Dynamics of proteinopathies in Alzheimer’s disease as measured by PET and CSF biomarkers

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the extracellular aggregation of the amyloid-β (Aβ; amyloid) peptide and the intraneuronal accumulation of the protein tau. Independently, and in concert, these protein opathies lead to the loss of synapses and neurons (neurodegeneration). These processes can be measured in living individuals using positron emission tomography (PET) and cerebrospinal fluid (CSF) based measurements (biomarkers). Biomarkers for AD include the retention in the brain of varied PET ligands (e.g. [C]PIB and [F]flutemetamol, Aβ; [F]THK5317, tau; and [F]FDG, glucose metabolism, a proxy for synaptic integrity), as well as CSF levels of Aβ1-42, and tau phosphorylated at threonine 181 (p-tau181p), and total-tau (t-tau), reflecting Aβ, the formation tau tangle pathology, and axonal damage, respectively. The aim of this thesis, which comprises five studies, was to obtain new insight into how these biomarkers interrelate in AD, and to examine their potential utility from a clinical standpoint. In study I, agreement between dichotomised (i.e. normal/abnormal) [C]PIB PET and CSF Aβ1-42 in AD and related disorders was found to persist after controlling for potential methodological confounds tied to CSF, suggesting biological underpinnings to biomarker mismatches. Concordance, however, was substantially improved across patient groups when using Aβ1-42 in ratio with Aβ1-40. In study II, the impact of amyloid imaging with [F]flutemetamol PET was examined in a cohort of diagnostically unclear patients, drawn from a tertiary memory clinic. [F]Flutemetamol investigations resulted in substantial changes to pre-amyloid PET diagnoses and an incease in the use of cholinesterase inhibitors, with the greatest impact seen among patients with a pre-[F]flutemetamol diagnosis of MCI. In study III, the relationship between [F]THK5317 tau PET and CSF tau, including measures derived from assays capturing novel fragments, was shown to vary by isocortical hypometabolism, suggesting that the relationship between tau biomarkers may vary by disease stage. Novel CSF markers better tracked longitudinal PET, as compared to p-tau181p and t-tau, and improved concordance with [F]THK5317. Moreover, comparison of cross-sectional and rate of change findings suggest a temporal delay between tau pathology and synaptic impairment. In studies IV and V, perfusion information derived from [F]THK5317 tau PET scans was shown to strongly correlate with [F]FDG PET metabolic imaging; though our cross-sectional data support the use of perfusion parameters as a substitute for [F]FDG, longitudinal findings suggest that the coupling between perfusion and metabolism may vary as a function of disease stage, warranting further studies. LIST OF PUBLICATIONS This thesis is based on the following original articles: I Leuzy A, Chiotis K, Hasselbalch SG, Rinne JO, de Mendonça, Otto M, Lleó A, Castelo-Branco M, Santana I, Johansson J, von Arnim CAF, Beer A, Blesa R, Fortea J, Herukka SK, Portelius E, Pannee J, Zetterberg H, Blennow K, Nordberg A. Pittsburgh compound B imaging and cerebrospinal fluid amyloid-beta in a multicentre European memory clinic study. Brain. 2016;139(Pt 9):2540-2553. II Leuzy A, Savitcheva I, Chiotis K, Lilja J, Andersen P, Bogdanovic N, Jelic V, Nordberg A. Clinical impact of [F]flutemetamol PET in memory clinic patients with an uncertain diagnosis. Manuscript. † Contributed equally III Leuzy A, Cicognola C, Chiotis K, Saint-Aubert L, Lemoine L, Andreasen N, Zetterberg H, Yei K, Blennow K, Höglund K, Nordberg A. Longitudinal tau and metabolic PET imaging in relation to novel CSF tau measures in Alzheimer’s disease. Manuscript. IV Rodriguez-Vieitez E, Leuzy A, Chiotis K, Saint-Aubert L, Wall A, Nordberg A. Comparability of [F]THK5317 and [C]PIB blood flow proxy images with [F]FDG positron emission tomography in Alzheimer’s disease. J Cereb Blood Flow Metab. 2017;37(2):740-749. † Contributed equally V Leuzy A, Rodriguez-Vieitez E, Saint-Aubert L, Chiotis K, Almkvist O, Savitcheva I, Jonasson M, Lubberink M, Wall A, Antoni G, Nordberg A. Longitudinal uncoupling of cerebral perfusion, glucose metabolism, and tau deposition in Alzheimer’s disease. Alzheimers Dement. 2018;14(5):652-663.