Abstract
BackgroundThe Centiloid scale has been developed to standardize measurements of amyloid PET imaging. Reference cut-off values of this continuous measurement enable the consistent operationalization of decision-making for multicentre research studies and clinical trials. In this study, we aimed at deriving reference Centiloid thresholds that maximize the agreement against core Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers in two large independent cohorts.MethodsA total of 516 participants of the ALFA+ Study (N = 205) and ADNI (N = 311) underwent amyloid PET imaging ([18F]flutemetamol and [18F]florbetapir, respectively) and core AD CSF biomarker determination using Elecsys® tests. Tracer uptake was quantified in Centiloid units (CL). Optimal Centiloid cut-offs were sought that maximize the agreement between PET and dichotomous determinations based on CSF levels of Aβ42, tTau, pTau, and their ratios, using pre-established reference cut-off values. To this end, a receiver operating characteristic analysis (ROC) was conducted, and Centiloid cut-offs were calculated as those that maximized the Youden’s J Index or the overall percentage agreement recorded.ResultsAll Centiloid cut-offs fell within the range of 25–35, except for CSF Aβ42 that rendered an optimal cut-off value of 12 CL. As expected, the agreement of tau/Aβ42 ratios was higher than that of CSF Aβ42. Centiloid cut-off robustness was confirmed even when established in an independent cohort and against variations of CSF cut-offs.ConclusionsA cut-off of 12 CL matches previously reported values derived against postmortem measures of AD neuropathology. Together with these previous findings, our results flag two relevant inflection points that would serve as boundary of different stages of amyloid pathology: one around 12 CL that marks the transition from the absence of pathology to subtle pathology and another one around 30 CL indicating the presence of established pathology. The derivation of robust and generalizable cut-offs for core AD biomarkers requires cohorts with adequate representation of intermediate levels.Trial registrationALFA+ Study, NCT02485730ALFA PET Sub-study, NCT02685969
Highlights
Aggregation of β-amyloid (Aβ) is a neuropathological hallmark of Alzheimer disease (AD) and occurs decades before the onset of clinical symptoms occur [1, 2]. Both amyloid positron emission tomography (PET) and cerebrospinal fluid (CSF) Aβ42 measurement are established biomarkers of Aβ deposition that highly correlate with post-mortem [3, 4] and brain biopsy findings [5] and serving as in vivo proxies of Alzheimer’s disease (AD) pathological findings that can be assessed in vivo
Another difference is that CSF Aβ42 may become abnormal before amyloid PET [21, 22], while amyloid PET has been suggested to be superior for grading early symptomatic AD stages [19]
In order to have generalizable results reflecting the whole AD continuum, 311 participants from Alzheimer's Disease Neuroimaging Initiative (ADNI) were included in this study selected according to the following inclusion criteria: (1) AD CSF core biomarkers analysed with the Elecsys® tests available, (2) amyloid PET scan acquired in less than a year from CSF collection available, and (3) magnetic resonance imaging (MRI) acquired with a difference from the time of the PET acquisition of less than a year
Summary
Aggregation of β-amyloid (Aβ) is a neuropathological hallmark of Alzheimer disease (AD) and occurs decades before the onset of clinical symptoms occur [1, 2] Both amyloid positron emission tomography (PET) and cerebrospinal fluid (CSF) Aβ42 measurement are established biomarkers of Aβ deposition that highly correlate with post-mortem [3, 4] and brain biopsy findings [5] and serving as in vivo proxies of AD pathological findings that can be assessed in vivo. We aimed at deriving reference Centiloid thresholds that maximize the agreement against core Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers in two large independent cohorts
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