Molecular imaging for diagnosis and treatment of neurodegenerative disorders at a prodromal stage

[Speaker] Makoto Higuchi:1
1:National Institutes for Quantum and Radiological Science and Technology, National Institute of Radiological Sciences, Japan

Numerous research works have implicated accumulations of pathological protein aggregates, including fibrils of amyloid-beta (Abeta), tau and alpha-synuclein, in the etiology of diverse neurodegenerative disorders as exemplified by Alzheimer's disease (AD) and Parkinson's disease (PD). By developing positron emission tomography (PET) imaging agents for Abeta deposits, in-vivo detection of Abeta pathologies characteristic of AD is currently possible in clinical settings, facilitating early diagnosis of this illness. Meanwhile, failures of clinical trials for anti-Abeta treatments in AD cases have implied needs for diagnostic and therapeutic approaches to tau pathologies, which are conceived to be more closely associated with neuronal deteriorations in AD than Abeta lesions. Based on this rationale, we generated radioligands for tau deposits, and provided the first demonstration that tau fibrils can be visualized by PET with these imaging agents in living patients with AD and various non-AD neurological diseases. This technology enabled us to reveal progressive expansion of tau depositions in the continuum from normal aging to advanced AD, offering an objective index of the disease severity. In addition, tau PET maps have clarified topologies of tau pathologies unique to each illness, which serve differentiation among a wide range of neurodegenerative disorders. Moreover, derivatives of the ligands for tau fibrils were found to react with alpha-synuclein assembles, which are neuropathological hallmarks in PD and related diseases. Diagnostic assessments of alph-synuclein deposits in living cases would accordingly be allowed by optimizing chemical structures of these compounds. Besides clinical and nonclinical PET studies, our imaging agents are applicable to in-vivo two-photon laser microscopy of animal brains, as these chemicals are self-fluorescent. Using this methodology, we have demonstrated a time course of the tau and alpha-synuclein fibrillogenesis in the living brain and loss of neurons burdened with these pathological assemblies. Finally, intravital microscopy of animal models with pharmacological interventions has illustrated critical roles played by activated astrocytes in the clearance of protein aggregates and by phagocytic microglia in elimination of fibril-bearing neurons. Hence, the present imaging platforms will contribute to the discoveries and characterization of candidate drugs capable of modifying neurodegenerative pathologies triggered by misfolded tau and alspha-synuclein species.
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