Tau pathology in Alzheimer's disease and other dementias : translational approach from in vitro autoradiography to in vivo PET imaging

Tauopathies, including Alzheimer's disease (AD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP), are complex neurodegenerative disorders characterized by the pathological accumulation of tau proteins in the brain. These often overlapping disorders, with intricate pathologies and growing prevalence, lack definitive treatments, highlighting the necessity for advanced research. Positron emission tomography (PET) imaging aids in the diagnosis and monitoring of diseases, by providing in vivo insights into pathological features.

This thesis focused on deciphering the binding properties and brain regional distribution of PET tracers for accurate disease differentiation. Spanning four studies, we aimed to bridge in vitro and in vivo PET data to investigate tau pathology and its association with dementia-related markers such as reactive astrogliosis, peripheral inflammation, and dopaminergic dysfunction. The 2nd generation tau PET tracers, 3H-MK6240 and 3H-PI2620, demonstrated high affinity and specificity in AD post-mortem brain tissues, especially in early-onset AD, compared to controls. 3H-PI2620, 3H-MK6240, and 3HRO948 displayed similar binding patterns in AD tissue, with multiple binding sites and equivalent high affinities (Papers I and II). 3H-PI2620 showed specificity in CBD and PSP tissues, in contrast to 3H-MK6240. However, differentiating CBD from PSP brains with 3H-PI2620 remained challenging in multiple brain regions, potentially due to complex tracer-target interactions (Papers II and III). Reactive astrogliosis PET tracers 3H-Deprenyl and 3H-BU99008 bound primarily to stable distinct high-affinity binding sites in AD, CBD and PSP, but also to transient binding sites, differing by brain region and condition. This pattern implied that these tracers may interact with similar or diverse subtypes or populations of astrocytes, expressing varying ratios of transient sites, which may vary depending on the brain location and the disease (Paper III). Using 3H-FEPE2I, we delineated a reduction in dopamine transporter (DAT) levels within the putamen across CBD, PSP and Parkinson's Disease (PD) brains. Concomitantly, elevated 3H-Raclopride binding reflected higher dopamine D2 receptor (D2R) levels in PSP and PD. Nonetheless, our observations underscored the heterogeneity inherent to these neurodegenerative pathologies, emphasizing the criticality of individual variability in neuropathological manifestations (Paper III). Lastly, we investigated late middle-aged cognitively unimpaired Hispanic individuals, in dichotomous groups of in vivo amyloid-β (Aβ) PET (18F-Florbetaben) and plasma neurofilament light (NfL) biomarkers. Our findings suggest that elevated plasma inflammation and tau burden as measured by 18FMK6240, can be detected at early preclinical stages of AD, offering potential for early diagnosis (Paper IV).

This thesis underscored the importance of PET imaging in advancing our understanding of tauopathies. The innovative use of multiple PET tracers provided crucial insights into their potential use in clinics to distinguish pathological features of AD, CBD and PSP. The findings emphasized the need for more studies applying a multifaceted approach to studying and managing these complex neurodegenerative disorders, combining advanced imaging techniques with a broad spectrum of biological markers.

List of scientific papers

I. Malarte ML, Nordberg A, Lemoine L. Characterization of MK6240, a tau PET tracer, in autopsy brain tissue from AD cases. Eur J Nucl Med Mol Imaging. 2021 Apr;48(4):1093-1102.
https://doi.org/10.1007/s00259-020-05035-y

II. Malarte ML, Gillberg PG, Kumar A, Bogdanovic N, Lemoine L, Nordberg A. Discriminative binding of tau PET tracers PI2620, MK6240 and RO948 in AD, corticobasal degeneration and progressive supranuclear palsy brains. Mol Psychiatry. 2023 Mar;28(3):1272-1283. Erratum in: Mol Psychiatry. 2023 Mar 8.
https://doi.org/10.1038/s41380-022-01875-2

III. Malarte ML, Rocha F and Kumar A. 2023. PET Tracers in 4R Tauopathies: A postmortem head-to-head study of tau, astroglial, and dopaminergic pathologies in corticobasal degeneration and progressive supranuclear palsy. [Manuscript]

IV. Malarte ML, Chiotis K, Ioannou K and Rodriguez-Vieitez E. 2023. In vivo 18F-MK6240 tau PET imaging in relation to peripheral inflammation and episodic memory in late middle-aged adults. [Manuscript]