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Amyloid and Tau Signatures of Brain Metabolic Decline in Preclinical Alzheimer's Disease

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Amyloid and Tau Signatures of Brain Metabolic Decline in Preclinical Alzheimer's Disease European Journal of Nuclear Medicine and Molecular Imaging https://doi.org/10.1007/s00259-018-3933-3 ORIGINAL ARTICLE Amyloid and tau signatures of brain metabolic decline in preclinical Alzheimer’s disease Tharick A. Pascoal1 & Sulantha Mathotaarachchi1 & Monica Shin1 & Ah Yeon Park2 & Sara Mohades1 & Andrea L. Benedet1 & Min Su Kang1 & Gassan Massarweh3 & Jean-Paul Soucy3,4 & Serge Gauthier5 & Pedro Rosa-Neto 1,3,5,6 & for the Alzheimer’s Disease Neuroimaging Initiative Received: 12 September 2017 /Accepted: 2 January 2018 # The Author(s) 2018. This article is an open access publication Abstract Purpose We aimed to determine the amyloid (Aβ) and tau biomarker levels associated with imminent Alzheimer’s disease (AD) - related metabolic decline in cognitively normal individuals. Methods A threshold analysis was performed in 120 cognitively normal elderly individuals by modelling 2-year declines in brain glucose metabolism measured with [18F]fluorodeoxyglucose ([18F]FDG) as a function of [18F]florbetapir Aβ positron emission tomography (PET) and cerebrospinal fluid phosphorylated tau biomarker thresholds. Additionally, using a novel voxel-wise analytical framework, we determined the sample sizes needed to test an estimated 25% drugeffect with 80% of power on changes in FDG uptake over 2 years at every brain voxel. Results The combination of [18F]florbetapir standardized uptake value ratios and phosphorylated-tau levels more than one standard deviation higher than their respective thresholds for biomarker abnormality was the best predictor of metabolic decline in individuals with preclinical AD. We also found that a clinical trial using these thresholds would require as few as 100 individuals to test a 25% drug effect on AD-related metabolic decline over 2 years. Conclusions These results highlight the new concept that combined Aβ and tau thresholds can predict imminent neurodegen- eration as an alternative framework with a high statistical power for testing the effect of disease-modifying therapies on [18F]FDG uptake decline over a typical 2-year clinical trial period in individuals with preclinical AD. Keywords Amyloid-PET . [18F]FDG PET . Preclinical Alzheimer’sdisease . Phosphorylated tau Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni. loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/ uploads/how_to_apply/ADNI_Acknowledgement_List.pdf Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00259-018-3933-3) contains supplementary material, which is available to authorized users. * Pedro Rosa-Neto 3 Montreal Neurological Institute, Montreal, Canada [email protected] 4 PERFORM Centre, Concordia University, Montreal, Canada 1 Translational Neuroimaging Laboratory, The McGill University 5 Alzheimer’s Disease Research Unit, The McGill University Research Research Centre for Studies in Aging, Douglas Hospital, McGill Centre for Studies in Aging, Douglas Hospital, McGill University, University, 6875 La Salle Blvd - FBC room 3149, Montreal, Canada Montreal, QC H4H 1R3, Canada 6 Department of Neurology and Neurosurgery, McGill University, 2 Statistical Laboratory, University of Cambridge, Cambridge, UK Montreal, Canada Eur J Nucl Med Mol Imaging Introduction pathologies associated with the triggering of their delete- rious synergy in potentiating neurodegeneration. The preclinical stages of Alzheimer’s disease (AD) have be- However, the fact that the majority of Aβ-positive plus come the main focus of therapeutic clinical trials given the tau-positive individuals with preclinical AD remain assumption that better outcomes can be achieved with changes pathophysiologically stable over long periods suggests in the course of the disease before the appearance of cognitive that these thresholds are greater than their respective in- symptoms [1, 2]. The International Working Group and the dividual thresholds for abnormality [1]. Thus, determina- American Alzheimer’s Association have recently character- tion of the Aβ and tau biomarker thresholds associated ized preclinical AD as the presence of amyloid-β (Aβ)and with imminent neurodegeneration might provide comple- tau abnormalities in cognitively normal persons [1]. Although mentary information in individuals with preclinical AD these individuals show greater rates of disease progression destined to develop AD-related progression. than cognitively normal biomarker-negative individuals, most In this study, we tested the hypothesis that the combination of them remain stable over typical clinical trial periods [1, 3]. of optimized Aβ and tau thresholds predictive of neurodegen- Therefore, a critical next step proposed by the working groups eration might provide an alternative framework with a high was to identify, from among individuals with preclinical AD, statistical power for testing the efficacy of the emerging those with the highest likelihood of disease progression within disease-modifying therapies. This framework has the potential time frames acceptable for clinical trial designs taking into to select preclinical individuals on the verge of AD-related account financial, medical, and ethical considerations [1]. progression, considering metabolic changes as indices of neu- Its slow rate of change makes the use of cognition as the rological decline. primary outcome of clinical trials in individuals with preclin- ical AD difficult because it leads to prohibitively high sample sizes and long follow-up times [4]. Hence, surrogate measure- ments of disease progression using established biomarkers of Materials and methods neurodegeneration might provide a useful alternative for such trials [5]. In fact, few studies have tested changes in structural Participants magnetic resonance imaging (MRI) as a possible surrogate marker for preclinical AD clinical trials. For example, a recent Data used in this study were obtained from the ADNI database study by the Alzheimer’s Disease Neuroimaging Initiative (adni.loni.usc.edu). The ADNI was launched in 2003 as a (ADNI) has suggested that to test for structural changes on public–private partnership led by the Principal Investigator MRI in a population of individuals with preclinical AD Michael W. Weiner. The primary goal of ADNI has been to enriched on the basis of Aβ and tau biomarker positivity, test whether serial MRI, PET, other biological markers, and sample size estimates are prohibitively large [3]. In this regard, clinical and neuropsychological assessment can be combined changes in [18F]fluorodeoxyglucose ([18F]FDG) uptake have to measure the progression of mild cognitive impairment and been suggested for following disease progression and moni- early AD. For the present analysis, we selected 120 toring therapeutic effects [6–11]. Indeed, [18F]FDG positron cognitively normal ADNI participants in whom emission tomography (PET) is one of the most important bio- cerebrospinal fluid (CSF) phosphorylated-tau (p-tau) was de- markers of AD with applications in the research and clinical termined and [18F]florbetapir PET was performed at the same settings. However, the characteristics of [18F]FDG uptake as a baseline visit, and [18F]FDG PET at the baseline visit and at surrogate marker of preclinical AD in clinical trials are not the 2-year follow-up visit. fully known. Indeed, the inclusion of cognitively normal in- dividuals harbouring Aβ and tau, and with abnormal [18F]FDG uptake could be argued as an interesting strategy CSF analysis for these trials, since such individuals have a higher probabil- ity of developing further neurodegeneration and cognitive CSF p-tau and CSF Aβ were quantified with the INNO- symptoms [1]. However, it is reasonable to suggest that the BIA AlzBio3 immunoassay using the multiplex xMAP absence of baseline neurodegeneration might offer a more Luminex platform (Luminex Corp, Austin, TX). The favourable pathophysiological scenario for preventive thera- CSF data used in the analysis were selected from the pies aiming to mitigate disease progression [2]. ADNI files BUPENNBIOMK5-8.csv^, and all the values Recent literature indicates that Aβ and tau pathologies for each subject were obtained from the same file. The may arise independently and, at some pathophysiological standard published ADNI threshold for p-tau abnormality point, synergistically potentiate imminent neurodegenera- of>23pg/mlwasusedinthisanalysis[15, 16]. Further tion in preclinical AD [2, 12–14]. Notably, this framework details of methods for CSF acquisition and quantification infers the existence of thresholds for Aβ and tau can be found at www.adni-info.org. Eur J Nucl Med Mol Imaging MRI/PET lower and the upper asymptote) at the unit of Y, c is the Δ[18F]FDG at the inflection point of the curve at the unit of MRI and PET acquisitions followed the ADNI protocols X,andd represents the curve steepness. The biomarker thresh- (http://adni.loni.usc.edu/methods). The MRI T1-weighted im- old for imminent metabolic decline was defined as the value ages underwent nonuniformity correction, brain masking and where the curvatures changed sign (X(c)). This point was as- segmentation using the Brain Extraction based on nonlocal sumed as the magnitude that needs to be reached by the bio- Segmentation Technique
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