Applicability of in vivo staging of regional amyloid burden in a cognitively normal cohort with subjective memory complaints: the INSIGHT-preAD study
Authors: Sakr Fatemah A. , Grothe Michel J. , Cavedo Enrica , Jelistratova Irina , Habert Marie-Odile , Dyrba Martin , Gonzalez-Escamilla Gabriel , Bertin Hugo , Locatelli Maxime , Lehericy Stephane , Teipel Stefan , Dubois Bruno , Hampel Harald ,   for the INSIGHT-preAD study group, Bakardjian Hovagim , Benali Habib , Bertin Hugo , Bonheur Joel , Boukadida Laurie , Boukerrou Nadia , Cavedo Enrica , Chiesa Patrizia , Colliot Olivier , Dubois Bruno , Dubois Marion , Epelbaum Stéphane , Gagliardi Geoffroy , Genthon Remy , Habert Marie-Odile , Hampel Harald , Houot Marion , Kas Aurélie , Lamari Foudil , Levy Marcel , Lista Simone , Metzinger Christiane , Mochel Fanny , Nyasse Francis , Poisson Catherine , Potier Marie-Claude , Revillon Marie , Santos Antonio , Andrade Katia Santos , Sole Marine , Surtee Mohmed , de Schotten Michel Thiebaud , Vergallo Andrea , Younsi Nadjia ,   the Alzheimer Precision Medicine Initiative (APMI), Aguilar Lisi Flores , Babiloni Claudio , Baldacci Filippo , Benda Norbert , Black Keith L. , Bokde Arun L. W. , Bonuccelli Ubaldo , Broich Karl , Bun René S. , Cacciola Francesco , Castrillo Juan , Cavedo Enrica , Ceravolo Roberto , Chiesa Patrizia A. , Colliot Olivier , Coman Cristina-Maria , Corvol Jean-Christophe , Cuello Augusto Claudio , Cummings Jeffrey L. , Depypere Herman , Dubois Bruno , Duggento Andrea , Durrleman Stanley , Escott-Price Valentina , Federoff Howard , Ferretti Maria Teresa , Fiandaca Massimo , Frank Richard A. , Garaci Francesco , Genthon Remy , George Nathalie , Giorgi Filippo S. , Graziani Manuela , Haberkamp Marion , Habert Marie-Odile , Hampel Harald , Herholz Karl , Karran Eric , Kim Seung H. , Koronyo Yosef , Koronyo-Hamaoui Maya , Lamari Foudil , Langevin Todd , Lehéricy Stéphane , Lista Simone , Lorenceau Jean , Mapstone Mark , Neri Christian , Nisticò Robert , Nyasse-Messene Francis , O’bryant Sid E. , Perry George , Ritchie Craig , Rojkova Katrine , Rossi Simone , Saidi Amira , Santarnecchi Emiliano , Schneider Lon S. , Sporns Olaf , Toschi Nicola , Verdooner Steven R. , Vergallo Andrea , Villain Nicolas , Welikovitch Lindsay A. , Woodcock Janet , Younesi Erfan 
Published: January 2019

Abstract
Background
Current methods of amyloid PET interpretation based on the binary classification of global amyloid signal fail to identify early phases of amyloid deposition. A recent analysis of 18F-florbetapir PET data from the Alzheimer’s disease Neuroimaging Initiative cohort suggested a hierarchical four-stage model of regional amyloid deposition that resembles neuropathologic estimates and can be used to stage an individual’s amyloid burden in vivo. Here, we evaluated the validity of this in vivo amyloid staging model in an independent cohort of older people with subjective memory complaints (SMC). We further examined its potential association with subtle cognitive impairments in this population at elevated risk for Alzheimer’s disease (AD).

Methods
The monocentric INSIGHT-preAD cohort includes 318 cognitively intact older individuals with SMC. All individuals underwent 18F-florbetapir PET scanning and extensive neuropsychological testing. We projected the regional amyloid uptake signal into the previously proposed hierarchical staging model of in vivo amyloid progression. We determined the adherence to this model across all cases and tested the association between increasing in vivo amyloid stage and cognitive performance using ANCOVA models.

Results
In total, 156 participants (49%) showed evidence of regional amyloid deposition, and all but 2 of these (99%) adhered to the hierarchical regional pattern implied by the in vivo amyloid progression model. According to a conventional binary classification based on global signal (SUVRCereb = 1.10), individuals in stages III and IV were classified as amyloid-positive (except one in stage III), but 99% of individuals in stage I and even 28% of individuals in stage II were classified as amyloid-negative. Neither in vivo amyloid stage nor conventional binary amyloid status was significantly associated with cognitive performance in this preclinical cohort.

Conclusions
The proposed hierarchical staging scheme of PET-evidenced amyloid deposition generalizes well to data from an independent cohort of older people at elevated risk for AD. Future studies will determine the prognostic value of the staging approach for predicting longitudinal cognitive decline in older individuals at increased risk for AD.