AD neuropathological changes including thus both Aβ and tau lesions as a gold standard (unlike CERAD plaque count), which may be closer to a dementia endpoint. A recent paper observed that a Centiloid threshold = 21 detected moderate or frequent plaque density while Centiloid = 10 was optimal for excluding neuritic plaques [ 27 ]. They also observed higher threshold (Centiloid = 49) against intermediate to high levels of AD neuropathological changes.…”

Comparison of ELISA- and SIMOA-based quantification of plasma Aβ ratios for early detection of cerebral amyloidosis

“…Intermediate amyloid burden was defined as CL values between 20 and 50 and high amyloid burden as CL ≥ 50 [ 23 ]. Twenty-two (14%) CN participants showed intermediate amyloid burden (CL range 22.2–47.8), while eight (5%) showed high amyloid burden (CL range 66.25–184.9).…”